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41.
Thanh, Nguyen; Phuc, Xuan; Sridhar, Srinivas
Nanoscale Magnetism in Next Generation Magnetic Nanoparticles Technical Report
UNIVERSITY COLLEGE LONDON London United Kingdom 2018.
@techreport{thanh2018nanoscale,
title = {Nanoscale Magnetism in Next Generation Magnetic Nanoparticles},
author = {Nguyen Thanh and Xuan Phuc and Srinivas Sridhar},
year = {2018},
date = {2018-01-01},
institution = {UNIVERSITY COLLEGE LONDON London United Kingdom},
abstract = {Short summary of most important research results that explain why the work was done, what was accomplished, and how it pushed scientific frontiers or advanced the field. This summary will be used for archival purposes and will be added to a searchable DoD database. Magnetic nanoparticles (MNPs) are key components of a variety of sensors for diverse applications in electronics and biotechnologies. Nanoparticle properties are critically affected both by nanoscale size as well as surface interactions with the environment. These interactions among the key fundamental properties such as magnetic moment and dynamic response that are required for use in applications. In this we have had a collaborative project between groups at Northeastern University (USA), University College London-UCL (UK) and Institute of Materials Science (Vietnam Academy of Science and Technology-VAST) to synthesis and understand the fundamental aspects of magnetism at the nanometer length scale in confined geometries in nanoparticles. At Northeastern University, we studied the dynamic relaxation of superparamagnetic iron oxide nanoparticles (SPIONs) in aqueous media. Using the MRI facilities at Northeastern University, MNPs from collaborators UCL and VAST as well as dextran coated SPIONs were studied. From the measured T1 and T2 relaxation times, a new method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) was developed. The method was tested in vivo and demonstrated to yield positive contrast angiograms with high clarity and definition, and enabled quantitative MRI in biological samples. At UCL, the work included (i) fabricating multi-element magnetic systems, and (ii) controlling interactions by surface modification using organic compounds. The project involves systematic matter property studies by fabrication of novel organically modified coating of MNPs, physical characterization at both macroscopic level such as magnetic moments and AC susceptibility as well as microscopic one. The results provided fundamental insights into the nature of nanoscale magnetism relevant to a variety of nanomagnetic applications.At Institute of Materials Science, Vietnam Academy of Science and Technology, apart from the effort to synthesize MNPs of high magnetization and monodispersity, we have also studied in details various parameters which may impact on magnetic heating power of MNPs of different materials, such as particle size, size distribution, ferrofluid viscosity etc. The 3-year collaborative project has resulted in 9 publications in peer-reviewed journals and 34 presentations in major conferences, meeting and workshops around the world.
},
keywords = {},
pubstate = {published},
tppubtype = {techreport}
}
Short summary of most important research results that explain why the work was done, what was accomplished, and how it pushed scientific frontiers or advanced the field. This summary will be used for archival purposes and will be added to a searchable DoD database. Magnetic nanoparticles (MNPs) are key components of a variety of sensors for diverse applications in electronics and biotechnologies. Nanoparticle properties are critically affected both by nanoscale size as well as surface interactions with the environment. These interactions among the key fundamental properties such as magnetic moment and dynamic response that are required for use in applications. In this we have had a collaborative project between groups at Northeastern University (USA), University College London-UCL (UK) and Institute of Materials Science (Vietnam Academy of Science and Technology-VAST) to synthesis and understand the fundamental aspects of magnetism at the nanometer length scale in confined geometries in nanoparticles. At Northeastern University, we studied the dynamic relaxation of superparamagnetic iron oxide nanoparticles (SPIONs) in aqueous media. Using the MRI facilities at Northeastern University, MNPs from collaborators UCL and VAST as well as dextran coated SPIONs were studied. From the measured T1 and T2 relaxation times, a new method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) was developed. The method was tested in vivo and demonstrated to yield positive contrast angiograms with high clarity and definition, and enabled quantitative MRI in biological samples. At UCL, the work included (i) fabricating multi-element magnetic systems, and (ii) controlling interactions by surface modification using organic compounds. The project involves systematic matter property studies by fabrication of novel organically modified coating of MNPs, physical characterization at both macroscopic level such as magnetic moments and AC susceptibility as well as microscopic one. The results provided fundamental insights into the nature of nanoscale magnetism relevant to a variety of nanomagnetic applications.At Institute of Materials Science, Vietnam Academy of Science and Technology, apart from the effort to synthesize MNPs of high magnetization and monodispersity, we have also studied in details various parameters which may impact on magnetic heating power of MNPs of different materials, such as particle size, size distribution, ferrofluid viscosity etc. The 3-year collaborative project has resulted in 9 publications in peer-reviewed journals and 34 presentations in major conferences, meeting and workshops around the world.
42.
Guthier, CV; D'Amico, AV; King, MT; Nguyen, PL; Orio, PF; Sridhar, S; Makrigiorgos, GM; Cormack, RA
Determining optimal eluter design by modeling physical dose enhancement in brachytherapy Journal Article
In: Medical physics, vol. 45, no. 8, pp. 3916–3925, 2018.
@article{guthier2018determining,
title = {Determining optimal eluter design by modeling physical dose enhancement in brachytherapy},
author = {CV Guthier and AV D'Amico and MT King and PL Nguyen and PF Orio and S Sridhar and GM Makrigiorgos and RA Cormack},
year = {2018},
date = {2018-01-01},
journal = {Medical physics},
volume = {45},
number = {8},
pages = {3916--3925},
abstract = {Purpose
In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio.
Materials and methods
The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for 125I permanent prostate implants. Compound concentrations were calculated using steady‐state solution to the diffusion equation including an elimination term characterized by the diffusion‐elimination modulus (ϕb). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (csat). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion‐elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other.
Results
The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm3, ϕb from 0.01 to 4 mm−1, csat from 0.05 to 7.5 times the steady‐state compound concentration released from the surface of the eluter. The number of used eluters (ne) was simulated from 10 to 60 eluters. For the region of (c sat , Φ)‐space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (c sat , Φ)‐space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations.
Conclusions
Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Purpose
In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio.
Materials and methods
The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for 125I permanent prostate implants. Compound concentrations were calculated using steady‐state solution to the diffusion equation including an elimination term characterized by the diffusion‐elimination modulus (ϕb). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (csat). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion‐elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other.
Results
The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm3, ϕb from 0.01 to 4 mm−1, csat from 0.05 to 7.5 times the steady‐state compound concentration released from the surface of the eluter. The number of used eluters (ne) was simulated from 10 to 60 eluters. For the region of (c sat , Φ)‐space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (c sat , Φ)‐space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations.
Conclusions
Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.
In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio.
Materials and methods
The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for 125I permanent prostate implants. Compound concentrations were calculated using steady‐state solution to the diffusion equation including an elimination term characterized by the diffusion‐elimination modulus (ϕb). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (csat). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion‐elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other.
Results
The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm3, ϕb from 0.01 to 4 mm−1, csat from 0.05 to 7.5 times the steady‐state compound concentration released from the surface of the eluter. The number of used eluters (ne) was simulated from 10 to 60 eluters. For the region of (c sat , Φ)‐space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (c sat , Φ)‐space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations.
Conclusions
Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.
43.
Vazquez-Pagan, Ana G; Baldwin, Paige; Ashtaputre, Ravina M; Kunjachan, Sijumon; Sridhar, Srinivas; Kumar, Rajiv; Berbeco, Ross
Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer Miscellaneous
2018.
@misc{vazquez2018nanoparticle,
title = {Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer},
author = {Ana G Vazquez-Pagan and Paige Baldwin and Ravina M Ashtaputre and Sijumon Kunjachan and Srinivas Sridhar and Rajiv Kumar and Ross Berbeco},
year = {2018},
date = {2018-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: More than 50% of cancer patients receive radiation therapy at some point during their care. Gold nanoparticles (GNPs) can amplify the radiation dose by facilitating the ejection of low-energy photoelectrons, resulting in increased DNA damage. One of the main challenges of radiation therapy in cancer is to sustain this damage for longer durations. DNA single-strand breaks (SSBs) are repaired by base excision repair, which utilizes Poly(ADP-ribose) polymerase (PARP). PARP inhibition during radiotherapy provides an attractive alternative in maximizing treatment outcomes. Here, we explore a strategy to combine the radiosensitizing effect of GNPs with the DNA-repair inhibiting ability of NanoTalazoparib (nTLZ), a liposomal formulation of the PARP inhibitor, talazoparib (TLZ).
Methods: GNPs were synthesized by reducing AuCl4 using Tetrakis(hydroxymethyl)phosphonium chloride and further PEGylating using heterobifunctional PEGs. A liposomal formulation of TLZ was synthesized using the Nanoassemblr, a microfluidics-based device. Physicochemical characterization of GNPs and nTLZ was carried out using TEM, DLS and release kinetics studies. In vitro studies were carried out to assess the toxicity of the GNPs using MTT assay in non-small cell lung cancer (NSCLC) cell line Calu-6. The therapeutic efficacy of combination treatment using GNPs, nTLZ and radiation was done using clonogenic survival assays. Clonogenic assay was carried out using Calu 6 cells, which were sequentially treated with GNPs (1mg/mL), TLZ (0.5 uM) and nTLZ (0.5 uM) with and without radiation. The radiation doses varied from 0-10Gy for each set of treatments.
Results: PEGylated GNP's showed a hydrodynamic diameter of ~10-12 nm with a spherical morphology whereas nTLZ size was 70 nm encapsulating TLZ at a concentration of ~200 ug/ml. MTT assay showed no toxicity for PEGylated GNPs treated upto a concentration of 3.0 mg/mL. Cells treated with either GNPs, TLZ or nTLZ did not show significant reduction in colony formation, but were reduced with increasing doses of radiation. The survival plots showed a highly additive antiproliferative effect for the GNP + nTLZ combination at all radiation doses, while the free TLZ + GNPs combination was not as effective at inhibiting colony formation. In vivo experiments assessing the combination therapy in a subcutaneous xenograft mice model using Calu 6 are currently under way.
Conclusions: The preliminary in vitro results indicate that the combination of radiosensitizing GNPs with a potent DNA repair enzyme inhibitor, TLZ, has an immense potential as a complimentary combination therapy in conjunction with radiation therapy in treatment of lung cancer.
This work is supported by the CaNCURE program (grant #1CA174650-02), American Lung Association, Dana-Farber Cancer Institute and Brigham and Women's Hospital.
Citation Format: Ana G. Vazquez-Pagan, Paige Baldwin, Ravina M. Ashtaputre, Sijumon Kunjachan, Srinivas Sridhar, Rajiv Kumar, Ross Berbeco. Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3710.
©2018 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Introduction: More than 50% of cancer patients receive radiation therapy at some point during their care. Gold nanoparticles (GNPs) can amplify the radiation dose by facilitating the ejection of low-energy photoelectrons, resulting in increased DNA damage. One of the main challenges of radiation therapy in cancer is to sustain this damage for longer durations. DNA single-strand breaks (SSBs) are repaired by base excision repair, which utilizes Poly(ADP-ribose) polymerase (PARP). PARP inhibition during radiotherapy provides an attractive alternative in maximizing treatment outcomes. Here, we explore a strategy to combine the radiosensitizing effect of GNPs with the DNA-repair inhibiting ability of NanoTalazoparib (nTLZ), a liposomal formulation of the PARP inhibitor, talazoparib (TLZ).
Methods: GNPs were synthesized by reducing AuCl4 using Tetrakis(hydroxymethyl)phosphonium chloride and further PEGylating using heterobifunctional PEGs. A liposomal formulation of TLZ was synthesized using the Nanoassemblr, a microfluidics-based device. Physicochemical characterization of GNPs and nTLZ was carried out using TEM, DLS and release kinetics studies. In vitro studies were carried out to assess the toxicity of the GNPs using MTT assay in non-small cell lung cancer (NSCLC) cell line Calu-6. The therapeutic efficacy of combination treatment using GNPs, nTLZ and radiation was done using clonogenic survival assays. Clonogenic assay was carried out using Calu 6 cells, which were sequentially treated with GNPs (1mg/mL), TLZ (0.5 uM) and nTLZ (0.5 uM) with and without radiation. The radiation doses varied from 0-10Gy for each set of treatments.
Results: PEGylated GNP's showed a hydrodynamic diameter of ~10-12 nm with a spherical morphology whereas nTLZ size was 70 nm encapsulating TLZ at a concentration of ~200 ug/ml. MTT assay showed no toxicity for PEGylated GNPs treated upto a concentration of 3.0 mg/mL. Cells treated with either GNPs, TLZ or nTLZ did not show significant reduction in colony formation, but were reduced with increasing doses of radiation. The survival plots showed a highly additive antiproliferative effect for the GNP + nTLZ combination at all radiation doses, while the free TLZ + GNPs combination was not as effective at inhibiting colony formation. In vivo experiments assessing the combination therapy in a subcutaneous xenograft mice model using Calu 6 are currently under way.
Conclusions: The preliminary in vitro results indicate that the combination of radiosensitizing GNPs with a potent DNA repair enzyme inhibitor, TLZ, has an immense potential as a complimentary combination therapy in conjunction with radiation therapy in treatment of lung cancer.
This work is supported by the CaNCURE program (grant #1CA174650-02), American Lung Association, Dana-Farber Cancer Institute and Brigham and Women's Hospital.
Citation Format: Ana G. Vazquez-Pagan, Paige Baldwin, Ravina M. Ashtaputre, Sijumon Kunjachan, Srinivas Sridhar, Rajiv Kumar, Ross Berbeco. Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3710.
©2018 American Association for Cancer Research.
Methods: GNPs were synthesized by reducing AuCl4 using Tetrakis(hydroxymethyl)phosphonium chloride and further PEGylating using heterobifunctional PEGs. A liposomal formulation of TLZ was synthesized using the Nanoassemblr, a microfluidics-based device. Physicochemical characterization of GNPs and nTLZ was carried out using TEM, DLS and release kinetics studies. In vitro studies were carried out to assess the toxicity of the GNPs using MTT assay in non-small cell lung cancer (NSCLC) cell line Calu-6. The therapeutic efficacy of combination treatment using GNPs, nTLZ and radiation was done using clonogenic survival assays. Clonogenic assay was carried out using Calu 6 cells, which were sequentially treated with GNPs (1mg/mL), TLZ (0.5 uM) and nTLZ (0.5 uM) with and without radiation. The radiation doses varied from 0-10Gy for each set of treatments.
Results: PEGylated GNP's showed a hydrodynamic diameter of ~10-12 nm with a spherical morphology whereas nTLZ size was 70 nm encapsulating TLZ at a concentration of ~200 ug/ml. MTT assay showed no toxicity for PEGylated GNPs treated upto a concentration of 3.0 mg/mL. Cells treated with either GNPs, TLZ or nTLZ did not show significant reduction in colony formation, but were reduced with increasing doses of radiation. The survival plots showed a highly additive antiproliferative effect for the GNP + nTLZ combination at all radiation doses, while the free TLZ + GNPs combination was not as effective at inhibiting colony formation. In vivo experiments assessing the combination therapy in a subcutaneous xenograft mice model using Calu 6 are currently under way.
Conclusions: The preliminary in vitro results indicate that the combination of radiosensitizing GNPs with a potent DNA repair enzyme inhibitor, TLZ, has an immense potential as a complimentary combination therapy in conjunction with radiation therapy in treatment of lung cancer.
This work is supported by the CaNCURE program (grant #1CA174650-02), American Lung Association, Dana-Farber Cancer Institute and Brigham and Women's Hospital.
Citation Format: Ana G. Vazquez-Pagan, Paige Baldwin, Ravina M. Ashtaputre, Sijumon Kunjachan, Srinivas Sridhar, Rajiv Kumar, Ross Berbeco. Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3710.
©2018 American Association for Cancer Research.
44.
Baldwin, Paige; Kumar, Rajiv; Sridhar, Srinivas
Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment Miscellaneous
2018.
@misc{baldwin2018targeted,
title = {Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment},
author = {Paige Baldwin and Rajiv Kumar and Srinivas Sridhar},
year = {2018},
date = {2018-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells. These drugs are currently delivered orally, but Talazoparib, the most potent PARP inhibitor, exhibits greater toxicity than the others. Systemic administration of nanoparticles bypasses the first-pass metabolism of oral drugs and nanoparticles preferentially accumulate in tumors due to the leaky tumor vasculature. Additionally, nanoparticles can be actively targeted to tumors by conjugating different moieties such as antibodies that recognize overexpressed markers on the tumor cells. NanoTalazoparib (NanoTLZ) has been previously formulated and extensively characterized in breast, ovarian, and lung cancer models. Here we describe further characterization of NanoTLZ and the development of a next generation fluorescently labeled EPCAM targeted formulation of NanoTLZ for the treatment of triple negative breast cancer (TNBC).
Methods: Animals with orthotopic TNBC xenografts were injected with NanoTLZ and at various time points tumor biopsies were taken to assay tumor PAR levels. Blood was collected at various time points and plasma separated for drug extraction and quantification. Pharmacokinetic modeling is underway. Fluorescently labeled NanoTLZ was developed with the addition of Cy5, followed by further improvement via conjugation of anti-EPCAM antibodies. Targeting capability was assessed via laser scanning confocal microscopy after treatment of the TNBC cell line MDA-MB-231 with either non-targeted or targeted NanoTLZ. Therapeutic efficacy studies with targeted NanoTLZ alone and in combination with radiation are underway in an MDA-MB-231 xenograft model.
Results: Pharmacodynamics indicated PAR suppression in tumors within 30 minutes of NanoTLZ treatment. Tumor PAR levels began to increase 24 hours after a single dose but remained significantly lower than control levels up to 72 hours (P<0.005). Characterization of NanoTLZ after the addition of Cy5 and after anti-EPCAM targeting indicated that the formulation remained under 100 nm in diameter with a charge of ~10 mV and equivalent drug loading and release. Cy 5 labeling allowed for visualization of nanoparticle uptake and intracellular fluorescence was 70% greater in cells when treated with EPCAM targeted NanoTLZ compared to non-targeted.
Conclusions: The sustained release of Talazoparib from the nanoformulation decreases tumor PAR levels for up to 72 hours after a single dose, allowing for less frequent administration than the current daily regime used for oral Talazoparib. The targeted formulation of NanoTLZ shares the same physicochemical properties as the untargeted formulation, but is taken up much faster in vitro, suggesting it will allow for greater accumulation at the tumor site making it more effective than the previously tested untargeted NanoTLZ. Supported by ARMY/W81XWH-16-1-0731 and Rivkin Foundation.
Citation Format: Paige Baldwin, Rajiv Kumar, Srinivas Sridhar. Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3715.
©2018 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Introduction: PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells. These drugs are currently delivered orally, but Talazoparib, the most potent PARP inhibitor, exhibits greater toxicity than the others. Systemic administration of nanoparticles bypasses the first-pass metabolism of oral drugs and nanoparticles preferentially accumulate in tumors due to the leaky tumor vasculature. Additionally, nanoparticles can be actively targeted to tumors by conjugating different moieties such as antibodies that recognize overexpressed markers on the tumor cells. NanoTalazoparib (NanoTLZ) has been previously formulated and extensively characterized in breast, ovarian, and lung cancer models. Here we describe further characterization of NanoTLZ and the development of a next generation fluorescently labeled EPCAM targeted formulation of NanoTLZ for the treatment of triple negative breast cancer (TNBC).
Methods: Animals with orthotopic TNBC xenografts were injected with NanoTLZ and at various time points tumor biopsies were taken to assay tumor PAR levels. Blood was collected at various time points and plasma separated for drug extraction and quantification. Pharmacokinetic modeling is underway. Fluorescently labeled NanoTLZ was developed with the addition of Cy5, followed by further improvement via conjugation of anti-EPCAM antibodies. Targeting capability was assessed via laser scanning confocal microscopy after treatment of the TNBC cell line MDA-MB-231 with either non-targeted or targeted NanoTLZ. Therapeutic efficacy studies with targeted NanoTLZ alone and in combination with radiation are underway in an MDA-MB-231 xenograft model.
Results: Pharmacodynamics indicated PAR suppression in tumors within 30 minutes of NanoTLZ treatment. Tumor PAR levels began to increase 24 hours after a single dose but remained significantly lower than control levels up to 72 hours (P<0.005). Characterization of NanoTLZ after the addition of Cy5 and after anti-EPCAM targeting indicated that the formulation remained under 100 nm in diameter with a charge of ~10 mV and equivalent drug loading and release. Cy 5 labeling allowed for visualization of nanoparticle uptake and intracellular fluorescence was 70% greater in cells when treated with EPCAM targeted NanoTLZ compared to non-targeted.
Conclusions: The sustained release of Talazoparib from the nanoformulation decreases tumor PAR levels for up to 72 hours after a single dose, allowing for less frequent administration than the current daily regime used for oral Talazoparib. The targeted formulation of NanoTLZ shares the same physicochemical properties as the untargeted formulation, but is taken up much faster in vitro, suggesting it will allow for greater accumulation at the tumor site making it more effective than the previously tested untargeted NanoTLZ. Supported by ARMY/W81XWH-16-1-0731 and Rivkin Foundation.
Citation Format: Paige Baldwin, Rajiv Kumar, Srinivas Sridhar. Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3715.
©2018 American Association for Cancer Research.
Methods: Animals with orthotopic TNBC xenografts were injected with NanoTLZ and at various time points tumor biopsies were taken to assay tumor PAR levels. Blood was collected at various time points and plasma separated for drug extraction and quantification. Pharmacokinetic modeling is underway. Fluorescently labeled NanoTLZ was developed with the addition of Cy5, followed by further improvement via conjugation of anti-EPCAM antibodies. Targeting capability was assessed via laser scanning confocal microscopy after treatment of the TNBC cell line MDA-MB-231 with either non-targeted or targeted NanoTLZ. Therapeutic efficacy studies with targeted NanoTLZ alone and in combination with radiation are underway in an MDA-MB-231 xenograft model.
Results: Pharmacodynamics indicated PAR suppression in tumors within 30 minutes of NanoTLZ treatment. Tumor PAR levels began to increase 24 hours after a single dose but remained significantly lower than control levels up to 72 hours (P<0.005). Characterization of NanoTLZ after the addition of Cy5 and after anti-EPCAM targeting indicated that the formulation remained under 100 nm in diameter with a charge of ~10 mV and equivalent drug loading and release. Cy 5 labeling allowed for visualization of nanoparticle uptake and intracellular fluorescence was 70% greater in cells when treated with EPCAM targeted NanoTLZ compared to non-targeted.
Conclusions: The sustained release of Talazoparib from the nanoformulation decreases tumor PAR levels for up to 72 hours after a single dose, allowing for less frequent administration than the current daily regime used for oral Talazoparib. The targeted formulation of NanoTLZ shares the same physicochemical properties as the untargeted formulation, but is taken up much faster in vitro, suggesting it will allow for greater accumulation at the tumor site making it more effective than the previously tested untargeted NanoTLZ. Supported by ARMY/W81XWH-16-1-0731 and Rivkin Foundation.
Citation Format: Paige Baldwin, Rajiv Kumar, Srinivas Sridhar. Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3715.
©2018 American Association for Cancer Research.
45.
Kunjachan, S; Kotb, S; Kumar, R; Pola, R; Pechar, M; Gremse, F; Taleei, R; Trichard, F; Motto-Ros, V; Sancey, L; others,
BEST IN PHYSICS (THERAPY): Enhanced Drug Delivery by Nanoparticle and Radiation-Mediated Tumor Vascular Modulation Proceedings Article
In: MEDICAL PHYSICS, pp. E535–E535, WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA 2018.
@inproceedings{kunjachan2018best,
title = {BEST IN PHYSICS (THERAPY): Enhanced Drug Delivery by Nanoparticle and Radiation-Mediated Tumor Vascular Modulation},
author = {S Kunjachan and S Kotb and R Kumar and R Pola and M Pechar and F Gremse and R Taleei and F Trichard and V Motto-Ros and L Sancey and others},
year = {2018},
date = {2018-01-01},
booktitle = {MEDICAL PHYSICS},
volume = {45},
number = {6},
pages = {E535--E535},
organization = {WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
46.
Zhang, Di; Baldwin, Paige; Sridhar, Srinivas; Liby, Karen
Nanoformulated Talazoparib enhances the efficacy and reduces the toxicity of this PARP inhibitor in a preclinical model of BRCA-deficient breast cancer Journal Article
In: The FASEB Journal, vol. 32, no. 1_supplement, pp. 565–10, 2018.
@article{zhang2018nanoformulated,
title = {Nanoformulated Talazoparib enhances the efficacy and reduces the toxicity of this PARP inhibitor in a preclinical model of BRCA-deficient breast cancer},
author = {Di Zhang and Paige Baldwin and Srinivas Sridhar and Karen Liby},
year = {2018},
date = {2018-01-01},
journal = {The FASEB Journal},
volume = {32},
number = {1_supplement},
pages = {565--10},
publisher = {The Federation of American Societies for Experimental Biology},
abstract = {BRCA mutations are the leading cause of hereditary breast cancer. PARP inhibitors have shown promising activities in clinical trials for breast cancer by inducing synthetic lethality, particularly in patients with BRCA deficiency. Moreover, the utility of PARP inhibitors could potentially extend beyond BRCA mutations by targeting defects in homologous recombination, and thus impact up to 75% of triple negative breast cancer patients and 33% of breast cancer patients overall. However, conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and significant off-target toxicities, thus compromising the therapeutic benefits and quality of life in patients. Therefore, we developed a new nanoparticle delivery system for PARP inhibitors and hypothesize that nanoformulated Talazoparib can enhance efficacy by increasing drug concentrations in the tumor and reduce off-target toxicities. The nanoparticle formulation includes polymer brushes to prolong the circulation time, enabling tumor accumulation through the enhanced permeability and retention effect. The therapeutic efficacy of Nano-Talazoparib (Nano-TLZ) was assessed after i.v. injection in Brca1Co/Co;MMTV-Cre; p53+/− mice with established tumors and compared to vehicle control (saline, i.v.), empty nanoparticles (i.v.), free Talazoparib (i.v.), and free Talazoparib (gavage). Treatment was started when the tumor was 4 mm in diameter and ended when the tumor size reached defined IACUC endpoints. Nano-TLZ significantly (p<0.05) prolonged the life span of BRCA deficient mice from 11.6±2.6 days with saline injection and 18.3±3.6 days with empty nanoparticles injection to 82.2±10.5 days with i.v. Nano-TLZ. Nano-TLZ induced growth arrest in 100% of the tumors and regression (> 50% reduction in tumor volume) in 80% of the tumors. Established tumors regressed more rapidly, and therefore progression free survival significantly improved in the nanoformulated Talazoparib group (p<0.05). Moreover, Nano-TLZ is better tolerated than free Talazoparib with no significant weight lost or alopecia. In a biomarker study following 10 days of treatment, Nano-TLZ increased double strand DNA breaks (γ-H2AX) and decreased proliferation (PCNA) compared to the saline controls. Interestingly, Nano-TLZ significantly (p<0.05) decreased myeloid derived suppressor cells in both the tumor (41.6±4.7% to 11.2±2.9%) and spleen (10.0±3.2% to 3.7±0.6%) compared to the saline control. Nano-TLZ also significantly (p<0.05) decreased the percentage of tumor-associated macrophages in the mammary gland from 7.4±2.0% in the saline control group to 2.5±0.2% in the Nano-TLZ group. The changes in immune populations suggest potential immunomodulatory effects of Talazoparib. These results demonstrate that the delivery of Talazoparib as a nanoformulation induces superior treatment outcomes with reduced off-target toxicity in BRCA deficient mice, and provides a novel delivery strategy for PARP inhibitors in patients.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BRCA mutations are the leading cause of hereditary breast cancer. PARP inhibitors have shown promising activities in clinical trials for breast cancer by inducing synthetic lethality, particularly in patients with BRCA deficiency. Moreover, the utility of PARP inhibitors could potentially extend beyond BRCA mutations by targeting defects in homologous recombination, and thus impact up to 75% of triple negative breast cancer patients and 33% of breast cancer patients overall. However, conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and significant off-target toxicities, thus compromising the therapeutic benefits and quality of life in patients. Therefore, we developed a new nanoparticle delivery system for PARP inhibitors and hypothesize that nanoformulated Talazoparib can enhance efficacy by increasing drug concentrations in the tumor and reduce off-target toxicities. The nanoparticle formulation includes polymer brushes to prolong the circulation time, enabling tumor accumulation through the enhanced permeability and retention effect. The therapeutic efficacy of Nano-Talazoparib (Nano-TLZ) was assessed after i.v. injection in Brca1Co/Co;MMTV-Cre; p53+/− mice with established tumors and compared to vehicle control (saline, i.v.), empty nanoparticles (i.v.), free Talazoparib (i.v.), and free Talazoparib (gavage). Treatment was started when the tumor was 4 mm in diameter and ended when the tumor size reached defined IACUC endpoints. Nano-TLZ significantly (p<0.05) prolonged the life span of BRCA deficient mice from 11.6±2.6 days with saline injection and 18.3±3.6 days with empty nanoparticles injection to 82.2±10.5 days with i.v. Nano-TLZ. Nano-TLZ induced growth arrest in 100% of the tumors and regression (> 50% reduction in tumor volume) in 80% of the tumors. Established tumors regressed more rapidly, and therefore progression free survival significantly improved in the nanoformulated Talazoparib group (p<0.05). Moreover, Nano-TLZ is better tolerated than free Talazoparib with no significant weight lost or alopecia. In a biomarker study following 10 days of treatment, Nano-TLZ increased double strand DNA breaks (γ-H2AX) and decreased proliferation (PCNA) compared to the saline controls. Interestingly, Nano-TLZ significantly (p<0.05) decreased myeloid derived suppressor cells in both the tumor (41.6±4.7% to 11.2±2.9%) and spleen (10.0±3.2% to 3.7±0.6%) compared to the saline control. Nano-TLZ also significantly (p<0.05) decreased the percentage of tumor-associated macrophages in the mammary gland from 7.4±2.0% in the saline control group to 2.5±0.2% in the Nano-TLZ group. The changes in immune populations suggest potential immunomodulatory effects of Talazoparib. These results demonstrate that the delivery of Talazoparib as a nanoformulation induces superior treatment outcomes with reduced off-target toxicity in BRCA deficient mice, and provides a novel delivery strategy for PARP inhibitors in patients.
47.
Mitra, Ronodeep; Qiao, Ju; Madhavan, Sudharsan; O’Neil, Gerard L; Ritchie, Bailey; Kulkarni, Praveen; Sridhar, Srinivas; van de Ven, Anne L; Kemmerling, Erica Cherry M; Ferris, Craig; others,
The comparative effects of high fat diet or disturbed blood flow on glycocalyx integrity and vascular inflammation Journal Article
In: Translational medicine communications, vol. 3, no. 1, pp. 1–15, 2018.
@article{mitra2018comparative,
title = {The comparative effects of high fat diet or disturbed blood flow on glycocalyx integrity and vascular inflammation},
author = {Ronodeep Mitra and Ju Qiao and Sudharsan Madhavan and Gerard L O’Neil and Bailey Ritchie and Praveen Kulkarni and Srinivas Sridhar and Anne L van de Ven and Erica Cherry M Kemmerling and Craig Ferris and others},
year = {2018},
date = {2018-01-01},
journal = {Translational medicine communications},
volume = {3},
number = {1},
pages = {1--15},
publisher = {BioMed Central},
abstract = {Background and aims
Endothelial surface glycocalyx shedding plays a role in endothelial dysfunction and increases vessel wall permeability, which can lead to inflammation and atherogenesis. We sought to elucidate whether a high fat diet (HFD) or disturbed blood flow conditions, both of which are atherogenic risk factors, would contribute more detrimentally to pre-atherosclerotic loss of endothelial glycocalyx integrity and vascular inflammation.
Methods
Six to seven week-old C57BL/6-background apolipoprotein-E-knockout (ApoE-KO) male mice were either fed a chow diet, fed a modified Western HFD, and/or subjected to a partial left carotid artery (LCA) ligation procedure to induce disturbed blood flow patterns in the LCA. Mice were sacrificed after 1 week of experimental conditions. Both LCA and right carotid artery (RCA) vessels were dissected and preserved to compare glycocalyx coverage and thickness as well as macrophage accumulation in carotid arterial walls amongst and between cohorts.
Results
Glycocalyx coverage of the endothelium was significantly reduced in the LCAs of HFD fed mice when compared to the control. More significant reduction in glycocalyx coverage occurred in the LCAs of mice exposed to disturbed flow by partial LCA ligation when compared to the control. No differences were found in glycocalyx coverage of RCAs from all cohorts. Regarding inflammation, no difference in macrophage accumulation in carotid arterial walls was observed when comparing the LCAs and RCAs of control and HFD fed mice. However, macrophage infiltration in vessel walls showed a 20-fold increase in the LCAs exposed to disturbed flow following ligation, when compared to control LCAs, while no such statistical difference was observed between the RCAs of the group.
Conclusions
In our mouse model, endothelial glycocalyx integrity was compromised more by disturbed blood flow patterns than by exposure of the carotid vessel to HFD conditions. The pathophysiological implications include endothelial dysfunction, which correlates to macrophage infiltration in vessel walls and promotes atherogenesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background and aims
Endothelial surface glycocalyx shedding plays a role in endothelial dysfunction and increases vessel wall permeability, which can lead to inflammation and atherogenesis. We sought to elucidate whether a high fat diet (HFD) or disturbed blood flow conditions, both of which are atherogenic risk factors, would contribute more detrimentally to pre-atherosclerotic loss of endothelial glycocalyx integrity and vascular inflammation.
Methods
Six to seven week-old C57BL/6-background apolipoprotein-E-knockout (ApoE-KO) male mice were either fed a chow diet, fed a modified Western HFD, and/or subjected to a partial left carotid artery (LCA) ligation procedure to induce disturbed blood flow patterns in the LCA. Mice were sacrificed after 1 week of experimental conditions. Both LCA and right carotid artery (RCA) vessels were dissected and preserved to compare glycocalyx coverage and thickness as well as macrophage accumulation in carotid arterial walls amongst and between cohorts.
Results
Glycocalyx coverage of the endothelium was significantly reduced in the LCAs of HFD fed mice when compared to the control. More significant reduction in glycocalyx coverage occurred in the LCAs of mice exposed to disturbed flow by partial LCA ligation when compared to the control. No differences were found in glycocalyx coverage of RCAs from all cohorts. Regarding inflammation, no difference in macrophage accumulation in carotid arterial walls was observed when comparing the LCAs and RCAs of control and HFD fed mice. However, macrophage infiltration in vessel walls showed a 20-fold increase in the LCAs exposed to disturbed flow following ligation, when compared to control LCAs, while no such statistical difference was observed between the RCAs of the group.
Conclusions
In our mouse model, endothelial glycocalyx integrity was compromised more by disturbed blood flow patterns than by exposure of the carotid vessel to HFD conditions. The pathophysiological implications include endothelial dysfunction, which correlates to macrophage infiltration in vessel walls and promotes atherogenesis.
Endothelial surface glycocalyx shedding plays a role in endothelial dysfunction and increases vessel wall permeability, which can lead to inflammation and atherogenesis. We sought to elucidate whether a high fat diet (HFD) or disturbed blood flow conditions, both of which are atherogenic risk factors, would contribute more detrimentally to pre-atherosclerotic loss of endothelial glycocalyx integrity and vascular inflammation.
Methods
Six to seven week-old C57BL/6-background apolipoprotein-E-knockout (ApoE-KO) male mice were either fed a chow diet, fed a modified Western HFD, and/or subjected to a partial left carotid artery (LCA) ligation procedure to induce disturbed blood flow patterns in the LCA. Mice were sacrificed after 1 week of experimental conditions. Both LCA and right carotid artery (RCA) vessels were dissected and preserved to compare glycocalyx coverage and thickness as well as macrophage accumulation in carotid arterial walls amongst and between cohorts.
Results
Glycocalyx coverage of the endothelium was significantly reduced in the LCAs of HFD fed mice when compared to the control. More significant reduction in glycocalyx coverage occurred in the LCAs of mice exposed to disturbed flow by partial LCA ligation when compared to the control. No differences were found in glycocalyx coverage of RCAs from all cohorts. Regarding inflammation, no difference in macrophage accumulation in carotid arterial walls was observed when comparing the LCAs and RCAs of control and HFD fed mice. However, macrophage infiltration in vessel walls showed a 20-fold increase in the LCAs exposed to disturbed flow following ligation, when compared to control LCAs, while no such statistical difference was observed between the RCAs of the group.
Conclusions
In our mouse model, endothelial glycocalyx integrity was compromised more by disturbed blood flow patterns than by exposure of the carotid vessel to HFD conditions. The pathophysiological implications include endothelial dysfunction, which correlates to macrophage infiltration in vessel walls and promotes atherogenesis.
48.
Baldwin, Paige; Ohman, Anders W; Tangutoori, Shifalika; Dinulescu, Daniela M; Sridhar, Srinivas
Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment Journal Article
In: International journal of nanomedicine, vol. 13, pp. 8063, 2018.
@article{baldwin2018intraperitoneal,
title = {Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment},
author = {Paige Baldwin and Anders W Ohman and Shifalika Tangutoori and Daniela M Dinulescu and Srinivas Sridhar},
year = {2018},
date = {2018-01-01},
journal = {International journal of nanomedicine},
volume = {13},
pages = {8063},
publisher = {Dove Press},
abstract = {Background
PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy. However, all orally-administered drugs, including Olaparib, must undergo first-pass metabolism. In contrast, a nanoparticle delivery system has the advantage of administering Olaparib directly into the peritoneal cavity for local treatment. Consequently, we sought to optimize the sustained-release formulation NanoOlaparib, previously deemed effective as an intravenous solid tumor treatment, for the local treatment of disseminated disease via intraperitoneal (i.p.) therapy.
Methods
The tumor cell line 404, which was derived from a Brca2−/−, Tp53−/−, Pten−/− genetically engineered mouse model, exhibited high sensitivity to Olaparib in vitro. It was chosen for use in developing an i.p. spread xenograft for testing nanotherapy efficacy in vivo. NanoOlaparib as a monotherapy or in combination with cisplatin was compared to oral Olaparib alone or in combination using two different dose schedules. A pilot biodistribution study was performed to determine drug accumulation in various organs following i.p. administration.
Results
Daily administration of NanoOlaparib reduced tumor growth and decreased the variability of the treatment response observed with daily oral Olaparib administration. However, systemic toxicity was observed in both the NanoOlaparib and vehicle (empty nanoparticle) treated groups. Scaling back the administration to twice weekly was well tolerated up to 100 mg/kg but reduced the effect on tumor growth. Biodistribution profiles indicated that NanoOlaparib began accumulating in tissues within an hour of administration and persisted for at least 72 hours after a single dose, exiting the peritoneal cavity faster than expected.
Conclusion
NanoOlaparib must be modified for use against disseminated disease. Future avenues to develop NanoOlaparib as an i.p. therapy include a modified surface-coating to retain it in the peritoneal cavity and prevent entry into systemic circulation, in addition to targeting moieties for localization in tumor cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background
PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy. However, all orally-administered drugs, including Olaparib, must undergo first-pass metabolism. In contrast, a nanoparticle delivery system has the advantage of administering Olaparib directly into the peritoneal cavity for local treatment. Consequently, we sought to optimize the sustained-release formulation NanoOlaparib, previously deemed effective as an intravenous solid tumor treatment, for the local treatment of disseminated disease via intraperitoneal (i.p.) therapy.
Methods
The tumor cell line 404, which was derived from a Brca2−/−, Tp53−/−, Pten−/− genetically engineered mouse model, exhibited high sensitivity to Olaparib in vitro. It was chosen for use in developing an i.p. spread xenograft for testing nanotherapy efficacy in vivo. NanoOlaparib as a monotherapy or in combination with cisplatin was compared to oral Olaparib alone or in combination using two different dose schedules. A pilot biodistribution study was performed to determine drug accumulation in various organs following i.p. administration.
Results
Daily administration of NanoOlaparib reduced tumor growth and decreased the variability of the treatment response observed with daily oral Olaparib administration. However, systemic toxicity was observed in both the NanoOlaparib and vehicle (empty nanoparticle) treated groups. Scaling back the administration to twice weekly was well tolerated up to 100 mg/kg but reduced the effect on tumor growth. Biodistribution profiles indicated that NanoOlaparib began accumulating in tissues within an hour of administration and persisted for at least 72 hours after a single dose, exiting the peritoneal cavity faster than expected.
Conclusion
NanoOlaparib must be modified for use against disseminated disease. Future avenues to develop NanoOlaparib as an i.p. therapy include a modified surface-coating to retain it in the peritoneal cavity and prevent entry into systemic circulation, in addition to targeting moieties for localization in tumor cells.
PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy. However, all orally-administered drugs, including Olaparib, must undergo first-pass metabolism. In contrast, a nanoparticle delivery system has the advantage of administering Olaparib directly into the peritoneal cavity for local treatment. Consequently, we sought to optimize the sustained-release formulation NanoOlaparib, previously deemed effective as an intravenous solid tumor treatment, for the local treatment of disseminated disease via intraperitoneal (i.p.) therapy.
Methods
The tumor cell line 404, which was derived from a Brca2−/−, Tp53−/−, Pten−/− genetically engineered mouse model, exhibited high sensitivity to Olaparib in vitro. It was chosen for use in developing an i.p. spread xenograft for testing nanotherapy efficacy in vivo. NanoOlaparib as a monotherapy or in combination with cisplatin was compared to oral Olaparib alone or in combination using two different dose schedules. A pilot biodistribution study was performed to determine drug accumulation in various organs following i.p. administration.
Results
Daily administration of NanoOlaparib reduced tumor growth and decreased the variability of the treatment response observed with daily oral Olaparib administration. However, systemic toxicity was observed in both the NanoOlaparib and vehicle (empty nanoparticle) treated groups. Scaling back the administration to twice weekly was well tolerated up to 100 mg/kg but reduced the effect on tumor growth. Biodistribution profiles indicated that NanoOlaparib began accumulating in tissues within an hour of administration and persisted for at least 72 hours after a single dose, exiting the peritoneal cavity faster than expected.
Conclusion
NanoOlaparib must be modified for use against disseminated disease. Future avenues to develop NanoOlaparib as an i.p. therapy include a modified surface-coating to retain it in the peritoneal cavity and prevent entry into systemic circulation, in addition to targeting moieties for localization in tumor cells.
49.
Zhang, Di; Baldwin, Paige; Sridhar, Srinivas; Liby, Karen
Developing a nanoformulation of the PARP inhibitor talazoparib as a novel delivery for treatment of BRCA-deficient breast cancer Miscellaneous
2018.
@misc{zhang2018developing,
title = {Developing a nanoformulation of the PARP inhibitor talazoparib as a novel delivery for treatment of BRCA-deficient breast cancer},
author = {Di Zhang and Paige Baldwin and Srinivas Sridhar and Karen Liby},
year = {2018},
date = {2018-01-01},
urldate = {2018-01-01},
publisher = {American Association for Cancer Research},
abstract = {BRCA mutations are the leading cause of hereditary breast cancer. PARP inhibitors have shown promising activities in clinical trials for breast cancer by inducing synthetic lethality, particularly in patients with BRCA deficiency. Moreover, the utility of PARP inhibitors could potentially extend beyond BRCA mutations by targeting defects in homologous recombination, and thus impact up to 33% of breast cancer patients overall. However, conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and significant off-target toxicities, thus compromising the therapeutic benefits and quality of life in patients. Therefore, we developed a new nanoparticle delivery system for PARP inhibitors and hypothesize that nanoformulated Talazoparib can enhance efficacy by increasing drug concentrations in the tumor and reduce off-target toxicities. The nanoparticle formulation includes polymer brushes to prolong the circulation time, enabling tumor accumulation through the enhanced permeability and retention effect. The therapeutic efficacy of Nano-Talazoparib (Nano-TLZ) was assessed after i.v. injection in Brca1Co/Co;MMTV-Cre;p53+/- mice with established tumors and compared to vehicle control (saline, i.v.), empty nanoparticles (i.v.), free Talazoparib (i.v.), and free Talazoparib (gavage). Treatment was started when the tumor was 4 mm in diameter and ended when the tumor size reached defined IACUC endpoints. Nano-TLZ significantly (p<0.05) prolonged the life span of BRCA deficient mice from 11.6±2.6 days with saline injection to 82.2±10.5 days with i.v. Nano-TLZ. Nano-TLZ induced growth arrest in 100% of the tumors and regression (> 50% reduction in tumor volume) in 80% of the tumors. Established tumors regressed more rapidly, and therefore progression free survival significantly improved in the nanoformulated Talazoparib group (p<0.05). Moreover, Nano-TLZ is better tolerated than free Talazoparib with no significant weight lost. In a biomarker study following 10 days of treatment, Nano-TLZ increased double strand DNA breaks (γ-H2AX) and decreased proliferation (PCNA) compared to controls. Interestingly, Nano-TLZ significantly (p<0.05) decreased myeloid derived suppressor cells in both the tumor (41.6±4.7% to 11.2±2.9%) and spleen (10.0±3.2% to 3.7±0.6%) compared to the saline control. Nano-TLZ also significantly (p<0.05) decreased the percentage of tumor-associated macrophages in the mammary gland from 7.4±2.0% in the saline control group to 2.5±0.2% in the Nano-TLZ group. The changes in immune populations suggest potential immunomodulatory effects of Talazoparib. These results demonstrate that the delivery of Talazoparib as a nanoformulation induces superior treatment outcomes with reduced off-target toxicity in BRCA deficient mice, and provides a novel delivery strategy for PARP inhibitors in patients.
Citation Format: Di Zhang, Paige Baldwin, Srinivas Sridhar, Karen Liby. Developing a nanoformulation of the PARP inhibitor talazoparib as a novel delivery for treatment of BRCA-deficient breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3874.
©2018 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
BRCA mutations are the leading cause of hereditary breast cancer. PARP inhibitors have shown promising activities in clinical trials for breast cancer by inducing synthetic lethality, particularly in patients with BRCA deficiency. Moreover, the utility of PARP inhibitors could potentially extend beyond BRCA mutations by targeting defects in homologous recombination, and thus impact up to 33% of breast cancer patients overall. However, conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and significant off-target toxicities, thus compromising the therapeutic benefits and quality of life in patients. Therefore, we developed a new nanoparticle delivery system for PARP inhibitors and hypothesize that nanoformulated Talazoparib can enhance efficacy by increasing drug concentrations in the tumor and reduce off-target toxicities. The nanoparticle formulation includes polymer brushes to prolong the circulation time, enabling tumor accumulation through the enhanced permeability and retention effect. The therapeutic efficacy of Nano-Talazoparib (Nano-TLZ) was assessed after i.v. injection in Brca1Co/Co;MMTV-Cre;p53+/- mice with established tumors and compared to vehicle control (saline, i.v.), empty nanoparticles (i.v.), free Talazoparib (i.v.), and free Talazoparib (gavage). Treatment was started when the tumor was 4 mm in diameter and ended when the tumor size reached defined IACUC endpoints. Nano-TLZ significantly (p<0.05) prolonged the life span of BRCA deficient mice from 11.6±2.6 days with saline injection to 82.2±10.5 days with i.v. Nano-TLZ. Nano-TLZ induced growth arrest in 100% of the tumors and regression (> 50% reduction in tumor volume) in 80% of the tumors. Established tumors regressed more rapidly, and therefore progression free survival significantly improved in the nanoformulated Talazoparib group (p<0.05). Moreover, Nano-TLZ is better tolerated than free Talazoparib with no significant weight lost. In a biomarker study following 10 days of treatment, Nano-TLZ increased double strand DNA breaks (γ-H2AX) and decreased proliferation (PCNA) compared to controls. Interestingly, Nano-TLZ significantly (p<0.05) decreased myeloid derived suppressor cells in both the tumor (41.6±4.7% to 11.2±2.9%) and spleen (10.0±3.2% to 3.7±0.6%) compared to the saline control. Nano-TLZ also significantly (p<0.05) decreased the percentage of tumor-associated macrophages in the mammary gland from 7.4±2.0% in the saline control group to 2.5±0.2% in the Nano-TLZ group. The changes in immune populations suggest potential immunomodulatory effects of Talazoparib. These results demonstrate that the delivery of Talazoparib as a nanoformulation induces superior treatment outcomes with reduced off-target toxicity in BRCA deficient mice, and provides a novel delivery strategy for PARP inhibitors in patients.
Citation Format: Di Zhang, Paige Baldwin, Srinivas Sridhar, Karen Liby. Developing a nanoformulation of the PARP inhibitor talazoparib as a novel delivery for treatment of BRCA-deficient breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3874.
©2018 American Association for Cancer Research.
Citation Format: Di Zhang, Paige Baldwin, Srinivas Sridhar, Karen Liby. Developing a nanoformulation of the PARP inhibitor talazoparib as a novel delivery for treatment of BRCA-deficient breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3874.
©2018 American Association for Cancer Research.
50.
Wilfred, NGWA; Kumar, Rajiv; Makrigiorgos, Gerassimos; Sridhar, Srinivas; Dougan, Stephanie
Biomaterials for combined radiotherapy and immunotherapy of cancer Miscellaneous
2018, (US Patent App. 15/752,099).
@misc{wilfred2018biomaterials,
title = {Biomaterials for combined radiotherapy and immunotherapy of cancer},
author = {NGWA Wilfred and Rajiv Kumar and Gerassimos Makrigiorgos and Srinivas Sridhar and Stephanie Dougan},
year = {2018},
date = {2018-00-01},
abstract = {Compositions and methods for the radiological and immunotherapeutic treatment of cancer are provided. Metallic nanoparticles conjugated with an immunoadjuvant are dispersed within a biodegradable polymer matrix that can be implanted in a patient and released gradually. The implant may be configured as, or be a component of, brachytherapy spacers and applicators, or radiotherapy fiducial markers. The composition may be combined with marginless radiotherapy, allowing for lower doses of radiation and enhancing the immune response against cancer, including at non-irradiated sites.},
note = {US Patent App. 15/752,099},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Compositions and methods for the radiological and immunotherapeutic treatment of cancer are provided. Metallic nanoparticles conjugated with an immunoadjuvant are dispersed within a biodegradable polymer matrix that can be implanted in a patient and released gradually. The implant may be configured as, or be a component of, brachytherapy spacers and applicators, or radiotherapy fiducial markers. The composition may be combined with marginless radiotherapy, allowing for lower doses of radiation and enhancing the immune response against cancer, including at non-irradiated sites.
51.
Geilich, Benjamin M; Gelfat, Ilia; Sridhar, Srinivas; van de Ven, Anne L; Webster, Thomas J
Superparamagnetic iron oxide-encapsulating polymersome nanocarriers for biofilm eradication Journal Article
In: Biomaterials, vol. 119, pp. 78–85, 2017.
@article{geilich2017superparamagnetic,
title = {Superparamagnetic iron oxide-encapsulating polymersome nanocarriers for biofilm eradication},
author = {Benjamin M Geilich and Ilia Gelfat and Srinivas Sridhar and Anne L van de Ven and Thomas J Webster},
year = {2017},
date = {2017-01-01},
journal = {Biomaterials},
volume = {119},
pages = {78--85},
publisher = {Elsevier},
abstract = {The rising prevalence and severity of antibiotic-resistant biofilm infections poses an alarming threat to public health worldwide. Here, biocompatible multi-compartment nanocarriers were synthesized to contain both hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) and the hydrophilic antibiotic methicillin for the treatment of medical device-associated infections. SPION co-encapsulation was found to confer unique properties, enhancing both nanocarrier relaxivity and magneticity compared to individual SPIONs. These iron oxide-encapsulating polymersomes (IOPs) penetrated 20 μm thick Staphylococcus epidermidis biofilms with high efficiency following the application of an external magnetic field. Three-dimensional laser scanning confocal microscopy revealed differential bacteria death as a function of drug and SPION loading. Complete eradication of all bacteria throughout the biofilm thickness was achieved using an optimized IOP formulation containing 40 μg/mL SPION and 20 μg/mL of methicillin. Importantly, this formulation was selectively toxic towards methicillin-resistant biofilm cells but not towards mammalian cells. These novel iron oxide-encapsulating polymersomes demonstrate that it is possible to overcome antibiotic-resistant biofilms by controlling the positioning of nanocarriers containing two or more therapeutics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The rising prevalence and severity of antibiotic-resistant biofilm infections poses an alarming threat to public health worldwide. Here, biocompatible multi-compartment nanocarriers were synthesized to contain both hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) and the hydrophilic antibiotic methicillin for the treatment of medical device-associated infections. SPION co-encapsulation was found to confer unique properties, enhancing both nanocarrier relaxivity and magneticity compared to individual SPIONs. These iron oxide-encapsulating polymersomes (IOPs) penetrated 20 μm thick Staphylococcus epidermidis biofilms with high efficiency following the application of an external magnetic field. Three-dimensional laser scanning confocal microscopy revealed differential bacteria death as a function of drug and SPION loading. Complete eradication of all bacteria throughout the biofilm thickness was achieved using an optimized IOP formulation containing 40 μg/mL SPION and 20 μg/mL of methicillin. Importantly, this formulation was selectively toxic towards methicillin-resistant biofilm cells but not towards mammalian cells. These novel iron oxide-encapsulating polymersomes demonstrate that it is possible to overcome antibiotic-resistant biofilms by controlling the positioning of nanocarriers containing two or more therapeutics.
52.
Paro, Autumn D; Shanmugam, Ilan; van de Ven, Anne; Kumar, Rajiv; Webster, Thomas J; Sridhar, Srinivas
Abstract B44: Biological mechanisms involved in nanoparticle-enhanced radiation therapy for pancreatic cancer Miscellaneous
2017.
@misc{paro2017abstract,
title = {Abstract B44: Biological mechanisms involved in nanoparticle-enhanced radiation therapy for pancreatic cancer},
author = {Autumn D Paro and Ilan Shanmugam and Anne van de Ven and Rajiv Kumar and Thomas J Webster and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: The objective of this project is to study the biological pathways activated in irradiated pancreatic cancer cells pre-treated with gold nanoparticles. Metallic nanoparticles emit Auger electrons and photoelectrons upon exposure to X-rays. When selectively delivered to tumors, these nanoparticles can locally enhance<?__anchored_object__ "ro_u170cins1e758"?><?__anchored_object__ "ro_u170cins1e759"?> the effects of radiation therapy. Previous in vitro work has primarily studied the effectiveness of nanoparticle-enhanced therapy, without elucidating the underlying biological mechanisms. Understanding the biological mechanisms (such as changes in gene expression) of how nanoparticles enhance radiation therapy can help in the further design of more effective nanoparticles.
Methods: Gold nanoparticle sensitization was tested using a human based pancreatic cancer cell line, Capan-1. Nanoparticle toxicity was tested using a combination of MTS and Alamar Blue assays after 24 hours of treatment. Gene expression was tested using immunofluorescence and western blot techniques. Cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation. Cells were then harvested at various time points to determine how gene expression changes over time. Radiosensitization was carried out using a clonogic cell survival assay where cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation and then re-plated at various densities 4 hours post radiation, and allowed to incubate for 14 days. Statistical differences were determined using ANOVA followed by student t-tests.
Results: The MTS and Alamar blue assays showed low gold nanoparticle toxicity towards cells up to a dose of 1mg for Capan-1 cells. Capan-1 cells pretreated with 0.8 mg gold nanoparticles for 24 hours prior to radiation showed lower cell survival than cells only treated with radiation. Western blots and immunofluorescence data showed that certain genes, such as γ-H2AX, were upregulated when pretreated with gold nanoparticles and irradiated compared to cells treated with radiation alone. It was also shown that γ-H2AX expression peaked around 30 minutes post radiation and then returned to basal levels after 24 hours.
Conclusions: Capan-1 cells experience more DNA damage when pretreated with gold nanoparticles than when only treated with radiation. γ-H2AX, which is a DNA damage-related protein, was upregulated in the combined dose showing that there was more DNA damage in the combined treatment. It was also shown that protein and gene expression analysis needs to be carried out at various time points post radiation to obtain a better understanding of the mechanisms involved in radiation induced damage to pancreatic cancer cells.
Supported by NSF-DGE- 0965843 and CA188833-02.
Citation Format: Autumn D. Paro, Ilan Shanmugam, Anne van de Ven, Rajiv Kumar, Thomas J. Webster, Srinivas Sridhar. Biological mechanisms involved in nanoparticle-enhanced radiation therapy for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B44.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Introduction: The objective of this project is to study the biological pathways activated in irradiated pancreatic cancer cells pre-treated with gold nanoparticles. Metallic nanoparticles emit Auger electrons and photoelectrons upon exposure to X-rays. When selectively delivered to tumors, these nanoparticles can locally enhance<?__anchored_object__ "ro_u170cins1e758"?><?__anchored_object__ "ro_u170cins1e759"?> the effects of radiation therapy. Previous in vitro work has primarily studied the effectiveness of nanoparticle-enhanced therapy, without elucidating the underlying biological mechanisms. Understanding the biological mechanisms (such as changes in gene expression) of how nanoparticles enhance radiation therapy can help in the further design of more effective nanoparticles.
Methods: Gold nanoparticle sensitization was tested using a human based pancreatic cancer cell line, Capan-1. Nanoparticle toxicity was tested using a combination of MTS and Alamar Blue assays after 24 hours of treatment. Gene expression was tested using immunofluorescence and western blot techniques. Cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation. Cells were then harvested at various time points to determine how gene expression changes over time. Radiosensitization was carried out using a clonogic cell survival assay where cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation and then re-plated at various densities 4 hours post radiation, and allowed to incubate for 14 days. Statistical differences were determined using ANOVA followed by student t-tests.
Results: The MTS and Alamar blue assays showed low gold nanoparticle toxicity towards cells up to a dose of 1mg for Capan-1 cells. Capan-1 cells pretreated with 0.8 mg gold nanoparticles for 24 hours prior to radiation showed lower cell survival than cells only treated with radiation. Western blots and immunofluorescence data showed that certain genes, such as γ-H2AX, were upregulated when pretreated with gold nanoparticles and irradiated compared to cells treated with radiation alone. It was also shown that γ-H2AX expression peaked around 30 minutes post radiation and then returned to basal levels after 24 hours.
Conclusions: Capan-1 cells experience more DNA damage when pretreated with gold nanoparticles than when only treated with radiation. γ-H2AX, which is a DNA damage-related protein, was upregulated in the combined dose showing that there was more DNA damage in the combined treatment. It was also shown that protein and gene expression analysis needs to be carried out at various time points post radiation to obtain a better understanding of the mechanisms involved in radiation induced damage to pancreatic cancer cells.
Supported by NSF-DGE- 0965843 and CA188833-02.
Citation Format: Autumn D. Paro, Ilan Shanmugam, Anne van de Ven, Rajiv Kumar, Thomas J. Webster, Srinivas Sridhar. Biological mechanisms involved in nanoparticle-enhanced radiation therapy for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B44.
©2016 American Association for Cancer Research.
Methods: Gold nanoparticle sensitization was tested using a human based pancreatic cancer cell line, Capan-1. Nanoparticle toxicity was tested using a combination of MTS and Alamar Blue assays after 24 hours of treatment. Gene expression was tested using immunofluorescence and western blot techniques. Cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation. Cells were then harvested at various time points to determine how gene expression changes over time. Radiosensitization was carried out using a clonogic cell survival assay where cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation and then re-plated at various densities 4 hours post radiation, and allowed to incubate for 14 days. Statistical differences were determined using ANOVA followed by student t-tests.
Results: The MTS and Alamar blue assays showed low gold nanoparticle toxicity towards cells up to a dose of 1mg for Capan-1 cells. Capan-1 cells pretreated with 0.8 mg gold nanoparticles for 24 hours prior to radiation showed lower cell survival than cells only treated with radiation. Western blots and immunofluorescence data showed that certain genes, such as γ-H2AX, were upregulated when pretreated with gold nanoparticles and irradiated compared to cells treated with radiation alone. It was also shown that γ-H2AX expression peaked around 30 minutes post radiation and then returned to basal levels after 24 hours.
Conclusions: Capan-1 cells experience more DNA damage when pretreated with gold nanoparticles than when only treated with radiation. γ-H2AX, which is a DNA damage-related protein, was upregulated in the combined dose showing that there was more DNA damage in the combined treatment. It was also shown that protein and gene expression analysis needs to be carried out at various time points post radiation to obtain a better understanding of the mechanisms involved in radiation induced damage to pancreatic cancer cells.
Supported by NSF-DGE- 0965843 and CA188833-02.
Citation Format: Autumn D. Paro, Ilan Shanmugam, Anne van de Ven, Rajiv Kumar, Thomas J. Webster, Srinivas Sridhar. Biological mechanisms involved in nanoparticle-enhanced radiation therapy for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B44.
©2016 American Association for Cancer Research.
53.
Baldwin, Paige; Ohman, Anders; Belz, Jodi; Thong, Jeremy; Ojo, Noelle Castilla; Liby, Karen; Dinulescu, Daniela; Sridhar, Srinivas
Abstract B29: Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib Miscellaneous
2017.
@misc{baldwin2017abstract,
title = {Abstract B29: Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib},
author = {Paige Baldwin and Anders Ohman and Jodi Belz and Jeremy Thong and Noelle Castilla Ojo and Karen Liby and Daniela Dinulescu and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib and Talazoparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents. Here we report the development of two different delivery techniques including nanoformulations of Olaparib and Talazoparib and a biodegradable implant for localized delivery of Talazoparib. The nanoformulations allow for intravenous or intraperitoneal delivery, providing greater bioavailability and tumor accumulation, while limiting systemic toxicities and the implant provides a sustained release for intratumoral delivery to enhance the dose at the tumor site thereby limiting systemic toxicity.
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and characterized via TEM, DLS, and HPLC to elucidate size, loading, and release before testing in vivo. In vitro experiments for testing nanoformulations include dose response with a panel of ovarian cancer cell lines. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells derived from BRCA2-/-, TP53-/-, PTEN-/- genetically engineered mouse models. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. The 1-2 mm long Talazoparib implant was characterized with SEM and HPLC for structure, loading, and release. A spontaneous tumor forming breast cancer model was used to test the Talazoparib implant. Implants were directly injected into the tumor of Brca1Co/Co;MMTV-Cre;p53+/- mice for a one time treatment.
Results: PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Both PTEN and BRCA deficiencies resulted in comparable IC50's likely due to synthetic lethality attributed to dysfunctional homologous recombination pathways. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50's. Bioluminescence images illustrated that NanoOlaparib administered IP daily in the ovarian cancer model resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The Talazoparib implant released therapeutically relevant doses of Talazoparib over multiple weeks. In vivo the implant reduced tumors 50% following the one time treatment, while untreated tumors increased significantly in size.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed and characterized. These results show that NanoOlaparib and NanoTalazoparib amplify the efficacy of PARP inhibitors in vivo. The Talazoparib implant provides a safe strategy for sustained local delivery of Talazoparib directly to the tumor. These strategies provide opportunities to increase the efficacy of PARP inhibitors via tailored delivery to the type of tumor.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092 and IGERT grant NSF-DGE- 0965843.
Citation Format: Paige Baldwin, Anders Ohman, Jodi Belz, Jeremy Thong, Noelle Castilla Ojo, Karen Liby, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B29.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Introduction: Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib and Talazoparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents. Here we report the development of two different delivery techniques including nanoformulations of Olaparib and Talazoparib and a biodegradable implant for localized delivery of Talazoparib. The nanoformulations allow for intravenous or intraperitoneal delivery, providing greater bioavailability and tumor accumulation, while limiting systemic toxicities and the implant provides a sustained release for intratumoral delivery to enhance the dose at the tumor site thereby limiting systemic toxicity.
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and characterized via TEM, DLS, and HPLC to elucidate size, loading, and release before testing in vivo. In vitro experiments for testing nanoformulations include dose response with a panel of ovarian cancer cell lines. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells derived from BRCA2-/-, TP53-/-, PTEN-/- genetically engineered mouse models. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. The 1-2 mm long Talazoparib implant was characterized with SEM and HPLC for structure, loading, and release. A spontaneous tumor forming breast cancer model was used to test the Talazoparib implant. Implants were directly injected into the tumor of Brca1Co/Co;MMTV-Cre;p53+/- mice for a one time treatment.
Results: PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Both PTEN and BRCA deficiencies resulted in comparable IC50's likely due to synthetic lethality attributed to dysfunctional homologous recombination pathways. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50's. Bioluminescence images illustrated that NanoOlaparib administered IP daily in the ovarian cancer model resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The Talazoparib implant released therapeutically relevant doses of Talazoparib over multiple weeks. In vivo the implant reduced tumors 50% following the one time treatment, while untreated tumors increased significantly in size.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed and characterized. These results show that NanoOlaparib and NanoTalazoparib amplify the efficacy of PARP inhibitors in vivo. The Talazoparib implant provides a safe strategy for sustained local delivery of Talazoparib directly to the tumor. These strategies provide opportunities to increase the efficacy of PARP inhibitors via tailored delivery to the type of tumor.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092 and IGERT grant NSF-DGE- 0965843.
Citation Format: Paige Baldwin, Anders Ohman, Jodi Belz, Jeremy Thong, Noelle Castilla Ojo, Karen Liby, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B29.
©2016 American Association for Cancer Research.
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and characterized via TEM, DLS, and HPLC to elucidate size, loading, and release before testing in vivo. In vitro experiments for testing nanoformulations include dose response with a panel of ovarian cancer cell lines. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells derived from BRCA2-/-, TP53-/-, PTEN-/- genetically engineered mouse models. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. The 1-2 mm long Talazoparib implant was characterized with SEM and HPLC for structure, loading, and release. A spontaneous tumor forming breast cancer model was used to test the Talazoparib implant. Implants were directly injected into the tumor of Brca1Co/Co;MMTV-Cre;p53+/- mice for a one time treatment.
Results: PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Both PTEN and BRCA deficiencies resulted in comparable IC50's likely due to synthetic lethality attributed to dysfunctional homologous recombination pathways. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50's. Bioluminescence images illustrated that NanoOlaparib administered IP daily in the ovarian cancer model resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The Talazoparib implant released therapeutically relevant doses of Talazoparib over multiple weeks. In vivo the implant reduced tumors 50% following the one time treatment, while untreated tumors increased significantly in size.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed and characterized. These results show that NanoOlaparib and NanoTalazoparib amplify the efficacy of PARP inhibitors in vivo. The Talazoparib implant provides a safe strategy for sustained local delivery of Talazoparib directly to the tumor. These strategies provide opportunities to increase the efficacy of PARP inhibitors via tailored delivery to the type of tumor.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092 and IGERT grant NSF-DGE- 0965843.
Citation Format: Paige Baldwin, Anders Ohman, Jodi Belz, Jeremy Thong, Noelle Castilla Ojo, Karen Liby, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B29.
©2016 American Association for Cancer Research.
54.
van de Ven, Anne L; Tangutoori, Shifalika; Baldwin, Paige; Qiao, Ju; Gharagouzloo, Codi; Seitzer, Nina; Clohessy, John; Korideck, Houari; Makrigiorgos, Mike G; Cormack, Robert; others,
Abstract B48: Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance Miscellaneous
2017.
@misc{van2017abstract,
title = {Abstract B48: Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance},
author = {Anne L van de Ven and Shifalika Tangutoori and Paige Baldwin and Ju Qiao and Codi Gharagouzloo and Nina Seitzer and John Clohessy and Houari Korideck and Mike G Makrigiorgos and Robert Cormack and others},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Prostate cancers with PTEN deletions are promising candidates for DNA repair inhibitors such as olaparib and talazoparib. Here we show that radiation-resistant cells and tumors derived from Ptenpc-/-;Trp53pc-/- mice are rendered radiation-sensitive following pre-treatment with liposomal nanoOlaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to nanoformulated Olaparib alone. In animals, twice-weekly intravenous administration of nanoOlaparib alone results in significant tumor growth inhibition. When nanoOlaparib is administered prior to radiation, we find that a single dose of radiation is sufficient to increase mouse survival time by as much as 10 weeks (study duration = 13 weeks). Using ferumoxytol as a surrogate nanoparticle, magnetic resonance imaging (MRI) studies revealed that nanoOlaparib administration enhances the ability of nanoparticles to accumulate in tumors. Compared to untreated and radiation-only controls, nanoOlaparib-treated tumors showed 18-fold higher nanoparticle accumulation, suggesting that the in vivo efficacy of nanoOlaparib may be potentiated by its ability to enhance its own accumulation in tumors.
Citation Format: Anne L. van de Ven, Shifalika Tangutoori, Paige Baldwin, Ju Qiao, Codi Gharagouzloo, Nina Seitzer, John Clohessy, Houari Korideck, G. Mike Makrigiorgos, Robert Cormack, Pier Paolo Pandolfi, Srinivas Sridhar. Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B48.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Prostate cancers with PTEN deletions are promising candidates for DNA repair inhibitors such as olaparib and talazoparib. Here we show that radiation-resistant cells and tumors derived from Ptenpc-/-;Trp53pc-/- mice are rendered radiation-sensitive following pre-treatment with liposomal nanoOlaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to nanoformulated Olaparib alone. In animals, twice-weekly intravenous administration of nanoOlaparib alone results in significant tumor growth inhibition. When nanoOlaparib is administered prior to radiation, we find that a single dose of radiation is sufficient to increase mouse survival time by as much as 10 weeks (study duration = 13 weeks). Using ferumoxytol as a surrogate nanoparticle, magnetic resonance imaging (MRI) studies revealed that nanoOlaparib administration enhances the ability of nanoparticles to accumulate in tumors. Compared to untreated and radiation-only controls, nanoOlaparib-treated tumors showed 18-fold higher nanoparticle accumulation, suggesting that the in vivo efficacy of nanoOlaparib may be potentiated by its ability to enhance its own accumulation in tumors.
Citation Format: Anne L. van de Ven, Shifalika Tangutoori, Paige Baldwin, Ju Qiao, Codi Gharagouzloo, Nina Seitzer, John Clohessy, Houari Korideck, G. Mike Makrigiorgos, Robert Cormack, Pier Paolo Pandolfi, Srinivas Sridhar. Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B48.
©2016 American Association for Cancer Research.
Citation Format: Anne L. van de Ven, Shifalika Tangutoori, Paige Baldwin, Ju Qiao, Codi Gharagouzloo, Nina Seitzer, John Clohessy, Houari Korideck, G. Mike Makrigiorgos, Robert Cormack, Pier Paolo Pandolfi, Srinivas Sridhar. Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B48.
©2016 American Association for Cancer Research.
55.
Kumar, Rajiv; Ngwa, Wilfred; Joshi, Vinit; Kunjachan, Sijumon; Berbeco, Ross; Makrigiorgos, Mike; Sridhar, Srinivas
Abstract B41: Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy Miscellaneous
2017.
@misc{kumar2017abstract,
title = {Abstract B41: Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy},
author = {Rajiv Kumar and Wilfred Ngwa and Vinit Joshi and Sijumon Kunjachan and Ross Berbeco and Mike Makrigiorgos and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and the unique properties associated with gold nanoparticles makes them as potent radiosensitizers for enhancing Radiotherapy (RT) treatments. The interaction of high Z materials with the X-rays results in photoelectric absorption which leads to generation of photoelectrons. These low energy photoelectrons can deliver lethal energy in the close proximity. The success of cancer radiation therapy relies heavily on the effective delivery of radiation dose to the tumor site sparing the surrounding normal tissues. To overcome the limitations associated with increasing the radiation dose, due to normal tissue toxicities, the feasibility of radiosensitizing the tumor using gold nanoparticles provide a promising alternative. Targeting gold nanoparticles based formulations to the tumor prior to radiation therapy will result in radiation dose enhancement, by generating secondary photoelectrons, locally inside the tumor and thereby minimizing the dose dependent toxicity to non-specific neighboring tissues. Here, we have developed different Gold nanoparticles based formulations to locally radiosensitize the tumor cells in three different cancer models.
For targeting pancreatic cancers, we have fabricated a new generation of GNPs formulation which are 3-4 nm in diameter and surface passivated with hetero-bifunctional PEG, fluorophore AlexaFlour 647 and peptide RGD. This formulation showed a 2.8-fold in vitro cell kill enhancement with X-rays, as demonstrated by clonogenic survival assays. In vivo studies confirmed the highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model. The combined treatment in animals treated with GNPs and radiation (10Gy) showed the maximum endothelial cells damage, as confirmed with confocal imaging of the tumor sections and CD31 immunostaining.
For targeting the lung cancer, we have used the same GNPs formulation but adopted a inhalation/instillation (INH) route for administering the nanoparticles in vivo in transgenic lung cancer mice model as opposed to customary intravenous (i.v) route. Fluorescence imaging and ex-vivo electron microcopy results showed a 4.7 times higher concentration of GNPs in the lung tumors of mice when using INH delivery compared to i.v. approach. The survival studies with these animals are currently underway.
For using these radiosensitizing nanoparticles in brachytherapy applications, we have incorporated GNPs in modified brachytherapy spacers to enhance radiation dose locally in tumor without any additional surgical intervention. These spacers are normally placed inside the tumor to spatially distribute the radioactive seeds. The incorporation of GNPs in these spacers allowed for enhancing the radiation dose by the GNPs released from the spacers. These spacers have same morphology (5 mm in length and 0.8 mm in diameter) as commercial spacers with additional radiosensitizing properties because of doped GNPs. We have shown the time dependent release of the GNPs as a function of size of GNPs from the spacers into the tumor by optical imaging. We have further incorporated the GNPs based brachytherapy spacer with the immunoadjuvants, anti-CD40 to combine the radiation and immunotherapy in a single platform. The preliminary results indicate that gold nanoparticles based nanoplatform shows promise as a potential theranostic radiosensitizer which allows for combining multiple therapies in a single platform.
This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Wilfred Ngwa, Vinit Joshi, Sijumon Kunjachan, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B41.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and the unique properties associated with gold nanoparticles makes them as potent radiosensitizers for enhancing Radiotherapy (RT) treatments. The interaction of high Z materials with the X-rays results in photoelectric absorption which leads to generation of photoelectrons. These low energy photoelectrons can deliver lethal energy in the close proximity. The success of cancer radiation therapy relies heavily on the effective delivery of radiation dose to the tumor site sparing the surrounding normal tissues. To overcome the limitations associated with increasing the radiation dose, due to normal tissue toxicities, the feasibility of radiosensitizing the tumor using gold nanoparticles provide a promising alternative. Targeting gold nanoparticles based formulations to the tumor prior to radiation therapy will result in radiation dose enhancement, by generating secondary photoelectrons, locally inside the tumor and thereby minimizing the dose dependent toxicity to non-specific neighboring tissues. Here, we have developed different Gold nanoparticles based formulations to locally radiosensitize the tumor cells in three different cancer models.
For targeting pancreatic cancers, we have fabricated a new generation of GNPs formulation which are 3-4 nm in diameter and surface passivated with hetero-bifunctional PEG, fluorophore AlexaFlour 647 and peptide RGD. This formulation showed a 2.8-fold in vitro cell kill enhancement with X-rays, as demonstrated by clonogenic survival assays. In vivo studies confirmed the highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model. The combined treatment in animals treated with GNPs and radiation (10Gy) showed the maximum endothelial cells damage, as confirmed with confocal imaging of the tumor sections and CD31 immunostaining.
For targeting the lung cancer, we have used the same GNPs formulation but adopted a inhalation/instillation (INH) route for administering the nanoparticles in vivo in transgenic lung cancer mice model as opposed to customary intravenous (i.v) route. Fluorescence imaging and ex-vivo electron microcopy results showed a 4.7 times higher concentration of GNPs in the lung tumors of mice when using INH delivery compared to i.v. approach. The survival studies with these animals are currently underway.
For using these radiosensitizing nanoparticles in brachytherapy applications, we have incorporated GNPs in modified brachytherapy spacers to enhance radiation dose locally in tumor without any additional surgical intervention. These spacers are normally placed inside the tumor to spatially distribute the radioactive seeds. The incorporation of GNPs in these spacers allowed for enhancing the radiation dose by the GNPs released from the spacers. These spacers have same morphology (5 mm in length and 0.8 mm in diameter) as commercial spacers with additional radiosensitizing properties because of doped GNPs. We have shown the time dependent release of the GNPs as a function of size of GNPs from the spacers into the tumor by optical imaging. We have further incorporated the GNPs based brachytherapy spacer with the immunoadjuvants, anti-CD40 to combine the radiation and immunotherapy in a single platform. The preliminary results indicate that gold nanoparticles based nanoplatform shows promise as a potential theranostic radiosensitizer which allows for combining multiple therapies in a single platform.
This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Wilfred Ngwa, Vinit Joshi, Sijumon Kunjachan, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B41.
©2016 American Association for Cancer Research.
For targeting pancreatic cancers, we have fabricated a new generation of GNPs formulation which are 3-4 nm in diameter and surface passivated with hetero-bifunctional PEG, fluorophore AlexaFlour 647 and peptide RGD. This formulation showed a 2.8-fold in vitro cell kill enhancement with X-rays, as demonstrated by clonogenic survival assays. In vivo studies confirmed the highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model. The combined treatment in animals treated with GNPs and radiation (10Gy) showed the maximum endothelial cells damage, as confirmed with confocal imaging of the tumor sections and CD31 immunostaining.
For targeting the lung cancer, we have used the same GNPs formulation but adopted a inhalation/instillation (INH) route for administering the nanoparticles in vivo in transgenic lung cancer mice model as opposed to customary intravenous (i.v) route. Fluorescence imaging and ex-vivo electron microcopy results showed a 4.7 times higher concentration of GNPs in the lung tumors of mice when using INH delivery compared to i.v. approach. The survival studies with these animals are currently underway.
For using these radiosensitizing nanoparticles in brachytherapy applications, we have incorporated GNPs in modified brachytherapy spacers to enhance radiation dose locally in tumor without any additional surgical intervention. These spacers are normally placed inside the tumor to spatially distribute the radioactive seeds. The incorporation of GNPs in these spacers allowed for enhancing the radiation dose by the GNPs released from the spacers. These spacers have same morphology (5 mm in length and 0.8 mm in diameter) as commercial spacers with additional radiosensitizing properties because of doped GNPs. We have shown the time dependent release of the GNPs as a function of size of GNPs from the spacers into the tumor by optical imaging. We have further incorporated the GNPs based brachytherapy spacer with the immunoadjuvants, anti-CD40 to combine the radiation and immunotherapy in a single platform. The preliminary results indicate that gold nanoparticles based nanoplatform shows promise as a potential theranostic radiosensitizer which allows for combining multiple therapies in a single platform.
This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Wilfred Ngwa, Vinit Joshi, Sijumon Kunjachan, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B41.
©2016 American Association for Cancer Research.
56.
Belz, Jodi; Ojo, Noelle Castilla; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne; Liby, Karen; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Abstract B30: Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer Miscellaneous
2017.
@misc{belz2017abstract,
title = {Abstract B30: Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer},
author = {Jodi Belz and Noelle Castilla Ojo and Paige Baldwin and Rajiv Kumar and Anne van de Ven and Karen Liby and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Sustained localized delivery of cancer therapeutics is a safe and effective unique option for local control of tumors. Here we report a novel biodegradable implant with the capability to encapsulate different therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ~50μg Talazoparib for BRCA1-mutated breast cancer studies and ~500μg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50's were determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice, W0069 and W780, and human-derived prostate cancer, PC3. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− spontaneous tumored mice for breast cancer studies. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both docetaxel and Talazoparib loading implants. Breast cancer cell lines W0069 and W780 were highly sensitive to Talazoparib, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of Talazoparib, tumors reduced in size by an average of 50%, while untreated tumors increased ~5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Docetaxel implants proved to be an effective method for prostate cancer in vivo with no significant weight loss observed. The local docetaxel spacer group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib and Docetaxel were observed in vitro and in vivo. Therapeutics-loaded implants represent a novel delivery route that are well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of Docetaxel is an effective chemotherapy option alone or in combination with radiation therapy. These results laid a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
This work was supported by the Army- W81XWH-14-1-0092, Breast Cancer Research Foundation and Northeastern University–Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar4. Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B30.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Sustained localized delivery of cancer therapeutics is a safe and effective unique option for local control of tumors. Here we report a novel biodegradable implant with the capability to encapsulate different therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ~50μg Talazoparib for BRCA1-mutated breast cancer studies and ~500μg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50's were determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice, W0069 and W780, and human-derived prostate cancer, PC3. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− spontaneous tumored mice for breast cancer studies. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both docetaxel and Talazoparib loading implants. Breast cancer cell lines W0069 and W780 were highly sensitive to Talazoparib, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of Talazoparib, tumors reduced in size by an average of 50%, while untreated tumors increased ~5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Docetaxel implants proved to be an effective method for prostate cancer in vivo with no significant weight loss observed. The local docetaxel spacer group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib and Docetaxel were observed in vitro and in vivo. Therapeutics-loaded implants represent a novel delivery route that are well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of Docetaxel is an effective chemotherapy option alone or in combination with radiation therapy. These results laid a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
This work was supported by the Army- W81XWH-14-1-0092, Breast Cancer Research Foundation and Northeastern University–Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar4. Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B30.
©2016 American Association for Cancer Research.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ~50μg Talazoparib for BRCA1-mutated breast cancer studies and ~500μg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50's were determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice, W0069 and W780, and human-derived prostate cancer, PC3. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− spontaneous tumored mice for breast cancer studies. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both docetaxel and Talazoparib loading implants. Breast cancer cell lines W0069 and W780 were highly sensitive to Talazoparib, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of Talazoparib, tumors reduced in size by an average of 50%, while untreated tumors increased ~5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Docetaxel implants proved to be an effective method for prostate cancer in vivo with no significant weight loss observed. The local docetaxel spacer group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib and Docetaxel were observed in vitro and in vivo. Therapeutics-loaded implants represent a novel delivery route that are well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of Docetaxel is an effective chemotherapy option alone or in combination with radiation therapy. These results laid a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
This work was supported by the Army- W81XWH-14-1-0092, Breast Cancer Research Foundation and Northeastern University–Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar4. Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B30.
©2016 American Association for Cancer Research.
57.
Belz, Jodi; Castilla-Ojo, Noelle; Sridhar, Srinivas; Kumar, Rajiv
Radiosensitizing silica nanoparticles encapsulating docetaxel for treatment of prostate cancer Book Section
In: Cancer Nanotechnology, pp. 403–409, Humana Press, New York, NY, 2017.
@incollection{belz2017radiosensitizing,
title = {Radiosensitizing silica nanoparticles encapsulating docetaxel for treatment of prostate cancer},
author = {Jodi Belz and Noelle Castilla-Ojo and Srinivas Sridhar and Rajiv Kumar},
year = {2017},
date = {2017-01-01},
booktitle = {Cancer Nanotechnology},
pages = {403--409},
publisher = {Humana Press, New York, NY},
abstract = {The applications of nanoparticles in oncology include enhanced drug delivery, efficient tumor targeting, treatment monitoring, and diagnostics. The “theranostic properties” associated with nanoparticles have shown enhanced delivery of chemotherapeutic drugs with superior imaging capabilities and minimal toxicities. In conventional chemotherapy, only a fraction of the administered drug reaches the tumor site or cancer cells. For successful translation of these formulations, it is imperative to evaluate the design and properties of these nanoparticles. Here, we describe the design of ultra-small silica nanoparticles to encapsulate a radiosensitizing drug for combined chemoradiation therapy. The small size of nanoparticles allows for better dispersion and uptake of the drug within the highly vascularized tumor tissue. Silica nanoparticles are synthesized using an oil-in-water microemulsion method. The microemulsion method provides a robust synthetic route in which the inner hydrophobic core is used to encapsulate chemotherapy drug, docetaxel while the outer hydrophilic region provides dispersibility of the synthesized nanoparticles in an aqueous environment. Docetaxel is commonly used for treatment of resistant or metastatic prostate cancer, and is known to have radiosensitizing properties. Here, we describe a systematic approach for synthesizing these theranostic nanoparticles for application in prostate cancer.},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
The applications of nanoparticles in oncology include enhanced drug delivery, efficient tumor targeting, treatment monitoring, and diagnostics. The “theranostic properties” associated with nanoparticles have shown enhanced delivery of chemotherapeutic drugs with superior imaging capabilities and minimal toxicities. In conventional chemotherapy, only a fraction of the administered drug reaches the tumor site or cancer cells. For successful translation of these formulations, it is imperative to evaluate the design and properties of these nanoparticles. Here, we describe the design of ultra-small silica nanoparticles to encapsulate a radiosensitizing drug for combined chemoradiation therapy. The small size of nanoparticles allows for better dispersion and uptake of the drug within the highly vascularized tumor tissue. Silica nanoparticles are synthesized using an oil-in-water microemulsion method. The microemulsion method provides a robust synthetic route in which the inner hydrophobic core is used to encapsulate chemotherapy drug, docetaxel while the outer hydrophilic region provides dispersibility of the synthesized nanoparticles in an aqueous environment. Docetaxel is commonly used for treatment of resistant or metastatic prostate cancer, and is known to have radiosensitizing properties. Here, we describe a systematic approach for synthesizing these theranostic nanoparticles for application in prostate cancer.
58.
Baldwin, Paige; Tangutoori, Shifalika; Sridhar, Srinivas
Generation of Dose--Response Curves and Improved IC50s for PARP Inhibitor Nanoformulations Book Section
In: Cancer Nanotechnology, pp. 337–342, Humana Press, New York, NY, 2017.
@incollection{baldwin2017generation,
title = {Generation of Dose--Response Curves and Improved IC50s for PARP Inhibitor Nanoformulations},
author = {Paige Baldwin and Shifalika Tangutoori and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
booktitle = {Cancer Nanotechnology},
pages = {337--342},
publisher = {Humana Press, New York, NY},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
59.
Guthier, Christian V; D'Amico, Anthony V; King, Martin T; Nguyen, Paul L; Orio, Peter F; Sridhar, Srinivas; Makrigiorgos, Mike G; Cormack, Robert A
Focal Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants Journal Article
In: Brachytherapy, vol. 16, no. 3, pp. S115, 2017.
@article{guthier2017focal,
title = {Focal Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants},
author = {Christian V Guthier and Anthony V D'Amico and Martin T King and Paul L Nguyen and Peter F Orio and Srinivas Sridhar and Mike G Makrigiorgos and Robert A Cormack},
year = {2017},
date = {2017-01-01},
journal = {Brachytherapy},
volume = {16},
number = {3},
pages = {S115},
publisher = {Elsevier},
abstract = {In-situ drug release concurrent with radiation therapy has been proposed as a means to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine which of the proposed methods is the preferred delivery approach.
Materials and Methods
The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In-situ drug release concurrent with radiation therapy has been proposed as a means to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine which of the proposed methods is the preferred delivery approach.
Materials and Methods
The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …
Materials and Methods
The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …
60.
van de Ven, Anne L; Tangutoori, Shifalika; Baldwin, Paige; Qiao, Ju; Gharagouzloo, Codi; Seitzer, Nina; Clohessy, John G; Makrigiorgos, Mike G; Cormack, Robert; Pandolfi, Pier Paolo; others,
Nanoformulation of olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation Journal Article
In: Molecular cancer therapeutics, vol. 16, no. 7, pp. 1279–1289, 2017.
@article{van2017nanoformulation,
title = {Nanoformulation of olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation},
author = {Anne L van de Ven and Shifalika Tangutoori and Paige Baldwin and Ju Qiao and Codi Gharagouzloo and Nina Seitzer and John G Clohessy and Mike G Makrigiorgos and Robert Cormack and Pier Paolo Pandolfi and others},
year = {2017},
date = {2017-01-01},
journal = {Molecular cancer therapeutics},
volume = {16},
number = {7},
pages = {1279--1289},
publisher = {American Association for Cancer Research},
abstract = {The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279–89. ©2017 AACR.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279–89. ©2017 AACR.
2015
78.
Debay, Ann Chiaramonti C; Ozturk, Birol; de Luna Bugallo, Andres; Panaitescu, Eugene; Liu, Fangze; Vargas, Anthony; Jiang, Xueping; Yavuzcetin, Ozgur; Alnaji, Majed; Zhao, Yongui; others,
Atomically thin layers of BNCO with tuneable composition Technical Report
2015.
Abstract | BibTeX | Tags: Nanomedicine
@techreport{debay2015atomically,
title = {Atomically thin layers of BNCO with tuneable composition},
author = {Ann Chiaramonti C Debay and Birol Ozturk and Andres de Luna Bugallo and Eugene Panaitescu and Fangze Liu and Anthony Vargas and Xueping Jiang and Ozgur Yavuzcetin and Majed Alnaji and Yongui Zhao and others},
year = {2015},
date = {2015-01-01},
abstract = {Atomically thin ternary compounds/alloys of boron, nitrogen and carbon have generated significant excitement as they provided the first instance of a tuneable 2D material that affords rich physics as well applications potentials. Interestingly, the crucial role and the possible inclusion of oxygen in the 2D-BNC lattice have never been investigated. Here, we present the first report on an atomically thin quaternary alloy of boron, nitrogen, carbon and oxygen, 2D-BNCO. Our experiments suggest and theoretical calculations corroborate stable configurations of a planar honeycomb 2D-BNCO lattice. We observed the growth of micron-scale 2D-BNCO domains within a graphene-rich matrix, and were able to control their area coverage and relative composition by varying the ratio of oxygen content in the growth setup. The introduction of oxygen into the BNC system induces a rich variety of electronic, optical, and magnetic properties.
CitationNano Letters},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {techreport}
}
Atomically thin ternary compounds/alloys of boron, nitrogen and carbon have generated significant excitement as they provided the first instance of a tuneable 2D material that affords rich physics as well applications potentials. Interestingly, the crucial role and the possible inclusion of oxygen in the 2D-BNC lattice have never been investigated. Here, we present the first report on an atomically thin quaternary alloy of boron, nitrogen, carbon and oxygen, 2D-BNCO. Our experiments suggest and theoretical calculations corroborate stable configurations of a planar honeycomb 2D-BNCO lattice. We observed the growth of micron-scale 2D-BNCO domains within a graphene-rich matrix, and were able to control their area coverage and relative composition by varying the ratio of oxygen content in the growth setup. The introduction of oxygen into the BNC system induces a rich variety of electronic, optical, and magnetic properties.
CitationNano Letters
CitationNano Letters
77.
Teh, James; Hanson, Robert; Sridhar, Srinivas
Targeting integrin alpha v beta 3 receptors with multivalent RGD peptidomimetics Proceedings Article
In: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA 2015.
BibTeX | Tags: Nanomedicine
@inproceedings{teh2015targeting,
title = {Targeting integrin alpha v beta 3 receptors with multivalent RGD peptidomimetics},
author = {James Teh and Robert Hanson and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
booktitle = {ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY},
volume = {249},
organization = {AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
76.
Wang, Haotian; Kumar, Rajiv; Nagesha, Dattatri; Jr, Richard I Duclos; Sridhar, Srinivas; Gatley, Samuel J
Integrity of 111In-radiolabeled superparamagnetic iron oxide nanoparticles in the mouse Journal Article
In: Nuclear medicine and biology, vol. 42, no. 1, pp. 65–70, 2015.
Abstract | BibTeX | Tags: MRI, Nanomedicine
@article{wang2015integrity,
title = {Integrity of 111In-radiolabeled superparamagnetic iron oxide nanoparticles in the mouse},
author = {Haotian Wang and Rajiv Kumar and Dattatri Nagesha and Richard I Duclos Jr and Srinivas Sridhar and Samuel J Gatley},
year = {2015},
date = {2015-01-01},
journal = {Nuclear medicine and biology},
volume = {42},
number = {1},
pages = {65--70},
publisher = {Elsevier},
abstract = {Introduction
Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo.
Methods
We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with 59Fe, 14C-oleic acid, and 111In.
Results
Mouse biodistributions showed 111In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of 59Fe than 111In in liver and spleen, but lower levels of 14C.
Conclusions
While there is some degree of dissociation between the 111In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component.},
keywords = {MRI, Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Introduction
Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo.
Methods
We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with 59Fe, 14C-oleic acid, and 111In.
Results
Mouse biodistributions showed 111In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of 59Fe than 111In in liver and spleen, but lower levels of 14C.
Conclusions
While there is some degree of dissociation between the 111In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component.
Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo.
Methods
We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with 59Fe, 14C-oleic acid, and 111In.
Results
Mouse biodistributions showed 111In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of 59Fe than 111In in liver and spleen, but lower levels of 14C.
Conclusions
While there is some degree of dissociation between the 111In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component.
75.
Gharagouzloo, Codi Amir; McMahon, Patrick N; Sridhar, Srinivas
Quantitative contrast-enhanced MRI with superparamagnetic nanoparticles using ultrashort time-to-echo pulse sequences Journal Article
In: Magnetic resonance in medicine, vol. 74, no. 2, pp. 431–441, 2015.
BibTeX | Tags: MRI, Nanomedicine
@article{gharagouzloo2015quantitative,
title = {Quantitative contrast-enhanced MRI with superparamagnetic nanoparticles using ultrashort time-to-echo pulse sequences},
author = {Codi Amir Gharagouzloo and Patrick N McMahon and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {Magnetic resonance in medicine},
volume = {74},
number = {2},
pages = {431--441},
keywords = {MRI, Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
74.
Sinha, Neeharika; Cifter, Gizem; Sajo, Erno; Kumar, Rajiv; Sridhar, Srinivas; Nguyen, Paul L; Cormack, Robert A; Makrigiorgos, Mike G; Ngwa, Wilfred
Brachytherapy application with in situ dose painting administered by gold nanoparticle eluters Journal Article
In: International Journal of Radiation Oncology* Biology* Physics, vol. 91, no. 2, pp. 385–392, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{sinha2015brachytherapy,
title = {Brachytherapy application with in situ dose painting administered by gold nanoparticle eluters},
author = {Neeharika Sinha and Gizem Cifter and Erno Sajo and Rajiv Kumar and Srinivas Sridhar and Paul L Nguyen and Robert A Cormack and Mike G Makrigiorgos and Wilfred Ngwa},
year = {2015},
date = {2015-01-01},
journal = {International Journal of Radiation Oncology* Biology* Physics},
volume = {91},
number = {2},
pages = {385--392},
publisher = {Elsevier},
abstract = {Purpose
Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS).
Method and Materials
An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using the Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131).
Results
Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125.
Conclusions
Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy application with in situ dose painting administered via gold nanoparticle eluters for prostate cancer.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose
Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS).
Method and Materials
An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using the Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131).
Results
Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125.
Conclusions
Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy application with in situ dose painting administered via gold nanoparticle eluters for prostate cancer.
Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS).
Method and Materials
An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using the Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131).
Results
Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125.
Conclusions
Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy application with in situ dose painting administered via gold nanoparticle eluters for prostate cancer.
73.
Cifter, G; Sajo, E; Korideck, H; Kumar, R; Sridhar, S; Cormack, R; Makrigiorgos, G; Ngwa, W
Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles: MO-FG-BRA-05 Journal Article
In: Medical Physics, vol. 42, no. 6, 2015.
BibTeX | Tags: Nanomedicine
@article{cifter2015next,
title = {Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles: MO-FG-BRA-05},
author = {G Cifter and E Sajo and H Korideck and R Kumar and S Sridhar and R Cormack and G Makrigiorgos and W Ngwa},
year = {2015},
date = {2015-01-01},
journal = {Medical Physics},
volume = {42},
number = {6},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
72.
Geilich, Benjamin M; van de Ven, Anne L; Singleton, Gloria L; Sepulveda, Liuda J; Sridhar, Srinivas; Webster, Thomas J
Silver nanoparticle-embedded polymersome nanocarriers for the treatment of antibiotic-resistant infections Journal Article
In: Nanoscale, vol. 7, no. 8, pp. 3511–3519, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{geilich2015silver,
title = {Silver nanoparticle-embedded polymersome nanocarriers for the treatment of antibiotic-resistant infections},
author = {Benjamin M Geilich and Anne L van de Ven and Gloria L Singleton and Liuda J Sepulveda and Srinivas Sridhar and Thomas J Webster},
year = {2015},
date = {2015-01-01},
journal = {Nanoscale},
volume = {7},
number = {8},
pages = {3511--3519},
publisher = {Royal Society of Chemistry},
abstract = {The rapidly diminishing number of effective antibiotics that can be used to treat infectious diseases and associated complications in a physician's arsenal is having a drastic impact on human health today. This study explored the development and optimization of a polymersome nanocarrier formed from a biodegradable diblock copolymer to overcome bacterial antibiotic resistance. Here, polymersomes were synthesized containing silver nanoparticles embedded in the hydrophobic compartment, and ampicillin in the hydrophilic compartment. Results showed for the first time that these silver nanoparticle-embedded polymersomes (AgPs) inhibited the growth of Escherichia coli transformed with a gene for ampicillin resistance (bla) in a dose-dependent fashion. Free ampicillin, AgPs without ampicillin, and ampicillin polymersomes without silver nanoparticles had no effect on bacterial growth. The relationship between the silver nanoparticles and ampicillin was determined to be synergistic and produced complete growth inhibition at a silver-to-ampicillin ratio of 1 : 0.64. In this manner, this study introduces a novel nanomaterial that can effectively treat problematic, antibiotic-resistant infections in an improved capacity which should be further examined for a wide range of medical applications.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The rapidly diminishing number of effective antibiotics that can be used to treat infectious diseases and associated complications in a physician's arsenal is having a drastic impact on human health today. This study explored the development and optimization of a polymersome nanocarrier formed from a biodegradable diblock copolymer to overcome bacterial antibiotic resistance. Here, polymersomes were synthesized containing silver nanoparticles embedded in the hydrophobic compartment, and ampicillin in the hydrophilic compartment. Results showed for the first time that these silver nanoparticle-embedded polymersomes (AgPs) inhibited the growth of Escherichia coli transformed with a gene for ampicillin resistance (bla) in a dose-dependent fashion. Free ampicillin, AgPs without ampicillin, and ampicillin polymersomes without silver nanoparticles had no effect on bacterial growth. The relationship between the silver nanoparticles and ampicillin was determined to be synergistic and produced complete growth inhibition at a silver-to-ampicillin ratio of 1 : 0.64. In this manner, this study introduces a novel nanomaterial that can effectively treat problematic, antibiotic-resistant infections in an improved capacity which should be further examined for a wide range of medical applications.
71.
Cifter, G; Sajo, E; Korideck, H; Kumar, R; Sridhar, S; Cormack, R; Makrigiorgos, G; Ngwa, W
MO-FG-BRA-05: Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles Journal Article
In: Medical physics, vol. 42, no. 6Part29, pp. 3565–3565, 2015.
BibTeX | Tags: Nanomedicine
@article{cifter2015mo,
title = {MO-FG-BRA-05: Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles},
author = {G Cifter and E Sajo and H Korideck and R Kumar and S Sridhar and R Cormack and G Makrigiorgos and W Ngwa},
year = {2015},
date = {2015-01-01},
urldate = {2015-01-01},
journal = {Medical physics},
volume = {42},
number = {6Part29},
pages = {3565--3565},
publisher = {American Association of Physicists in Medicine},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
2014
70.
Tangutoori, S; Korideck, H; Kumar, R; Sridhar, S; Makrigiorgos, G; Cormack, R
WE-G-BRE-08: Radiosensitization by Olaparib Eluting Nanospheres Journal Article
In: Medical Physics, vol. 41, no. 6Part30, pp. 518–518, 2014.
BibTeX | Tags: Nanomedicine
@article{tangutoori2014we,
title = {WE-G-BRE-08: Radiosensitization by Olaparib Eluting Nanospheres},
author = {S Tangutoori and H Korideck and R Kumar and S Sridhar and G Makrigiorgos and R Cormack},
year = {2014},
date = {2014-01-01},
journal = {Medical Physics},
volume = {41},
number = {6Part30},
pages = {518--518},
publisher = {American Association of Physicists in Medicine},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
69.
Belz, Jodi; Kumar, Rajiv; Markovic, Stacey; Niedre, Mark; Sridhar, Srinivas; Nguyen, Paul; Damico, Anthony; Makrigiorgos, Mike; Cormack, Robert
Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’implants Proceedings Article
In: 2014 40th Annual Northeast Bioengineering Conference (NEBEC), pp. 1–2, IEEE 2014.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{belz2014localized,
title = {Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’implants},
author = {Jodi Belz and Rajiv Kumar and Stacey Markovic and Mark Niedre and Srinivas Sridhar and Paul Nguyen and Anthony Damico and Mike Makrigiorgos and Robert Cormack},
year = {2014},
date = {2014-01-01},
booktitle = {2014 40th Annual Northeast Bioengineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Systemic chemotherapy is often used with radiation therapy in the management of prostate cancer, but leads to severe systemic toxicities. We have introduced a new modality of loco-regional chemoradiation therapy termed in-situ image guided radiation therapy (BIS-IGRT) that offers the potential to deliver planned, localized and sustained delivery of chemotherapy agent, without systemic toxicities, as part of routine minimally invasive image guided radiation therapy procedures. Such image guided chemoradiation therapy replaces inert spacers with no therapeutic impact currently used in brachytherapy, with drug eluting spacers that provide the same spatial benefit with the added localized chemotherapeutic. This new therapeutic modality requires characterization of the drug distribution produced by implantable drug eluters. This work presents imaging based means to measure and compare temporal and spatial properties of diffusion distributions around spacers loaded with multi-sized dye-doped nanoparticles or with free dye. The spacer with optimal diffusive properties was then loaded with chemotherapeutics and inserted intratumorally for efficacy of the local chemotherapy versus the standard systemic dosing.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
Systemic chemotherapy is often used with radiation therapy in the management of prostate cancer, but leads to severe systemic toxicities. We have introduced a new modality of loco-regional chemoradiation therapy termed in-situ image guided radiation therapy (BIS-IGRT) that offers the potential to deliver planned, localized and sustained delivery of chemotherapy agent, without systemic toxicities, as part of routine minimally invasive image guided radiation therapy procedures. Such image guided chemoradiation therapy replaces inert spacers with no therapeutic impact currently used in brachytherapy, with drug eluting spacers that provide the same spatial benefit with the added localized chemotherapeutic. This new therapeutic modality requires characterization of the drug distribution produced by implantable drug eluters. This work presents imaging based means to measure and compare temporal and spatial properties of diffusion distributions around spacers loaded with multi-sized dye-doped nanoparticles or with free dye. The spacer with optimal diffusive properties was then loaded with chemotherapeutics and inserted intratumorally for efficacy of the local chemotherapy versus the standard systemic dosing.
68.
Sridhar, S; Tangutoori, S; Baldwin, P
361 Nanoformulations of the PARP inhibitors olaparib and BMN 673 for cancer nanotherapy Journal Article
In: European Journal of Cancer, vol. 50, pp. 116, 2014.
Abstract | BibTeX | Tags: Nanomedicine
@article{sridhar2014361,
title = {361 Nanoformulations of the PARP inhibitors olaparib and BMN 673 for cancer nanotherapy},
author = {S Sridhar and S Tangutoori and P Baldwin},
year = {2014},
date = {2014-01-01},
journal = {European Journal of Cancer},
volume = {50},
pages = {116},
publisher = {Elsevier},
abstract = {Background: Intensive investigations are ongoing to identify and validate predictive molecular markers for anti-angiogenic agents in metastatic renal cell carcinoma (mRCC) and other solid tumour types. However, this proves to be challenging due to multiple resistance mechanisms. Maturing understanding of immuno-oncology functions, including tumour-infiltrating lymphocytes (TIL) and tumour-associated macrophages (TAM), and their influence on mRCC biology provides the opportunity for new insights into sensitivity to anti-angiogenic agents.
Materials and Methods: Archival tumour samples were collected on an optional basis and prior to axitinib dosing from 52 patients with mRCC treated with axitinib following 1 prior systemic first-line regimen in the phase III AXIS trial (NCT00678392). Samples were assessed for macrophage (CD68+) and lymphocyte (CD3+) infiltration using immunohistochemistry. Potential associations between these tumourassociated immune cells and clinical efficacy following axitinib treatment were investigated by Kaplan–Meier analysis using median CD68+(0.08 cells/mm2) and CD3+(399.5 cells/mm2) levels as thresholds and by receiver operating characteristics (ROC) analysis. Results: Higher CD68+ levels were associated with longer median progression-free survival (PFS) of 12.0 months for⩾ median CD68+ cells/mm2 vs 3.7 months for< median CD68+ cells/mm2 (hazard ratio= 0.42, log-rank P< 0.01; not subjected to multivariate analysis accounting for clinical variables). Multivariate analysis is ongoing. ROC analysis of PFS at 2, 4, 6, and 8 months generated optimised cut-points for CD68+ cells/mm2; the …},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Background: Intensive investigations are ongoing to identify and validate predictive molecular markers for anti-angiogenic agents in metastatic renal cell carcinoma (mRCC) and other solid tumour types. However, this proves to be challenging due to multiple resistance mechanisms. Maturing understanding of immuno-oncology functions, including tumour-infiltrating lymphocytes (TIL) and tumour-associated macrophages (TAM), and their influence on mRCC biology provides the opportunity for new insights into sensitivity to anti-angiogenic agents.
Materials and Methods: Archival tumour samples were collected on an optional basis and prior to axitinib dosing from 52 patients with mRCC treated with axitinib following 1 prior systemic first-line regimen in the phase III AXIS trial (NCT00678392). Samples were assessed for macrophage (CD68+) and lymphocyte (CD3+) infiltration using immunohistochemistry. Potential associations between these tumourassociated immune cells and clinical efficacy following axitinib treatment were investigated by Kaplan–Meier analysis using median CD68+(0.08 cells/mm2) and CD3+(399.5 cells/mm2) levels as thresholds and by receiver operating characteristics (ROC) analysis. Results: Higher CD68+ levels were associated with longer median progression-free survival (PFS) of 12.0 months for⩾ median CD68+ cells/mm2 vs 3.7 months for< median CD68+ cells/mm2 (hazard ratio= 0.42, log-rank P< 0.01; not subjected to multivariate analysis accounting for clinical variables). Multivariate analysis is ongoing. ROC analysis of PFS at 2, 4, 6, and 8 months generated optimised cut-points for CD68+ cells/mm2; the …
Materials and Methods: Archival tumour samples were collected on an optional basis and prior to axitinib dosing from 52 patients with mRCC treated with axitinib following 1 prior systemic first-line regimen in the phase III AXIS trial (NCT00678392). Samples were assessed for macrophage (CD68+) and lymphocyte (CD3+) infiltration using immunohistochemistry. Potential associations between these tumourassociated immune cells and clinical efficacy following axitinib treatment were investigated by Kaplan–Meier analysis using median CD68+(0.08 cells/mm2) and CD3+(399.5 cells/mm2) levels as thresholds and by receiver operating characteristics (ROC) analysis. Results: Higher CD68+ levels were associated with longer median progression-free survival (PFS) of 12.0 months for⩾ median CD68+ cells/mm2 vs 3.7 months for< median CD68+ cells/mm2 (hazard ratio= 0.42, log-rank P< 0.01; not subjected to multivariate analysis accounting for clinical variables). Multivariate analysis is ongoing. ROC analysis of PFS at 2, 4, 6, and 8 months generated optimised cut-points for CD68+ cells/mm2; the …
67.
Berbeco, RI; Korideck, H; Kumar, R; Sridhar, S; Detappe, A; Ngwa, W; Makrigiorgos, M
Targeted gold nanoparticles as vascular disrupting agents during radiation therapy Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 90, no. 1, pp. S198, 2014.
Abstract | BibTeX | Tags: Nanomedicine
@article{berbeco2014targeted,
title = {Targeted gold nanoparticles as vascular disrupting agents during radiation therapy},
author = {RI Berbeco and H Korideck and R Kumar and S Sridhar and A Detappe and W Ngwa and M Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {90},
number = {1},
pages = {S198},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Recent developments in anti-angiogenic and vascular-disrupting therapies have shown the great potential of tumor vasculature as a therapeutic target for cancer medicine. We have an original idea for using targeted gold nanoparticles as vascular disruptive agents in conjunction with clinical megavoltage (MV) photon beams. Unlike competing approaches, we recognize that gold nanoparticles tend to accumulate in, and can even be targeted for, tumor blood vessels and that these structures may be more important for anti-cancer therapy than clonogenic cell death alone. Due to the short distance traveled by x-ray induced photoelectrons, the endothelial cells of the tumor will receive a sizable boost in dose, even for MV irradiation.
Materials/Methods
We have developed and characterized a novel 4th generation gold nanoparticle platform which includes PEGylation for long circulation, Arginylglycylaspartic acid (RGD) for neovascular targeting and AF647 for fluorescence imaging. Theoretical studies were performed using a combination of Monte Carlo and analytical methods. In vitro experiments were performed using a clinical 6 MV photon beam with the HeLa cell line. In vivo imaging experiments were performed in an orthotopic pancreatic cancer model.
Results
The targeted gold nanoparticle platform is non-toxic and stable over six months. TEM imaging demonstrated consistent gold nanoparticle size of 2-3 nm and confocal microscopy showed robust in vitro cell uptake. Theoretical studies predict a 50% dose enhancement to adjacent tumor endothelial cells. Experimental studies in a 6 MV beam found 40-60% damage enhancement with the effect greatest for deeper targets and with the linear accelerator operating in flattening filter free mode. Fluorescence and TEM imaging studies 24 hours post IV injection confirmed (1) preferential uptake in the tumor, (2) low uptake in normal tissue, (3) infiltration of the tumor endothelial cells, and (4) renal clearing of the gold nanoparticles.
Conclusions
Our studies have demonstrated that a substantial therapy enhancement is expected when gold nanoparticles are targeted to tumor endothelial cells prior to clinical radiation therapy. Our concept is compatible with current clinical practice and could offer an important clinical benefit with minimal patient risk.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose/Objective(s)
Recent developments in anti-angiogenic and vascular-disrupting therapies have shown the great potential of tumor vasculature as a therapeutic target for cancer medicine. We have an original idea for using targeted gold nanoparticles as vascular disruptive agents in conjunction with clinical megavoltage (MV) photon beams. Unlike competing approaches, we recognize that gold nanoparticles tend to accumulate in, and can even be targeted for, tumor blood vessels and that these structures may be more important for anti-cancer therapy than clonogenic cell death alone. Due to the short distance traveled by x-ray induced photoelectrons, the endothelial cells of the tumor will receive a sizable boost in dose, even for MV irradiation.
Materials/Methods
We have developed and characterized a novel 4th generation gold nanoparticle platform which includes PEGylation for long circulation, Arginylglycylaspartic acid (RGD) for neovascular targeting and AF647 for fluorescence imaging. Theoretical studies were performed using a combination of Monte Carlo and analytical methods. In vitro experiments were performed using a clinical 6 MV photon beam with the HeLa cell line. In vivo imaging experiments were performed in an orthotopic pancreatic cancer model.
Results
The targeted gold nanoparticle platform is non-toxic and stable over six months. TEM imaging demonstrated consistent gold nanoparticle size of 2-3 nm and confocal microscopy showed robust in vitro cell uptake. Theoretical studies predict a 50% dose enhancement to adjacent tumor endothelial cells. Experimental studies in a 6 MV beam found 40-60% damage enhancement with the effect greatest for deeper targets and with the linear accelerator operating in flattening filter free mode. Fluorescence and TEM imaging studies 24 hours post IV injection confirmed (1) preferential uptake in the tumor, (2) low uptake in normal tissue, (3) infiltration of the tumor endothelial cells, and (4) renal clearing of the gold nanoparticles.
Conclusions
Our studies have demonstrated that a substantial therapy enhancement is expected when gold nanoparticles are targeted to tumor endothelial cells prior to clinical radiation therapy. Our concept is compatible with current clinical practice and could offer an important clinical benefit with minimal patient risk.
Recent developments in anti-angiogenic and vascular-disrupting therapies have shown the great potential of tumor vasculature as a therapeutic target for cancer medicine. We have an original idea for using targeted gold nanoparticles as vascular disruptive agents in conjunction with clinical megavoltage (MV) photon beams. Unlike competing approaches, we recognize that gold nanoparticles tend to accumulate in, and can even be targeted for, tumor blood vessels and that these structures may be more important for anti-cancer therapy than clonogenic cell death alone. Due to the short distance traveled by x-ray induced photoelectrons, the endothelial cells of the tumor will receive a sizable boost in dose, even for MV irradiation.
Materials/Methods
We have developed and characterized a novel 4th generation gold nanoparticle platform which includes PEGylation for long circulation, Arginylglycylaspartic acid (RGD) for neovascular targeting and AF647 for fluorescence imaging. Theoretical studies were performed using a combination of Monte Carlo and analytical methods. In vitro experiments were performed using a clinical 6 MV photon beam with the HeLa cell line. In vivo imaging experiments were performed in an orthotopic pancreatic cancer model.
Results
The targeted gold nanoparticle platform is non-toxic and stable over six months. TEM imaging demonstrated consistent gold nanoparticle size of 2-3 nm and confocal microscopy showed robust in vitro cell uptake. Theoretical studies predict a 50% dose enhancement to adjacent tumor endothelial cells. Experimental studies in a 6 MV beam found 40-60% damage enhancement with the effect greatest for deeper targets and with the linear accelerator operating in flattening filter free mode. Fluorescence and TEM imaging studies 24 hours post IV injection confirmed (1) preferential uptake in the tumor, (2) low uptake in normal tissue, (3) infiltration of the tumor endothelial cells, and (4) renal clearing of the gold nanoparticles.
Conclusions
Our studies have demonstrated that a substantial therapy enhancement is expected when gold nanoparticles are targeted to tumor endothelial cells prior to clinical radiation therapy. Our concept is compatible with current clinical practice and could offer an important clinical benefit with minimal patient risk.
66.
Gharagouzloo, Codi; McMahon, Patrick N; Sridhar, Srinivas
UTE angiography with ferumoxytol Proceedings Article
In: 2014 40th Annual Northeast Bioengineering Conference (NEBEC), pp. 1–2, IEEE 2014.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{gharagouzloo2014ute,
title = {UTE angiography with ferumoxytol},
author = {Codi Gharagouzloo and Patrick N McMahon and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
booktitle = {2014 40th Annual Northeast Bioengineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Magnetic Resonance Imaging (MRI) is arguably the most clinically pertinent, non-destructive imaging modality for probing deep tissue in the human body. Clinical contrast-enhanced MRI with superparamagnetic iron oxide nanoparticles (SPIONs) is typically performed with T2-weighted imaging. Here we show that ultra-short TE (UTE) imaging with SPIONs produces unambiguous, positive-contrast signals in vivo in mice. Experiments were performed using a SPION containing pharmaceutical, ferumoxytol, in phantoms and in systemic circulation of mice at 7T. 3D UTE angiography was not hampered by susceptibility artifacts or influenced by flow. By negating these effects we were able to produce high SNR and CNR images of the entire vascular system, including the lungs and the heart.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
Magnetic Resonance Imaging (MRI) is arguably the most clinically pertinent, non-destructive imaging modality for probing deep tissue in the human body. Clinical contrast-enhanced MRI with superparamagnetic iron oxide nanoparticles (SPIONs) is typically performed with T2-weighted imaging. Here we show that ultra-short TE (UTE) imaging with SPIONs produces unambiguous, positive-contrast signals in vivo in mice. Experiments were performed using a SPION containing pharmaceutical, ferumoxytol, in phantoms and in systemic circulation of mice at 7T. 3D UTE angiography was not hampered by susceptibility artifacts or influenced by flow. By negating these effects we were able to produce high SNR and CNR images of the entire vascular system, including the lungs and the heart.
65.
Berbeco, R; Korideck, H; Kumar, R; Sridhar, S; Makrigiorgos, M
20: Targeted Gold Nanoparticles as Vascular Disrupting Agents during Radiotherapy Journal Article
In: Radiotherapy and Oncology, vol. 110, pp. S10–S11, 2014.
Abstract | BibTeX | Tags: Nanomedicine
@article{berbeco201420,
title = {20: Targeted Gold Nanoparticles as Vascular Disrupting Agents during Radiotherapy},
author = {R Berbeco and H Korideck and R Kumar and S Sridhar and M Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {Radiotherapy and Oncology},
volume = {110},
pages = {S10--S11},
publisher = {Elsevier},
abstract = {Results: More than 100 patients with various indications within the broad therapeutic spectrum covered at HIT received one or more post-therapeutic PET/CT measurements. Especially for proton induced activity, we could considerably improve the predictive power of the activity calculation by the refinement of the used crosssections for radionuclide production and, for brain tumour subjects, a refinement of tissue classification based on a novel multi-modal patient model. The initial clinical experience allows identifying the anatomical locations which benefit most from PET-based verification, as well as the shortcomings of the offline data acquisition. Conclusions: Post-therapeutic PET/CT-based treatment verification is fully integrated into the clinical workflow at HIT. Despite the comparatively low signal due to decay and washout during the transfer time distinct to the offline workflow, valuable treatment quality …},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Results: More than 100 patients with various indications within the broad therapeutic spectrum covered at HIT received one or more post-therapeutic PET/CT measurements. Especially for proton induced activity, we could considerably improve the predictive power of the activity calculation by the refinement of the used crosssections for radionuclide production and, for brain tumour subjects, a refinement of tissue classification based on a novel multi-modal patient model. The initial clinical experience allows identifying the anatomical locations which benefit most from PET-based verification, as well as the shortcomings of the offline data acquisition. Conclusions: Post-therapeutic PET/CT-based treatment verification is fully integrated into the clinical workflow at HIT. Despite the comparatively low signal due to decay and washout during the transfer time distinct to the offline workflow, valuable treatment quality …
64.
Navarro, Gemma; Essex, Sean; Sawant, Rupa R; Biswas, Swati; Nagesha, Dattatri; Sridhar, Srinivas; de ILarduya, Conchita Tros; Torchilin, Vladimir P
Phospholipid-modified polyethylenimine-based nanopreparations for siRNA--mediated gene silencing: Implications for transfection and the role of lipid components Journal Article
In: Nanomedicine: Nanotechnology, Biology and Medicine, vol. 10, no. 2, pp. 411–419, 2014.
BibTeX | Tags: Nanomedicine
@article{navarro2014phospholipid,
title = {Phospholipid-modified polyethylenimine-based nanopreparations for siRNA--mediated gene silencing: Implications for transfection and the role of lipid components},
author = {Gemma Navarro and Sean Essex and Rupa R Sawant and Swati Biswas and Dattatri Nagesha and Srinivas Sridhar and Conchita Tros de ILarduya and Vladimir P Torchilin},
year = {2014},
date = {2014-01-01},
journal = {Nanomedicine: Nanotechnology, Biology and Medicine},
volume = {10},
number = {2},
pages = {411--419},
publisher = {Elsevier},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
63.
Ngwa, Wilfred; Kumar, Rajiv; Sridhar, Srinivas; Korideck, Houari; Zygmanski, Piotr; Cormack, Robert A; Berbeco, Ross; Makrigiorgos, Mike G
Targeted radiotherapy with gold nanoparticles: current status and future perspectives Journal Article
In: Nanomedicine, vol. 9, no. 7, pp. 1063–1082, 2014.
Abstract | BibTeX | Tags: Nanomedicine
@article{ngwa2014targeted,
title = {Targeted radiotherapy with gold nanoparticles: current status and future perspectives},
author = {Wilfred Ngwa and Rajiv Kumar and Srinivas Sridhar and Houari Korideck and Piotr Zygmanski and Robert A Cormack and Ross Berbeco and Mike G Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {Nanomedicine},
volume = {9},
number = {7},
pages = {1063--1082},
publisher = {Future Medicine},
abstract = {Radiation therapy (RT) is the treatment of cancer and other diseases with ionizing radiation. The ultimate goal of RT is to destroy all the disease cells while sparing healthy tissue. Towards this goal, RT has advanced significantly over the past few decades in part due to new technologies including: multileaf collimator-assisted modulation of radiation beams, improved computer-assisted inverse treatment planning, image guidance, robotics with more precision, better motion management strategies, stereotactic treatments and hypofractionation. With recent advances in nanotechnology, targeted RT with gold nanoparticles (GNPs) is actively being investigated as a means to further increase the RT therapeutic ratio. In this review, we summarize the current status of research and development towards the use of GNPs to enhance RT. We highlight the promising emerging modalities for targeted RT with GNPs and the corresponding preclinical evidence supporting such promise towards potential clinical translation. Future prospects and perspectives are discussed.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Radiation therapy (RT) is the treatment of cancer and other diseases with ionizing radiation. The ultimate goal of RT is to destroy all the disease cells while sparing healthy tissue. Towards this goal, RT has advanced significantly over the past few decades in part due to new technologies including: multileaf collimator-assisted modulation of radiation beams, improved computer-assisted inverse treatment planning, image guidance, robotics with more precision, better motion management strategies, stereotactic treatments and hypofractionation. With recent advances in nanotechnology, targeted RT with gold nanoparticles (GNPs) is actively being investigated as a means to further increase the RT therapeutic ratio. In this review, we summarize the current status of research and development towards the use of GNPs to enhance RT. We highlight the promising emerging modalities for targeted RT with GNPs and the corresponding preclinical evidence supporting such promise towards potential clinical translation. Future prospects and perspectives are discussed.
62.
Belz, Jodi E; Ngwa, Wilfred; Korideck, Houari; Cormack, Robert A; Berbeco, Ross; Makrigiorgos, Mike; Sridhar, Srinivas; Kumar, Rajiv
Multifunctional nanoparticles in radiation oncology: an emerging paradigm Book Section
In: The Science and Function of Nanomaterials: From Synthesis to Application, pp. 75–106, American Chemical Society, 2014.
Abstract | BibTeX | Tags: Nanomedicine
@incollection{belz2014multifunctional,
title = {Multifunctional nanoparticles in radiation oncology: an emerging paradigm},
author = {Jodi E Belz and Wilfred Ngwa and Houari Korideck and Robert A Cormack and Ross Berbeco and Mike Makrigiorgos and Srinivas Sridhar and Rajiv Kumar},
year = {2014},
date = {2014-01-01},
booktitle = {The Science and Function of Nanomaterials: From Synthesis to Application},
pages = {75--106},
publisher = {American Chemical Society},
abstract = {The parallel advances in the field of radiation oncology and nanotechnology have created a paradigm changing opportunity to improve the therapeutic outcome in oncology. The integration of nanomedicine in clinical oncology has led to the appreciation of the use of ‘theranostic nanoparticles’ in not only understanding various biological mechanisms associated with cancer, but also in successfully targeting these pathways to modulate the efficacy of treatment. This chapter focuses on the application of various nanoparticle-based formulations to improve radiation therapy. The emphasis is on the functionality of nanoparticles that can modulate the tumor response to radiation, target the molecular pathways, minimize normal tissue toxicities and improve the imaging efficacy for better disease staging and treatment planning. We believe addressing these factors using nanoparticles can shape the future of radiation therapy, facilitating their use towards a personalized medicine approach.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {incollection}
}
The parallel advances in the field of radiation oncology and nanotechnology have created a paradigm changing opportunity to improve the therapeutic outcome in oncology. The integration of nanomedicine in clinical oncology has led to the appreciation of the use of ‘theranostic nanoparticles’ in not only understanding various biological mechanisms associated with cancer, but also in successfully targeting these pathways to modulate the efficacy of treatment. This chapter focuses on the application of various nanoparticle-based formulations to improve radiation therapy. The emphasis is on the functionality of nanoparticles that can modulate the tumor response to radiation, target the molecular pathways, minimize normal tissue toxicities and improve the imaging efficacy for better disease staging and treatment planning. We believe addressing these factors using nanoparticles can shape the future of radiation therapy, facilitating their use towards a personalized medicine approach.
61.
Kumar, Rajiv; Belz, Jodi; Markovic, Stacey; Niedre, Mark; Ngwa, Wilfred; Korideck, Houari; Cormack, Robert; Nguyen, Paul; D'Amico, Anthony; Makrigiorgos, Mike; others,
Smart brachytherapy spacers eluting nanoencapsulated radiosensitizers for chemo-radiation therapy Miscellaneous
2014.
Abstract | BibTeX | Tags: Nanomedicine
@misc{kumar2014smart,
title = {Smart brachytherapy spacers eluting nanoencapsulated radiosensitizers for chemo-radiation therapy},
author = {Rajiv Kumar and Jodi Belz and Stacey Markovic and Mark Niedre and Wilfred Ngwa and Houari Korideck and Robert Cormack and Paul Nguyen and Anthony D'Amico and Mike Makrigiorgos and others},
year = {2014},
date = {2014-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: We have developed a new approach for chemoradiation therapy (CRT), termed Biological In-Situ Image Guided Radiation Therapy BIS-IGRT, which involves the coating of spacers routinely used during prostate I-125-based brachytherapy with radiosensitizing drugs (e.g. docetaxel DTX and gold nanoparticles). This approach provides localized in-situ delivery of the sensitizer to the tumor and avoids the toxicity associated with current systemic delivery of radiosensitizers. BIS-IGRT adds radiosensitization capability to the standard brachytherapy procedure providing sustained delivery and drug concentration and with minimal additional inconvenience to the patient. Thereby BIS-IGRT improves the therapeutic ratio of radiation therapy without introducing additional patient interventions over current brachytherapy procedures.
Methods: We have fabricated a nanoparticles based smart ‘INCeRT’ (Implantable Nanoplatform for Chemo-Radiation Therapy) implant for localized delivery of radiosensitizing nanoparticles/ drugs in prostate cancer in conjunction with brachytherapy. These implants are physically similar to the clinically used brachytherapy spacers but have the added capability of imaging and local drug delivery. We have fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA impregnated with nanoparticles encapsulating imaging probe (Cyanine 7.5) and chemotherapeutic drug, docetaxel (DTX). Using a similar approach, we have also fabricated PLGA spacers impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE: High Z-Customizable Radiotherapy Enhancement) for effectively boosting the radiation dose locally. The morphology, composition and nanoparticle's distribution inside the spacers was studied by SEM (scanning electron microscopy) and EDS (Energy-dispersive X-ray spectroscopy). Further, preliminary in vivo imaging experiments with subcutaneous prostate cancer tumored mice implanted with INCeRT spacers showed a size dependent diffusion of nanoparticles from the spacers in the tumor matrix. Also, from in vivo therapeutic studies with these spacers showed a sustained and slow release of the DTX from the spacers and showed a better response in suppressing the tumor as opposed to control mice with saline injections. Further experiments for studying the combined chemo-radiation therapy are underway.
Conclusions: BIS-IGRT is a powerful approach to locally radio-sensitize the prostate to enable prostate cancer (PCa) cure with the use of lower radiation doses, thereby leading to less rectal toxicity. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. This work was supported partially by NSF-DGE-0965843, HHS/1U54CA151881 CORE1, 1R03 CA164645-01 and a seed grant from the BWH Biomedical Research Institute.
Note: This abstract was not presented at the meeting.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Mark Niedre, Wilfred Ngwa, Houari Korideck, Robert Cormack, Paul Nguyen, Anthony D'Amico, Mike Makrigiorgos, Srinivas Sridhar. Smart brachytherapy spacers eluting nanoencapsulated radiosensitizers for chemo-radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2014-4917
©2014 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Introduction: We have developed a new approach for chemoradiation therapy (CRT), termed Biological In-Situ Image Guided Radiation Therapy BIS-IGRT, which involves the coating of spacers routinely used during prostate I-125-based brachytherapy with radiosensitizing drugs (e.g. docetaxel DTX and gold nanoparticles). This approach provides localized in-situ delivery of the sensitizer to the tumor and avoids the toxicity associated with current systemic delivery of radiosensitizers. BIS-IGRT adds radiosensitization capability to the standard brachytherapy procedure providing sustained delivery and drug concentration and with minimal additional inconvenience to the patient. Thereby BIS-IGRT improves the therapeutic ratio of radiation therapy without introducing additional patient interventions over current brachytherapy procedures.
Methods: We have fabricated a nanoparticles based smart ‘INCeRT’ (Implantable Nanoplatform for Chemo-Radiation Therapy) implant for localized delivery of radiosensitizing nanoparticles/ drugs in prostate cancer in conjunction with brachytherapy. These implants are physically similar to the clinically used brachytherapy spacers but have the added capability of imaging and local drug delivery. We have fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA impregnated with nanoparticles encapsulating imaging probe (Cyanine 7.5) and chemotherapeutic drug, docetaxel (DTX). Using a similar approach, we have also fabricated PLGA spacers impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE: High Z-Customizable Radiotherapy Enhancement) for effectively boosting the radiation dose locally. The morphology, composition and nanoparticle's distribution inside the spacers was studied by SEM (scanning electron microscopy) and EDS (Energy-dispersive X-ray spectroscopy). Further, preliminary in vivo imaging experiments with subcutaneous prostate cancer tumored mice implanted with INCeRT spacers showed a size dependent diffusion of nanoparticles from the spacers in the tumor matrix. Also, from in vivo therapeutic studies with these spacers showed a sustained and slow release of the DTX from the spacers and showed a better response in suppressing the tumor as opposed to control mice with saline injections. Further experiments for studying the combined chemo-radiation therapy are underway.
Conclusions: BIS-IGRT is a powerful approach to locally radio-sensitize the prostate to enable prostate cancer (PCa) cure with the use of lower radiation doses, thereby leading to less rectal toxicity. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. This work was supported partially by NSF-DGE-0965843, HHS/1U54CA151881 CORE1, 1R03 CA164645-01 and a seed grant from the BWH Biomedical Research Institute.
Note: This abstract was not presented at the meeting.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Mark Niedre, Wilfred Ngwa, Houari Korideck, Robert Cormack, Paul Nguyen, Anthony D'Amico, Mike Makrigiorgos, Srinivas Sridhar. Smart brachytherapy spacers eluting nanoencapsulated radiosensitizers for chemo-radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2014-4917
©2014 American Association for Cancer Research.
Methods: We have fabricated a nanoparticles based smart ‘INCeRT’ (Implantable Nanoplatform for Chemo-Radiation Therapy) implant for localized delivery of radiosensitizing nanoparticles/ drugs in prostate cancer in conjunction with brachytherapy. These implants are physically similar to the clinically used brachytherapy spacers but have the added capability of imaging and local drug delivery. We have fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA impregnated with nanoparticles encapsulating imaging probe (Cyanine 7.5) and chemotherapeutic drug, docetaxel (DTX). Using a similar approach, we have also fabricated PLGA spacers impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE: High Z-Customizable Radiotherapy Enhancement) for effectively boosting the radiation dose locally. The morphology, composition and nanoparticle's distribution inside the spacers was studied by SEM (scanning electron microscopy) and EDS (Energy-dispersive X-ray spectroscopy). Further, preliminary in vivo imaging experiments with subcutaneous prostate cancer tumored mice implanted with INCeRT spacers showed a size dependent diffusion of nanoparticles from the spacers in the tumor matrix. Also, from in vivo therapeutic studies with these spacers showed a sustained and slow release of the DTX from the spacers and showed a better response in suppressing the tumor as opposed to control mice with saline injections. Further experiments for studying the combined chemo-radiation therapy are underway.
Conclusions: BIS-IGRT is a powerful approach to locally radio-sensitize the prostate to enable prostate cancer (PCa) cure with the use of lower radiation doses, thereby leading to less rectal toxicity. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. This work was supported partially by NSF-DGE-0965843, HHS/1U54CA151881 CORE1, 1R03 CA164645-01 and a seed grant from the BWH Biomedical Research Institute.
Note: This abstract was not presented at the meeting.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Mark Niedre, Wilfred Ngwa, Houari Korideck, Robert Cormack, Paul Nguyen, Anthony D'Amico, Mike Makrigiorgos, Srinivas Sridhar. Smart brachytherapy spacers eluting nanoencapsulated radiosensitizers for chemo-radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2014-4917
©2014 American Association for Cancer Research.
60.
Tangutoori, Shifalika; Baldwin, Paige; Korideck, Houari; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas
Nanoformulations of PARP inhibtors for cancer therapy Miscellaneous
2014.
Abstract | BibTeX | Tags: Nanomedicine
@misc{tangutoori2014nanoformulations,
title = {Nanoformulations of PARP inhibtors for cancer therapy},
author = {Shifalika Tangutoori and Paige Baldwin and Houari Korideck and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction:
Poly ADP Ribose Polymerase inhibitor therapy (PARPi) exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib and BMN-673 are potent PARP inhibitors that are currently indicated for oral PARPi in several clinical trials for a variety of cancers. Oral administration in general results in poor bioavailability and tumor accumulation. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN) , thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity. Our nanoplatform is also tailored for the combinatorial chemotherapy and radio-sensitization in several cancers including prostate, ovarian and breast cancer cell lines with and without the BRCA mutations.
Methods:
Two nanoparticle formulations NanoOlaparib and NanoBMN have been successfully formulated and tested in vitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and PARPi nanoformulations defined by ∼163 nm diameter, zeta potential ∼ +10mV, and loaded with olaparib (2.3mM) or BMN-673 (200µM) and cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using MTS assay and EC50's were determined using Prism. The synergism due to radiosensitization using 220 keV beam was studied for both therapies using isobolograms developed from clonogenic assays on prostate and breast cancer cells. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on ovarian cancer cell lines including PA-1, KURAMOCHI etc. The functionality of nanoPARPi/combination formulations on all the cancers, reflected by inhibition of PARylation, γ-H2AX and RAD-51 was determined by immunoflourescence assays.
Results:
Radiosensitization showed strong radiosensitization, achieving long-term cell kill of more than 90% with NanOlaparib and 4 Gy radiation in prostate cancer PC3, VCaP and LNCaP cell lines. VCaP which carries a TMPRSS2: ERG fusion was more responsive than PC3 for monotherapy using NanoOlaparib alone, and had better radiation sensitization compared to the other cell lines tested so far. In all studies NanoOlaparib showed better efficacy in combination with radiation than free Olaparib. Similar studies with nanoBMN are underway.
Conclusions:
Robust nanoparticle formulations NanoOlaparib and NanoOlaparibPt have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN formulations as chemo and radio-sensitizers enabling several therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Baldwin, Houari Korideck, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Nanoformulations of PARP inhibtors for cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2014-2397
©2014 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Introduction:
Poly ADP Ribose Polymerase inhibitor therapy (PARPi) exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib and BMN-673 are potent PARP inhibitors that are currently indicated for oral PARPi in several clinical trials for a variety of cancers. Oral administration in general results in poor bioavailability and tumor accumulation. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN) , thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity. Our nanoplatform is also tailored for the combinatorial chemotherapy and radio-sensitization in several cancers including prostate, ovarian and breast cancer cell lines with and without the BRCA mutations.
Methods:
Two nanoparticle formulations NanoOlaparib and NanoBMN have been successfully formulated and tested in vitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and PARPi nanoformulations defined by ∼163 nm diameter, zeta potential ∼ +10mV, and loaded with olaparib (2.3mM) or BMN-673 (200µM) and cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using MTS assay and EC50's were determined using Prism. The synergism due to radiosensitization using 220 keV beam was studied for both therapies using isobolograms developed from clonogenic assays on prostate and breast cancer cells. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on ovarian cancer cell lines including PA-1, KURAMOCHI etc. The functionality of nanoPARPi/combination formulations on all the cancers, reflected by inhibition of PARylation, γ-H2AX and RAD-51 was determined by immunoflourescence assays.
Results:
Radiosensitization showed strong radiosensitization, achieving long-term cell kill of more than 90% with NanOlaparib and 4 Gy radiation in prostate cancer PC3, VCaP and LNCaP cell lines. VCaP which carries a TMPRSS2: ERG fusion was more responsive than PC3 for monotherapy using NanoOlaparib alone, and had better radiation sensitization compared to the other cell lines tested so far. In all studies NanoOlaparib showed better efficacy in combination with radiation than free Olaparib. Similar studies with nanoBMN are underway.
Conclusions:
Robust nanoparticle formulations NanoOlaparib and NanoOlaparibPt have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN formulations as chemo and radio-sensitizers enabling several therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Baldwin, Houari Korideck, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Nanoformulations of PARP inhibtors for cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2014-2397
©2014 American Association for Cancer Research.
Poly ADP Ribose Polymerase inhibitor therapy (PARPi) exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib and BMN-673 are potent PARP inhibitors that are currently indicated for oral PARPi in several clinical trials for a variety of cancers. Oral administration in general results in poor bioavailability and tumor accumulation. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN) , thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity. Our nanoplatform is also tailored for the combinatorial chemotherapy and radio-sensitization in several cancers including prostate, ovarian and breast cancer cell lines with and without the BRCA mutations.
Methods:
Two nanoparticle formulations NanoOlaparib and NanoBMN have been successfully formulated and tested in vitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and PARPi nanoformulations defined by ∼163 nm diameter, zeta potential ∼ +10mV, and loaded with olaparib (2.3mM) or BMN-673 (200µM) and cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using MTS assay and EC50's were determined using Prism. The synergism due to radiosensitization using 220 keV beam was studied for both therapies using isobolograms developed from clonogenic assays on prostate and breast cancer cells. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on ovarian cancer cell lines including PA-1, KURAMOCHI etc. The functionality of nanoPARPi/combination formulations on all the cancers, reflected by inhibition of PARylation, γ-H2AX and RAD-51 was determined by immunoflourescence assays.
Results:
Radiosensitization showed strong radiosensitization, achieving long-term cell kill of more than 90% with NanOlaparib and 4 Gy radiation in prostate cancer PC3, VCaP and LNCaP cell lines. VCaP which carries a TMPRSS2: ERG fusion was more responsive than PC3 for monotherapy using NanoOlaparib alone, and had better radiation sensitization compared to the other cell lines tested so far. In all studies NanoOlaparib showed better efficacy in combination with radiation than free Olaparib. Similar studies with nanoBMN are underway.
Conclusions:
Robust nanoparticle formulations NanoOlaparib and NanoOlaparibPt have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN formulations as chemo and radio-sensitizers enabling several therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Baldwin, Houari Korideck, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Nanoformulations of PARP inhibtors for cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2014-2397
©2014 American Association for Cancer Research.
59.
Khabiry, Masoud; Jalili, Nader; Sridhar, Srinivas
Automated cell counting method for microgroove based microfluidic device Proceedings Article
In: 2014 40th Annual Northeast Bioengineering Conference (NEBEC), pp. 1–2, IEEE 2014.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{khabiry2014automated,
title = {Automated cell counting method for microgroove based microfluidic device},
author = {Masoud Khabiry and Nader Jalili and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
booktitle = {2014 40th Annual Northeast Bioengineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Microfluidic grooves and channels enable the control of cell positioning and capturing of cells in cell-based biosensor applications. Microfluidic devices also provide a platform for cell-based biological assays. Microfluidic channels have been used to capture cells for various cell-based diagnostics and screening applications. The number of cells and cell locations are important factors which will affect the flow pattern in the microfluidic device and consequently induced shear stresses. Moreover, manual cell counting and cell information extraction is a time consuming and tedious task. Automated techniques reduce human errors and expedite the process. Furthermore, it facilitates extraction of information from obtained images for further fluidic analysis.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
Microfluidic grooves and channels enable the control of cell positioning and capturing of cells in cell-based biosensor applications. Microfluidic devices also provide a platform for cell-based biological assays. Microfluidic channels have been used to capture cells for various cell-based diagnostics and screening applications. The number of cells and cell locations are important factors which will affect the flow pattern in the microfluidic device and consequently induced shear stresses. Moreover, manual cell counting and cell information extraction is a time consuming and tedious task. Automated techniques reduce human errors and expedite the process. Furthermore, it facilitates extraction of information from obtained images for further fluidic analysis.
58.
van de Ven, Anne L; Geilich, Benjamin; Gharagouzloo, Codi; Barlow, Jacob; Webster, Thomas; Sridhar, Srinivas
Polymersomes for image-guided therapy Proceedings Article
In: 2014 40th Annual Northeast Bioengineering Conference (NEBEC), pp. 1–2, IEEE 2014.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{van2014polymersomes,
title = {Polymersomes for image-guided therapy},
author = {Anne L van de Ven and Benjamin Geilich and Codi Gharagouzloo and Jacob Barlow and Thomas Webster and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
booktitle = {2014 40th Annual Northeast Bioengineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Polymersomes are a promising avenue for image-guided therapy of cancer, since they can stably encapsulate a broad range of therapeutic molecules and offer both targeting capacity and stimuli responsiveness. We have formulated highly stable, magnetically activatable polymersomes capable of continuous and pulsed small molecule release. In the proof-of-concept provided here, we demonstrate that these particles are responsive to both external and heat and magnetic fields. At physiologic temperatures, these particles display a sustained release profile that can be reversibly triggered for transient increases in release. The incorporation of fluorescent and iron oxide contrast sources make these particles amenable for quantitative imaging techniques including intravital microscopy (IVM) and ultra-short time-to-echo (UTE) magnetic resonance imaging (MRI). Thus we believe this formulation is uniquely suited for the in vivo study and optimization of externally triggered tumor growth inhibition.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
Polymersomes are a promising avenue for image-guided therapy of cancer, since they can stably encapsulate a broad range of therapeutic molecules and offer both targeting capacity and stimuli responsiveness. We have formulated highly stable, magnetically activatable polymersomes capable of continuous and pulsed small molecule release. In the proof-of-concept provided here, we demonstrate that these particles are responsive to both external and heat and magnetic fields. At physiologic temperatures, these particles display a sustained release profile that can be reversibly triggered for transient increases in release. The incorporation of fluorescent and iron oxide contrast sources make these particles amenable for quantitative imaging techniques including intravital microscopy (IVM) and ultra-short time-to-echo (UTE) magnetic resonance imaging (MRI). Thus we believe this formulation is uniquely suited for the in vivo study and optimization of externally triggered tumor growth inhibition.
57.
Ngwa, W; Altundal, Y; Korideck, H; Kumar, R; Sridhar, S; Cormack, R; Makrigiorgos, M
Radiation Therapy Biomaterials for Response Assessment and Nodal Detection (Brand) Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 90, no. 1, pp. S856, 2014.
Abstract | BibTeX | Tags: Nanomedicine
@article{ngwa2014radiation,
title = {Radiation Therapy Biomaterials for Response Assessment and Nodal Detection (Brand)},
author = {W Ngwa and Y Altundal and H Korideck and R Kumar and S Sridhar and R Cormack and M Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {90},
number = {1},
pages = {S856},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
We propose that routinely used inert radiation therapy (RT) biomaterials (e.g. fiducials, spacers) can be upgraded to smart ones by incorporating multifunctional non-toxic gold nanoparticles (GNPs) for sustained in-situ release. Our hypothesis is that the GNPs released, after implantation of the smart biomaterial in tumor, can be programmed to label/brand metastatic or circulating tumor cells (CTCs) at their source before they are shed into hematogenous or lymphatic circulation. This would enable significantly enhanced CTCs detection by different methods. In this work, we developed and characterized such prototype smart biomaterials. We also assessed the potential for released GNPs to label/brand CTCs over time for enhanced detection by photoacoustic methods.
Materials/Methods
Prototype smart biomaterials were produced by coating inert fiducials with a polymer film loaded with GNPs. In vitro release of GNPs was monitored by UV-Vis Spectroscopy over time. An experimentally determined diffusion coefficient (D) for 10 nm nanoparticles in mouse prostate tumor model was employed to estimate D for other nanoparticle sizes using the Stoke-Einstein equation. The error function diffusion model in the experimental study was applied to calculate the diffusion time required to label any CTCs within the tumor volume. CTCs were considered labeled when in contact with an experimentally determined minimum GNPs concentration (37ng/g) detectable by photoacoustic methods. The study was done for a range of tumor sizes and initial concentrations.
Results
Our prototype smart biomaterial showed sustained customizable release of GNP in vitro, with release profile reaching steady state after 2 hours. Meanwhile, for the experimentally determined D, results using an initial concentration of 7 mg/g showed it would take 7.6-17.3 days for the released GNP to brand any CTCs located within the tumor volume of diameter 2-3 cm. The labeling time decreased with decrease in GNP size or increase in initial concentration.
Conclusions
Considered together, our results demonstrate potential for labeling CTCs right from the source tumor, with the labeling customizable through nanoparticle design: size, initial concentration, etc. The highest clinical impact of this innovative approach is anticipated in significantly enhancing the isolation and detection efficiency of CTCs in circulation or lymph nodes towards improved characterization of tumor aggressiveness, treatment response, or prognosis. The ability to brand and track CTCs right from their source could also lead to a better understanding of mechanisms contributing to cancer progression or metastasis. The innovative approach would come at no additional inconvenience to RT patients who are candidates for the currently used inert RT biomaterials.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose/Objective(s)
We propose that routinely used inert radiation therapy (RT) biomaterials (e.g. fiducials, spacers) can be upgraded to smart ones by incorporating multifunctional non-toxic gold nanoparticles (GNPs) for sustained in-situ release. Our hypothesis is that the GNPs released, after implantation of the smart biomaterial in tumor, can be programmed to label/brand metastatic or circulating tumor cells (CTCs) at their source before they are shed into hematogenous or lymphatic circulation. This would enable significantly enhanced CTCs detection by different methods. In this work, we developed and characterized such prototype smart biomaterials. We also assessed the potential for released GNPs to label/brand CTCs over time for enhanced detection by photoacoustic methods.
Materials/Methods
Prototype smart biomaterials were produced by coating inert fiducials with a polymer film loaded with GNPs. In vitro release of GNPs was monitored by UV-Vis Spectroscopy over time. An experimentally determined diffusion coefficient (D) for 10 nm nanoparticles in mouse prostate tumor model was employed to estimate D for other nanoparticle sizes using the Stoke-Einstein equation. The error function diffusion model in the experimental study was applied to calculate the diffusion time required to label any CTCs within the tumor volume. CTCs were considered labeled when in contact with an experimentally determined minimum GNPs concentration (37ng/g) detectable by photoacoustic methods. The study was done for a range of tumor sizes and initial concentrations.
Results
Our prototype smart biomaterial showed sustained customizable release of GNP in vitro, with release profile reaching steady state after 2 hours. Meanwhile, for the experimentally determined D, results using an initial concentration of 7 mg/g showed it would take 7.6-17.3 days for the released GNP to brand any CTCs located within the tumor volume of diameter 2-3 cm. The labeling time decreased with decrease in GNP size or increase in initial concentration.
Conclusions
Considered together, our results demonstrate potential for labeling CTCs right from the source tumor, with the labeling customizable through nanoparticle design: size, initial concentration, etc. The highest clinical impact of this innovative approach is anticipated in significantly enhancing the isolation and detection efficiency of CTCs in circulation or lymph nodes towards improved characterization of tumor aggressiveness, treatment response, or prognosis. The ability to brand and track CTCs right from their source could also lead to a better understanding of mechanisms contributing to cancer progression or metastasis. The innovative approach would come at no additional inconvenience to RT patients who are candidates for the currently used inert RT biomaterials.
We propose that routinely used inert radiation therapy (RT) biomaterials (e.g. fiducials, spacers) can be upgraded to smart ones by incorporating multifunctional non-toxic gold nanoparticles (GNPs) for sustained in-situ release. Our hypothesis is that the GNPs released, after implantation of the smart biomaterial in tumor, can be programmed to label/brand metastatic or circulating tumor cells (CTCs) at their source before they are shed into hematogenous or lymphatic circulation. This would enable significantly enhanced CTCs detection by different methods. In this work, we developed and characterized such prototype smart biomaterials. We also assessed the potential for released GNPs to label/brand CTCs over time for enhanced detection by photoacoustic methods.
Materials/Methods
Prototype smart biomaterials were produced by coating inert fiducials with a polymer film loaded with GNPs. In vitro release of GNPs was monitored by UV-Vis Spectroscopy over time. An experimentally determined diffusion coefficient (D) for 10 nm nanoparticles in mouse prostate tumor model was employed to estimate D for other nanoparticle sizes using the Stoke-Einstein equation. The error function diffusion model in the experimental study was applied to calculate the diffusion time required to label any CTCs within the tumor volume. CTCs were considered labeled when in contact with an experimentally determined minimum GNPs concentration (37ng/g) detectable by photoacoustic methods. The study was done for a range of tumor sizes and initial concentrations.
Results
Our prototype smart biomaterial showed sustained customizable release of GNP in vitro, with release profile reaching steady state after 2 hours. Meanwhile, for the experimentally determined D, results using an initial concentration of 7 mg/g showed it would take 7.6-17.3 days for the released GNP to brand any CTCs located within the tumor volume of diameter 2-3 cm. The labeling time decreased with decrease in GNP size or increase in initial concentration.
Conclusions
Considered together, our results demonstrate potential for labeling CTCs right from the source tumor, with the labeling customizable through nanoparticle design: size, initial concentration, etc. The highest clinical impact of this innovative approach is anticipated in significantly enhancing the isolation and detection efficiency of CTCs in circulation or lymph nodes towards improved characterization of tumor aggressiveness, treatment response, or prognosis. The ability to brand and track CTCs right from their source could also lead to a better understanding of mechanisms contributing to cancer progression or metastasis. The innovative approach would come at no additional inconvenience to RT patients who are candidates for the currently used inert RT biomaterials.
56.
Cormack, R; Ngwa, W; Tangutoori, S; Rajiv, K; Sridhar, S; Makrigiorgos, G
SU-F-19A-08: Optimal Time Release Schedule of In-Situ Drug Release During Permanent Prostate Brachytherapy Journal Article
In: Medical Physics, vol. 41, no. 6Part22, pp. 389–390, 2014.
BibTeX | Tags: Nanomedicine
@article{cormack2014f,
title = {SU-F-19A-08: Optimal Time Release Schedule of In-Situ Drug Release During Permanent Prostate Brachytherapy},
author = {R Cormack and W Ngwa and S Tangutoori and K Rajiv and S Sridhar and G Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {Medical Physics},
volume = {41},
number = {6Part22},
pages = {389--390},
publisher = {American Association of Physicists in Medicine},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
2013
55.
Ngwa, Wilfred; Korideck, Houari; Kassis, Amin I; Kumar, Rajiv; Sridhar, Srinivas; Makrigiorgos, Mike G; Cormack, Robert A
In vitro radiosensitization by gold nanoparticles during continuous low-dose-rate gamma irradiation with I-125 brachytherapy seeds Journal Article
In: Nanomedicine: Nanotechnology, Biology and Medicine, vol. 9, no. 1, pp. 25–27, 2013.
Abstract | BibTeX | Tags: Nanomedicine
@article{ngwa2013vitro,
title = {In vitro radiosensitization by gold nanoparticles during continuous low-dose-rate gamma irradiation with I-125 brachytherapy seeds},
author = {Wilfred Ngwa and Houari Korideck and Amin I Kassis and Rajiv Kumar and Srinivas Sridhar and Mike G Makrigiorgos and Robert A Cormack},
year = {2013},
date = {2013-01-01},
journal = {Nanomedicine: Nanotechnology, Biology and Medicine},
volume = {9},
number = {1},
pages = {25--27},
publisher = {Elsevier},
abstract = {This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources.
This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources. HeLa cell cultures incubated with and without AuNP were irradiated with an I-125 seed plaque designed to produce a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at low-dose rates ranging from 2.1 to 4.5 cGy/h. Residual γH2AX was measured 24 h after irradiation and used to compare radiation damage to the cells with and without AuNP. The data demonstrate that the biological effect when irradiating in the presence of 0.2 mg/ml concentration of AuNP is about 70%–130% greater than without AuNP. Meanwhile, without radiation, the AuNP showed minimal effect on the cancer cells. These findings provide in vitro evidence that AuNP may be employed as radiosensitizers during continuous LDR brachytherapy.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources.
This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources. HeLa cell cultures incubated with and without AuNP were irradiated with an I-125 seed plaque designed to produce a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at low-dose rates ranging from 2.1 to 4.5 cGy/h. Residual γH2AX was measured 24 h after irradiation and used to compare radiation damage to the cells with and without AuNP. The data demonstrate that the biological effect when irradiating in the presence of 0.2 mg/ml concentration of AuNP is about 70%–130% greater than without AuNP. Meanwhile, without radiation, the AuNP showed minimal effect on the cancer cells. These findings provide in vitro evidence that AuNP may be employed as radiosensitizers during continuous LDR brachytherapy.
This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources. HeLa cell cultures incubated with and without AuNP were irradiated with an I-125 seed plaque designed to produce a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at low-dose rates ranging from 2.1 to 4.5 cGy/h. Residual γH2AX was measured 24 h after irradiation and used to compare radiation damage to the cells with and without AuNP. The data demonstrate that the biological effect when irradiating in the presence of 0.2 mg/ml concentration of AuNP is about 70%–130% greater than without AuNP. Meanwhile, without radiation, the AuNP showed minimal effect on the cancer cells. These findings provide in vitro evidence that AuNP may be employed as radiosensitizers during continuous LDR brachytherapy.
54.
Rivera-Chacon, DM; Alvarado-Velez, M; Acevedo-Morantes, CY; Singh, SP; Gultepe, E; Nagesha, D; Sridhar, S; Ramirez-Vick, JE
Fibronectin and vitronectin promote human fetal osteoblast cell attachment and proliferation on nanoporous titanium surfaces Journal Article
In: Journal of biomedical nanotechnology, vol. 9, no. 6, pp. 1092–1097, 2013.
Abstract | BibTeX | Tags: Nanomedicine
@article{rivera2013fibronectin,
title = {Fibronectin and vitronectin promote human fetal osteoblast cell attachment and proliferation on nanoporous titanium surfaces},
author = {DM Rivera-Chacon and M Alvarado-Velez and CY Acevedo-Morantes and SP Singh and E Gultepe and D Nagesha and S Sridhar and JE Ramirez-Vick},
year = {2013},
date = {2013-01-01},
journal = {Journal of biomedical nanotechnology},
volume = {9},
number = {6},
pages = {1092--1097},
publisher = {American Scientific Publishers},
abstract = {We studied the influence of the serum proteins fibronectin (FN) and vitronectin (VN) with nanoporous TiO2 on osteoblast cell attachment. Taken together, these results suggest that the nanoporous surface topography results in increased adsorbtion of FN and VN the slow release of these proteins are important factors in osteoblast attachment to titanium alloys.
Improvements in osteoconduction of implant biomaterials require focusing on the bone-implant interface, which is a complex multifactorial system. Surface topography of implants plays a crucial role at this interface. Nanostructured surfaces have been shown to promote serum protein adsorption and osteoblast adhesion when compared to micro-structured surfaces for bone-implant materials. We studied the influence of the serum proteins fibronectin and vitronectin on the attachment and proliferation of osteoblasts onto nanostructured titania surfaces. Human fetal osteoblastic cells hFOB 1.19 were used as model osteoblasts and were grown on nanoporous TiO2 templates, using Ti6Al4V and commercially pure Ti substrates as controls. Results show a significant increase in cell proliferation on nanoporous TiO2 over flat substrates. Initial cell attachment data exhibited a significant effect by either fibronectin or vitronectin on cell adhesion at the surface of any of the tested materials. In addition, the extent of cell adhesion was significantly different between the nanoporous TiO2 and both Ti6Al4V and commercially pure Ti substrates, with the first showing the highest surface coverage. There was no significant difference on osteoblast attachment or proliferation between the presence of fibronectin or vitronectin using any of the material substrates. Taken together, these results suggest that the increase in osteoblast attachment and proliferation shown on the nanoporous TiO2 is due to an increase in the adsorption of fibronectin and vitronectin because of the higher surface area and to an enhanced protein unfolding, which allows access to osteoblast binding motifs within these proteins.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
We studied the influence of the serum proteins fibronectin (FN) and vitronectin (VN) with nanoporous TiO2 on osteoblast cell attachment. Taken together, these results suggest that the nanoporous surface topography results in increased adsorbtion of FN and VN the slow release of these proteins are important factors in osteoblast attachment to titanium alloys.
Improvements in osteoconduction of implant biomaterials require focusing on the bone-implant interface, which is a complex multifactorial system. Surface topography of implants plays a crucial role at this interface. Nanostructured surfaces have been shown to promote serum protein adsorption and osteoblast adhesion when compared to micro-structured surfaces for bone-implant materials. We studied the influence of the serum proteins fibronectin and vitronectin on the attachment and proliferation of osteoblasts onto nanostructured titania surfaces. Human fetal osteoblastic cells hFOB 1.19 were used as model osteoblasts and were grown on nanoporous TiO2 templates, using Ti6Al4V and commercially pure Ti substrates as controls. Results show a significant increase in cell proliferation on nanoporous TiO2 over flat substrates. Initial cell attachment data exhibited a significant effect by either fibronectin or vitronectin on cell adhesion at the surface of any of the tested materials. In addition, the extent of cell adhesion was significantly different between the nanoporous TiO2 and both Ti6Al4V and commercially pure Ti substrates, with the first showing the highest surface coverage. There was no significant difference on osteoblast attachment or proliferation between the presence of fibronectin or vitronectin using any of the material substrates. Taken together, these results suggest that the increase in osteoblast attachment and proliferation shown on the nanoporous TiO2 is due to an increase in the adsorption of fibronectin and vitronectin because of the higher surface area and to an enhanced protein unfolding, which allows access to osteoblast binding motifs within these proteins.
Improvements in osteoconduction of implant biomaterials require focusing on the bone-implant interface, which is a complex multifactorial system. Surface topography of implants plays a crucial role at this interface. Nanostructured surfaces have been shown to promote serum protein adsorption and osteoblast adhesion when compared to micro-structured surfaces for bone-implant materials. We studied the influence of the serum proteins fibronectin and vitronectin on the attachment and proliferation of osteoblasts onto nanostructured titania surfaces. Human fetal osteoblastic cells hFOB 1.19 were used as model osteoblasts and were grown on nanoporous TiO2 templates, using Ti6Al4V and commercially pure Ti substrates as controls. Results show a significant increase in cell proliferation on nanoporous TiO2 over flat substrates. Initial cell attachment data exhibited a significant effect by either fibronectin or vitronectin on cell adhesion at the surface of any of the tested materials. In addition, the extent of cell adhesion was significantly different between the nanoporous TiO2 and both Ti6Al4V and commercially pure Ti substrates, with the first showing the highest surface coverage. There was no significant difference on osteoblast attachment or proliferation between the presence of fibronectin or vitronectin using any of the material substrates. Taken together, these results suggest that the increase in osteoblast attachment and proliferation shown on the nanoporous TiO2 is due to an increase in the adsorption of fibronectin and vitronectin because of the higher surface area and to an enhanced protein unfolding, which allows access to osteoblast binding motifs within these proteins.
53.
Chapman, Sandra; Dobrovolskaia, Marina; Farahani, Keyvan; Goodwin, Andrew; Joshi, Amit; Lee, Hakho; Meade, Thomas; Pomper, Martin; Ptak, Krzysztof; Rao, Jianghong; others,
Nanoparticles for cancer imaging: The good, the bad, and the promise Journal Article
In: Nano today, vol. 8, no. 5, pp. 454–460, 2013.
Abstract | BibTeX | Tags: Nanomedicine
@article{chapman2013nanoparticles,
title = {Nanoparticles for cancer imaging: The good, the bad, and the promise},
author = {Sandra Chapman and Marina Dobrovolskaia and Keyvan Farahani and Andrew Goodwin and Amit Joshi and Hakho Lee and Thomas Meade and Martin Pomper and Krzysztof Ptak and Jianghong Rao and others},
year = {2013},
date = {2013-01-01},
journal = {Nano today},
volume = {8},
number = {5},
pages = {454--460},
publisher = {Elsevier},
abstract = {Recent advances in molecular imaging and nanotechnology are providing new opportunities for biomedical imaging with great promise for the development of novel imaging agents. The unique optical, magnetic, and chemical properties of materials at the scale of nanometers allow the creation of imaging probes with better contrast enhancement, increased sensitivity, controlled biodistribution, better spatial and temporal information, multi-functionality and multi-modal imaging across MRI, PET, SPECT, and ultrasound. These features could ultimately translate to clinical advantages such as earlier detection, real time assessment of disease progression and personalized medicine. However, several years of investigation into the application of these materials to cancer research has revealed challenges that have delayed the successful application of these agents to the field of biomedical imaging. Understanding these challenges is critical to take full advantage of the benefits offered by nano-sized imaging agents. Therefore, this article presents the lessons learned and challenges encountered by a group of leading researchers in this field, and suggests ways forward to develop nanoparticle probes for cancer imaging.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Recent advances in molecular imaging and nanotechnology are providing new opportunities for biomedical imaging with great promise for the development of novel imaging agents. The unique optical, magnetic, and chemical properties of materials at the scale of nanometers allow the creation of imaging probes with better contrast enhancement, increased sensitivity, controlled biodistribution, better spatial and temporal information, multi-functionality and multi-modal imaging across MRI, PET, SPECT, and ultrasound. These features could ultimately translate to clinical advantages such as earlier detection, real time assessment of disease progression and personalized medicine. However, several years of investigation into the application of these materials to cancer research has revealed challenges that have delayed the successful application of these agents to the field of biomedical imaging. Understanding these challenges is critical to take full advantage of the benefits offered by nano-sized imaging agents. Therefore, this article presents the lessons learned and challenges encountered by a group of leading researchers in this field, and suggests ways forward to develop nanoparticle probes for cancer imaging.
52.
Kumar, Rajiv; Korideck, Houari; Ngwa, Wilfred; Berbeco, Ross I; Makrigiorgos, Mike G; Sridhar, Srinivas
Third generation gold nanoplatform optimized for radiation therapy Journal Article
In: Translational cancer research, vol. 2, no. 4, 2013.
Abstract | BibTeX | Tags: Nanomedicine
@article{kumar2013third,
title = {Third generation gold nanoplatform optimized for radiation therapy},
author = {Rajiv Kumar and Houari Korideck and Wilfred Ngwa and Ross I Berbeco and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
journal = {Translational cancer research},
volume = {2},
number = {4},
publisher = {NIH Public Access},
abstract = {We report the design and fabrication of third generation ultrasmall PEGylated gold nanoparticles based platform (AuRad™) optimized for applications in radiation therapy. The AuRad™ nanoplatform has the following key features: (I) surface coating of hetero-bifunctional-PEG with amine, carboxyl, methoxy functional groups, which make this a versatile nanoplatform to conjugate various moieties like fluorophores, peptides, drugs, radiolabels; (II) size that is optimized for longer circulation, higher tumor uptake and modulated clearance; (III) high radiation enhancement. We have synthesized ultrasmall 2–3 nm gold nanoparticles, followed by attachment of hetero-bifunctional PEG and further conjugation of fluorophore AlexaFlour 647 for optical imaging, with a stability of more than 6 months. Confocal bioimaging with HeLa cells showed robust uptake of biocompatible nanoparticles in cells. Irradiation experiments X-rays showed greater than 2.8-fold cell kill enhancement as demonstrated by clonogenic survival assays. The results indicate that AuRad nanoplatform can act as potential theranostic agent in radiation therapy.
Keywords: Gold nanoparticles, PEGylation, multifunctional nanoparticles, clonogenic assay, radiation therapy},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
We report the design and fabrication of third generation ultrasmall PEGylated gold nanoparticles based platform (AuRad™) optimized for applications in radiation therapy. The AuRad™ nanoplatform has the following key features: (I) surface coating of hetero-bifunctional-PEG with amine, carboxyl, methoxy functional groups, which make this a versatile nanoplatform to conjugate various moieties like fluorophores, peptides, drugs, radiolabels; (II) size that is optimized for longer circulation, higher tumor uptake and modulated clearance; (III) high radiation enhancement. We have synthesized ultrasmall 2–3 nm gold nanoparticles, followed by attachment of hetero-bifunctional PEG and further conjugation of fluorophore AlexaFlour 647 for optical imaging, with a stability of more than 6 months. Confocal bioimaging with HeLa cells showed robust uptake of biocompatible nanoparticles in cells. Irradiation experiments X-rays showed greater than 2.8-fold cell kill enhancement as demonstrated by clonogenic survival assays. The results indicate that AuRad nanoplatform can act as potential theranostic agent in radiation therapy.
Keywords: Gold nanoparticles, PEGylation, multifunctional nanoparticles, clonogenic assay, radiation therapy
Keywords: Gold nanoparticles, PEGylation, multifunctional nanoparticles, clonogenic assay, radiation therapy
51.
Petrov, Yury; Sridhar, Srinivas
Electric field encephalography as a tool for functional brain research: a modeling study Journal Article
In: PloS one, vol. 8, no. 7, 2013.
Abstract | BibTeX | Tags: Nanomedicine, Neurotechnology
@article{petrov2013electric,
title = {Electric field encephalography as a tool for functional brain research: a modeling study},
author = {Yury Petrov and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
journal = {PloS one},
volume = {8},
number = {7},
publisher = {Public Library of Science},
abstract = {We introduce the notion of Electric Field Encephalography (EFEG) based on measuring electric fields of the brain and demonstrate, using computer modeling, that given the appropriate electric field sensors this technique may have significant advantages over the current EEG technique. Unlike EEG, EFEG can be used to measure brain activity in a contactless and reference-free manner at significant distances from the head surface. Principal component analysis using simulated cortical sources demonstrated that electric field sensors positioned 3 cm away from the scalp and characterized by the same signal-to-noise ratio as EEG sensors provided the same number of uncorrelated signals as scalp EEG. When positioned on the scalp, EFEG sensors provided 2–3 times more uncorrelated signals. This significant increase in the number of uncorrelated signals can be used for more accurate assessment of brain states for non-invasive brain-computer interfaces and neurofeedback applications. It also may lead to major improvements in source localization precision. Source localization simulations for the spherical and Boundary Element Method (BEM) head models demonstrated that the localization errors are reduced two-fold when using electric fields instead of electric potentials. We have identified several techniques that could be adapted for the measurement of the electric field vector required for EFEG and anticipate that this study will stimulate new experimental approaches to utilize this new tool for functional brain research.},
keywords = {Nanomedicine, Neurotechnology},
pubstate = {published},
tppubtype = {article}
}
We introduce the notion of Electric Field Encephalography (EFEG) based on measuring electric fields of the brain and demonstrate, using computer modeling, that given the appropriate electric field sensors this technique may have significant advantages over the current EEG technique. Unlike EEG, EFEG can be used to measure brain activity in a contactless and reference-free manner at significant distances from the head surface. Principal component analysis using simulated cortical sources demonstrated that electric field sensors positioned 3 cm away from the scalp and characterized by the same signal-to-noise ratio as EEG sensors provided the same number of uncorrelated signals as scalp EEG. When positioned on the scalp, EFEG sensors provided 2–3 times more uncorrelated signals. This significant increase in the number of uncorrelated signals can be used for more accurate assessment of brain states for non-invasive brain-computer interfaces and neurofeedback applications. It also may lead to major improvements in source localization precision. Source localization simulations for the spherical and Boundary Element Method (BEM) head models demonstrated that the localization errors are reduced two-fold when using electric fields instead of electric potentials. We have identified several techniques that could be adapted for the measurement of the electric field vector required for EFEG and anticipate that this study will stimulate new experimental approaches to utilize this new tool for functional brain research.
50.
Ngwa, W; Korideck, H; Kumar, R; Sridhar, S; David, K; Paul, N; Berbeco, R; Cormack, R; Makrigiorgos, G
Toward Customizable Radiation Therapy Enhancement (CuRE) With Gold Nanoparticles Released, In Situ, From Gold-Loaded Brachytherapy Spacers Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 87, no. 2, pp. S151, 2013.
Abstract | BibTeX | Tags: Nanomedicine
@article{ngwa2013toward,
title = {Toward Customizable Radiation Therapy Enhancement (CuRE) With Gold Nanoparticles Released, In Situ, From Gold-Loaded Brachytherapy Spacers},
author = {W Ngwa and H Korideck and R Kumar and S Sridhar and K David and N Paul and R Berbeco and R Cormack and G Makrigiorgos},
year = {2013},
date = {2013-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {87},
number = {2},
pages = {S151},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Loading routinely used brachytherapy spacers with non-toxic/biocompatible gold nanoparticles (AuNP), which can be released in situ to serve as radiosensitizers is a novel potential strategy for prostate tumor sub-volume boosting or dose-painting. This study investigates the release and diffusion of the AuNP from the brachytherapy spacer in vivo using CT imaging.
Materials/Methods
Gold-loaded brachytherapy spacers (GBS) (ca. 0.8 mm x 5 mm) were produced using AuNP and biodegradable PLGA copolymer. The GBS was implanted in mice using a brachytherapy needle and CBCT-imaged over time using the small animal radiation research platform (SARRP). The CT images were exported to imageJ and the intensity of the implanted spacer evaluated at different time points. Also, to simulate a burst release of the AuNP from an implanted spacer, 20 mg Au/mL concentration of 15 nm polymer coated AuNP suspended in 20 μL phosphate-buffered saline at pH 7.4, was injected intratumorally, and the AuNP diffusion monitored via serial CT imaging over 5 time points in hours: 0.5, 48, 120, 144, and 160. The CT images were then exported to imageJ and the pixel intensities for 5 sample tumor regions of interest (at: left, right, center, anterior, posterior) extracted to assess AuNP diffusion.
Results
Results for the implanted GBS showed that the CT intensity of the spacer decreased over time, indicating the release of the AuNP as the PLGA degrades in vivo. Meanwhile, the CBCT images from the AuNP burst release study showed clear evidence of AuNP diffusion. For example, at the site of AuNP release, the CT image intensity decreased by over 160% during the investigated time range (0.5 h – 160 h). During the same time, the intensity in the tumor subvolume or ROI on the opposite side of the release site increased by over 140%. The diffusion results also showed that for the 15 nm AuNP size, potent AuNP concentrations can reside within the tumor sub-volume for a sustained period of time.
Conclusions
The results provide the first in vivo evidence of AuNP release from gold loaded brachytherapy spacers. The sustained residence of potent AuNP concentrations in the tumor sub-volume could allow for significant dose boosting during brachytherapy. Such boosting could be further customized (e.g., by varying AuNP size, functionalization, spacer degradation time, etc.) since the intra-tumor biodistribution depends on such parameters. Overall, the results provide a useful basis for future R&D towards the development of Customizable Radiation therapy Enhancement (CuRE) with AuNP for prostate cancer. Potential clinical applications for such a new approach are anticipated in salvage brachytherapy, and sub-volume radiation boosting during initial treatment to help prevent prostate cancer recurrence.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose/Objective(s)
Loading routinely used brachytherapy spacers with non-toxic/biocompatible gold nanoparticles (AuNP), which can be released in situ to serve as radiosensitizers is a novel potential strategy for prostate tumor sub-volume boosting or dose-painting. This study investigates the release and diffusion of the AuNP from the brachytherapy spacer in vivo using CT imaging.
Materials/Methods
Gold-loaded brachytherapy spacers (GBS) (ca. 0.8 mm x 5 mm) were produced using AuNP and biodegradable PLGA copolymer. The GBS was implanted in mice using a brachytherapy needle and CBCT-imaged over time using the small animal radiation research platform (SARRP). The CT images were exported to imageJ and the intensity of the implanted spacer evaluated at different time points. Also, to simulate a burst release of the AuNP from an implanted spacer, 20 mg Au/mL concentration of 15 nm polymer coated AuNP suspended in 20 μL phosphate-buffered saline at pH 7.4, was injected intratumorally, and the AuNP diffusion monitored via serial CT imaging over 5 time points in hours: 0.5, 48, 120, 144, and 160. The CT images were then exported to imageJ and the pixel intensities for 5 sample tumor regions of interest (at: left, right, center, anterior, posterior) extracted to assess AuNP diffusion.
Results
Results for the implanted GBS showed that the CT intensity of the spacer decreased over time, indicating the release of the AuNP as the PLGA degrades in vivo. Meanwhile, the CBCT images from the AuNP burst release study showed clear evidence of AuNP diffusion. For example, at the site of AuNP release, the CT image intensity decreased by over 160% during the investigated time range (0.5 h – 160 h). During the same time, the intensity in the tumor subvolume or ROI on the opposite side of the release site increased by over 140%. The diffusion results also showed that for the 15 nm AuNP size, potent AuNP concentrations can reside within the tumor sub-volume for a sustained period of time.
Conclusions
The results provide the first in vivo evidence of AuNP release from gold loaded brachytherapy spacers. The sustained residence of potent AuNP concentrations in the tumor sub-volume could allow for significant dose boosting during brachytherapy. Such boosting could be further customized (e.g., by varying AuNP size, functionalization, spacer degradation time, etc.) since the intra-tumor biodistribution depends on such parameters. Overall, the results provide a useful basis for future R&D towards the development of Customizable Radiation therapy Enhancement (CuRE) with AuNP for prostate cancer. Potential clinical applications for such a new approach are anticipated in salvage brachytherapy, and sub-volume radiation boosting during initial treatment to help prevent prostate cancer recurrence.
Loading routinely used brachytherapy spacers with non-toxic/biocompatible gold nanoparticles (AuNP), which can be released in situ to serve as radiosensitizers is a novel potential strategy for prostate tumor sub-volume boosting or dose-painting. This study investigates the release and diffusion of the AuNP from the brachytherapy spacer in vivo using CT imaging.
Materials/Methods
Gold-loaded brachytherapy spacers (GBS) (ca. 0.8 mm x 5 mm) were produced using AuNP and biodegradable PLGA copolymer. The GBS was implanted in mice using a brachytherapy needle and CBCT-imaged over time using the small animal radiation research platform (SARRP). The CT images were exported to imageJ and the intensity of the implanted spacer evaluated at different time points. Also, to simulate a burst release of the AuNP from an implanted spacer, 20 mg Au/mL concentration of 15 nm polymer coated AuNP suspended in 20 μL phosphate-buffered saline at pH 7.4, was injected intratumorally, and the AuNP diffusion monitored via serial CT imaging over 5 time points in hours: 0.5, 48, 120, 144, and 160. The CT images were then exported to imageJ and the pixel intensities for 5 sample tumor regions of interest (at: left, right, center, anterior, posterior) extracted to assess AuNP diffusion.
Results
Results for the implanted GBS showed that the CT intensity of the spacer decreased over time, indicating the release of the AuNP as the PLGA degrades in vivo. Meanwhile, the CBCT images from the AuNP burst release study showed clear evidence of AuNP diffusion. For example, at the site of AuNP release, the CT image intensity decreased by over 160% during the investigated time range (0.5 h – 160 h). During the same time, the intensity in the tumor subvolume or ROI on the opposite side of the release site increased by over 140%. The diffusion results also showed that for the 15 nm AuNP size, potent AuNP concentrations can reside within the tumor sub-volume for a sustained period of time.
Conclusions
The results provide the first in vivo evidence of AuNP release from gold loaded brachytherapy spacers. The sustained residence of potent AuNP concentrations in the tumor sub-volume could allow for significant dose boosting during brachytherapy. Such boosting could be further customized (e.g., by varying AuNP size, functionalization, spacer degradation time, etc.) since the intra-tumor biodistribution depends on such parameters. Overall, the results provide a useful basis for future R&D towards the development of Customizable Radiation therapy Enhancement (CuRE) with AuNP for prostate cancer. Potential clinical applications for such a new approach are anticipated in salvage brachytherapy, and sub-volume radiation boosting during initial treatment to help prevent prostate cancer recurrence.
49.
Tangutoori, Shifalika; Korideck, Houari; Makrigiorgos, Mike; Cormack, Robert; Sridhar, Srinivas
Abstract A81: A novel nano-formulation for systemic administration of PARPi-olaparib (Nano-Olaparib) for radiosensitization, chemosensitization, and combinatorial therapy in prostate cancer. Miscellaneous
2013.
BibTeX | Tags: Nanomedicine
@misc{tangutoori2013abstract,
title = {Abstract A81: A novel nano-formulation for systemic administration of PARPi-olaparib (Nano-Olaparib) for radiosensitization, chemosensitization, and combinatorial therapy in prostate cancer.},
author = {Shifalika Tangutoori and Houari Korideck and Mike Makrigiorgos and Robert Cormack and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
publisher = {American Association for Cancer Research},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
48.
Kumar, Rajiv; Kulkarni, Apurva; Nabulsi, Jude; Nagesha, Dattatri K; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas
Facile synthesis of PEGylated PLGA nanoparticles encapsulating doxorubicin and its in vitro evaluation as potent drug delivery vehicle Journal Article
In: Drug delivery and translational research, vol. 3, no. 4, pp. 299–308, 2013.
Abstract | BibTeX | Tags: Nanomedicine
@article{kumar2013facile,
title = {Facile synthesis of PEGylated PLGA nanoparticles encapsulating doxorubicin and its in vitro evaluation as potent drug delivery vehicle},
author = {Rajiv Kumar and Apurva Kulkarni and Jude Nabulsi and Dattatri K Nagesha and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
journal = {Drug delivery and translational research},
volume = {3},
number = {4},
pages = {299--308},
publisher = {Springer US},
abstract = {The advent of nanotechnology has bolstered a variety of nanoparticle-based platforms for different biomedical applications. A better understanding for engineering novel nanoparticles for applications in cancer staging and therapy requires careful assessment of the nanoparticle’s physico-chemical properties. Herein we report a facile synthesis method for PEGylated PLGA nanoparticles encapsulating anti-cancer drug doxorubicin for cancer imaging and therapy. The simple nanoprecipitation method reported here resulted in very robust PEGylated PLGA nanoparticles with close to 95 % drug encapsulation efficiency. The nanoparticles showed a size of ~110 nm as characterized by TEM and DLS. The nanoparticles were further characterized by optical UV–Visible and fluorescence spectroscopy. The encapsulated doxorubicin showed a sustained release (>80 %) from the nanoparticles matrix over a period of 8 days. The drug delivery efficiency of the nanoparticles was confirmed in vitro confocal imaging with PC3 and HeLa cell lines. In vitro quantitative estimation of drug accumulation in PC3 cell line showed a 22 times higher concentration of drug in case of nanoparticle-based formulation in comparison to free drug and this was further reflected in the in vitro cytotoxicity assays. Overall the synthesis method reported here provides a simple and robust PLGA-based platform for efficient drug delivery and imaging of cancer cells in vitro and in vivo.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The advent of nanotechnology has bolstered a variety of nanoparticle-based platforms for different biomedical applications. A better understanding for engineering novel nanoparticles for applications in cancer staging and therapy requires careful assessment of the nanoparticle’s physico-chemical properties. Herein we report a facile synthesis method for PEGylated PLGA nanoparticles encapsulating anti-cancer drug doxorubicin for cancer imaging and therapy. The simple nanoprecipitation method reported here resulted in very robust PEGylated PLGA nanoparticles with close to 95 % drug encapsulation efficiency. The nanoparticles showed a size of ~110 nm as characterized by TEM and DLS. The nanoparticles were further characterized by optical UV–Visible and fluorescence spectroscopy. The encapsulated doxorubicin showed a sustained release (>80 %) from the nanoparticles matrix over a period of 8 days. The drug delivery efficiency of the nanoparticles was confirmed in vitro confocal imaging with PC3 and HeLa cell lines. In vitro quantitative estimation of drug accumulation in PC3 cell line showed a 22 times higher concentration of drug in case of nanoparticle-based formulation in comparison to free drug and this was further reflected in the in vitro cytotoxicity assays. Overall the synthesis method reported here provides a simple and robust PLGA-based platform for efficient drug delivery and imaging of cancer cells in vitro and in vivo.
47.
Teh, James L; Hanson, Robert N; Sridhar, Srinivas
Synthesis and characterization of Arg-Gly-Asp (RGD) peptidomimetics functionalized onto gold nanoparticles Proceedings Article
In: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA 2013.
BibTeX | Tags: Nanomedicine
@inproceedings{teh2013synthesis,
title = {Synthesis and characterization of Arg-Gly-Asp (RGD) peptidomimetics functionalized onto gold nanoparticles},
author = {James L Teh and Robert N Hanson and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
booktitle = {ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY},
volume = {245},
organization = {AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
46.
Kumar, Rajiv; Belz, Jodi; Markovic, Stacey; Jadhav, Tej; Nguyen, Paul; Niedre, Mark; DAmico, Anthony; Makrigiorgos, Mike; Cormack, Robert; Sridhar, Srinivas
Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy. Miscellaneous
2013.
Abstract | BibTeX | Tags: Nanomedicine
@misc{kumar2013sustained,
title = {Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy.},
author = {Rajiv Kumar and Jodi Belz and Stacey Markovic and Tej Jadhav and Paul Nguyen and Mark Niedre and Anthony DAmico and Mike Makrigiorgos and Robert Cormack and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
publisher = {American Association for Cancer Research},
abstract = {Systemic chemotherapy is often used with radiation therapy in the management of prostate, cervix and lung cancer patients, but leads to severe systemic toxicities. We have introduced a new modality of loco-regional chemoradiation therapy termed in-situ image guided radiation therapy (BIS-IGRT) that offers the potential to deliver planned, localized and sustained delivery of chemotherapy agent, without systemic toxicities, as part of routine minimally invasive image guided radiation therapy procedures. Such image guided chemoradiation therapy requires characterization of the drug distribution produced by implantable drug eluters. This work presents imaging based means to measure temporal and spatial properties of diffusion distributions around spacers coated with dye-loaded nanoparticles.
The distribution of 250nm silica nanoparticles (NP) conjugated to Cyanine 7.5 dye was evaluated with a custom built high-speed near-infrared small animal imaging platform providing 0.1 millimeter spatial resolution with >1Hz image acquisition rate. A brachytherapy spacer loaded with the Cy7.5/silica NP was injected subcutaneously on the left hind flank of a mouse and one was inserted into a xenograft tumor on the opposite flank as part of an approved animal research protocol. The mouse was imaged more than 36 days.
The in vivo imaging experiments show that the area of high signal increases with time suggesting that NP accumulate in the vicinity of a spacer without diffusing to the rest of the body. The spatial and temporal characteristics of NP accumulation indicate that a BIS-IGRT approach may provide an effective means to improve the therapeutic ratio of brachytherapy.
Conclusion: In-vivo measurements demonstrate that NP remain resident in the vicinity of the implanted eluting spacers with accumulation over times appropriate to improve brachytherapy's therapeutic ratio. Future work will optimize the NP and substrate properties of an implantable spacer to attain the optimal chemotherapy distributions for simultaneous placement during image guided brachytherapy implants.
We acknowledge partial support from NSF DGE 0965843 and HHS/5U54CA151881-02.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Tej Jadhav, Paul Nguyen, Mark Niedre, Anthony DAmico, Mike Makrigiorgos, Robert Cormack, Srinivas Sridhar. Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1594. doi:10.1158/1538-7445.AM2013-1594
©2013 American Association for Cancer Research},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Systemic chemotherapy is often used with radiation therapy in the management of prostate, cervix and lung cancer patients, but leads to severe systemic toxicities. We have introduced a new modality of loco-regional chemoradiation therapy termed in-situ image guided radiation therapy (BIS-IGRT) that offers the potential to deliver planned, localized and sustained delivery of chemotherapy agent, without systemic toxicities, as part of routine minimally invasive image guided radiation therapy procedures. Such image guided chemoradiation therapy requires characterization of the drug distribution produced by implantable drug eluters. This work presents imaging based means to measure temporal and spatial properties of diffusion distributions around spacers coated with dye-loaded nanoparticles.
The distribution of 250nm silica nanoparticles (NP) conjugated to Cyanine 7.5 dye was evaluated with a custom built high-speed near-infrared small animal imaging platform providing 0.1 millimeter spatial resolution with >1Hz image acquisition rate. A brachytherapy spacer loaded with the Cy7.5/silica NP was injected subcutaneously on the left hind flank of a mouse and one was inserted into a xenograft tumor on the opposite flank as part of an approved animal research protocol. The mouse was imaged more than 36 days.
The in vivo imaging experiments show that the area of high signal increases with time suggesting that NP accumulate in the vicinity of a spacer without diffusing to the rest of the body. The spatial and temporal characteristics of NP accumulation indicate that a BIS-IGRT approach may provide an effective means to improve the therapeutic ratio of brachytherapy.
Conclusion: In-vivo measurements demonstrate that NP remain resident in the vicinity of the implanted eluting spacers with accumulation over times appropriate to improve brachytherapy's therapeutic ratio. Future work will optimize the NP and substrate properties of an implantable spacer to attain the optimal chemotherapy distributions for simultaneous placement during image guided brachytherapy implants.
We acknowledge partial support from NSF DGE 0965843 and HHS/5U54CA151881-02.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Tej Jadhav, Paul Nguyen, Mark Niedre, Anthony DAmico, Mike Makrigiorgos, Robert Cormack, Srinivas Sridhar. Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1594. doi:10.1158/1538-7445.AM2013-1594
©2013 American Association for Cancer Research
The distribution of 250nm silica nanoparticles (NP) conjugated to Cyanine 7.5 dye was evaluated with a custom built high-speed near-infrared small animal imaging platform providing 0.1 millimeter spatial resolution with >1Hz image acquisition rate. A brachytherapy spacer loaded with the Cy7.5/silica NP was injected subcutaneously on the left hind flank of a mouse and one was inserted into a xenograft tumor on the opposite flank as part of an approved animal research protocol. The mouse was imaged more than 36 days.
The in vivo imaging experiments show that the area of high signal increases with time suggesting that NP accumulate in the vicinity of a spacer without diffusing to the rest of the body. The spatial and temporal characteristics of NP accumulation indicate that a BIS-IGRT approach may provide an effective means to improve the therapeutic ratio of brachytherapy.
Conclusion: In-vivo measurements demonstrate that NP remain resident in the vicinity of the implanted eluting spacers with accumulation over times appropriate to improve brachytherapy's therapeutic ratio. Future work will optimize the NP and substrate properties of an implantable spacer to attain the optimal chemotherapy distributions for simultaneous placement during image guided brachytherapy implants.
We acknowledge partial support from NSF DGE 0965843 and HHS/5U54CA151881-02.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Tej Jadhav, Paul Nguyen, Mark Niedre, Anthony DAmico, Mike Makrigiorgos, Robert Cormack, Srinivas Sridhar. Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1594. doi:10.1158/1538-7445.AM2013-1594
©2013 American Association for Cancer Research
45.
Kumar, Rajiv; Belz, Jodi E; Markovic, Stacey; Korideck, Houari; Ngwa, Wilfred F; Niedre, Mark; Berbeco, Ross I; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas
Abstract A82: Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’implants. Miscellaneous
2013.
Abstract | BibTeX | Tags: Nanomedicine
@misc{kumar2013abstract,
title = {Abstract A82: Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’implants.},
author = {Rajiv Kumar and Jodi E Belz and Stacey Markovic and Houari Korideck and Wilfred F Ngwa and Mark Niedre and Ross I Berbeco and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
publisher = {American Association for Cancer Research},
abstract = {In cancer therapy, effective delivery of the therapeutic plays a critical role in determining the success of the treatment planning system. In last decade, there is a major thrust in developing novel nanoparticles based delivery systems to improve the therapeutic benefits in cancer. An efficient delivery system should be able to target the diseased site with minimal systemic toxicity and a slow sustained release of the drug. Here, we have fabricated a nanoparticles based smart ‘INCeRT’ (Implantable Nanoplatform for Chemo-Radiation Therapy) implant for localized delivery of radiosensitizing nanoparticles/ drugs in prostate cancer in conjunction with brachytherapy. These implants are physically similar to the clinically used brachytherapy spacers but have the added capability of imaging and local drug delivery. We have fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA (poly-(lactide-co-glycolide)) impregnated with nanoparticles encapsulating imaging probe (Cyanine 7.5) and chemotherapeutic drug, docetaxel (DTX). Using a similar approach, we have also fabricated PLGA spacers impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE: High Z-Customizable Radiotherapy Enhancement) for effectively boosting the radiation dose locally. The morphology, composition and nanoparticle's distribution inside the spacers was studied by SEM (scanning electron microscopy) and EDS (Energy-dispersive X-ray spectroscopy). Further, preliminary in vivo imaging experiments with subcutaneous prostate cancer tumored mice implanted with INCeRT spacers showed a size dependent diffusion of nanoparticles from the spacers in the tumor matrix. Also, from in vivo therapeutic studies with these spacers showed a sustained and slow release of the DTX from the spacers and showed a better response in suppressing the tumor as opposed control mice with saline injections. Further experiments for studying the combined chemo-radiation therapy are underway. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. This work was supported partially by NSF-DGE-0965843, HHS/1U54CA151881 CORE1, 1R03 CA164645-01 and a seed grant from the BWH Biomedical Research Institute.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A82.
Citation Format: Rajiv Kumar, Jodi E. Belz, Stacey Markovic, Houari Korideck, Wilfred F. Ngwa, Mark Niedre, Ross I. Berbeco, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’ implants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A82.
Copyright © November 2013, American Association for Cancer Research},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
In cancer therapy, effective delivery of the therapeutic plays a critical role in determining the success of the treatment planning system. In last decade, there is a major thrust in developing novel nanoparticles based delivery systems to improve the therapeutic benefits in cancer. An efficient delivery system should be able to target the diseased site with minimal systemic toxicity and a slow sustained release of the drug. Here, we have fabricated a nanoparticles based smart ‘INCeRT’ (Implantable Nanoplatform for Chemo-Radiation Therapy) implant for localized delivery of radiosensitizing nanoparticles/ drugs in prostate cancer in conjunction with brachytherapy. These implants are physically similar to the clinically used brachytherapy spacers but have the added capability of imaging and local drug delivery. We have fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA (poly-(lactide-co-glycolide)) impregnated with nanoparticles encapsulating imaging probe (Cyanine 7.5) and chemotherapeutic drug, docetaxel (DTX). Using a similar approach, we have also fabricated PLGA spacers impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE: High Z-Customizable Radiotherapy Enhancement) for effectively boosting the radiation dose locally. The morphology, composition and nanoparticle's distribution inside the spacers was studied by SEM (scanning electron microscopy) and EDS (Energy-dispersive X-ray spectroscopy). Further, preliminary in vivo imaging experiments with subcutaneous prostate cancer tumored mice implanted with INCeRT spacers showed a size dependent diffusion of nanoparticles from the spacers in the tumor matrix. Also, from in vivo therapeutic studies with these spacers showed a sustained and slow release of the DTX from the spacers and showed a better response in suppressing the tumor as opposed control mice with saline injections. Further experiments for studying the combined chemo-radiation therapy are underway. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. This work was supported partially by NSF-DGE-0965843, HHS/1U54CA151881 CORE1, 1R03 CA164645-01 and a seed grant from the BWH Biomedical Research Institute.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A82.
Citation Format: Rajiv Kumar, Jodi E. Belz, Stacey Markovic, Houari Korideck, Wilfred F. Ngwa, Mark Niedre, Ross I. Berbeco, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’ implants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A82.
Copyright © November 2013, American Association for Cancer Research
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A82.
Citation Format: Rajiv Kumar, Jodi E. Belz, Stacey Markovic, Houari Korideck, Wilfred F. Ngwa, Mark Niedre, Ross I. Berbeco, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’ implants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A82.
Copyright © November 2013, American Association for Cancer Research
44.
Campbell, Robert B; Sridhar, Srinivas
Magnetic nanoplatforms for theranostic and multi-modal imaging applications Miscellaneous
2013, (US Patent App. 13/583,616).
Abstract | BibTeX | Tags: Nanomedicine
@misc{campbell2013magnetic,
title = {Magnetic nanoplatforms for theranostic and multi-modal imaging applications},
author = {Robert B Campbell and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
abstract = {Disclosed are nanoparticle compositions comprising paramagnetic particles, radiolabels, fluorophores, and/or positron emission tomography agents encapsulated within a biocompatible vehicle. In addition, methods of multi-modal diagnostic imaging and treating diseased tissues are disclosed, wherein the methods comprises administering a nanoparticle composition to a subject in which the nanoparticle composition comprises paramagnetic particles, radiolabels, fluorophores, and positron emission tomography agents encapsulated within a biocompatible vehicle.},
note = {US Patent App. 13/583,616},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Disclosed are nanoparticle compositions comprising paramagnetic particles, radiolabels, fluorophores, and/or positron emission tomography agents encapsulated within a biocompatible vehicle. In addition, methods of multi-modal diagnostic imaging and treating diseased tissues are disclosed, wherein the methods comprises administering a nanoparticle composition to a subject in which the nanoparticle composition comprises paramagnetic particles, radiolabels, fluorophores, and positron emission tomography agents encapsulated within a biocompatible vehicle.
2012
43.
Anderson, D; Archakov, A; Avgoustakis, K; Baumgartner, A; Bawa, R; Bernardo, M; Biricova, V; Brayner, R; Brechbiel, MW; Buse, J; others,
Our thanks to all those who have helped with this issue of Nanomedicine. Listed below are authors, referees and others who have kindly given their time, effort and expertise; their generosity has helped establish this publication. Journal Article
In: 2012.
BibTeX | Tags: Nanomedicine
@article{andersonour,
title = {Our thanks to all those who have helped with this issue of Nanomedicine. Listed below are authors, referees and others who have kindly given their time, effort and expertise; their generosity has helped establish this publication.},
author = {D Anderson and A Archakov and K Avgoustakis and A Baumgartner and R Bawa and M Bernardo and V Biricova and R Brayner and MW Brechbiel and J Buse and others},
year = {2012},
date = {2012-12-20},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
42.
Kumar, Rajiv; Patel, Janki; Korideck, Houari; Berbeco, Ross I; Makrigiorgos, Mike G; Sridhar, Srinivas
Comprehensive evaluation of PEGylated gold nanorods for two photon photoluminescence image guided radiation therapy enhancement Miscellaneous
2012.
Abstract | BibTeX | Tags: Nanomedicine
@misc{kumar2012comprehensive,
title = {Comprehensive evaluation of PEGylated gold nanorods for two photon photoluminescence image guided radiation therapy enhancement},
author = {Rajiv Kumar and Janki Patel and Houari Korideck and Ross I Berbeco and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2012},
date = {2012-01-01},
publisher = {American Association for Cancer Research},
abstract = {Nanoparticle formulations of gold have shown a tremendous potential in various biomedical applications. The use of high atomic number (Z) materials presents an attractive approach in enhancing the therapeutic efficacy of the radiation therapy. The high Z number for gold (Z=79) makes them an ideal candidate for radiosensitization enhancement. The ability of the anisotropic gold nanorods to sustain the resonating surface plasmon with minimal damping results in highly efficient two-photon induced photoluminescence imaging. Here we present the synthesis and in vitro characterization of PEGylated gold nanorods as efficient radiosensitizing agents which can be imaged using inherent two-photon photoluminescence without a conjugated fluorophore. We have synthesized gold nanorods with an aspect ratio of 2.5 and functionalized the surface with different ratios of methoxy and amine PEG for modulating the charge and imparting the functional groups. The cellular uptake behavior in prostate cancer cell line PC3 was studied and the results indicated a robust uptake of the amine functionalized nanorods. The quantitative estimation of the nanorods uptake was performed with BCA assay as amount of nanorods present in per microgram of protein. Two photon photoluminescence imaging also confirmed a robust cellular uptake of the amine functionalized nanorods. The radiation damage enhancement of the gold nanorods was confirmed using PC3 cells. The cells treated with gold nanorods were irradiated with kilovoltage X-rays. A γH2AX assay was used for quantitation of the DNA damage with and without nanorods as controls. The results indicated an increased highly efficient DNA damage in cells treated with gold nanorods. The outcome of this research will enable further application of targeted nanorods in advanced animal models as efficient radiation dose enhancement agents wherein two-photon photoluminescence imaging will provide a real time assessment of the therapeutic response and disease progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1472. doi:1538-7445.AM2012-1472
©2012 American Association for Cancer Research},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Nanoparticle formulations of gold have shown a tremendous potential in various biomedical applications. The use of high atomic number (Z) materials presents an attractive approach in enhancing the therapeutic efficacy of the radiation therapy. The high Z number for gold (Z=79) makes them an ideal candidate for radiosensitization enhancement. The ability of the anisotropic gold nanorods to sustain the resonating surface plasmon with minimal damping results in highly efficient two-photon induced photoluminescence imaging. Here we present the synthesis and in vitro characterization of PEGylated gold nanorods as efficient radiosensitizing agents which can be imaged using inherent two-photon photoluminescence without a conjugated fluorophore. We have synthesized gold nanorods with an aspect ratio of 2.5 and functionalized the surface with different ratios of methoxy and amine PEG for modulating the charge and imparting the functional groups. The cellular uptake behavior in prostate cancer cell line PC3 was studied and the results indicated a robust uptake of the amine functionalized nanorods. The quantitative estimation of the nanorods uptake was performed with BCA assay as amount of nanorods present in per microgram of protein. Two photon photoluminescence imaging also confirmed a robust cellular uptake of the amine functionalized nanorods. The radiation damage enhancement of the gold nanorods was confirmed using PC3 cells. The cells treated with gold nanorods were irradiated with kilovoltage X-rays. A γH2AX assay was used for quantitation of the DNA damage with and without nanorods as controls. The results indicated an increased highly efficient DNA damage in cells treated with gold nanorods. The outcome of this research will enable further application of targeted nanorods in advanced animal models as efficient radiation dose enhancement agents wherein two-photon photoluminescence imaging will provide a real time assessment of the therapeutic response and disease progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1472. doi:1538-7445.AM2012-1472
©2012 American Association for Cancer Research
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1472. doi:1538-7445.AM2012-1472
©2012 American Association for Cancer Research
41.
Kumar, Rajiv; Kulkarni, Apurva; Nagesha, Dattatri; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Nanocoated brachytherapy spacers eluting radiosensitizers for biological in situ image-guided radiation therapy of prostate cancer Miscellaneous
2012.
Abstract | BibTeX | Tags: Nanomedicine
@misc{kumar2012nanocoated,
title = {Nanocoated brachytherapy spacers eluting radiosensitizers for biological in situ image-guided radiation therapy of prostate cancer},
author = {Rajiv Kumar and Apurva Kulkarni and Dattatri Nagesha and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2012},
date = {2012-01-01},
publisher = {American Association for Cancer Research},
abstract = {The overall goal of this project is to develop means to locally radio-sensitize the prostate to enable prostate cancer (PCa) cure with the use of lower radiation doses, thereby leading to less rectal toxicity. This new approach for chemoradiation therapy (CRT), termed Biological In-Situ Image Guided Radiation Therapy BIS-IGRT, involves the coating of spacers routinely used during prostate I-125-based brachytherapy with radiosensitizing drugs (e.g. docetaxel DTX for PCa). This approach provides localized in-situ delivery of the sensitizer to the tumor and avoids the toxicity associated with current systemic delivery of radiosensitizers. BIS-IGRT adds radiosensitization capability to the standard brachytherapy procedure and with minimal additional inconvenience to the patient. Current CRT with adjuvant systemic chemotherapy does not provide the sustained delivery and drug concentration needed for efficient radiosensitization. Thereby BIS-IGRT improves the therapeutic ratio of radiation therapy without introducing additional patient interventions over current brachytherapy procedures. We have established the following: 1. We have shown through modeling that drug distributions can be achieved that can lead to increased efficiency of image-guided brachytherapy (drug-coated spacers) or image guided external beam therapy (drug-coated fiducials). 2. Doxorubicine-coated fiducials (Dox/PLGA-PEG/CHIT) show release characteristics over 40 days in aqueous media, which is tailored to the time scales required for BIS-IGRT. The cytotoxicity of Dox/ PLGA-PEG NP is comparable to that of free Dox, so that there is no reduction of activity upon encapsulation in the NP. 3. Localized bolus injection of dye-loaded PLGA-PEG nanoparticles (NPs) distributes within 24 hours throughout the tumor, indicating that the sustained release from coated brachytherapy spacers has the potential to achieve the desired biological dose-painting of the tumor. BIS-IGRT could proffer radiation oncologists and medical physicists with a new treatment option for substantially enhancing therapeutic ratio and boosting cure rate for the hundreds of thousands of Americans diagnosed with prostate cancer each year. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. BIS-IGRT can still be accompanied by IV administration of chemotherapeutics, particularly for micro-metastasis, so that existing therapeutic approaches are not compromised. In addition BIS-IGRT could potentially become a mainstream treatment for patients newly diagnosed with prostate or other cancers, where radiation therapy is a common treatment modality.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1473. doi:1538-7445.AM2012-1473
©2012 American Association for Cancer Research},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
The overall goal of this project is to develop means to locally radio-sensitize the prostate to enable prostate cancer (PCa) cure with the use of lower radiation doses, thereby leading to less rectal toxicity. This new approach for chemoradiation therapy (CRT), termed Biological In-Situ Image Guided Radiation Therapy BIS-IGRT, involves the coating of spacers routinely used during prostate I-125-based brachytherapy with radiosensitizing drugs (e.g. docetaxel DTX for PCa). This approach provides localized in-situ delivery of the sensitizer to the tumor and avoids the toxicity associated with current systemic delivery of radiosensitizers. BIS-IGRT adds radiosensitization capability to the standard brachytherapy procedure and with minimal additional inconvenience to the patient. Current CRT with adjuvant systemic chemotherapy does not provide the sustained delivery and drug concentration needed for efficient radiosensitization. Thereby BIS-IGRT improves the therapeutic ratio of radiation therapy without introducing additional patient interventions over current brachytherapy procedures. We have established the following: 1. We have shown through modeling that drug distributions can be achieved that can lead to increased efficiency of image-guided brachytherapy (drug-coated spacers) or image guided external beam therapy (drug-coated fiducials). 2. Doxorubicine-coated fiducials (Dox/PLGA-PEG/CHIT) show release characteristics over 40 days in aqueous media, which is tailored to the time scales required for BIS-IGRT. The cytotoxicity of Dox/ PLGA-PEG NP is comparable to that of free Dox, so that there is no reduction of activity upon encapsulation in the NP. 3. Localized bolus injection of dye-loaded PLGA-PEG nanoparticles (NPs) distributes within 24 hours throughout the tumor, indicating that the sustained release from coated brachytherapy spacers has the potential to achieve the desired biological dose-painting of the tumor. BIS-IGRT could proffer radiation oncologists and medical physicists with a new treatment option for substantially enhancing therapeutic ratio and boosting cure rate for the hundreds of thousands of Americans diagnosed with prostate cancer each year. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. BIS-IGRT can still be accompanied by IV administration of chemotherapeutics, particularly for micro-metastasis, so that existing therapeutic approaches are not compromised. In addition BIS-IGRT could potentially become a mainstream treatment for patients newly diagnosed with prostate or other cancers, where radiation therapy is a common treatment modality.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1473. doi:1538-7445.AM2012-1473
©2012 American Association for Cancer Research
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1473. doi:1538-7445.AM2012-1473
©2012 American Association for Cancer Research
40.
Kumar, Rajiv; Kulkarni, Apurva; Nagesha, Dattatri K; Sridhar, Srinivas
In vitro evaluation of theranostic polymeric micelles for imaging and drug delivery in cancer Journal Article
In: Theranostics, vol. 2, no. 7, pp. 714, 2012.
Abstract | BibTeX | Tags: Nanomedicine
@article{kumar2012vitro,
title = {In vitro evaluation of theranostic polymeric micelles for imaging and drug delivery in cancer},
author = {Rajiv Kumar and Apurva Kulkarni and Dattatri K Nagesha and Srinivas Sridhar},
year = {2012},
date = {2012-01-01},
journal = {Theranostics},
volume = {2},
number = {7},
pages = {714},
publisher = {Ivyspring International Publisher},
abstract = {We describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.
For the past decade engineered nanoplatforms have seen a momentous progress in developing a multimodal theranostic formulation which can be simultaneously used for imaging and therapy. In this report we describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. CdSe quantum dots (QDs) and anti-cancer drug, doxorubicin (Dox), were co-encapsulated into the hydrophobic core of the micelles. The micelles are characterized using optical spectroscopy for characteristic absorbance and fluorescence features of QDs and Dox. TEM and DLS studies yielded a size of <50 nm for the micellar formulations with very narrow size distribution. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.
Keywords: Theranostic Polymeric Micelles, Imaging, Drug Delivery, Cancer
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
We describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.
For the past decade engineered nanoplatforms have seen a momentous progress in developing a multimodal theranostic formulation which can be simultaneously used for imaging and therapy. In this report we describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. CdSe quantum dots (QDs) and anti-cancer drug, doxorubicin (Dox), were co-encapsulated into the hydrophobic core of the micelles. The micelles are characterized using optical spectroscopy for characteristic absorbance and fluorescence features of QDs and Dox. TEM and DLS studies yielded a size of <50 nm for the micellar formulations with very narrow size distribution. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.
Keywords: Theranostic Polymeric Micelles, Imaging, Drug Delivery, Cancer
For the past decade engineered nanoplatforms have seen a momentous progress in developing a multimodal theranostic formulation which can be simultaneously used for imaging and therapy. In this report we describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. CdSe quantum dots (QDs) and anti-cancer drug, doxorubicin (Dox), were co-encapsulated into the hydrophobic core of the micelles. The micelles are characterized using optical spectroscopy for characteristic absorbance and fluorescence features of QDs and Dox. TEM and DLS studies yielded a size of <50 nm for the micellar formulations with very narrow size distribution. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.
Keywords: Theranostic Polymeric Micelles, Imaging, Drug Delivery, Cancer
39.
Berbeco, Ross I; Korideck, Houari; Ngwa, Wilfred; Kumar, Rajiv; Patel, Janki; Sridhar, Srinivas; Johnson, Sarah; Price, Brendan D; Kimmelman, Alec; Makrigiorgos, Mike G
DNA damage enhancement from gold nanoparticles for clinical MV photon beams Journal Article
In: Radiation research, vol. 178, no. 6, pp. 604–608, 2012.
Abstract | BibTeX | Tags: Nanomedicine
@article{berbeco2012dna,
title = {DNA damage enhancement from gold nanoparticles for clinical MV photon beams},
author = {Ross I Berbeco and Houari Korideck and Wilfred Ngwa and Rajiv Kumar and Janki Patel and Srinivas Sridhar and Sarah Johnson and Brendan D Price and Alec Kimmelman and Mike G Makrigiorgos},
year = {2012},
date = {2012-01-01},
journal = {Radiation research},
volume = {178},
number = {6},
pages = {604--608},
publisher = {The Radiation Research Society},
abstract = {OTHER| NOVEMBER 13 2012
DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams
Ross I. Berbeco; Houari Korideck; Wilfred Ngwa; Rajiv Kumar; Janki Patel; Srinivas Sridhar; Sarah Johnson; Brendan D. Price; Alec Kimmelman; G. Mike Makrigiorgos
Radiat Res (2012) 178 (6): 604–608.
https://doi.org/10.1667/RR3001.1
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In this study, we quantify the relative damage enhancement due to the presence of gold nanoparticles (GNP) in vitro in a clinical 6 MV beam for various delivery parameters and depths. It is expected that depths and delivery modes that produce a larger proportions of low-energy photons will have a larger effect on the cell samples containing GNP. HeLa cells with and without 50 nm GNP were irradiated at depths of 1.5, 5, 10, 15 and 20 cm. Conventional beams with square aperture sizes 5, 10 and 15 cm at isocenter, and flattening filter free (FFF) beams were used. Relative DNA damage enhancement with GNP was evaluated by γ-H2AX staining. Statistically significant increases in DNA damage with GNP, compared to the absence of GNP, were observed for all depths and delivery modes. Relative to the shallowest depth, damage enhancement was observed to increase as a function of increasing depth for all deliveries. For the conventional (open field) delivery, DNA damage enhancement with GNP was seen to increase as a function of field size. For FFF delivery, a substantial increase in enhancement was found relative to the conventional field delivery. The measured relative DNA damage enhancement validates the theoretically predicted trends as a function of depth and delivery mode for clinical MV photon beams. The results of this study open new possibilities for the clinical development of gold nanoparticle-aided radiation therapy.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
OTHER| NOVEMBER 13 2012
DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams
Ross I. Berbeco; Houari Korideck; Wilfred Ngwa; Rajiv Kumar; Janki Patel; Srinivas Sridhar; Sarah Johnson; Brendan D. Price; Alec Kimmelman; G. Mike Makrigiorgos
Radiat Res (2012) 178 (6): 604–608.
https://doi.org/10.1667/RR3001.1
Share Icon
Share
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Tools
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In this study, we quantify the relative damage enhancement due to the presence of gold nanoparticles (GNP) in vitro in a clinical 6 MV beam for various delivery parameters and depths. It is expected that depths and delivery modes that produce a larger proportions of low-energy photons will have a larger effect on the cell samples containing GNP. HeLa cells with and without 50 nm GNP were irradiated at depths of 1.5, 5, 10, 15 and 20 cm. Conventional beams with square aperture sizes 5, 10 and 15 cm at isocenter, and flattening filter free (FFF) beams were used. Relative DNA damage enhancement with GNP was evaluated by γ-H2AX staining. Statistically significant increases in DNA damage with GNP, compared to the absence of GNP, were observed for all depths and delivery modes. Relative to the shallowest depth, damage enhancement was observed to increase as a function of increasing depth for all deliveries. For the conventional (open field) delivery, DNA damage enhancement with GNP was seen to increase as a function of field size. For FFF delivery, a substantial increase in enhancement was found relative to the conventional field delivery. The measured relative DNA damage enhancement validates the theoretically predicted trends as a function of depth and delivery mode for clinical MV photon beams. The results of this study open new possibilities for the clinical development of gold nanoparticle-aided radiation therapy.
DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams
Ross I. Berbeco; Houari Korideck; Wilfred Ngwa; Rajiv Kumar; Janki Patel; Srinivas Sridhar; Sarah Johnson; Brendan D. Price; Alec Kimmelman; G. Mike Makrigiorgos
Radiat Res (2012) 178 (6): 604–608.
https://doi.org/10.1667/RR3001.1
Share Icon
Share
Tools Icon
Tools
Search Site
In this study, we quantify the relative damage enhancement due to the presence of gold nanoparticles (GNP) in vitro in a clinical 6 MV beam for various delivery parameters and depths. It is expected that depths and delivery modes that produce a larger proportions of low-energy photons will have a larger effect on the cell samples containing GNP. HeLa cells with and without 50 nm GNP were irradiated at depths of 1.5, 5, 10, 15 and 20 cm. Conventional beams with square aperture sizes 5, 10 and 15 cm at isocenter, and flattening filter free (FFF) beams were used. Relative DNA damage enhancement with GNP was evaluated by γ-H2AX staining. Statistically significant increases in DNA damage with GNP, compared to the absence of GNP, were observed for all depths and delivery modes. Relative to the shallowest depth, damage enhancement was observed to increase as a function of increasing depth for all deliveries. For the conventional (open field) delivery, DNA damage enhancement with GNP was seen to increase as a function of field size. For FFF delivery, a substantial increase in enhancement was found relative to the conventional field delivery. The measured relative DNA damage enhancement validates the theoretically predicted trends as a function of depth and delivery mode for clinical MV photon beams. The results of this study open new possibilities for the clinical development of gold nanoparticle-aided radiation therapy.
38.
Berbeco, R; Korideck, H; Ngwa, W; Kumar, R; Patel, J; Sridhar, S; Johnson, S; Price, B; Kimmelman, A; Makrigiorgos, M
TU-C-BRB-11: In Vitro Dose Enhancement from Gold Nanoparticles under Different Clinical MV Photon Beam Configurations Journal Article
In: Medical Physics, vol. 39, no. 6Part23, pp. 3900–3901, 2012.
BibTeX | Tags: Nanomedicine
@article{berbeco2012tu,
title = {TU-C-BRB-11: In Vitro Dose Enhancement from Gold Nanoparticles under Different Clinical MV Photon Beam Configurations},
author = {R Berbeco and H Korideck and W Ngwa and R Kumar and J Patel and S Sridhar and S Johnson and B Price and A Kimmelman and M Makrigiorgos},
year = {2012},
date = {2012-01-01},
journal = {Medical Physics},
volume = {39},
number = {6Part23},
pages = {3900--3901},
publisher = {American Association of Physicists in Medicine},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
37.
Ngwa, W; Korideck, H; Kimmelman, A; Kassis, AI; Kumar, R; Sridhar, S; Makrigiorgos, M; Cormack, RA
In vitro dose enhancement from gold nanoparticles during low-dose-rate gamma irradiation with I-125 brachytherapy seeds Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 84, no. 3, pp. S134, 2012.
Abstract | BibTeX | Tags: Nanomedicine
@article{ngwa2012vitro,
title = {In vitro dose enhancement from gold nanoparticles during low-dose-rate gamma irradiation with I-125 brachytherapy seeds},
author = {W Ngwa and H Korideck and A Kimmelman and AI Kassis and R Kumar and S Sridhar and M Makrigiorgos and RA Cormack},
year = {2012},
date = {2012-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {84},
number = {3},
pages = {S134},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Recent studies have predicted substantial dose enhancement to tumors when gold nanoparticles (AuNP) are employed as adjuvants to radiation therapy at kV energies. Because the enhancement results from processes at kV energies, some studies proposed gold nanoparticle-aided brachytherapy as a radiation therapy approach with potential to meet technical and clinical requirements for implementation. To the best of our knowledge, there has been no study providing clear experimental evidence to corroborate the substantial dose enhancement predictions when irradiating with low dose rate gamma photons from brachytherapy sources. This study investigates the in vitro dose enhancement of AuNP during irradiation of cancer cells by I-125 low dose rate brachytherapy sources.
Materials/Methods
HeLa cell cultures were incubated with and without gold nanoparticles (AuNP) in alternate wells of an 8 well-chamber slide; 4 wells on each slide had cell cultures with AuNP while 4 wells contained cell cultures with no AuNP. Two slides were prepared for each experiment: one slide to be irradiated while the other serves as sham-irradiation control. The cells were irradiated with gamma photons from I-125 brachytherapy seeds in a plaque contained in a custom-built irradiation jig. The plaque was designed to achieve a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at 370C at dose rates ranging from 2.1 cGy/hr to 4.5 cGy/hr. The dose rates were varied by varying the height of the cell culture slide above the plaque containing the I-125 seeds. Residual gammaH2AX was measured 24 hours after irradiation and used to compare the dose response of the cells with and without AuNP. In addition, the relative dose enhancement factor (DEF), representing the ratio of the dose to the cells with and without the presence of AuNP, was estimated from the data.
Results
From the dose response behavior, the results show that the biologic effect when irradiating with 0.2 mg/mL concentration of AuNP is up to 2.3 times greater than without AuNP. This major increase in radiation damage to cancer cells incubated with AuNP corresponds to an estimated DEF of over 3.5.
Conclusions
Our findings provide the first experimental evidence of substantial dose enhancement from gold nanoparticles during low dose rate gamma irradiation from brachytherapy sources. These in vitro study results provide impetus for further preclinical and clinical investigations in the development of gold nanoparticle-aided brachytherapy.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose/Objective(s)
Recent studies have predicted substantial dose enhancement to tumors when gold nanoparticles (AuNP) are employed as adjuvants to radiation therapy at kV energies. Because the enhancement results from processes at kV energies, some studies proposed gold nanoparticle-aided brachytherapy as a radiation therapy approach with potential to meet technical and clinical requirements for implementation. To the best of our knowledge, there has been no study providing clear experimental evidence to corroborate the substantial dose enhancement predictions when irradiating with low dose rate gamma photons from brachytherapy sources. This study investigates the in vitro dose enhancement of AuNP during irradiation of cancer cells by I-125 low dose rate brachytherapy sources.
Materials/Methods
HeLa cell cultures were incubated with and without gold nanoparticles (AuNP) in alternate wells of an 8 well-chamber slide; 4 wells on each slide had cell cultures with AuNP while 4 wells contained cell cultures with no AuNP. Two slides were prepared for each experiment: one slide to be irradiated while the other serves as sham-irradiation control. The cells were irradiated with gamma photons from I-125 brachytherapy seeds in a plaque contained in a custom-built irradiation jig. The plaque was designed to achieve a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at 370C at dose rates ranging from 2.1 cGy/hr to 4.5 cGy/hr. The dose rates were varied by varying the height of the cell culture slide above the plaque containing the I-125 seeds. Residual gammaH2AX was measured 24 hours after irradiation and used to compare the dose response of the cells with and without AuNP. In addition, the relative dose enhancement factor (DEF), representing the ratio of the dose to the cells with and without the presence of AuNP, was estimated from the data.
Results
From the dose response behavior, the results show that the biologic effect when irradiating with 0.2 mg/mL concentration of AuNP is up to 2.3 times greater than without AuNP. This major increase in radiation damage to cancer cells incubated with AuNP corresponds to an estimated DEF of over 3.5.
Conclusions
Our findings provide the first experimental evidence of substantial dose enhancement from gold nanoparticles during low dose rate gamma irradiation from brachytherapy sources. These in vitro study results provide impetus for further preclinical and clinical investigations in the development of gold nanoparticle-aided brachytherapy.
Recent studies have predicted substantial dose enhancement to tumors when gold nanoparticles (AuNP) are employed as adjuvants to radiation therapy at kV energies. Because the enhancement results from processes at kV energies, some studies proposed gold nanoparticle-aided brachytherapy as a radiation therapy approach with potential to meet technical and clinical requirements for implementation. To the best of our knowledge, there has been no study providing clear experimental evidence to corroborate the substantial dose enhancement predictions when irradiating with low dose rate gamma photons from brachytherapy sources. This study investigates the in vitro dose enhancement of AuNP during irradiation of cancer cells by I-125 low dose rate brachytherapy sources.
Materials/Methods
HeLa cell cultures were incubated with and without gold nanoparticles (AuNP) in alternate wells of an 8 well-chamber slide; 4 wells on each slide had cell cultures with AuNP while 4 wells contained cell cultures with no AuNP. Two slides were prepared for each experiment: one slide to be irradiated while the other serves as sham-irradiation control. The cells were irradiated with gamma photons from I-125 brachytherapy seeds in a plaque contained in a custom-built irradiation jig. The plaque was designed to achieve a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at 370C at dose rates ranging from 2.1 cGy/hr to 4.5 cGy/hr. The dose rates were varied by varying the height of the cell culture slide above the plaque containing the I-125 seeds. Residual gammaH2AX was measured 24 hours after irradiation and used to compare the dose response of the cells with and without AuNP. In addition, the relative dose enhancement factor (DEF), representing the ratio of the dose to the cells with and without the presence of AuNP, was estimated from the data.
Results
From the dose response behavior, the results show that the biologic effect when irradiating with 0.2 mg/mL concentration of AuNP is up to 2.3 times greater than without AuNP. This major increase in radiation damage to cancer cells incubated with AuNP corresponds to an estimated DEF of over 3.5.
Conclusions
Our findings provide the first experimental evidence of substantial dose enhancement from gold nanoparticles during low dose rate gamma irradiation from brachytherapy sources. These in vitro study results provide impetus for further preclinical and clinical investigations in the development of gold nanoparticle-aided brachytherapy.
36.
Cormack, R; Nguyen, P; D'Amico, AV; Sridhar, S; Makrigiorgos, GM
Locally Drug Enhanced Brachytherapy: A Comparison of 2 Approaches Based on Biologically Effective Dose Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 84, no. 3, pp. S854–S855, 2012.
Abstract | BibTeX | Tags: Nanomedicine
@article{cormack2012locally,
title = {Locally Drug Enhanced Brachytherapy: A Comparison of 2 Approaches Based on Biologically Effective Dose},
author = {R Cormack and P Nguyen and AV D'Amico and S Sridhar and GM Makrigiorgos},
year = {2012},
date = {2012-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {84},
number = {3},
pages = {S854--S855},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Permanent prostate brachytherapy may be enhanced by delivering radiosensitizer to the target during the implant process. Nanoparticles released from a substrate can deliver drug over an extended period of time and can be engineered to adjust their diffusion parameters. Nanoparticle eluting polymers have been proposed to coat radioactive sources or to form brachytherapy spacers as a way of delivering drug to the prostate. This work determines whether it is preferable to deliver radiosensitizer from sources or spacers.
Materials/Methods
The relative effectiveness of spacers or sources as sources of sensitizer was evaluated by comparing biologic effective dose (BED) of the combined effect of radiation and drug distributions within the prostate. Treatment plans of six patients receiving 125I prostate implants were analyzed under an IRB approved protocol. Target contours were extracted as were the locations of radioactive sources and spacers. Radiation dose was calculated according to AAPM TG43 methodology. Drug distributions were calculated from a solution of the diffusion equation, relative to the steady state concentration at the eluter's surface, for a range of diffusion-elimination modulus (φb) values and concentration needed for maximum sensitization (Cs). φb is viewed as a variable because the properties of the nanoparticles can be adjusted to affect diffusion and time of residence. Cs is treated as a variable because the amplitude of the drug distribution depends on the capacity of the implanted object and the time frame of release. BED calculations of the composite effect were done. The calculations were compared to an approach where the location of the spacers was allowed to be adjusted.
Results
The ratio of the BED for the two delivery approaches is presented in the 2D parameter space of φb and Cs. A full sensitization region, corresponding to low values of φb and Cs, shows no difference between approaches. The majority of the remaining parameter space, showed that using spacers to radiosensitize results in a greater BED. Changing the spacer locations from fixed by the treatment plan to adjustable allowed further increase of BED.
Conclusions
Using brachytherapy spacers as a vehicle to deliver radiosensitizing nanoparticles offers a greater potential to increase the effectiveness of prostate brachytherapy by in-situ radiosensitization. Further increase was achieved by treating spacer location as planning parameter. Using implanted non-radioactive devices for local radiosensitization suggests the potential of planned chemical distributions in conjunction with radiation planning to produce an optimal combined result.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose/Objective(s)
Permanent prostate brachytherapy may be enhanced by delivering radiosensitizer to the target during the implant process. Nanoparticles released from a substrate can deliver drug over an extended period of time and can be engineered to adjust their diffusion parameters. Nanoparticle eluting polymers have been proposed to coat radioactive sources or to form brachytherapy spacers as a way of delivering drug to the prostate. This work determines whether it is preferable to deliver radiosensitizer from sources or spacers.
Materials/Methods
The relative effectiveness of spacers or sources as sources of sensitizer was evaluated by comparing biologic effective dose (BED) of the combined effect of radiation and drug distributions within the prostate. Treatment plans of six patients receiving 125I prostate implants were analyzed under an IRB approved protocol. Target contours were extracted as were the locations of radioactive sources and spacers. Radiation dose was calculated according to AAPM TG43 methodology. Drug distributions were calculated from a solution of the diffusion equation, relative to the steady state concentration at the eluter's surface, for a range of diffusion-elimination modulus (φb) values and concentration needed for maximum sensitization (Cs). φb is viewed as a variable because the properties of the nanoparticles can be adjusted to affect diffusion and time of residence. Cs is treated as a variable because the amplitude of the drug distribution depends on the capacity of the implanted object and the time frame of release. BED calculations of the composite effect were done. The calculations were compared to an approach where the location of the spacers was allowed to be adjusted.
Results
The ratio of the BED for the two delivery approaches is presented in the 2D parameter space of φb and Cs. A full sensitization region, corresponding to low values of φb and Cs, shows no difference between approaches. The majority of the remaining parameter space, showed that using spacers to radiosensitize results in a greater BED. Changing the spacer locations from fixed by the treatment plan to adjustable allowed further increase of BED.
Conclusions
Using brachytherapy spacers as a vehicle to deliver radiosensitizing nanoparticles offers a greater potential to increase the effectiveness of prostate brachytherapy by in-situ radiosensitization. Further increase was achieved by treating spacer location as planning parameter. Using implanted non-radioactive devices for local radiosensitization suggests the potential of planned chemical distributions in conjunction with radiation planning to produce an optimal combined result.
Permanent prostate brachytherapy may be enhanced by delivering radiosensitizer to the target during the implant process. Nanoparticles released from a substrate can deliver drug over an extended period of time and can be engineered to adjust their diffusion parameters. Nanoparticle eluting polymers have been proposed to coat radioactive sources or to form brachytherapy spacers as a way of delivering drug to the prostate. This work determines whether it is preferable to deliver radiosensitizer from sources or spacers.
Materials/Methods
The relative effectiveness of spacers or sources as sources of sensitizer was evaluated by comparing biologic effective dose (BED) of the combined effect of radiation and drug distributions within the prostate. Treatment plans of six patients receiving 125I prostate implants were analyzed under an IRB approved protocol. Target contours were extracted as were the locations of radioactive sources and spacers. Radiation dose was calculated according to AAPM TG43 methodology. Drug distributions were calculated from a solution of the diffusion equation, relative to the steady state concentration at the eluter's surface, for a range of diffusion-elimination modulus (φb) values and concentration needed for maximum sensitization (Cs). φb is viewed as a variable because the properties of the nanoparticles can be adjusted to affect diffusion and time of residence. Cs is treated as a variable because the amplitude of the drug distribution depends on the capacity of the implanted object and the time frame of release. BED calculations of the composite effect were done. The calculations were compared to an approach where the location of the spacers was allowed to be adjusted.
Results
The ratio of the BED for the two delivery approaches is presented in the 2D parameter space of φb and Cs. A full sensitization region, corresponding to low values of φb and Cs, shows no difference between approaches. The majority of the remaining parameter space, showed that using spacers to radiosensitize results in a greater BED. Changing the spacer locations from fixed by the treatment plan to adjustable allowed further increase of BED.
Conclusions
Using brachytherapy spacers as a vehicle to deliver radiosensitizing nanoparticles offers a greater potential to increase the effectiveness of prostate brachytherapy by in-situ radiosensitization. Further increase was achieved by treating spacer location as planning parameter. Using implanted non-radioactive devices for local radiosensitization suggests the potential of planned chemical distributions in conjunction with radiation planning to produce an optimal combined result.
2011
35.
D.Plouffea, Brian; K.Nagesha, Dattatri; S.DiPietro, Robert; Sridhar, Srinvas; Heimand, Don; K.Murthya, Shashi; H.Lewisa, Lewis
Thermomagnetic determination of Fe3O4 magnetic nanoparticle diameters for biomedical applications Journal Article
In: Journal of Magnetism and Magnetic Materials, vol. 323, no. 17, pp. 2310-2317, 2011.
Abstract | Links | BibTeX | Tags: featured, Nanomedicine
@article{H.Lewisa2011,
title = {Thermomagnetic determination of Fe3O4 magnetic nanoparticle diameters for biomedical applications},
author = {Brian D.Plouffea and Dattatri K.Nagesha and Robert S.DiPietro and Srinvas Sridhar and Don Heimand and Shashi K.Murthya and Lewis H.Lewisa
},
doi = {S0304885311002423},
year = {2011},
date = {2011-09-01},
journal = {Journal of Magnetism and Magnetic Materials},
volume = {323},
number = {17},
pages = {2310-2317},
abstract = {The utility and promise of magnetic nanoparticles (MagNPs) for biomedicine rely heavily on accurate determination of the particle diameter attributes. While the average functional size and size distribution of the magnetic nanoparticles directly impact the implementation and optimization of nanobiotechnology applications in which they are employed, the determination of these attributes using electron microscopy techniques can be time-consuming and misrepresentative of the full nanoparticle population. In this work the average particle diameter and distribution of an ensemble of Fe3O4 ferrimagnetic nanoparticles are determined solely from temperature-dependent magnetization measurements; the results compare favorably to those obtained from extensive electron microscopy observations. The attributes of a population of biocompatible Fe3O4 nanoparticles synthesized by a thermal decomposition method are obtained from quantitative evaluation of a model that incorporates the distribution of superparamagnetic blocking temperatures represented through thermomagnetization data. The average size and size distributions are determined from magnetization data via temperature-dependent zero-field-cooled magnetization. The current work is unique from existing approaches based on magnetic measurement for the characterization of a nanoparticle ensemble as it provides both the average particle size as well as the particle size distribution.
},
keywords = {featured, Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The utility and promise of magnetic nanoparticles (MagNPs) for biomedicine rely heavily on accurate determination of the particle diameter attributes. While the average functional size and size distribution of the magnetic nanoparticles directly impact the implementation and optimization of nanobiotechnology applications in which they are employed, the determination of these attributes using electron microscopy techniques can be time-consuming and misrepresentative of the full nanoparticle population. In this work the average particle diameter and distribution of an ensemble of Fe3O4 ferrimagnetic nanoparticles are determined solely from temperature-dependent magnetization measurements; the results compare favorably to those obtained from extensive electron microscopy observations. The attributes of a population of biocompatible Fe3O4 nanoparticles synthesized by a thermal decomposition method are obtained from quantitative evaluation of a model that incorporates the distribution of superparamagnetic blocking temperatures represented through thermomagnetization data. The average size and size distributions are determined from magnetization data via temperature-dependent zero-field-cooled magnetization. The current work is unique from existing approaches based on magnetic measurement for the characterization of a nanoparticle ensemble as it provides both the average particle size as well as the particle size distribution.
34.
Makrigiorgos, Robert A. Cormack; Paul L. Nguyen; Anthony V. D'Amico; Sri Sridhar; Mike
Optimal drug release schedule for in-situ radiosensitization of image guided permanent prostate implants Journal Article
In: Proceedings Volume 7964, Medical Imaging 2011: Visualization, Image-Guided Procedures, and Modeling, vol. 7964, no. 2011, 2011.
Abstract | Links | BibTeX | Tags: featured, Nanomedicine
@article{Makrigiorgos2011,
title = {Optimal drug release schedule for in-situ radiosensitization of image guided permanent prostate implants},
author = {Robert A. Cormack; Paul L. Nguyen; Anthony V. D'Amico; Sri Sridhar; Mike Makrigiorgos
},
doi = {10.1117/12.878139},
year = {2011},
date = {2011-03-03},
journal = {Proceedings Volume 7964, Medical Imaging 2011: Visualization, Image-Guided Procedures, and Modeling},
volume = {7964},
number = {2011},
abstract = {Planned in-situ radiosensitization may improve the therapeutic ratio of image guided 125I prostate brachytherapy. Spacers used in permanent implants may be manufactured from a radiosensitizer-releasing polymer to deliver protracted localized sensitization of the prostate. Such devices will have a limited drug-loading capacity, and the drug release schedule that optimizes outcome, under such a constraint, is not known. This work determines the optimal elution schedules for 125I prostate brachytherapy. The interaction between brachytherapy dose distributions and drug distribution around drug eluting spacers is modeled using a linear-quadratic (LQ) model of cell kill. Clinical brachytherapy plans were used to calculate the biologic effective dose (BED) for planned radiation dose distributions while adding the spatial distributions of radiosensitizer while varying the temporal release schedule subject to a constraint on the drug capacity of the eluting spacers. Results: The greatest increase in BED is achieved by schedules with the greatest sensitization early in the implant. Making brachytherapy spacers from radiosensitizer eluting polymer transforms inert parts of the implant process into a means of enhancing the effect of the brachytherapy radiation. Such an approach may increase the therapeutic ratio of prostate brachytherapy or offer a means of locally boosting the radiation effect without increasing the radiation dose to surrounding tissues.
},
keywords = {featured, Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Planned in-situ radiosensitization may improve the therapeutic ratio of image guided 125I prostate brachytherapy. Spacers used in permanent implants may be manufactured from a radiosensitizer-releasing polymer to deliver protracted localized sensitization of the prostate. Such devices will have a limited drug-loading capacity, and the drug release schedule that optimizes outcome, under such a constraint, is not known. This work determines the optimal elution schedules for 125I prostate brachytherapy. The interaction between brachytherapy dose distributions and drug distribution around drug eluting spacers is modeled using a linear-quadratic (LQ) model of cell kill. Clinical brachytherapy plans were used to calculate the biologic effective dose (BED) for planned radiation dose distributions while adding the spatial distributions of radiosensitizer while varying the temporal release schedule subject to a constraint on the drug capacity of the eluting spacers. Results: The greatest increase in BED is achieved by schedules with the greatest sensitization early in the implant. Making brachytherapy spacers from radiosensitizer eluting polymer transforms inert parts of the implant process into a means of enhancing the effect of the brachytherapy radiation. Such an approach may increase the therapeutic ratio of prostate brachytherapy or offer a means of locally boosting the radiation effect without increasing the radiation dose to surrounding tissues.
33.
Alvarado-Velez, Melissa; Rivera-Chacon, Delva M; Acevedo-Morantes, Claudia Y; Menon, Latika; Nagesha, Dattatri; Gultepe, Evin; Sridhar, Srinivas; Ramirez-Vick, Jaime E; Singh, Surinder P
Effects of fibronectin and vitronectin on human fetal osteoblast cell attachment and proliferation on nanostructured titania surfaces Proceedings Article
In: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA 2011.
BibTeX | Tags: Nanomedicine
@inproceedings{alvarado2011effects,
title = {Effects of fibronectin and vitronectin on human fetal osteoblast cell attachment and proliferation on nanostructured titania surfaces},
author = {Melissa Alvarado-Velez and Delva M Rivera-Chacon and Claudia Y Acevedo-Morantes and Latika Menon and Dattatri Nagesha and Evin Gultepe and Srinivas Sridhar and Jaime E Ramirez-Vick and Surinder P Singh},
year = {2011},
date = {2011-01-01},
booktitle = {ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY},
volume = {241},
organization = {AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
32.
Sridhar, Srinivas; Nagesha, Dattatri; Tada, Dayane; Kumar, Rajiv; Makrigiorgos, Mike G; Cormack, Robert
Radio-sensitizer eluting nanoporous coatings on fiducials markers: Biological in-situ dose-painting for IGRT Miscellaneous
2011.
Abstract | BibTeX | Tags: Nanomedicine
@misc{sridhar2011radio,
title = {Radio-sensitizer eluting nanoporous coatings on fiducials markers: Biological in-situ dose-painting for IGRT},
author = {Srinivas Sridhar and Dattatri Nagesha and Dayane Tada and Rajiv Kumar and Mike G Makrigiorgos and Robert Cormack},
year = {2011},
date = {2011-01-01},
publisher = {American Association for Cancer Research},
abstract = {Image-guided radiation treatments routinely utilize implantable devices, such as radio-opaque fiducials or brachytherapy spacers, for improved spatial accuracy. We study the hypothesis that the therapeutic efficiency of IGRT can be further enhanced by biological in-situ dose painting (BIS-IGRT) using local delivery of radiosensitizers embedded within nanoparticles and nanoporous polymer matrices coating gold fiducial markers. Biocompatible polymers loaded with model molecules were coated as a thin film on gold fiducials. The nanoporous morphology of the polymer coatings allowed the controlled release of the molecules and nanoparticles. Two experimental approaches were studied: (i) a free drug release system Doxorubicin, a hydrophilic drug in Poly(methyl methacrylate (PMMA) coating and (ii) Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles loaded with Coumarin-6, a model for a fluorescent hydrophobic drug, in a chitosan matrix applied as fiducial coating. Temporal release kinetics measurements in buffer were carried out using fluorescence spectroscopy. For flat gold films and gold fiducials coated with Doxorubicin in PMMA matrix, an initial release of Dox within the first few hours was followed by a sustained release over the course of next 3 months. Release of Dox from within PMMA matrix is dependent on the concentration of Dox, ratio of PMMA/Dox, thickness of PMMA/Dox coating on gold surface. The release profile of coumarin-6 loaded nanoparticles from chitosan film on gold fiducials showed a continuous release of NPs from the coating during forty days. (63±10)% of NPs were released in twenty days. After that, the release became slower and additional 37% of release was observed after twenty-days. Spatial release profiles in an agarose phantom were also measured and compared with release kinetics models. Results show that dosage and rate of release of these radiosensitizers can be precisely tailored to achieve the desired release profile for BIS-IGRT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2674. doi:10.1158/1538-7445.AM2011-2674
©2011 American Association for Cancer Research},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Image-guided radiation treatments routinely utilize implantable devices, such as radio-opaque fiducials or brachytherapy spacers, for improved spatial accuracy. We study the hypothesis that the therapeutic efficiency of IGRT can be further enhanced by biological in-situ dose painting (BIS-IGRT) using local delivery of radiosensitizers embedded within nanoparticles and nanoporous polymer matrices coating gold fiducial markers. Biocompatible polymers loaded with model molecules were coated as a thin film on gold fiducials. The nanoporous morphology of the polymer coatings allowed the controlled release of the molecules and nanoparticles. Two experimental approaches were studied: (i) a free drug release system Doxorubicin, a hydrophilic drug in Poly(methyl methacrylate (PMMA) coating and (ii) Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles loaded with Coumarin-6, a model for a fluorescent hydrophobic drug, in a chitosan matrix applied as fiducial coating. Temporal release kinetics measurements in buffer were carried out using fluorescence spectroscopy. For flat gold films and gold fiducials coated with Doxorubicin in PMMA matrix, an initial release of Dox within the first few hours was followed by a sustained release over the course of next 3 months. Release of Dox from within PMMA matrix is dependent on the concentration of Dox, ratio of PMMA/Dox, thickness of PMMA/Dox coating on gold surface. The release profile of coumarin-6 loaded nanoparticles from chitosan film on gold fiducials showed a continuous release of NPs from the coating during forty days. (63±10)% of NPs were released in twenty days. After that, the release became slower and additional 37% of release was observed after twenty-days. Spatial release profiles in an agarose phantom were also measured and compared with release kinetics models. Results show that dosage and rate of release of these radiosensitizers can be precisely tailored to achieve the desired release profile for BIS-IGRT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2674. doi:10.1158/1538-7445.AM2011-2674
©2011 American Association for Cancer Research
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2674. doi:10.1158/1538-7445.AM2011-2674
©2011 American Association for Cancer Research
2010
31.
Gultepe, Evin; Nagesha, Dattatri; Sridhar, Srinivas; Amiji, Mansoor
Nanoporous inorganic membranes or coatings for sustained drug delivery in implantable devices Journal Article
In: Advanced drug delivery reviews, vol. 62, no. 3, pp. 305–315, 2010.
Abstract | BibTeX | Tags: Nanomedicine
@article{gultepe2010nanoporous,
title = {Nanoporous inorganic membranes or coatings for sustained drug delivery in implantable devices},
author = {Evin Gultepe and Dattatri Nagesha and Srinivas Sridhar and Mansoor Amiji},
year = {2010},
date = {2010-01-01},
journal = {Advanced drug delivery reviews},
volume = {62},
number = {3},
pages = {305--315},
publisher = {Elsevier},
abstract = {The characteristics of nanoporous inorganic coatings on implants or on implantable devices are reviewed. The commonly used nanoporous materials, such as aluminum oxide (Al2O3), titanium oxide (TiO2) and porous silicon are highlighted with illustrative examples. The critical issues for sustained release systems are examined and the elution pro?les of nanoporous coatings are discussed. The available data shows that these systems can be used effectively for sustained release applications. They satisfy the basic biocompatibility tests, meet the requirements of drug loading and sustained release pro?les extending to several weeks and also are compatible with current implant technologies. Nanoporous inorganic coatings are well suited to provide improved ef?cacy and integration of implants in a variety of therapeutic situations.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The characteristics of nanoporous inorganic coatings on implants or on implantable devices are reviewed. The commonly used nanoporous materials, such as aluminum oxide (Al2O3), titanium oxide (TiO2) and porous silicon are highlighted with illustrative examples. The critical issues for sustained release systems are examined and the elution pro?les of nanoporous coatings are discussed. The available data shows that these systems can be used effectively for sustained release applications. They satisfy the basic biocompatibility tests, meet the requirements of drug loading and sustained release pro?les extending to several weeks and also are compatible with current implant technologies. Nanoporous inorganic coatings are well suited to provide improved ef?cacy and integration of implants in a variety of therapeutic situations.
30.
Stambaugh, C; Tada, D; Nagesha, D; Jost, E; Levy, C; Cormack, RA; Makrigiorgos, M; Sridhar, S
WE-E-204B-02: Release Kinetics of Radio-Sensitizers from Nanoporous Coatings on Gold Fiducials: Biological In-Situ Dose-Painting for IGRT Journal Article
In: Medical Physics, vol. 37, no. 6Part13, pp. 3437–3438, 2010.
BibTeX | Tags: Nanomedicine
@article{stambaugh2010we,
title = {WE-E-204B-02: Release Kinetics of Radio-Sensitizers from Nanoporous Coatings on Gold Fiducials: Biological In-Situ Dose-Painting for IGRT},
author = {C Stambaugh and D Tada and D Nagesha and E Jost and C Levy and RA Cormack and M Makrigiorgos and S Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Medical Physics},
volume = {37},
number = {6Part13},
pages = {3437--3438},
publisher = {American Association of Physicists in Medicine},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
29.
Cormack, Robert A; Nagesha, Dattatri; Gultepe, Evin; Nguyen, Paul; D'Amico, Anthony V; Sridhar, Srinivas; Makrigiorgos, Mike
Drug Eluting Brachytherapy Spacers: A Potential for Biologically-Enhanced Brachytherapy Journal Article
In: Brachytherapy, vol. 9, pp. S48–S49, 2010.
Abstract | BibTeX | Tags: Nanomedicine
@article{cormack2010drug,
title = {Drug Eluting Brachytherapy Spacers: A Potential for Biologically-Enhanced Brachytherapy},
author = {Robert A Cormack and Dattatri Nagesha and Evin Gultepe and Paul Nguyen and Anthony V D'Amico and Srinivas Sridhar and Mike Makrigiorgos},
year = {2010},
date = {2010-01-01},
journal = {Brachytherapy},
volume = {9},
pages = {S48--S49},
publisher = {Elsevier},
abstract = {Purpose: Ultrasound-guided prostate brachytherapy routinely implants spacers between the 125I radiation sources, that provide no therapeutic benefit although they are essential to the technical completion of the implant. The spacers offer a vehicle for in-situ delivery of radio-sensitizer, or other agents, which could increase the biologic effective dose of the radiation. This work studies the achievable drug coverage as a function of the chemical and physical properties of the drugs and devices.
Materials and Methods: Fluorescent doxorubicin in a polymer suspension and gold substrate were used to evaluate the ability to create a radio-opaque drug eluter. Elution kinetics from polymer coating of gold substrate was measured via fluorescence spectrometry. An analytic solution to the diffusion elimination equation was used to perform computer modeling of drug distributions produced by configurations of eluters placed within ultrasound guided prostate implants. Measures of tumor coverage and normal tissue involvement are evaluated for multiple combinations of eluter sizes and diffusion elimination moduli φb.
Results: Timed-release of doxorubicin from a polymer coating on a gold substrate, as shown in the top half of the figure, is technically possible. The many spacers used in prostate brachytherapy are sufficient to sensitize a portion of the prostate with values of φb close to the calculated ones. The use of drug-eluting brachytherapy spacers would enable a more localized enhancement in biologic effective dose than what can be delivered by a local brachytherapy boost. The bottom half of the figure shows a prostate implant at treated at our institution and and how it could be locally enhanced with the addition of a small number of drug eluting spacers.
Conclusions: IGRT techniques, such as ultrasound-guided brachytherapy, already implant devices within tumors as part of the standard of care. These devices may be enhanced with drug-eluting coatings to provide an in-situ increase in biologic effective dose without increasing the physical dose involved in the therapy. Generalization of this biologically in-situ enhanced IGRT (BIS-IGRT) to other agents in combination with advances in biologic imaging may provide an opportunity for personalized biologically in-situ enhanced brachytherapy.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose: Ultrasound-guided prostate brachytherapy routinely implants spacers between the 125I radiation sources, that provide no therapeutic benefit although they are essential to the technical completion of the implant. The spacers offer a vehicle for in-situ delivery of radio-sensitizer, or other agents, which could increase the biologic effective dose of the radiation. This work studies the achievable drug coverage as a function of the chemical and physical properties of the drugs and devices.
Materials and Methods: Fluorescent doxorubicin in a polymer suspension and gold substrate were used to evaluate the ability to create a radio-opaque drug eluter. Elution kinetics from polymer coating of gold substrate was measured via fluorescence spectrometry. An analytic solution to the diffusion elimination equation was used to perform computer modeling of drug distributions produced by configurations of eluters placed within ultrasound guided prostate implants. Measures of tumor coverage and normal tissue involvement are evaluated for multiple combinations of eluter sizes and diffusion elimination moduli φb.
Results: Timed-release of doxorubicin from a polymer coating on a gold substrate, as shown in the top half of the figure, is technically possible. The many spacers used in prostate brachytherapy are sufficient to sensitize a portion of the prostate with values of φb close to the calculated ones. The use of drug-eluting brachytherapy spacers would enable a more localized enhancement in biologic effective dose than what can be delivered by a local brachytherapy boost. The bottom half of the figure shows a prostate implant at treated at our institution and and how it could be locally enhanced with the addition of a small number of drug eluting spacers.
Conclusions: IGRT techniques, such as ultrasound-guided brachytherapy, already implant devices within tumors as part of the standard of care. These devices may be enhanced with drug-eluting coatings to provide an in-situ increase in biologic effective dose without increasing the physical dose involved in the therapy. Generalization of this biologically in-situ enhanced IGRT (BIS-IGRT) to other agents in combination with advances in biologic imaging may provide an opportunity for personalized biologically in-situ enhanced brachytherapy.
Materials and Methods: Fluorescent doxorubicin in a polymer suspension and gold substrate were used to evaluate the ability to create a radio-opaque drug eluter. Elution kinetics from polymer coating of gold substrate was measured via fluorescence spectrometry. An analytic solution to the diffusion elimination equation was used to perform computer modeling of drug distributions produced by configurations of eluters placed within ultrasound guided prostate implants. Measures of tumor coverage and normal tissue involvement are evaluated for multiple combinations of eluter sizes and diffusion elimination moduli φb.
Results: Timed-release of doxorubicin from a polymer coating on a gold substrate, as shown in the top half of the figure, is technically possible. The many spacers used in prostate brachytherapy are sufficient to sensitize a portion of the prostate with values of φb close to the calculated ones. The use of drug-eluting brachytherapy spacers would enable a more localized enhancement in biologic effective dose than what can be delivered by a local brachytherapy boost. The bottom half of the figure shows a prostate implant at treated at our institution and and how it could be locally enhanced with the addition of a small number of drug eluting spacers.
Conclusions: IGRT techniques, such as ultrasound-guided brachytherapy, already implant devices within tumors as part of the standard of care. These devices may be enhanced with drug-eluting coatings to provide an in-situ increase in biologic effective dose without increasing the physical dose involved in the therapy. Generalization of this biologically in-situ enhanced IGRT (BIS-IGRT) to other agents in combination with advances in biologic imaging may provide an opportunity for personalized biologically in-situ enhanced brachytherapy.
