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2015
382.
Kumar, Rajiv; Belz, Jodi; Markovic, Stacey; Jadhav, Tej; Fowle, William; Niedre, Mark; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas
Nanoparticle-based brachytherapy spacers for delivery of localized combined chemoradiation therapy Journal Article
In: International Journal of Radiation Oncology* Biology* Physics, vol. 91, no. 2, pp. 393–400, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{kumar2015nanoparticle,
title = {Nanoparticle-based brachytherapy spacers for delivery of localized combined chemoradiation therapy},
author = {Rajiv Kumar and Jodi Belz and Stacey Markovic and Tej Jadhav and William Fowle and Mark Niedre and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {International Journal of Radiation Oncology* Biology* Physics},
volume = {91},
number = {2},
pages = {393--400},
publisher = {Elsevier},
abstract = {Purpose
In radiation therapy (RT), brachytherapy-inert source spacers are commonly used in clinical practice to achieve high spatial accuracy. These implanted devices are critical technical components of precise radiation delivery but provide no direct therapeutic benefits.
Methods and Materials
Here we have fabricated implantable nanoplatforms or chemoradiation therapy (INCeRT) spacers loaded with silica nanoparticles (SNPs) conjugated containing a drug, to act as a slow-release drug depot for simultaneous localized chemoradiation therapy. The spacers are made of poly(lactic-co-glycolic) acid (PLGA) as matrix and are physically identical in size to the commercially available brachytherapy spacers (5 mm × 0.8 mm). The silica nanoparticles, 250 nm in diameter, were conjugated with near infrared fluorophore Cy7.5 as a model drug, and the INCeRT spacers were characterized in terms of size, morphology, and composition using different instrumentation techniques. The spacers were further doped with an anticancer drug, docetaxel. We evaluated the in vivo stability, biocompatibility, and biodegradation of these spacers in live mouse tissues.
Results
The electron microscopy studies showed that nanoparticles were distributed throughout the spacers. These INCeRT spacers remained stable and can be tracked by the use of optical fluorescence. In vivo optical imaging studies showed a slow diffusion of nanoparticles from the spacer to the adjacent tissue in contrast to the control Cy7.5-PLGA spacer, which showed rapid disintegration in a few days with a burst release of Cy7.5. The docetaxel spacers showed suppression of tumor growth in contrast to control mice over 16 days.
Conclusions
The imaging with the Cy7.5 spacer and therapeutic efficacy with docetaxel spacers supports the hypothesis that INCeRT spacers can be used for delivering the drugs in a slow, sustained manner in conjunction with brachytherapy, in contrast to the rapid clearance of the drugs when administered systemically. The results demonstrate that these spacers with tailored release profiles have potential in improving the combined therapeutic efficacy of chemoradiation therapy.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose
In radiation therapy (RT), brachytherapy-inert source spacers are commonly used in clinical practice to achieve high spatial accuracy. These implanted devices are critical technical components of precise radiation delivery but provide no direct therapeutic benefits.
Methods and Materials
Here we have fabricated implantable nanoplatforms or chemoradiation therapy (INCeRT) spacers loaded with silica nanoparticles (SNPs) conjugated containing a drug, to act as a slow-release drug depot for simultaneous localized chemoradiation therapy. The spacers are made of poly(lactic-co-glycolic) acid (PLGA) as matrix and are physically identical in size to the commercially available brachytherapy spacers (5 mm × 0.8 mm). The silica nanoparticles, 250 nm in diameter, were conjugated with near infrared fluorophore Cy7.5 as a model drug, and the INCeRT spacers were characterized in terms of size, morphology, and composition using different instrumentation techniques. The spacers were further doped with an anticancer drug, docetaxel. We evaluated the in vivo stability, biocompatibility, and biodegradation of these spacers in live mouse tissues.
Results
The electron microscopy studies showed that nanoparticles were distributed throughout the spacers. These INCeRT spacers remained stable and can be tracked by the use of optical fluorescence. In vivo optical imaging studies showed a slow diffusion of nanoparticles from the spacer to the adjacent tissue in contrast to the control Cy7.5-PLGA spacer, which showed rapid disintegration in a few days with a burst release of Cy7.5. The docetaxel spacers showed suppression of tumor growth in contrast to control mice over 16 days.
Conclusions
The imaging with the Cy7.5 spacer and therapeutic efficacy with docetaxel spacers supports the hypothesis that INCeRT spacers can be used for delivering the drugs in a slow, sustained manner in conjunction with brachytherapy, in contrast to the rapid clearance of the drugs when administered systemically. The results demonstrate that these spacers with tailored release profiles have potential in improving the combined therapeutic efficacy of chemoradiation therapy.
In radiation therapy (RT), brachytherapy-inert source spacers are commonly used in clinical practice to achieve high spatial accuracy. These implanted devices are critical technical components of precise radiation delivery but provide no direct therapeutic benefits.
Methods and Materials
Here we have fabricated implantable nanoplatforms or chemoradiation therapy (INCeRT) spacers loaded with silica nanoparticles (SNPs) conjugated containing a drug, to act as a slow-release drug depot for simultaneous localized chemoradiation therapy. The spacers are made of poly(lactic-co-glycolic) acid (PLGA) as matrix and are physically identical in size to the commercially available brachytherapy spacers (5 mm × 0.8 mm). The silica nanoparticles, 250 nm in diameter, were conjugated with near infrared fluorophore Cy7.5 as a model drug, and the INCeRT spacers were characterized in terms of size, morphology, and composition using different instrumentation techniques. The spacers were further doped with an anticancer drug, docetaxel. We evaluated the in vivo stability, biocompatibility, and biodegradation of these spacers in live mouse tissues.
Results
The electron microscopy studies showed that nanoparticles were distributed throughout the spacers. These INCeRT spacers remained stable and can be tracked by the use of optical fluorescence. In vivo optical imaging studies showed a slow diffusion of nanoparticles from the spacer to the adjacent tissue in contrast to the control Cy7.5-PLGA spacer, which showed rapid disintegration in a few days with a burst release of Cy7.5. The docetaxel spacers showed suppression of tumor growth in contrast to control mice over 16 days.
Conclusions
The imaging with the Cy7.5 spacer and therapeutic efficacy with docetaxel spacers supports the hypothesis that INCeRT spacers can be used for delivering the drugs in a slow, sustained manner in conjunction with brachytherapy, in contrast to the rapid clearance of the drugs when administered systemically. The results demonstrate that these spacers with tailored release profiles have potential in improving the combined therapeutic efficacy of chemoradiation therapy.
381.
Tangutoori, Shifalika; Baldwin, Paige; Sridhar, Srinivas
PARP inhibitors: A new era of targeted therapy Journal Article
In: Maturitas, vol. 81, no. 1, pp. 5–9, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{tangutoori2015parp,
title = {PARP inhibitors: A new era of targeted therapy},
author = {Shifalika Tangutoori and Paige Baldwin and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {Maturitas},
volume = {81},
number = {1},
pages = {5--9},
publisher = {Elsevier},
abstract = {Personalized medicine seeks to utilize targeted therapies with increased selectivity and efficacy in preselected patient cohorts. One such molecularly targeted therapy is enabled by inhibiting the enzyme poly(ADP-ribose) polymerase (PARP) by small molecule inhibitors in tumors which have a defect in the homologous DNA recombination pathway, most characteristically due to BRCA mutations. Olaparib, a highly potent PARP inhibitor, has recently been the approved for ovarian cancer therapy by the FDA and European commission in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with BRCA1 or BRCA2 mutations. Currently, clinical trials with several PARP inhibitors are being conducted to assess the toxicities, the efficacies and the benefit of the drugs as monotherapies or combined with radiation or other chemotherapeutic agents, in ovarian, breast, prostate, rectal, lung, pancreatic, peritoneal, head and neck, brain, squamous cell carcinomas and sarcomas, to list a few. In this review, our focus is to outline the emerging molecular mechanisms, preclinical evidence and clinical applications of PARP inhibitors especially in nonBRCA cancers, and review the combination strategies compatible with PARP inhibitor therapy.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Personalized medicine seeks to utilize targeted therapies with increased selectivity and efficacy in preselected patient cohorts. One such molecularly targeted therapy is enabled by inhibiting the enzyme poly(ADP-ribose) polymerase (PARP) by small molecule inhibitors in tumors which have a defect in the homologous DNA recombination pathway, most characteristically due to BRCA mutations. Olaparib, a highly potent PARP inhibitor, has recently been the approved for ovarian cancer therapy by the FDA and European commission in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with BRCA1 or BRCA2 mutations. Currently, clinical trials with several PARP inhibitors are being conducted to assess the toxicities, the efficacies and the benefit of the drugs as monotherapies or combined with radiation or other chemotherapeutic agents, in ovarian, breast, prostate, rectal, lung, pancreatic, peritoneal, head and neck, brain, squamous cell carcinomas and sarcomas, to list a few. In this review, our focus is to outline the emerging molecular mechanisms, preclinical evidence and clinical applications of PARP inhibitors especially in nonBRCA cancers, and review the combination strategies compatible with PARP inhibitor therapy.
380.
Cheng, Ming; Homayoni, Homa; Kumar, Rajiv; Sridhar, Srinivas; Webster, Thomas; Ebong, Eno
Endothelial Glycocalyx Health Plays Critical Role in Nanoparticle Uptake Journal Article
In: The FASEB Journal, vol. 29, no. 1_supplement, pp. LB168, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{cheng2015endothelial,
title = {Endothelial Glycocalyx Health Plays Critical Role in Nanoparticle Uptake},
author = {Ming Cheng and Homa Homayoni and Rajiv Kumar and Srinivas Sridhar and Thomas Webster and Eno Ebong},
year = {2015},
date = {2015-01-01},
journal = {The FASEB Journal},
volume = {29},
number = {1_supplement},
pages = {LB168},
publisher = {The Federation of American Societies for Experimental Biology},
abstract = {The endothelial cells in the blood vessels are lined with a meshwork of polysaccharides called the glycocalyx (GCX). There is evidence this protective layer is dysfunctional in patients suffering from various diseases including diabetes, atherosclerosis, and metastatic cancer. GCX dysfunction may impair or amplify the effect of drugs delivered to treat disease, and particularly drugs delivered using nanoparticle vehicles that are becoming very popular. However, there is currently no in vitro process of screening nanoparticle-based drug delivery that tests the role of GCX health in delivery of the nanoparticles or drug itself. To address this issue, we are using ultra-small PEGylated gold nanoparticles (NP) to visualize the effects of GCX on nanoparticle uptake by rat fat pad endothelial cells. We are examining the effect of intact GCX. In addition, two types of GCX dysfunction are modeled: degradation due to the addition of heparinase III enzyme that degrades the heparan sulfate component of the glycocalyx, and collapse due to culturing the cells in low serum media. In another model, we induce GCX regeneration through addition of heparan sulfate after heparinase III treatment. The cells are then incubated with nanoparticles overnight, fixed and stained, then imaged through confocal microscopy. Both cell cultures with damaged GCX showed significantly higher NP uptake compared to the cultures with intact or regenerated GCX. This work indicates that the GCX integrity and composition does influence NP uptake for the endothelial cells.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The endothelial cells in the blood vessels are lined with a meshwork of polysaccharides called the glycocalyx (GCX). There is evidence this protective layer is dysfunctional in patients suffering from various diseases including diabetes, atherosclerosis, and metastatic cancer. GCX dysfunction may impair or amplify the effect of drugs delivered to treat disease, and particularly drugs delivered using nanoparticle vehicles that are becoming very popular. However, there is currently no in vitro process of screening nanoparticle-based drug delivery that tests the role of GCX health in delivery of the nanoparticles or drug itself. To address this issue, we are using ultra-small PEGylated gold nanoparticles (NP) to visualize the effects of GCX on nanoparticle uptake by rat fat pad endothelial cells. We are examining the effect of intact GCX. In addition, two types of GCX dysfunction are modeled: degradation due to the addition of heparinase III enzyme that degrades the heparan sulfate component of the glycocalyx, and collapse due to culturing the cells in low serum media. In another model, we induce GCX regeneration through addition of heparan sulfate after heparinase III treatment. The cells are then incubated with nanoparticles overnight, fixed and stained, then imaged through confocal microscopy. Both cell cultures with damaged GCX showed significantly higher NP uptake compared to the cultures with intact or regenerated GCX. This work indicates that the GCX integrity and composition does influence NP uptake for the endothelial cells.
379.
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}
}
378.
Adedoyin, AA; Kumar, R; Sridhar, S; Ekenseair, AK
Injectable bionanocomposite hybrid scaffolds with responsive control for enhanced osteochondral tissue regeneration Proceedings Article
In: 2015 41st Annual Northeast Biomedical Engineering Conference (NEBEC), pp. 1–2, IEEE 2015.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{adedoyin2015injectable,
title = {Injectable bionanocomposite hybrid scaffolds with responsive control for enhanced osteochondral tissue regeneration},
author = {AA Adedoyin and R Kumar and S Sridhar and AK Ekenseair},
year = {2015},
date = {2015-01-01},
booktitle = {2015 41st Annual Northeast Biomedical Engineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Restoration of articular hyaline cartilage within osteochondral tissue defects has been a principal target in the field of tissue engineering due to poor functional regeneration of this avascular and heterogeneous tissue following current treatment options. The major focus thus far has been in constructing implantable scaffolds, which can be readily designed to offer appropriate mechanical properties. However, the use of implantable scaffolds requires open surgery and often cannot be readily applied to defects of irregular shape. Thus, it has become of high interest to develop minimally invasive and degradable hydrogel-based materials capable of delivering and maintaining encapsulated cells in a non-toxic manner and encouraging functional tissue regeneration. This paper reports on the synthesis and characterization of a novel class of injectable, thermally and chemically dual-gelling bionanocomposite hydrogels from thermogelling macromers (TGMs) based on poly(N-isopropylacrylamide) (pNiPAAm), degradable polyamidoamine (PAMAMs) crosslinking macromers, and functional hybrid inorganic iron oxide (Fe 3 O 4 ) nanoparticles capable of responding to an external magnetic field to stimulate cell activity and control the regenerative process in situ in a spatiotemporal manner.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
Restoration of articular hyaline cartilage within osteochondral tissue defects has been a principal target in the field of tissue engineering due to poor functional regeneration of this avascular and heterogeneous tissue following current treatment options. The major focus thus far has been in constructing implantable scaffolds, which can be readily designed to offer appropriate mechanical properties. However, the use of implantable scaffolds requires open surgery and often cannot be readily applied to defects of irregular shape. Thus, it has become of high interest to develop minimally invasive and degradable hydrogel-based materials capable of delivering and maintaining encapsulated cells in a non-toxic manner and encouraging functional tissue regeneration. This paper reports on the synthesis and characterization of a novel class of injectable, thermally and chemically dual-gelling bionanocomposite hydrogels from thermogelling macromers (TGMs) based on poly(N-isopropylacrylamide) (pNiPAAm), degradable polyamidoamine (PAMAMs) crosslinking macromers, and functional hybrid inorganic iron oxide (Fe 3 O 4 ) nanoparticles capable of responding to an external magnetic field to stimulate cell activity and control the regenerative process in situ in a spatiotemporal manner.
377.
Ozturk, Birol; de-Luna-Bugallo, Andres; Panaitescu, Eugen; Chiaramonti, Ann N; Liu, Fangze; Vargas, Anthony; Jiang, Xueping; Kharche, Neerav; Yavuzcetin, Ozgur; Alnaji, Majed; others,
Atomically thin layers of B--N--C--O with tunable composition Journal Article
In: Science advances, vol. 1, no. 6, pp. e1500094, 2015.
BibTeX | Tags: Metamaterials and Nanophotonics, Nanomaterials
@article{ozturk2015atomically,
title = {Atomically thin layers of B--N--C--O with tunable composition},
author = {Birol Ozturk and Andres de-Luna-Bugallo and Eugen Panaitescu and Ann N Chiaramonti and Fangze Liu and Anthony Vargas and Xueping Jiang and Neerav Kharche and Ozgur Yavuzcetin and Majed Alnaji and others},
year = {2015},
date = {2015-01-01},
urldate = {2015-01-01},
journal = {Science advances},
volume = {1},
number = {6},
pages = {e1500094},
publisher = {American Association for the Advancement of Science},
keywords = {Metamaterials and Nanophotonics, Nanomaterials},
pubstate = {published},
tppubtype = {article}
}
376.
Kumar, Rajiv; Belz, Jodi; Korideck, Houari; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{kumar2015local,
title = {Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models},
author = {Rajiv Kumar and Jodi Belz and Houari Korideck and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Systemic chemotherapy which is often used in combination with radiation therapy in the treatment of prostate cancer, often leads to severe systemic toxicities. Localized chemotherapy has the potential of delivering a high and effective dose directly to the tumor while minimizing adverse toxicities to healthy tissue. An efficient local delivery system should be able to deliver the therapeutic drug at the diseased site in a slow and sustained manner with minimal systemic toxicity. We have fabricated an Implantable Nanoplatform for Chemo-Radiation Therapy (INCeRT) spacer that can deliver planned, localized, and sustained delivery of a chemotherapeutic and imaging agent. Delivery of this new chemotherapy modality can leverage technology used in a routine clinical brachytherapy procedure that uses image guidance to insert radioactive seeds into the prostate using thin needles. The current procedure uses inert plastic spacers with no therapeutic impact to guide the spatial delivery of the radioactive seeds.
This work presents the fabrication, characterization, and therapeutic benefit of a docetaxel loaded spacer in the treatment of prostate-tumored mice. First, INCeRT spacers were fabricated and characterized using optical imaging to track free dye and multi-sized fluorescent silica nanoparticles from spacers in vivo to optimize the temporal and spatial properties of diffusion distribution from a degrading biocompatible polymer matrix. In vivo optical imaging of spacers doped with free dye demonstrates a spatial and temporal release profile appropriate for sustained localized exposure of a chemotherapeutic during the course of brachytherapy. The optimized spacer were loaded with chemotherapeutics and inserted intratumorally for efficacy and toxicity of the localized chemotherapy in comparison to the standard systemic dosing. The in vivo results suggest that local chemotherapy is not only feasible, but as effective as current treatment options. An intratumoral free docetaxel spacer showed to be as effective as a one-time equivalent dose of the clinically used systemic taxotere without the associated adverse toxicities. This new localized chemo-treatment shows great potential for increasing tumor regression while decreasing systemic toxicity. Further experiments for studying the combined chemo-radiation therapy are underway. This demonstrates that local chemotherapy and chemo-radiation therapy has the potential to be a superior treatment option to current chemo-treatments.
This work was supported partially by ARMY/ W81XWH-12-1-0154, NSF-DGE-0965843, HHS/1U54CA151881 CORE1 and a seed grant from the BWH Biomedical Research Institute.
Citation Format: Rajiv Kumar, Jodi Belz, Houari Korideck, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2015-1806
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Systemic chemotherapy which is often used in combination with radiation therapy in the treatment of prostate cancer, often leads to severe systemic toxicities. Localized chemotherapy has the potential of delivering a high and effective dose directly to the tumor while minimizing adverse toxicities to healthy tissue. An efficient local delivery system should be able to deliver the therapeutic drug at the diseased site in a slow and sustained manner with minimal systemic toxicity. We have fabricated an Implantable Nanoplatform for Chemo-Radiation Therapy (INCeRT) spacer that can deliver planned, localized, and sustained delivery of a chemotherapeutic and imaging agent. Delivery of this new chemotherapy modality can leverage technology used in a routine clinical brachytherapy procedure that uses image guidance to insert radioactive seeds into the prostate using thin needles. The current procedure uses inert plastic spacers with no therapeutic impact to guide the spatial delivery of the radioactive seeds.
This work presents the fabrication, characterization, and therapeutic benefit of a docetaxel loaded spacer in the treatment of prostate-tumored mice. First, INCeRT spacers were fabricated and characterized using optical imaging to track free dye and multi-sized fluorescent silica nanoparticles from spacers in vivo to optimize the temporal and spatial properties of diffusion distribution from a degrading biocompatible polymer matrix. In vivo optical imaging of spacers doped with free dye demonstrates a spatial and temporal release profile appropriate for sustained localized exposure of a chemotherapeutic during the course of brachytherapy. The optimized spacer were loaded with chemotherapeutics and inserted intratumorally for efficacy and toxicity of the localized chemotherapy in comparison to the standard systemic dosing. The in vivo results suggest that local chemotherapy is not only feasible, but as effective as current treatment options. An intratumoral free docetaxel spacer showed to be as effective as a one-time equivalent dose of the clinically used systemic taxotere without the associated adverse toxicities. This new localized chemo-treatment shows great potential for increasing tumor regression while decreasing systemic toxicity. Further experiments for studying the combined chemo-radiation therapy are underway. This demonstrates that local chemotherapy and chemo-radiation therapy has the potential to be a superior treatment option to current chemo-treatments.
This work was supported partially by ARMY/ W81XWH-12-1-0154, NSF-DGE-0965843, HHS/1U54CA151881 CORE1 and a seed grant from the BWH Biomedical Research Institute.
Citation Format: Rajiv Kumar, Jodi Belz, Houari Korideck, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2015-1806
©2015 American Association for Cancer Research.
This work presents the fabrication, characterization, and therapeutic benefit of a docetaxel loaded spacer in the treatment of prostate-tumored mice. First, INCeRT spacers were fabricated and characterized using optical imaging to track free dye and multi-sized fluorescent silica nanoparticles from spacers in vivo to optimize the temporal and spatial properties of diffusion distribution from a degrading biocompatible polymer matrix. In vivo optical imaging of spacers doped with free dye demonstrates a spatial and temporal release profile appropriate for sustained localized exposure of a chemotherapeutic during the course of brachytherapy. The optimized spacer were loaded with chemotherapeutics and inserted intratumorally for efficacy and toxicity of the localized chemotherapy in comparison to the standard systemic dosing. The in vivo results suggest that local chemotherapy is not only feasible, but as effective as current treatment options. An intratumoral free docetaxel spacer showed to be as effective as a one-time equivalent dose of the clinically used systemic taxotere without the associated adverse toxicities. This new localized chemo-treatment shows great potential for increasing tumor regression while decreasing systemic toxicity. Further experiments for studying the combined chemo-radiation therapy are underway. This demonstrates that local chemotherapy and chemo-radiation therapy has the potential to be a superior treatment option to current chemo-treatments.
This work was supported partially by ARMY/ W81XWH-12-1-0154, NSF-DGE-0965843, HHS/1U54CA151881 CORE1 and a seed grant from the BWH Biomedical Research Institute.
Citation Format: Rajiv Kumar, Jodi Belz, Houari Korideck, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2015-1806
©2015 American Association for Cancer Research.
375.
Tangutoori, Shifalika; Bladwin, Paige; Ohman, Anders; Korideck, Houari; Cormack, Robert; Dinulescu, Daniela; Makrigiorgos, Mike; Sridhar, Srinivas
NanoPARPi inhibitors for ovarian and prostate cancer therapy Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{tangutoori2015nanoparpi,
title = {NanoPARPi inhibitors for ovarian and prostate cancer therapy},
author = {Shifalika Tangutoori and Paige Bladwin and Anders Ohman and Houari Korideck and Robert Cormack and Daniela Dinulescu and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly ADP Ribose Polymerase (PARP) inhibitor therapy 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 chronic therapy in several clinical trials for a variety of cancers. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN-673), 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-673 have been successfully formulated and tested invitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and each of the PARP inhibitors and the nanoformulation is defined by nanoparticles ∼120 nm diameter, zeta potential ∼ +30mV, and loaded with Olaparib (18mM) 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 various customized assays and EC50's were determined. The synergism due to radiosensitization was studied for both therapies using isobolograms. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on GEMM models of endometrial cancers. The functionality of nanoPARPi formulations, reflected by inhibition of PARylation, and cleaved PARP was determined by immunoflourescence assays.
Results: NanoPARPi inhibitors were assayed on atleast 8 ovarian cancer cells using various cell based assays. NanoBMN was the most potent PARP inhibitor which is not functionally dependent on BRCA sensitive cells lines whereas nanoOlaparib, seems to be sensitive towards triple negative GEMM derived Ovarian cells (403, 404). PTEN deficient prostate cancer cells were more susceptible to radiosensitization with both nanoPARPi inhibitors (Olaparib, BMN-673), achieving significant long-term cell kill. In all studies NanoBMN-673 showed better efficacy in combination with radiation than NanoOlaparib. In vivo studies with irradiation are underway.
Conclusions: Robust nanoformulations, NanoOlaparib and nanoBMN-673 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-673 as chemo and radio-sensitizers enabling several combination therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Bladwin, Anders Ohman, Houari Korideck, Robert Cormack, Daniela Dinulescu, Mike Makrigiorgos, Srinivas Sridhar. NanoPARPi inhibitors for ovarian and prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2015-3670
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Introduction: Poly ADP Ribose Polymerase (PARP) inhibitor therapy 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 chronic therapy in several clinical trials for a variety of cancers. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN-673), 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-673 have been successfully formulated and tested invitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and each of the PARP inhibitors and the nanoformulation is defined by nanoparticles ∼120 nm diameter, zeta potential ∼ +30mV, and loaded with Olaparib (18mM) 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 various customized assays and EC50's were determined. The synergism due to radiosensitization was studied for both therapies using isobolograms. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on GEMM models of endometrial cancers. The functionality of nanoPARPi formulations, reflected by inhibition of PARylation, and cleaved PARP was determined by immunoflourescence assays.
Results: NanoPARPi inhibitors were assayed on atleast 8 ovarian cancer cells using various cell based assays. NanoBMN was the most potent PARP inhibitor which is not functionally dependent on BRCA sensitive cells lines whereas nanoOlaparib, seems to be sensitive towards triple negative GEMM derived Ovarian cells (403, 404). PTEN deficient prostate cancer cells were more susceptible to radiosensitization with both nanoPARPi inhibitors (Olaparib, BMN-673), achieving significant long-term cell kill. In all studies NanoBMN-673 showed better efficacy in combination with radiation than NanoOlaparib. In vivo studies with irradiation are underway.
Conclusions: Robust nanoformulations, NanoOlaparib and nanoBMN-673 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-673 as chemo and radio-sensitizers enabling several combination therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Bladwin, Anders Ohman, Houari Korideck, Robert Cormack, Daniela Dinulescu, Mike Makrigiorgos, Srinivas Sridhar. NanoPARPi inhibitors for ovarian and prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2015-3670
©2015 American Association for Cancer Research.
Methods: Two nanoparticle formulations, NanoOlaparib and NanoBMN-673 have been successfully formulated and tested invitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and each of the PARP inhibitors and the nanoformulation is defined by nanoparticles ∼120 nm diameter, zeta potential ∼ +30mV, and loaded with Olaparib (18mM) 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 various customized assays and EC50's were determined. The synergism due to radiosensitization was studied for both therapies using isobolograms. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on GEMM models of endometrial cancers. The functionality of nanoPARPi formulations, reflected by inhibition of PARylation, and cleaved PARP was determined by immunoflourescence assays.
Results: NanoPARPi inhibitors were assayed on atleast 8 ovarian cancer cells using various cell based assays. NanoBMN was the most potent PARP inhibitor which is not functionally dependent on BRCA sensitive cells lines whereas nanoOlaparib, seems to be sensitive towards triple negative GEMM derived Ovarian cells (403, 404). PTEN deficient prostate cancer cells were more susceptible to radiosensitization with both nanoPARPi inhibitors (Olaparib, BMN-673), achieving significant long-term cell kill. In all studies NanoBMN-673 showed better efficacy in combination with radiation than NanoOlaparib. In vivo studies with irradiation are underway.
Conclusions: Robust nanoformulations, NanoOlaparib and nanoBMN-673 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-673 as chemo and radio-sensitizers enabling several combination therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Bladwin, Anders Ohman, Houari Korideck, Robert Cormack, Daniela Dinulescu, Mike Makrigiorgos, Srinivas Sridhar. NanoPARPi inhibitors for ovarian and prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2015-3670
©2015 American Association for Cancer Research.
374.
Tangutoori, Shifalika; Baldwin, Paige; Medina, Jamie; Ohman, Anders; Dinulescu, Daniela; Sridhar, Srinivas
Abstract AS29: PARP inhibitor nano-therapy in ovarian cancer models Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{tangutoori2015abstract,
title = {Abstract AS29: PARP inhibitor nano-therapy in ovarian cancer models},
author = {Shifalika Tangutoori and Paige Baldwin and Jamie Medina and Anders Ohman and Daniela Dinulescu and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib is a potent PARP inhibitors that is currently indicated for oral inhibitor therapy in several clinical trials for a variety of cancers. Oral administration of these inhibitors in general results in poor bioavailability and tumor accumulation. Here we report the first novel nanoformulations customized for olaparib (NanoOlaparib), 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.
Methods: Two nanoparticle (120nm size) formulations NanoOlaparib and NanoOlaparibPt have been successfully formulated and tested in vitro on several cancer cell lines. Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines PA-1, KURAMOCHI, OVSAHO, SKOV3, and 4306, were generated using MTS assay and EC50's were determined using Prism. The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from delayed viability assay.
Results: In vitro studies Cell viability studies were carried out with NanoOlaparib and NanoOlaparibPt in OvCa cell lines. The highly Pt-sensitive cell line PA-1 is strongly responsive to NanoOlaparib (blue) and NanoOlaparibPt (grey) although it is not known to carry a germline BrCa mutation. The multi-drug resistant cell line SKOV-3 is also more responsive to NanoOlaparib and combination NanoOlaparibPt. In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images (Fig. 2) show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated.
Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+ Olaparib/DMSO. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with NanoOlaparib when compared to olaparib alone. Increased tumor accumulation and therapeutic efficacy were observed in prostate and breast cancer GEM models. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP inhibition and imply a very promising role for the nano-olaparib formulation in ovarian and other cancers.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Introduction: Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib is a potent PARP inhibitors that is currently indicated for oral inhibitor therapy in several clinical trials for a variety of cancers. Oral administration of these inhibitors in general results in poor bioavailability and tumor accumulation. Here we report the first novel nanoformulations customized for olaparib (NanoOlaparib), 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.
Methods: Two nanoparticle (120nm size) formulations NanoOlaparib and NanoOlaparibPt have been successfully formulated and tested in vitro on several cancer cell lines. Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines PA-1, KURAMOCHI, OVSAHO, SKOV3, and 4306, were generated using MTS assay and EC50's were determined using Prism. The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from delayed viability assay.
Results: In vitro studies Cell viability studies were carried out with NanoOlaparib and NanoOlaparibPt in OvCa cell lines. The highly Pt-sensitive cell line PA-1 is strongly responsive to NanoOlaparib (blue) and NanoOlaparibPt (grey) although it is not known to carry a germline BrCa mutation. The multi-drug resistant cell line SKOV-3 is also more responsive to NanoOlaparib and combination NanoOlaparibPt. In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images (Fig. 2) show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated.
Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+ Olaparib/DMSO. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with NanoOlaparib when compared to olaparib alone. Increased tumor accumulation and therapeutic efficacy were observed in prostate and breast cancer GEM models. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP inhibition and imply a very promising role for the nano-olaparib formulation in ovarian and other cancers.
Methods: Two nanoparticle (120nm size) formulations NanoOlaparib and NanoOlaparibPt have been successfully formulated and tested in vitro on several cancer cell lines. Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines PA-1, KURAMOCHI, OVSAHO, SKOV3, and 4306, were generated using MTS assay and EC50's were determined using Prism. The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from delayed viability assay.
Results: In vitro studies Cell viability studies were carried out with NanoOlaparib and NanoOlaparibPt in OvCa cell lines. The highly Pt-sensitive cell line PA-1 is strongly responsive to NanoOlaparib (blue) and NanoOlaparibPt (grey) although it is not known to carry a germline BrCa mutation. The multi-drug resistant cell line SKOV-3 is also more responsive to NanoOlaparib and combination NanoOlaparibPt. In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images (Fig. 2) show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated.
Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+ Olaparib/DMSO. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with NanoOlaparib when compared to olaparib alone. Increased tumor accumulation and therapeutic efficacy were observed in prostate and breast cancer GEM models. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP inhibition and imply a very promising role for the nano-olaparib formulation in ovarian and other cancers.
373.
Kunjachan, Sijumon; Detappe, Alexandre; Kumar, Rajiv; Ireland, Thomas; Cameron, Lisa; Biancur, Douglas E; Motto-Ros, Vincent; Sancey, Lucie; Sridhar, Srinivas; Makrigiorgos, Mike G; others,
Nanoparticle mediated tumor vascular disruption: a novel strategy in radiation therapy Journal Article
In: Nano letters, vol. 15, no. 11, pp. 7488–7496, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{kunjachan2015nanoparticle,
title = {Nanoparticle mediated tumor vascular disruption: a novel strategy in radiation therapy},
author = {Sijumon Kunjachan and Alexandre Detappe and Rajiv Kumar and Thomas Ireland and Lisa Cameron and Douglas E Biancur and Vincent Motto-Ros and Lucie Sancey and Srinivas Sridhar and Mike G Makrigiorgos and others},
year = {2015},
date = {2015-01-01},
journal = {Nano letters},
volume = {15},
number = {11},
pages = {7488--7496},
publisher = {American Chemical Society},
abstract = {More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.
372.
Adedoyin, AA; Kumar, R; Sridhar, S; Ekenseair, AK
Synthesis and Characterization of Injectable Bionanocomposite Hybrid Scaffolds with Responsive Control for Osteochondral Tissue Regeneration Proceedings Article
In: TISSUE ENGINEERING PART A, pp. S307–S307, MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA 2015.
BibTeX | Tags: Nanomedicine
@inproceedings{adedoyin2015synthesis,
title = {Synthesis and Characterization of Injectable Bionanocomposite Hybrid Scaffolds with Responsive Control for Osteochondral Tissue Regeneration},
author = {AA Adedoyin and R Kumar and S Sridhar and AK Ekenseair},
year = {2015},
date = {2015-01-01},
booktitle = {TISSUE ENGINEERING PART A},
volume = {21},
pages = {S307--S307},
organization = {MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
371.
Cheng, MJ; Kumar, R; Sridhar, S; Webster, TJ; Ebong, EE
Glycocalyx Integrity Influences Nanoparticle Uptake by Endothelial Cells Proceedings Article
In: TISSUE ENGINEERING PART A, pp. S401–S401, MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA 2015.
BibTeX | Tags: Nanomedicine
@inproceedings{cheng2015glycocalyx,
title = {Glycocalyx Integrity Influences Nanoparticle Uptake by Endothelial Cells},
author = {MJ Cheng and R Kumar and S Sridhar and TJ Webster and EE Ebong},
year = {2015},
date = {2015-01-01},
booktitle = {TISSUE ENGINEERING PART A},
volume = {21},
pages = {S401--S401},
organization = {MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
370.
Ozturk, Birol; Yavuzcetin, Ozgur; Sridhar, Srinivas
A novel coupled resonator photonic crystal design in lithium niobate for electrooptic applications Journal Article
In: International Journal of Optics, vol. 2015, 2015.
Abstract | BibTeX | Tags: Nanomedicine, Sensors
@article{ozturk2015novel,
title = {A novel coupled resonator photonic crystal design in lithium niobate for electrooptic applications},
author = {Birol Ozturk and Ozgur Yavuzcetin and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {International Journal of Optics},
volume = {2015},
publisher = {Hindawi},
abstract = {High-aspect-ratio photonic crystal air-hole fabrication on bulk Lithium Niobate (LN) substrates is extremely difficult due to its inherent resistance to etching, resulting in conical structures and high insertion losses. Here, we propose a novel coupled resonator photonic crystal (CRPC) design, combining a coupled resonator approach with that of Bragg gratings. CRPC design parameters were optimized by analytical calculations and FDTD simulations. CRPC structures with optimized parameters were fabricated and electrooptically tested on bulk LN annealed proton exchange waveguides. Low insertion loss and large electrooptic effect were observed with the fabricated devices, making the CRPC design a promising structure for electrooptic device applications.},
keywords = {Nanomedicine, Sensors},
pubstate = {published},
tppubtype = {article}
}
High-aspect-ratio photonic crystal air-hole fabrication on bulk Lithium Niobate (LN) substrates is extremely difficult due to its inherent resistance to etching, resulting in conical structures and high insertion losses. Here, we propose a novel coupled resonator photonic crystal (CRPC) design, combining a coupled resonator approach with that of Bragg gratings. CRPC design parameters were optimized by analytical calculations and FDTD simulations. CRPC structures with optimized parameters were fabricated and electrooptically tested on bulk LN annealed proton exchange waveguides. Low insertion loss and large electrooptic effect were observed with the fabricated devices, making the CRPC design a promising structure for electrooptic device applications.
369.
Baldwin, Paige; Shanmugam, Ilanchezhian; Tangutoori, Shifalika; Ohman, Anders; Dinulescu, Daniela; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Abstract B35: Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{baldwin2015abstract,
title = {Abstract B35: Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy},
author = {Paige Baldwin and Ilanchezhian Shanmugam and Shifalika Tangutoori and Anders Ohman and Daniela Dinulescu and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in ovarian cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Here we report the first novel nanoformulations of PARP inhibitors NanoTalazoparib and NanoOlaparib, thus enabling a platform which provides a safe vehicle for parenteral administration specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Three nanoparticle (∼120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, were successfully formulated and tested in vitro and in vivo on several cancer cell lines. Ovarian Cancer cell lines tested include KURAMOCHI, SKOV3, and OVSAHO, JHOS2 PA1, COV318, 403/ 404 (derived from tumors of BRCA2-/-¬, PTEN-/-, / TP53mut mice) and 4306 / 4412 (developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP) mice. IC50s were determined with an MTS assay. Radiosensitization studies with NanoOlaparib were carried out on prostate cancer cell lines LNCAP, PC3, and FK01 (derived from PTEN-/P53- mice tumors). In vivo studies were carried out with iv or ip administration.
Results: In vitro studies The murine cell lines, 403, 404 were highly sensitive to this treatment due to the triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. The PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Strong radiosensitization was observed in the prostate cancer cell lines.
NanoTalazoparib is 10-100 times more potent than NanoOlaparib. The cell line dependence is similar to NanoOlaparib except for the overall lower magnitudes.
In vivo studies In a pilot study in an endometrial OvCa murine model with KRaS-PTEN deletion, bioluminescence images show tumor suppression of more than a nearly a factor of 3. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut OvCa GEMM also showed good therapeutic response to i.p. administration. In vivo studies in prostate cancer models showed greater tumor accumulation and tumor reduction with NanoOlaparib.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. All formulations were well tolerated.. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Ilanchezhian Shanmugam, Shifalika Tangutoori, Anders Ohman, Daniela Dinulescu, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B35.
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in ovarian cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Here we report the first novel nanoformulations of PARP inhibitors NanoTalazoparib and NanoOlaparib, thus enabling a platform which provides a safe vehicle for parenteral administration specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Three nanoparticle (∼120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, were successfully formulated and tested in vitro and in vivo on several cancer cell lines. Ovarian Cancer cell lines tested include KURAMOCHI, SKOV3, and OVSAHO, JHOS2 PA1, COV318, 403/ 404 (derived from tumors of BRCA2-/-¬, PTEN-/-, / TP53mut mice) and 4306 / 4412 (developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP) mice. IC50s were determined with an MTS assay. Radiosensitization studies with NanoOlaparib were carried out on prostate cancer cell lines LNCAP, PC3, and FK01 (derived from PTEN-/P53- mice tumors). In vivo studies were carried out with iv or ip administration.
Results: In vitro studies The murine cell lines, 403, 404 were highly sensitive to this treatment due to the triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. The PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Strong radiosensitization was observed in the prostate cancer cell lines.
NanoTalazoparib is 10-100 times more potent than NanoOlaparib. The cell line dependence is similar to NanoOlaparib except for the overall lower magnitudes.
In vivo studies In a pilot study in an endometrial OvCa murine model with KRaS-PTEN deletion, bioluminescence images show tumor suppression of more than a nearly a factor of 3. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut OvCa GEMM also showed good therapeutic response to i.p. administration. In vivo studies in prostate cancer models showed greater tumor accumulation and tumor reduction with NanoOlaparib.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. All formulations were well tolerated.. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Ilanchezhian Shanmugam, Shifalika Tangutoori, Anders Ohman, Daniela Dinulescu, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B35.
©2015 American Association for Cancer Research.
Methods: Three nanoparticle (∼120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, were successfully formulated and tested in vitro and in vivo on several cancer cell lines. Ovarian Cancer cell lines tested include KURAMOCHI, SKOV3, and OVSAHO, JHOS2 PA1, COV318, 403/ 404 (derived from tumors of BRCA2-/-¬, PTEN-/-, / TP53mut mice) and 4306 / 4412 (developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP) mice. IC50s were determined with an MTS assay. Radiosensitization studies with NanoOlaparib were carried out on prostate cancer cell lines LNCAP, PC3, and FK01 (derived from PTEN-/P53- mice tumors). In vivo studies were carried out with iv or ip administration.
Results: In vitro studies The murine cell lines, 403, 404 were highly sensitive to this treatment due to the triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. The PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Strong radiosensitization was observed in the prostate cancer cell lines.
NanoTalazoparib is 10-100 times more potent than NanoOlaparib. The cell line dependence is similar to NanoOlaparib except for the overall lower magnitudes.
In vivo studies In a pilot study in an endometrial OvCa murine model with KRaS-PTEN deletion, bioluminescence images show tumor suppression of more than a nearly a factor of 3. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut OvCa GEMM also showed good therapeutic response to i.p. administration. In vivo studies in prostate cancer models showed greater tumor accumulation and tumor reduction with NanoOlaparib.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. All formulations were well tolerated.. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Ilanchezhian Shanmugam, Shifalika Tangutoori, Anders Ohman, Daniela Dinulescu, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B35.
©2015 American Association for Cancer Research.
368.
Belz, Jodi; Liby, Karen; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne L; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Abstract B42: Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{belz2015abstract,
title = {Abstract B42: Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer},
author = {Jodi Belz and Karen Liby and Paige Baldwin and Rajiv Kumar and Anne L van de Ven and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The breast cancer-associated gene 1 (Brca1) is the most frequently mutated tumor suppressor gene found in familial breast cancers. Mutations of the gene modulate many cellular functions including DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy can produce cell death in cancers with genetic predispositions for impaired DNA repair or transcription pathways such as Brca1 mutants. Here we report a novel biodegradable implant for the local delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib in contrast to low bioavailability and toxicity associated with oral delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib. 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 was determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− mice. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: In vitro studies
The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses. Breast cancer cell lines W0069 and W780, derived from Brca1 Co/Co; MMTV-Cre; p53+/− mice were highly sensitive to Talazoparib, most likely due to Brca1 mutation. PARP expression was examined via western blot analysis.
In vivo studies
In vivo studies using sustained drug release implants loaded with Talazoparib were also carried out in Brca1Co/Co;MMTV-Cre;p53+/- genetically engineered mice with 1 or more spontaneous breast tumors. Following a one-time implantation, 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. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib was observed in vitro and in vivo. The Talazoparib-loaded implants represent a novel delivery route that was well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition and is a promising new route for the treatment of highly aggressive breast cancer models.
We would like to acknowledge the Breast Cancer Research Foundation. This work was supported by the Army- W81XWH-14-1-0092 and Northeastern University – Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Karen Liby, Paige Baldwin, Rajiv Kumar, Anne L. van de Ven, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B42.
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The breast cancer-associated gene 1 (Brca1) is the most frequently mutated tumor suppressor gene found in familial breast cancers. Mutations of the gene modulate many cellular functions including DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy can produce cell death in cancers with genetic predispositions for impaired DNA repair or transcription pathways such as Brca1 mutants. Here we report a novel biodegradable implant for the local delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib in contrast to low bioavailability and toxicity associated with oral delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib. 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 was determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− mice. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: In vitro studies
The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses. Breast cancer cell lines W0069 and W780, derived from Brca1 Co/Co; MMTV-Cre; p53+/− mice were highly sensitive to Talazoparib, most likely due to Brca1 mutation. PARP expression was examined via western blot analysis.
In vivo studies
In vivo studies using sustained drug release implants loaded with Talazoparib were also carried out in Brca1Co/Co;MMTV-Cre;p53+/- genetically engineered mice with 1 or more spontaneous breast tumors. Following a one-time implantation, 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. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib was observed in vitro and in vivo. The Talazoparib-loaded implants represent a novel delivery route that was well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition and is a promising new route for the treatment of highly aggressive breast cancer models.
We would like to acknowledge the Breast Cancer Research Foundation. This work was supported by the Army- W81XWH-14-1-0092 and Northeastern University – Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Karen Liby, Paige Baldwin, Rajiv Kumar, Anne L. van de Ven, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B42.
©2015 American Association for Cancer Research.
Abstract
The breast cancer-associated gene 1 (Brca1) is the most frequently mutated tumor suppressor gene found in familial breast cancers. Mutations of the gene modulate many cellular functions including DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy can produce cell death in cancers with genetic predispositions for impaired DNA repair or transcription pathways such as Brca1 mutants. Here we report a novel biodegradable implant for the local delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib in contrast to low bioavailability and toxicity associated with oral delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib. 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 was determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− mice. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: In vitro studies
The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses. Breast cancer cell lines W0069 and W780, derived from Brca1 Co/Co; MMTV-Cre; p53+/− mice were highly sensitive to Talazoparib, most likely due to Brca1 mutation. PARP expression was examined via western blot analysis.
In vivo studies
In vivo studies using sustained drug release implants loaded with Talazoparib were also carried out in Brca1Co/Co;MMTV-Cre;p53+/- genetically engineered mice with 1 or more spontaneous breast tumors. Following a one-time implantation, 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. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib was observed in vitro and in vivo. The Talazoparib-loaded implants represent a novel delivery route that was well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition and is a promising new route for the treatment of highly aggressive breast cancer models.
We would like to acknowledge the Breast Cancer Research Foundation. This work was supported by the Army- W81XWH-14-1-0092 and Northeastern University – Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Karen Liby, Paige Baldwin, Rajiv Kumar, Anne L. van de Ven, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B42.
©2015 American Association for Cancer Research.
367.
Kumar, Rajiv; Belz, Jodi; Shanmugam, Ilanchezhian; Ngwa, Wilfred; Berbeco, Ross; Makrigiorgos, Mike; Sridhar, Srinivas
Abstract C147: Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{kumar2015abstract,
title = {Abstract C147: Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy},
author = {Rajiv Kumar and Jodi Belz and Ilanchezhian Shanmugam and Wilfred Ngwa and Ross Berbeco and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and gold nanoparticles (GNPs) have established themselves as potent radiosensitizer to significantly enhance Radiotherapy (RT) treatment. The understanding of the biochemical pathways accompanying GNPs radiation amplification can provide information on the molecular pathways relevant to therapeutic efficacy and thus will pave the way for designing novel therapeutic platforms by targeting these pathways. However, there are significant limitations in the ability to deliver sufficiently potent concentration of GNPs to tumor cells and currently there is very limited understanding of the biology of the radiosensitization using GNPs.
Thus, to improve the efficacy of radiosensitization and subsequently study the impact of radiosensitization on biochemical pathways, we have fabricated a new generation of targeted GNPs formulation. These ultrasmall 2-3 nm gold nanoparticles were functionalized with hetero-bifunctional PEG, imaging agent- AlexaFlour 647 and targeting peptide- RGD. The in vitro studies showed a robust uptake of these GNPs in different cancer cells lines and clonogenic survival assays have demonstrated a 2.8-fold cell kill enhancement with X-rays in HeLa cell line. To evaluate that these GNPs are targeted to the tumor site, we have injected these nanoparticles via different routes in two different tumor animal models and studied the uptake using in vivo optical imaging. The imaging studies showed highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model injected intravenously with RGD targeted GNPs. The administration of same RGD targeted GNPs formulation via inhalation/instillation (INH) route as opposed to customary intravenous (i.v) route was studied in transgenic lung cancer mice model. Fluorescence imaging and ex-vivo electron microcopy results showed a significantly higher concentration of GNPs (4.7 times) in the lung tumors of mice when using INH delivery compared to i.v. approach. Further, to understand the radiobiology of GNPs in vitro, we have studied the protein expression of γH2aX and RAD51 using western blots. The studies involving the radiation induced alterations in presence of GNPs to study the impact on cell cycle and DNA damage/repair are currently underway. The studies will help identify the specific pathways that are critical to GNP radiotherapy which can be targeted subsequently to further boost the efficacy of GNP radiotherapy. 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, Jodi Belz, Ilanchezhian Shanmugam, Wilfred Ngwa, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C147.
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and gold nanoparticles (GNPs) have established themselves as potent radiosensitizer to significantly enhance Radiotherapy (RT) treatment. The understanding of the biochemical pathways accompanying GNPs radiation amplification can provide information on the molecular pathways relevant to therapeutic efficacy and thus will pave the way for designing novel therapeutic platforms by targeting these pathways. However, there are significant limitations in the ability to deliver sufficiently potent concentration of GNPs to tumor cells and currently there is very limited understanding of the biology of the radiosensitization using GNPs.
Thus, to improve the efficacy of radiosensitization and subsequently study the impact of radiosensitization on biochemical pathways, we have fabricated a new generation of targeted GNPs formulation. These ultrasmall 2-3 nm gold nanoparticles were functionalized with hetero-bifunctional PEG, imaging agent- AlexaFlour 647 and targeting peptide- RGD. The in vitro studies showed a robust uptake of these GNPs in different cancer cells lines and clonogenic survival assays have demonstrated a 2.8-fold cell kill enhancement with X-rays in HeLa cell line. To evaluate that these GNPs are targeted to the tumor site, we have injected these nanoparticles via different routes in two different tumor animal models and studied the uptake using in vivo optical imaging. The imaging studies showed highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model injected intravenously with RGD targeted GNPs. The administration of same RGD targeted GNPs formulation via inhalation/instillation (INH) route as opposed to customary intravenous (i.v) route was studied in transgenic lung cancer mice model. Fluorescence imaging and ex-vivo electron microcopy results showed a significantly higher concentration of GNPs (4.7 times) in the lung tumors of mice when using INH delivery compared to i.v. approach. Further, to understand the radiobiology of GNPs in vitro, we have studied the protein expression of γH2aX and RAD51 using western blots. The studies involving the radiation induced alterations in presence of GNPs to study the impact on cell cycle and DNA damage/repair are currently underway. The studies will help identify the specific pathways that are critical to GNP radiotherapy which can be targeted subsequently to further boost the efficacy of GNP radiotherapy. 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, Jodi Belz, Ilanchezhian Shanmugam, Wilfred Ngwa, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C147.
©2015 American Association for Cancer Research.
Abstract
The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and gold nanoparticles (GNPs) have established themselves as potent radiosensitizer to significantly enhance Radiotherapy (RT) treatment. The understanding of the biochemical pathways accompanying GNPs radiation amplification can provide information on the molecular pathways relevant to therapeutic efficacy and thus will pave the way for designing novel therapeutic platforms by targeting these pathways. However, there are significant limitations in the ability to deliver sufficiently potent concentration of GNPs to tumor cells and currently there is very limited understanding of the biology of the radiosensitization using GNPs.
Thus, to improve the efficacy of radiosensitization and subsequently study the impact of radiosensitization on biochemical pathways, we have fabricated a new generation of targeted GNPs formulation. These ultrasmall 2-3 nm gold nanoparticles were functionalized with hetero-bifunctional PEG, imaging agent- AlexaFlour 647 and targeting peptide- RGD. The in vitro studies showed a robust uptake of these GNPs in different cancer cells lines and clonogenic survival assays have demonstrated a 2.8-fold cell kill enhancement with X-rays in HeLa cell line. To evaluate that these GNPs are targeted to the tumor site, we have injected these nanoparticles via different routes in two different tumor animal models and studied the uptake using in vivo optical imaging. The imaging studies showed highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model injected intravenously with RGD targeted GNPs. The administration of same RGD targeted GNPs formulation via inhalation/instillation (INH) route as opposed to customary intravenous (i.v) route was studied in transgenic lung cancer mice model. Fluorescence imaging and ex-vivo electron microcopy results showed a significantly higher concentration of GNPs (4.7 times) in the lung tumors of mice when using INH delivery compared to i.v. approach. Further, to understand the radiobiology of GNPs in vitro, we have studied the protein expression of γH2aX and RAD51 using western blots. The studies involving the radiation induced alterations in presence of GNPs to study the impact on cell cycle and DNA damage/repair are currently underway. The studies will help identify the specific pathways that are critical to GNP radiotherapy which can be targeted subsequently to further boost the efficacy of GNP radiotherapy. 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, Jodi Belz, Ilanchezhian Shanmugam, Wilfred Ngwa, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C147.
©2015 American Association for Cancer Research.
366.
TANGUTOORI, Shifalika; Sridhar, Srinivas
Nanoparticle drug delivery system and method of treating cancer and neurotrauma Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{tangutoori2015nanoparticle,
title = {Nanoparticle drug delivery system and method of treating cancer and neurotrauma},
author = {Shifalika TANGUTOORI and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
abstract = {The invention provides pharmaceutical formulations of inhibitors for poly (ADP-ribose) polymerase (PARP) enzyme. The formulations can be used in the treatment and prevention of cancer as well as the treatment of neurotrauma and neurodegenerative diseases. The PARP inhibitor is delivered in the form of nanoparticles that provide efficient delivery of the inhibitor into cancer cells or other cells and release of the inhibitor within the cells. In treating cancer, the result is killing of tumor cells, whereas in treatment of neurotrauma and neurodegenerative disease, the result is preservation of cell function.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
The invention provides pharmaceutical formulations of inhibitors for poly (ADP-ribose) polymerase (PARP) enzyme. The formulations can be used in the treatment and prevention of cancer as well as the treatment of neurotrauma and neurodegenerative diseases. The PARP inhibitor is delivered in the form of nanoparticles that provide efficient delivery of the inhibitor into cancer cells or other cells and release of the inhibitor within the cells. In treating cancer, the result is killing of tumor cells, whereas in treatment of neurotrauma and neurodegenerative disease, the result is preservation of cell function.
365.
Clarke, Nicole; Biscocho, Jewison; Kwei, Kevin A; Davidson, Jean M; Sridhar, Sushmita; Gong, Xue; Pollack, Jonathan R
Integrative genomics implicates EGFR as a downstream mediator in NKX2-1 amplified non-small cell lung cancer Journal Article
In: PloS one, vol. 10, no. 11, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{clarke2015integrative,
title = {Integrative genomics implicates EGFR as a downstream mediator in NKX2-1 amplified non-small cell lung cancer},
author = {Nicole Clarke and Jewison Biscocho and Kevin A Kwei and Jean M Davidson and Sushmita Sridhar and Xue Gong and Jonathan R Pollack},
year = {2015},
date = {2015-01-01},
journal = {PloS one},
volume = {10},
number = {11},
publisher = {Public Library of Science},
abstract = {NKX2-1, encoding a homeobox transcription factor, is amplified in approximately 15% of non-small cell lung cancers (NSCLC), where it is thought to drive cancer cell proliferation and survival. However, its mechanism of action remains largely unknown. To identify relevant downstream transcriptional targets, here we carried out a combined NKX2-1 transcriptome (NKX2-1 knockdown followed by RNAseq) and cistrome (NKX2-1 binding sites by ChIPseq) analysis in four NKX2-1-amplified human NSCLC cell lines. While NKX2-1 regulated genes differed among the four cell lines assayed, cell proliferation emerged as a common theme. Moreover, in 3 of the 4 cell lines, epidermal growth factor receptor (EGFR) was among the top NKX2-1 upregulated targets, which we confirmed at the protein level by western blot. Interestingly, EGFR knockdown led to upregulation of NKX2-1, suggesting a negative feedback loop. Consistent with this finding, combined knockdown of NKX2-1 and EGFR in NCI-H1819 lung cancer cells reduced cell proliferation (as well as MAP-kinase and PI3-kinase signaling) more than knockdown of either alone. Likewise, NKX2-1 knockdown enhanced the growth-inhibitory effect of the EGFR-inhibitor erlotinib. Taken together, our findings implicate EGFR as a downstream effector of NKX2-1 in NKX2-1 amplified NSCLC, with possible clinical implications, and provide a rich dataset for investigating additional mediators of NKX2-1 driven oncogenesis.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
NKX2-1, encoding a homeobox transcription factor, is amplified in approximately 15% of non-small cell lung cancers (NSCLC), where it is thought to drive cancer cell proliferation and survival. However, its mechanism of action remains largely unknown. To identify relevant downstream transcriptional targets, here we carried out a combined NKX2-1 transcriptome (NKX2-1 knockdown followed by RNAseq) and cistrome (NKX2-1 binding sites by ChIPseq) analysis in four NKX2-1-amplified human NSCLC cell lines. While NKX2-1 regulated genes differed among the four cell lines assayed, cell proliferation emerged as a common theme. Moreover, in 3 of the 4 cell lines, epidermal growth factor receptor (EGFR) was among the top NKX2-1 upregulated targets, which we confirmed at the protein level by western blot. Interestingly, EGFR knockdown led to upregulation of NKX2-1, suggesting a negative feedback loop. Consistent with this finding, combined knockdown of NKX2-1 and EGFR in NCI-H1819 lung cancer cells reduced cell proliferation (as well as MAP-kinase and PI3-kinase signaling) more than knockdown of either alone. Likewise, NKX2-1 knockdown enhanced the growth-inhibitory effect of the EGFR-inhibitor erlotinib. Taken together, our findings implicate EGFR as a downstream effector of NKX2-1 in NKX2-1 amplified NSCLC, with possible clinical implications, and provide a rich dataset for investigating additional mediators of NKX2-1 driven oncogenesis.
364.
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
363.
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}
}
362.
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.
361.
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}
}
360.
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.
359.
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}
}
358.
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.
2014
357.
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}
}
356.
Petrov, Yury; Nador, Jeffrey; Hughes, Christopher; Tran, Stanley; Yavuzcetin, Ozgur; Sridhar, Srinivas
Ultra-dense EEG sampling results in two-fold increase of functional brain information Journal Article
In: Neuroimage, vol. 90, pp. 140–145, 2014.
Abstract | BibTeX | Tags: Neurotechnology
@article{petrov2014ultra,
title = {Ultra-dense EEG sampling results in two-fold increase of functional brain information},
author = {Yury Petrov and Jeffrey Nador and Christopher Hughes and Stanley Tran and Ozgur Yavuzcetin and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
journal = {Neuroimage},
volume = {90},
pages = {140--145},
publisher = {Academic Press},
abstract = {We used an ultra-density electroencephalography (ud-EEG) sensor array with improved electrical characteristics to reveal unexpected strong potential variation at 1 cm scale. A new classification paradigm demonstrates that ud-EEG provides twice the signal to noise ratio for data classification compared with contemporary hd-EEG. These results suggest a paradigm shift from current thinking by showing that higher spatial resolution sampling of EEG is required and leads to increased functional brain information that is useful for diverse neurological applications. Contemporary high-density electroencephalographic systems (hd-EEG) comprising up to 256 electrodes have inter-electrode separations of 2–4 cm. Because electric currents of the brain are believed to strongly diffuse before reaching the scalp surface, higher-density electrode coverage is often deemed unnecessary. We used an ultra-dense electroencephalography (ud-EEG) sensor array to reveal strong potential variation at 1 cm scale and discovered that it reflects functional brain activity. A new classification paradigm demonstrates that ud-EEG provides twice the signal to noise ratio for brain-response classification compared with contemporary hd-EEG. These results suggest a paradigm shift from current thinking by showing that higher spatial resolution sampling of EEG is required and leads to increased functional brain information that is useful for diverse neurological applications.},
keywords = {Neurotechnology},
pubstate = {published},
tppubtype = {article}
}
We used an ultra-density electroencephalography (ud-EEG) sensor array with improved electrical characteristics to reveal unexpected strong potential variation at 1 cm scale. A new classification paradigm demonstrates that ud-EEG provides twice the signal to noise ratio for data classification compared with contemporary hd-EEG. These results suggest a paradigm shift from current thinking by showing that higher spatial resolution sampling of EEG is required and leads to increased functional brain information that is useful for diverse neurological applications. Contemporary high-density electroencephalographic systems (hd-EEG) comprising up to 256 electrodes have inter-electrode separations of 2–4 cm. Because electric currents of the brain are believed to strongly diffuse before reaching the scalp surface, higher-density electrode coverage is often deemed unnecessary. We used an ultra-dense electroencephalography (ud-EEG) sensor array to reveal strong potential variation at 1 cm scale and discovered that it reflects functional brain activity. A new classification paradigm demonstrates that ud-EEG provides twice the signal to noise ratio for brain-response classification compared with contemporary hd-EEG. These results suggest a paradigm shift from current thinking by showing that higher spatial resolution sampling of EEG is required and leads to increased functional brain information that is useful for diverse neurological applications.
355.
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.
354.
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 …
353.
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.
352.
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.
351.
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 …
350.
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}
}
349.
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.
348.
Faegh, Samira; Jalili, Nader; Sridhar, Srinivas
Ultrasensitive piezoelectric-based microcantilever biosensor: Theory and experiment Journal Article
In: IEEE/ASME Transactions on Mechatronics, vol. 20, no. 1, pp. 308–312, 2014.
Abstract | BibTeX | Tags: Sensors
@article{faegh2014ultrasensitive,
title = {Ultrasensitive piezoelectric-based microcantilever biosensor: Theory and experiment},
author = {Samira Faegh and Nader Jalili and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
journal = {IEEE/ASME Transactions on Mechatronics},
volume = {20},
number = {1},
pages = {308--312},
publisher = {IEEE},
abstract = {Microcantilever (MC)-based sensors have become an advantageous tool for detection of ultrasmall masses and biological species. Exploiting high affinity of biomolecules, MCs offer a simple, inexpensive, and highly sensitive platform for high throughput diagnosis and analytical sensing. A number of methods have been reported targeting sensitivity enhancement of MC-based systems including geometry modification, employing nanoparticle-enhanced MCs, and operating MCs in lateral and torsional modes. High mode resonating MCs have been reported as a promising sensitivity enhancement method. Although being investigated, there have not been enough analytical high fidelity models describing all dynamics and behavior of MCs operating in high modes with experimental proof. In this study, experimental results of a piezoelectric self-sensing MC operating as a biological sensor at ultrahigh mode along with theoretical verification are presented. Effect of absorbed mass on the frequency shift was investigated using self-sensing and optical measurement methodologies. Mode convergence theory was adopted in order to get the best estimation of resonance frequencies at different modes. Amino groups of aminothenethaiol solution are immobilized over MC. Shift in resonance frequencies in higher modes are measured and the quality factor is calculated proving the fact that sensitivity of MC to detect absorbed masses enhances as the number of modes increases.},
keywords = {Sensors},
pubstate = {published},
tppubtype = {article}
}
Microcantilever (MC)-based sensors have become an advantageous tool for detection of ultrasmall masses and biological species. Exploiting high affinity of biomolecules, MCs offer a simple, inexpensive, and highly sensitive platform for high throughput diagnosis and analytical sensing. A number of methods have been reported targeting sensitivity enhancement of MC-based systems including geometry modification, employing nanoparticle-enhanced MCs, and operating MCs in lateral and torsional modes. High mode resonating MCs have been reported as a promising sensitivity enhancement method. Although being investigated, there have not been enough analytical high fidelity models describing all dynamics and behavior of MCs operating in high modes with experimental proof. In this study, experimental results of a piezoelectric self-sensing MC operating as a biological sensor at ultrahigh mode along with theoretical verification are presented. Effect of absorbed mass on the frequency shift was investigated using self-sensing and optical measurement methodologies. Mode convergence theory was adopted in order to get the best estimation of resonance frequencies at different modes. Amino groups of aminothenethaiol solution are immobilized over MC. Shift in resonance frequencies in higher modes are measured and the quality factor is calculated proving the fact that sensitivity of MC to detect absorbed masses enhances as the number of modes increases.
347.
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.
346.
Sridhar, S; Kumar, Rajesh P; Ramanaiah, KV
Wavelet Transform Techniques for Image Compression-An Evaluation Journal Article
In: International journal of image, graphics and signal processing, vol. 6, no. 2, pp. 54, 2014.
@article{sridhar2014wavelet,
title = {Wavelet Transform Techniques for Image Compression-An Evaluation},
author = {S Sridhar and Rajesh P Kumar and KV Ramanaiah},
year = {2014},
date = {2014-01-01},
journal = {International journal of image, graphics and signal processing},
volume = {6},
number = {2},
pages = {54},
publisher = {Modern Education and Computer Science Press},
abstract = {A vital problem in evaluating the picture quality of an image compression system is the difficulty in describing the amount of degradation in reconstructed image, Wavelet transforms are set of mathematical functions that have established their viability in image compression applications owing to the computational simplicity that comes in the form of filter bank implementation. The choice of wavelet family depends on the application and the content of image. Proposed work is carried out by the application of different hand designed wavelet families like Haar, Daubechies, Biorthogonal, Coiflets and Symlets etc on a variety of bench mark images. Selected benchmark images of choice are decomposed twice using appropriate family of wavelets to produce the approximation and detail coefficients. The highly accurate approximation coefficients so produced are further quantized and later Huffman encoded to eliminate the psychovisual and coding redundancies. However the less accurate detailed coefficients are neglected. In this paper the relative merits of different Wavelet transform techniques are evaluated using objective fidelity measures- PSNR and MSE, results obtained provide a basis for application developers to choose the right family of wavelet for image compression matching their application.},
keywords = {MRI},
pubstate = {published},
tppubtype = {article}
}
A vital problem in evaluating the picture quality of an image compression system is the difficulty in describing the amount of degradation in reconstructed image, Wavelet transforms are set of mathematical functions that have established their viability in image compression applications owing to the computational simplicity that comes in the form of filter bank implementation. The choice of wavelet family depends on the application and the content of image. Proposed work is carried out by the application of different hand designed wavelet families like Haar, Daubechies, Biorthogonal, Coiflets and Symlets etc on a variety of bench mark images. Selected benchmark images of choice are decomposed twice using appropriate family of wavelets to produce the approximation and detail coefficients. The highly accurate approximation coefficients so produced are further quantized and later Huffman encoded to eliminate the psychovisual and coding redundancies. However the less accurate detailed coefficients are neglected. In this paper the relative merits of different Wavelet transform techniques are evaluated using objective fidelity measures- PSNR and MSE, results obtained provide a basis for application developers to choose the right family of wavelet for image compression matching their application.
345.
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.
344.
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.
343.
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.
342.
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.
341.
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.
340.
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
339.
Petrov, Yury; Sridhar, Srinivas
Electric Field Encephalography: Electric fields and their application to functional brain imaging. Journal Article
In: 2013.
Abstract | BibTeX | Tags: Neurotechnology
@article{petrovelectric,
title = {Electric Field Encephalography: Electric fields and their application to functional brain imaging.},
author = {Yury Petrov and Srinivas Sridhar},
year = {2013},
date = {2013-07-03},
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
},
keywords = {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
338.
Yavuzcetin, O; Perry, Nicholas R; Malley, Sean T; Dally, Rebecca L; Novikov, Herman P; Ozturk, Birol; Sridhar, Srinivas
Fabrication and characterization of single mode annealed proton exchanged waveguides in-x-cut lithium niobate Journal Article
In: Optical Materials, vol. 36, no. 2, pp. 372–375, 2013.
Abstract | BibTeX | Tags: Sensors
@article{yavuzcetin2013fabrication,
title = {Fabrication and characterization of single mode annealed proton exchanged waveguides in-x-cut lithium niobate},
author = {O Yavuzcetin and Nicholas R Perry and Sean T Malley and Rebecca L Dally and Herman P Novikov and Birol Ozturk and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
journal = {Optical Materials},
volume = {36},
number = {2},
pages = {372--375},
publisher = {North-Holland},
abstract = {Lithium niobate is a key, well-known material in optical communication that maintains its importance due to its high speed in electro-optical modulators and other optical devices. Using a benzoic acid proton exchange method and annealing in wet O2, we have fabricated waveguides along the y-axis of -x-cut lithium niobate substrate. We have optimized proton exchange and annealing time to make waveguides with the highest transmission we observed to date. The optical transmission was measured in waveguides between 3 μm and 7 μm in width, and 10 mm in length. The near-field mode properties of the waveguides were also examined. In addition, we discovered that the transmission through waveguides is reduced by the surface residues which are underestimated in most fabrication processes. This paper outlines the full fabrication process as well as characterization methods in detail, including a supercontinuum laser source.},
keywords = {Sensors},
pubstate = {published},
tppubtype = {article}
}
Lithium niobate is a key, well-known material in optical communication that maintains its importance due to its high speed in electro-optical modulators and other optical devices. Using a benzoic acid proton exchange method and annealing in wet O2, we have fabricated waveguides along the y-axis of -x-cut lithium niobate substrate. We have optimized proton exchange and annealing time to make waveguides with the highest transmission we observed to date. The optical transmission was measured in waveguides between 3 μm and 7 μm in width, and 10 mm in length. The near-field mode properties of the waveguides were also examined. In addition, we discovered that the transmission through waveguides is reduced by the surface residues which are underestimated in most fabrication processes. This paper outlines the full fabrication process as well as characterization methods in detail, including a supercontinuum laser source.
337.
Gharagouzloo, CA; Madi, S; Seethamraju, RT; Harisinghani, M; Sridhar, S
Ultrashort TE imaging with SPIONs: bright prospects for in vivo applications Proceedings Article
In: JOURNAL OF NUCLEAR MEDICINE, pp. 9–9, SOC NUCLEAR MEDICINE INC 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA 2013.
@inproceedings{gharagouzloo2013ultrashort,
title = {Ultrashort TE imaging with SPIONs: bright prospects for in vivo applications},
author = {CA Gharagouzloo and S Madi and RT Seethamraju and M Harisinghani and S Sridhar},
year = {2013},
date = {2013-01-01},
booktitle = {JOURNAL OF NUCLEAR MEDICINE},
volume = {54},
pages = {9--9},
organization = {SOC NUCLEAR MEDICINE INC 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA},
keywords = {MRI},
pubstate = {published},
tppubtype = {inproceedings}
}
336.
Gharagouzloo, Codi; Jillela, Manasa; Kumar, Rajiv; Nagesha, Dattatri; Sridhar, Srinivas
Positive contrast imaging of magnetic nanoplatforms for image-guided drug delivery. Miscellaneous
2013.
@misc{gharagouzloo2013positive,
title = {Positive contrast imaging of magnetic nanoplatforms for image-guided drug delivery.},
author = {Codi Gharagouzloo and Manasa Jillela and Rajiv Kumar and Dattatri Nagesha and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
publisher = {American Association for Cancer Research},
abstract = {During the last 2 decades no new clinical MRI agents have been approved for clinical use. While Gadolinium based agents have been very popular, Gd cannot be used in emerging multi-functional nano platforms that have the potential to be retained in the body leading to severe toxicity. Superparamagnetic iron-oxide nanoparticles (SPIONs) are most attractive as offering a significant alternative that is far less toxic than Gd based agents. They can be incorporated into nanoplatforms combining other therapeutic agents to achieve image guided drug delivery. Conventionally, SPIONs are imaged via T2 and T2* weighted techniques which manifest signal voids for SPION-containing media. This proves to be disadvantageous in most circumstances because of the difficulty in discriminating signal loss from tissue associated partial voluming, perivascular effects, susceptibility artifacts and motion or flow artifacts. The unique combination of SPIONs with ultra-short TE (UTE) imaging has the specific advantages of rendering positive contrast with high SNR and high CNR, since non-SPION containing regions are dramatically dark due to native tissue's comparatively higher T1. With UTE, it may be possible to take advantage of SPION's inherent biocompatibility allowing for incorporation into drug loaded nanoplatforms leading to bright contrast and the possibility of in vivo quantification.
Here, we report on a systematic study of positive contrast MR imaging using magnetic nanoplatforms incorporating SPIONs of varying particle size and functionalization. In the first step, nanoparticles of various sizes from 4 nm to 20 nm were synthesized by the thermal decomposition method in organic solvents and then coated with phospholipids containing PEG. The use of PEGylated phospholipid enables water solubility, imparts better dispersity and long circulation in blood stream. This results in a core-shell like morphology with iron oxide nanoparticle forming the core and phospholipid PEG forming the shell. The nanoparticles were characterized for their size and morphology using dynamic light scattering (DLS) and transmission electron microscopy (TEM). UTE was optimized on a Bruker 7T Biospec at the Center for Translational Neuroimaging (CTNI) at Northeastern University. High-contrast images were obtained by modification of various imaging parameters such as TE, TR, flip angle, pulse length, polar under-sampling, bandwidth and FOV/Geometry. The results are compared in vivo with Feraheme and show good promise for this approach to MR nanoparticle imaging.
We acknowledge partial support from NSF DGE 0965843, HHS/5U54CA151881-02, and the Electronics Materials Research Institute at Northeastern University.
Citation Format: Codi Gharagouzloo, Manasa Jillela, Rajiv Kumar, Dattatri Nagesha, Srinivas Sridhar. Positive contrast imaging of magnetic nanoplatforms for image-guided drug delivery. [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 2673. doi:10.1158/1538-7445.AM2013-2673
©2013 American Association for Cancer Research},
keywords = {MRI},
pubstate = {published},
tppubtype = {misc}
}
During the last 2 decades no new clinical MRI agents have been approved for clinical use. While Gadolinium based agents have been very popular, Gd cannot be used in emerging multi-functional nano platforms that have the potential to be retained in the body leading to severe toxicity. Superparamagnetic iron-oxide nanoparticles (SPIONs) are most attractive as offering a significant alternative that is far less toxic than Gd based agents. They can be incorporated into nanoplatforms combining other therapeutic agents to achieve image guided drug delivery. Conventionally, SPIONs are imaged via T2 and T2* weighted techniques which manifest signal voids for SPION-containing media. This proves to be disadvantageous in most circumstances because of the difficulty in discriminating signal loss from tissue associated partial voluming, perivascular effects, susceptibility artifacts and motion or flow artifacts. The unique combination of SPIONs with ultra-short TE (UTE) imaging has the specific advantages of rendering positive contrast with high SNR and high CNR, since non-SPION containing regions are dramatically dark due to native tissue's comparatively higher T1. With UTE, it may be possible to take advantage of SPION's inherent biocompatibility allowing for incorporation into drug loaded nanoplatforms leading to bright contrast and the possibility of in vivo quantification.
Here, we report on a systematic study of positive contrast MR imaging using magnetic nanoplatforms incorporating SPIONs of varying particle size and functionalization. In the first step, nanoparticles of various sizes from 4 nm to 20 nm were synthesized by the thermal decomposition method in organic solvents and then coated with phospholipids containing PEG. The use of PEGylated phospholipid enables water solubility, imparts better dispersity and long circulation in blood stream. This results in a core-shell like morphology with iron oxide nanoparticle forming the core and phospholipid PEG forming the shell. The nanoparticles were characterized for their size and morphology using dynamic light scattering (DLS) and transmission electron microscopy (TEM). UTE was optimized on a Bruker 7T Biospec at the Center for Translational Neuroimaging (CTNI) at Northeastern University. High-contrast images were obtained by modification of various imaging parameters such as TE, TR, flip angle, pulse length, polar under-sampling, bandwidth and FOV/Geometry. The results are compared in vivo with Feraheme and show good promise for this approach to MR nanoparticle imaging.
We acknowledge partial support from NSF DGE 0965843, HHS/5U54CA151881-02, and the Electronics Materials Research Institute at Northeastern University.
Citation Format: Codi Gharagouzloo, Manasa Jillela, Rajiv Kumar, Dattatri Nagesha, Srinivas Sridhar. Positive contrast imaging of magnetic nanoplatforms for image-guided drug delivery. [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 2673. doi:10.1158/1538-7445.AM2013-2673
©2013 American Association for Cancer Research
Here, we report on a systematic study of positive contrast MR imaging using magnetic nanoplatforms incorporating SPIONs of varying particle size and functionalization. In the first step, nanoparticles of various sizes from 4 nm to 20 nm were synthesized by the thermal decomposition method in organic solvents and then coated with phospholipids containing PEG. The use of PEGylated phospholipid enables water solubility, imparts better dispersity and long circulation in blood stream. This results in a core-shell like morphology with iron oxide nanoparticle forming the core and phospholipid PEG forming the shell. The nanoparticles were characterized for their size and morphology using dynamic light scattering (DLS) and transmission electron microscopy (TEM). UTE was optimized on a Bruker 7T Biospec at the Center for Translational Neuroimaging (CTNI) at Northeastern University. High-contrast images were obtained by modification of various imaging parameters such as TE, TR, flip angle, pulse length, polar under-sampling, bandwidth and FOV/Geometry. The results are compared in vivo with Feraheme and show good promise for this approach to MR nanoparticle imaging.
We acknowledge partial support from NSF DGE 0965843, HHS/5U54CA151881-02, and the Electronics Materials Research Institute at Northeastern University.
Citation Format: Codi Gharagouzloo, Manasa Jillela, Rajiv Kumar, Dattatri Nagesha, Srinivas Sridhar. Positive contrast imaging of magnetic nanoplatforms for image-guided drug delivery. [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 2673. doi:10.1158/1538-7445.AM2013-2673
©2013 American Association for Cancer Research
335.
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.
334.
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.
333.
Faegh, Samira; Jalili, Nader; Sridhar, Srinivas
A self-sensing piezoelectric microcantilever biosensor for detection of ultrasmall adsorbed masses: theory and experiments Journal Article
In: Sensors, vol. 13, no. 5, pp. 6089–6108, 2013.
Abstract | BibTeX | Tags: Sensors
@article{faegh2013self,
title = {A self-sensing piezoelectric microcantilever biosensor for detection of ultrasmall adsorbed masses: theory and experiments},
author = {Samira Faegh and Nader Jalili and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
urldate = {2013-01-01},
journal = {Sensors},
volume = {13},
number = {5},
pages = {6089--6108},
publisher = {Multidisciplinary Digital Publishing Institute},
abstract = {Detection of ultrasmall masses such as proteins and pathogens has been made possible as a result of advancements in nanotechnology. Development of label-free and highly sensitive biosensors has enabled the transduction of molecular recognition into detectable physical quantities. Microcantilever (MC)-based systems have played a widespread role in developing such biosensors. One of the most important drawbacks of all of the available biosensors is that they all come at a very high cost. Moreover, there are certain limitations in the measurement equipments attached to the biosensors which are mostly optical measurement systems. A unique self-sensing detection technique is proposed in this paper in order to address most of the limitations of the current measurement systems. A self-sensing bridge is used to excite piezoelectric MC-based sensor functioning in dynamic mode, which simultaneously measures the system’s response through the self-induced voltage generated in the piezoelectric material. As a result, the need for bulky, expensive read-out equipment is eliminated. A comprehensive mathematical model is presented for the proposed self-sensing detection platform using distributed-parameters system modeling. An adaptation strategy is then implemented in the second part in order to compensate for the time-variation of piezoelectric properties which dynamically improves the behavior of the system. Finally, results are reported from an extensive experimental investigation carried out to prove the capability of the proposed platform. Experimental results verified the proposed mathematical modeling presented in the first part of the study with accuracy of 97.48%. Implementing the adaptation strategy increased the accuracy to 99.82%. These results proved the measurement capability of the proposed self-sensing strategy. It enables development of a cost-effective, sensitive and miniaturized mass sensing platform.
Keywords: microcantilever; biosensor; distributed-parameter modeling; mass detection},
keywords = {Sensors},
pubstate = {published},
tppubtype = {article}
}
Detection of ultrasmall masses such as proteins and pathogens has been made possible as a result of advancements in nanotechnology. Development of label-free and highly sensitive biosensors has enabled the transduction of molecular recognition into detectable physical quantities. Microcantilever (MC)-based systems have played a widespread role in developing such biosensors. One of the most important drawbacks of all of the available biosensors is that they all come at a very high cost. Moreover, there are certain limitations in the measurement equipments attached to the biosensors which are mostly optical measurement systems. A unique self-sensing detection technique is proposed in this paper in order to address most of the limitations of the current measurement systems. A self-sensing bridge is used to excite piezoelectric MC-based sensor functioning in dynamic mode, which simultaneously measures the system’s response through the self-induced voltage generated in the piezoelectric material. As a result, the need for bulky, expensive read-out equipment is eliminated. A comprehensive mathematical model is presented for the proposed self-sensing detection platform using distributed-parameters system modeling. An adaptation strategy is then implemented in the second part in order to compensate for the time-variation of piezoelectric properties which dynamically improves the behavior of the system. Finally, results are reported from an extensive experimental investigation carried out to prove the capability of the proposed platform. Experimental results verified the proposed mathematical modeling presented in the first part of the study with accuracy of 97.48%. Implementing the adaptation strategy increased the accuracy to 99.82%. These results proved the measurement capability of the proposed self-sensing strategy. It enables development of a cost-effective, sensitive and miniaturized mass sensing platform.
Keywords: microcantilever; biosensor; distributed-parameter modeling; mass detection
Keywords: microcantilever; biosensor; distributed-parameter modeling; mass detection
