Publications

@article{cheng2020targeted,

title = {Targeted Intravenous Nanoparticle Delivery: Role of Flow and Endothelial Glycocalyx Integrity},

author = {Ming J Cheng and Ronodeep Mitra and Chinedu C Okorafor and Alina A Nersesyan and Ian C Harding and Nandita N Bal and Rajiv Kumar and Hanjoong Jo and Srinivas Sridhar and Eno E Ebong},

year  = {2020},

date = {2020-01-01},

journal = {Annals of Biomedical Engineering},

pages = {1--14},

abstract = {Therapies for atherosclerotic cardiovascular disease should target early disease stages and specific vascular sites where disease occurs. Endothelial glycocalyx (GCX) degradation compromises endothelial barrier function and increases vascular permeability. This initiates pro-atherosclerotic lipids and inflammatory cells to penetrate vessel walls, and at the same time this can be leveraged for targeted drug delivery. In prior cell culture studies, GCX degradation significantly increased endothelial cell uptake of nanoparticle vehicles that are designed for drug delivery, compared to the effects of intact GCX. The present study assessed if the cell culture findings translate to selective nanoparticle uptake in animal vessels. In mice, the left carotid artery (LCA) was partially ligated to disturb blood flow, which induces GCX degradation, endothelial dysfunction, and atherosclerosis. After ligation, the LCA vessel wall exhibited.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{versek2020portable,

title = {Portable Objective Diagnostics using Visual Evoked Potentials for Age-related Macular Degeneration},

author = {Craig William Versek and Mohammad Ali S Banijamali and Peter J Bex and Kameran Lashkari and Sagar V Kamarthi and Srinivas Sridhar},

year  = {2020},

date = {2020-01-01},

journal = {medRxiv},

publisher = {Cold Spring Harbor Laboratory Press},

abstract = {Delayed Dark Adapted vision Recovery (DAR) is a biomarker for Age-related Macular Degeneration (AMD); however, its measurement is burdensome for patients and examiners. We developed a portable, wireless, quick-setup system that employs a headset with a smartphone to deliver and analyze controlled dichoptic photobleach and pattern reversal stimuli, and with custom electroencephalography (EEG) electrodes, to measure objective Dark Adapted Visual Evoked Potentials (DAVEP) at multiple locations of the visual field in one comfortable 20-minute session, without requiring subject reporting. DAVEP responses post photobleach (up to 15 minutes), were measured concurrently in both eyes of 13 patients with AMD and 8 others not diagnosed with AMD. New unexpected features were observed in the DAVEP responses at high latencies to scotopic stimulus intensities. The amplitude recovery of the DAVEP response was significantly delayed in AMD patients compared with controls. We developed DAVEP1 scores, a simple metric for DAR, using it to successfully identify all 100% of AMD subjects and correctly classify 90% of subject eyes. Deficits in DAR in patients with AMD can be identified with this objective VEP based system using the DAVEP1 metric, a promising new objective biomarker for this disease that can be easily tested in a clinic.},

keywords = {Neurotechnology, Opthalmology},

pubstate = {published},

tppubtype = {article}

}

@article{baldwin2019nanoformulationb,

title = {Nanoformulation of talazoparib increases maximum tolerated doses in combination with temozolomide for treatment of Ewing sarcoma},

author = {Paige Baldwin and Rostislav Likhotvorik and Nabeela Baig and Jodie Cropper and Ruth Carlson and Raushan Kurmasheva and Srinivas Sridhar},

year  = {2019},

date = {2019-01-01},

journal = {Frontiers in Oncology},

volume = {9},

pages = {1416},

publisher = {Frontiers},

abstract = {The Pediatric Preclinical Testing Program previously identified the PARP inhibitor talazoparib (TLZ) as a means to potentiate temozolomide (TMZ) activity for the treatment of Ewing sarcoma. However, the combination of TLZ and TMZ has been toxic in both preclinical and clinical testing, necessitating TMZ dose reduction to ~15% of the single agent maximum tolerated dose. We have synthesized a nanoparticle formulation of talazoparib (NanoTLZ) to be administered intravenously in an effort to modulate the toxicity profile of this combination treatment. Results in Ewing sarcoma xenograft models are presented to demonstrate the utility of this delivery method both alone and in combination with TMZ. NanoTLZ reduced gross toxicity and had a higher maximum tolerated dose than oral TLZ. The dose of TMZ did not have to be reduced when combined with NanoTLZ as was required when combined with oral TLZ. This indicated the NanoTLZ delivery system may be advantageous in decreasing the systemic toxicity associated with the combination of oral TLZ and TMZ.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{kunjachan2019selective,

title = {Selective priming of tumor Blood Vessels by Radiation therapy enhances nanodrug Delivery},

author = {Sijumon Kunjachan and Shady Kotb and Robert Pola and Michal Pechar and Rajiv Kumar and Bijay Singh and Felix Gremse and Reza Taleeli and Florian Trichard and Vincent Motto-Ros and others},

year  = {2019},

date = {2019-01-01},

journal = {Scientific reports},

volume = {9},

number = {1},

pages = {1--14},

publisher = {Nature Publishing Group},

abstract = {Effective drug delivery is restricted by pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, poorly-permeable blood vessels limit the intratumoral permeation and penetration of chemo or nanotherapeutic drugs. New and clinically viable strategies are urgently sought to breach the neoplastic barriers that prevent effective drug delivery. Here, we present an original idea to boost drug delivery by selectively knocking down the tumor vascular barrier in a human pancreatic cancer model. Clinical radiation activates the tumor endothelial-targeted gold nanoparticles to induce a physical vascular damage due to the high photoelectric interactions. Active modulation of these tumor neovessels lead to distinct changes in tumor vascular permeability. Noninvasive MRI and fluorescence studies, using a short-circulating nanocarrier with MR-sensitive gadolinium and a long-circulating nanocarrier with fluorescence-sensitive nearinfrared dye, demonstrate more than two-fold increase in nanodrug delivery, post tumor vascular modulation. Functional changes in altered tumor blood vessels and its downstream parameters, particularly, changes in Ktrans (permeability), Kep (flux rate), and Ve (extracellular interstitial volume), reflect changes that relate to augmented drug delivery. The proposed dual-targeted therapy effectively invades the tumor vascular barrier and improve nanodrug delivery in a human pancreatic tumor model and it may also be applied to other nonresectable, intransigent tumors that barely respond to standard drug therapies.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{qiao2019data,

title = {Data on MRI brain lesion segmentation using K-means and Gaussian Mixture Model-Expectation Maximization},

author = {Ju Qiao and Xuezhu Cai and Qian Xiao and Zhengxi Chen and Praveen Kulkarni and Craig Ferris and Sagar Kamarthi and Srinivas Sridhar},

year  = {2019},

date = {2019-01-01},

journal = {Data in brief},

volume = {27},

pages = {104628},

publisher = {Elsevier},

abstract = {The data in this article provide details about MRI lesion segmentation using K-means and Gaussian Mixture Model-Expectation Maximization (GMM-EM) algorithms. Both K-means and GMM-EM algorithms can segment lesion area from the rest of brain MRI automatically. The performance metrics (accuracy, sensitivity, specificity, false positive rate, misclassification rate) were estimated for the algorithms and there was no significant difference between K-means and GMM-EM. In addition, lesion size does not affect the accuracy and sensitivity for either method.},

keywords = {MRI},

pubstate = {published},

tppubtype = {article}

}

@article{di2019nano,

title = {A nano-liposome formulation of the PARP inhibitor Talazoparib enhances treatment efficacy and modulates immune cell populations in mammary tumors of BRCA-deficient mice},

author = {Paige Baldwin Di Zhang and Ana S Leal and Sarah Carapellucci and Srinivas Sridhar and Karen T Liby},

year  = {2019},

date = {2019-01-01},

journal = {Theranostics},

volume = {9},

number = {21},

pages = {6224},

publisher = {Ivyspring International Publisher},

abstract = {Two recently approved PARP inhibitors provide an important new therapeutic option for patients with BRCA-mutated metastatic breast cancer. PARP inhibitors significantly prolong progression-free survival in patients, but conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and off-target toxicities, thus compromising the therapeutic benefits and quality of life for patients. Here, we developed a new delivery system, in which the PARP inhibitor Talazoparib is encapsulated in the bilayer of a nano-liposome, to overcome these limitations.



Methods: Nano-Talazoparib (NanoTLZ) was characterized both in vitro and in vivo. The therapeutic efficacy and toxicity of Nano-Talazoparib (NanoTLZ) were evaluated in BRCA-deficient mice. The regulation of NanoTLZ on gene transcription and immunomodulation were further investigated in spontaneous BRCA-deficient tumors.



Results: NanoTLZ significantly (p<0.05) prolonged the overall survival of BRCA-deficient mice compared to all of the other experimental groups, including saline control, empty nanoparticles, and free Talazoparib groups (oral and i.v.). Moreover, NanoTLZ was better tolerated than treatment with free Talazoparib, with no significant weight lost or alopecia as was observed with the free drug. After 5 doses, NanoTLZ altered the expression of over 140 genes and induced DNA damage, cell cycle arrest and inhibition of cell proliferation in the tumor. In addition, NanoTLZ favorably modulated immune cell populations in vivo and significantly (p<0.05) decreased the percentage of myeloid derived suppressor cells in both the tumor and spleen compared to control groups.



Conclusions: Our results demonstrate that delivering nanoformulated Talazoparib not only enhances treatment efficacy but also reduces off-target toxicities in BRCA-deficient mice; the same potential is predicted for patients with BRCA-deficient breast cancer.



Keywords: PARP inhibitor, Talazoparib, Nanoparticle, BRCA-deficient breast cancer, immunomodulation},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{sridhar2019portable,

title = {Portable VEP Diagnostics for NeuroVisual Disorders},

author = {Srinivas Sridhar and Craig Versek and Ali Banijamali and Anthony Tran and Armando Cardozo and Kameran Lashkari and Peter Bex},

year  = {2019},

date = {2019-01-01},

journal = {Investigative Ophthalmology & Visual Science},

volume = {60},

number = {9},

pages = {3591--3591},

publisher = {The Association for Research in Vision and Ophthalmology},

abstract = {Purpose: Visual Evoked Potentials (VEPs) provide objective neuro-opthalmologic assessments that avoid patient task performance but utilizes invasive and cumbersome apparatus. We have developed a system that combines a scalp neuroelectric potential and field sensor with a smartphone in a portable wireless display headset called the NeuroDotVR (Figure 1). The system records VEPs and Fields (VEPF) in response to dichoptic stimuli presented on the smartphone display for a range of neuro-oplthalmologic disorders. We evaluate the NeuroDotVR for Dark Adaptation Recovers (DAR), a key biomarker for age-related macular degeneration (AMD).

Methods: DAR was measured simultaneously in both eyes of# patients with AMD and# age-matched controls. Following a 60s photobleach (400 cd/m 2 white cellphone screen), recovery of visual sensitivity was recorded with VEPFs to pattern reversal checkerboard …},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{versek2019portable,

title = {Portable system for neuro-optical diagnostics using virtual reality display},

author = {Craig Versek and Armen Rissmiller and Anthony Tran and Munish Taya and Kaushik Chowdhury and Peter Bex and Srinivas Sridhar},

year  = {2019},

date = {2019-01-01},

journal = {Military medicine},

volume = {184},

number = {Supplement_1},

pages = {584--592},

publisher = {Oxford University Press},

abstract = {A new product prototype system for diagnosing vision and neurological disorders, called NeuroDotVR, is described herein: this system utilizes a novel wireless NeuroDot brain sensor [Versek C et al. J Neural Eng. 2018 Aug; 15(4):046027] that quantitatively measures visual evoked potentials and fields resulting from custom visual stimuli displayed on a smartphone housed in a virtual reality headset. The NeuroDot brain sensor is unique in that it can be operated both in regular electroencephalography mode, as well as a new electric field encephalography mode, which yields improvements in signal sensitivity and provides new diagnostic information. Steady state and transient visual evoked potentials and fields using reversing checkerboard stimuli are presented with case studies in amblyopia, glaucoma, and dark adaptation. These preliminary data sets highlight potential clinical applications that may be …},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{baldwin2019nanoformulation,

title = {Nanoformulation of talazoparib delays tumor progression and ascites formation in a late stage cancer model},

author = {Paige Baldwin and Anders W Ohman and Jamie Edward Medina and Eric Timothy McCarthy and Daniela M Dinulescu and Srinivas Sridhar},

year  = {2019},

date = {2019-01-01},

journal = {Frontiers in oncology},

volume = {9},

pages = {353},

publisher = {Frontiers},

abstract = {Talazoparib, a potent PARP inhibitor, induces synthetic lethality in BRCA-deficient cancers making it an attractive candidate for ovarian cancer treatment. However, its potency lends itself to side effects associated more closely with traditional chemotherapeutics than other clinically approved PARP inhbitors. We sought to formulate Talazoparib in a nanoparticle delivery system, which allows the drug to be administered intraperitoneally. This was done to specifically target peritoneal dissemination of late stage metastatic ovarian cancer and increase talazoparib’s therapeutic efficacy while minimizing toxic side effects. NanoTalazoparib was developed and characterized with regard to its size, loading, and surface charge. Talazoparib and NanoTalazoparib were tested on a panel of murine and human BRCA cell lines and the dose response was compared to Olaparib’s, the currently used PARP inhibitor. Therapeutic efficacy was tested in vivo in a Brca peritoneal cancer model that mimics late stage disseminated disease. NanoTalazoparib has a diameter of about 70 nm with a neutral surface charge and ~75% encapsulation efficiency, which slowly releases the drug over several hours. Dose response analysis indicated that the murine cell lines with conditional BRCA1/2, PTEN, and TP53 deletions had the lowest IC50s. NanoTalazoparib administered on a schedule of three doses weekly slowed disease progression and resulted in significantly less mice with ascites at the end point compared to controls. These results indicate that the slow release nanoformulation, NanoTalazoparib, effectively delivers PARP inhibitor therapy to the peritoneal cavity for …},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{cheng2019ultrasmall,

title = {Ultrasmall gold nanorods: synthesis and glycocalyx-related permeability in human endothelial cells},

author = {Ming J Cheng and Nandita N Bal and Priya Prabakaran and Rajiv Kumar and Thomas J Webster and Srinivas Sridhar and Eno E Ebong},

year  = {2019},

date = {2019-01-01},

journal = {International journal of nanomedicine},

volume = {14},

pages = {319},

publisher = {Dove Press},

abstract = {Clinical data show shed endothelial glycocalyx (GCX) components in blood samples of atherosclerotic patients, linking atherosclerotic development to endothelial GCX integrity. Healthy GCX has pores no> 7 nm, and shed GCX has even larger pores. Therefore, we suggest targeting and treating atherosclerosis-prone blood vessels by using nanoscale vehicles to deliver drugs via the nanoscale GCX as it becomes dysfunctional.

Materials and methods

To test our idea, we investigated permeability of nanoparticles in endothelium, as related to a GCX expression. The present work involves nanorods, which are expected to interact with larger portions of endothelial cell (EC) membranes, due to surface area of the nanorod long axis. Conventional nanorod diameters are orders of magnitude larger than the GCX pore size, so we adapted conventional synthesis methods to fabricate ultrasmall gold nanorods …},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{sridhar2018costs,

title = {The Costs of Healthcare in Prison and Custody: Systematic Review of Current Estimates and Proposed Guidelines for Future Reporting},

author = {Shivpriya Sridhar and Robert Cornish and Seena Fazel},

year  = {2018},

date = {2018-01-01},

journal = {Frontiers in psychiatry},

volume = {9},

pages = {716},

publisher = {Frontiers},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{baldwin2018intraperitoneal,

title = {Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment},

author = {Paige Baldwin and Anders W Ohman and Shifalika Tangutoori and Daniela M Dinulescu and Srinivas Sridhar},

year  = {2018},

date = {2018-01-01},

journal = {International journal of nanomedicine},

volume = {13},

pages = {8063},

publisher = {Dove Press},

abstract = {Background

PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy. However, all orally-administered drugs, including Olaparib, must undergo first-pass metabolism. In contrast, a nanoparticle delivery system has the advantage of administering Olaparib directly into the peritoneal cavity for local treatment. Consequently, we sought to optimize the sustained-release formulation NanoOlaparib, previously deemed effective as an intravenous solid tumor treatment, for the local treatment of disseminated disease via intraperitoneal (i.p.) therapy.



Methods

The tumor cell line 404, which was derived from a Brca2−/−, Tp53−/−, Pten−/− genetically engineered mouse model, exhibited high sensitivity to Olaparib in vitro. It was chosen for use in developing an i.p. spread xenograft for testing nanotherapy efficacy in vivo. NanoOlaparib as a monotherapy or in combination with cisplatin was compared to oral Olaparib alone or in combination using two different dose schedules. A pilot biodistribution study was performed to determine drug accumulation in various organs following i.p. administration.



Results

Daily administration of NanoOlaparib reduced tumor growth and decreased the variability of the treatment response observed with daily oral Olaparib administration. However, systemic toxicity was observed in both the NanoOlaparib and vehicle (empty nanoparticle) treated groups. Scaling back the administration to twice weekly was well tolerated up to 100 mg/kg but reduced the effect on tumor growth. Biodistribution profiles indicated that NanoOlaparib began accumulating in tissues within an hour of administration and persisted for at least 72 hours after a single dose, exiting the peritoneal cavity faster than expected.



Conclusion

NanoOlaparib must be modified for use against disseminated disease. Future avenues to develop NanoOlaparib as an i.p. therapy include a modified surface-coating to retain it in the peritoneal cavity and prevent entry into systemic circulation, in addition to targeting moieties for localization in tumor cells.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{mitra2018comparative,

title = {The comparative effects of high fat diet or disturbed blood flow on glycocalyx integrity and vascular inflammation},

author = {Ronodeep Mitra and Ju Qiao and Sudharsan Madhavan and Gerard L O’Neil and Bailey Ritchie and Praveen Kulkarni and Srinivas Sridhar and Anne L van de Ven and Erica Cherry M Kemmerling and Craig Ferris and others},

year  = {2018},

date = {2018-01-01},

journal = {Translational medicine communications},

volume = {3},

number = {1},

pages = {1--15},

publisher = {BioMed Central},

abstract = {Background and aims

Endothelial surface glycocalyx shedding plays a role in endothelial dysfunction and increases vessel wall permeability, which can lead to inflammation and atherogenesis. We sought to elucidate whether a high fat diet (HFD) or disturbed blood flow conditions, both of which are atherogenic risk factors, would contribute more detrimentally to pre-atherosclerotic loss of endothelial glycocalyx integrity and vascular inflammation.



Methods

Six to seven week-old C57BL/6-background apolipoprotein-E-knockout (ApoE-KO) male mice were either fed a chow diet, fed a modified Western HFD, and/or subjected to a partial left carotid artery (LCA) ligation procedure to induce disturbed blood flow patterns in the LCA. Mice were sacrificed after 1 week of experimental conditions. Both LCA and right carotid artery (RCA) vessels were dissected and preserved to compare glycocalyx coverage and thickness as well as macrophage accumulation in carotid arterial walls amongst and between cohorts.



Results

Glycocalyx coverage of the endothelium was significantly reduced in the LCAs of HFD fed mice when compared to the control. More significant reduction in glycocalyx coverage occurred in the LCAs of mice exposed to disturbed flow by partial LCA ligation when compared to the control. No differences were found in glycocalyx coverage of RCAs from all cohorts. Regarding inflammation, no difference in macrophage accumulation in carotid arterial walls was observed when comparing the LCAs and RCAs of control and HFD fed mice. However, macrophage infiltration in vessel walls showed a 20-fold increase in the LCAs exposed to disturbed flow following ligation, when compared to control LCAs, while no such statistical difference was observed between the RCAs of the group.



Conclusions

In our mouse model, endothelial glycocalyx integrity was compromised more by disturbed blood flow patterns than by exposure of the carotid vessel to HFD conditions. The pathophysiological implications include endothelial dysfunction, which correlates to macrophage infiltration in vessel walls and promotes atherogenesis.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{zhang2018nanoformulated,

title = {Nanoformulated Talazoparib enhances the efficacy and reduces the toxicity of this PARP inhibitor in a preclinical model of BRCA-deficient breast cancer},

author = {Di Zhang and Paige Baldwin and Srinivas Sridhar and Karen Liby},

year  = {2018},

date = {2018-01-01},

journal = {The FASEB Journal},

volume = {32},

number = {1_supplement},

pages = {565--10},

publisher = {The Federation of American Societies for Experimental Biology},

abstract = {BRCA mutations are the leading cause of hereditary breast cancer. PARP inhibitors have shown promising activities in clinical trials for breast cancer by inducing synthetic lethality, particularly in patients with BRCA deficiency. Moreover, the utility of PARP inhibitors could potentially extend beyond BRCA mutations by targeting defects in homologous recombination, and thus impact up to 75% of triple negative breast cancer patients and 33% of breast cancer patients overall. However, conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and significant off-target toxicities, thus compromising the therapeutic benefits and quality of life in patients. Therefore, we developed a new nanoparticle delivery system for PARP inhibitors and hypothesize that nanoformulated Talazoparib can enhance efficacy by increasing drug concentrations in the tumor and reduce off-target toxicities. The nanoparticle formulation includes polymer brushes to prolong the circulation time, enabling tumor accumulation through the enhanced permeability and retention effect. The therapeutic efficacy of Nano-Talazoparib (Nano-TLZ) was assessed after i.v. injection in Brca1Co/Co;MMTV-Cre; p53+/− mice with established tumors and compared to vehicle control (saline, i.v.), empty nanoparticles (i.v.), free Talazoparib (i.v.), and free Talazoparib (gavage). Treatment was started when the tumor was 4 mm in diameter and ended when the tumor size reached defined IACUC endpoints. Nano-TLZ significantly (p<0.05) prolonged the life span of BRCA deficient mice from 11.6±2.6 days with saline injection and 18.3±3.6 days with empty nanoparticles injection to 82.2±10.5 days with i.v. Nano-TLZ. Nano-TLZ induced growth arrest in 100% of the tumors and regression (> 50% reduction in tumor volume) in 80% of the tumors. Established tumors regressed more rapidly, and therefore progression free survival significantly improved in the nanoformulated Talazoparib group (p<0.05). Moreover, Nano-TLZ is better tolerated than free Talazoparib with no significant weight lost or alopecia. In a biomarker study following 10 days of treatment, Nano-TLZ increased double strand DNA breaks (γ-H2AX) and decreased proliferation (PCNA) compared to the saline controls. Interestingly, Nano-TLZ significantly (p<0.05) decreased myeloid derived suppressor cells in both the tumor (41.6±4.7% to 11.2±2.9%) and spleen (10.0±3.2% to 3.7±0.6%) compared to the saline control. Nano-TLZ also significantly (p<0.05) decreased the percentage of tumor-associated macrophages in the mammary gland from 7.4±2.0% in the saline control group to 2.5±0.2% in the Nano-TLZ group. The changes in immune populations suggest potential immunomodulatory effects of Talazoparib. These results demonstrate that the delivery of Talazoparib as a nanoformulation induces superior treatment outcomes with reduced off-target toxicity in BRCA deficient mice, and provides a novel delivery strategy for PARP inhibitors in patients.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{amutha2018green,

title = {Green synthesis of magnetic iron oxide nanoparticle using leaves of Glycosmis mauritiana and their antibacterial activity against human pathogens},

author = {S Amutha and S Sridhar},

year  = {2018},

date = {2018-01-01},

journal = {Journal of Innovations in Pharmaceutical and Biological Sciences},

volume = {5},

pages = {22--26},

abstract = {The potential effect of Glycosmis mauritiana leaf extract for the formation of iron oxide nanoparticles and its application on antibacterial activity was discussed. The efficiency of G. mauritiana leaves are used as a bio-material for the first time as reducing agent. Synthesized iron oxide nanoparticles were characterized by UV–Vis spectrometry, DLS, XRD, FT-IR, SEM and TEM analysis. The results revealed that iron oxide nanoparticles has the absorption peak at 404 nm, spherical shaped and average size of particle is found to be below 100 nm. The green synthesized iron oxide nanoparticles showed good antibacterial activity against the tested pathogens. The present study highlights the potential application of iron oxide nanoparticles can be explored for biomedical industries.

},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{guthier2018determining,

title = {Determining optimal eluter design by modeling physical dose enhancement in brachytherapy},

author = {CV Guthier and AV D'Amico and MT King and PL Nguyen and PF Orio and S Sridhar and GM Makrigiorgos and RA Cormack},

year  = {2018},

date = {2018-01-01},

journal = {Medical physics},

volume = {45},

number = {8},

pages = {3916--3925},

abstract = {Purpose

In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio.



Materials and methods

The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for 125I permanent prostate implants. Compound concentrations were calculated using steady‐state solution to the diffusion equation including an elimination term characterized by the diffusion‐elimination modulus (ϕb). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (csat). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion‐elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other.



Results

The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm3, ϕb from 0.01 to 4 mm−1, csat from 0.05 to 7.5 times the steady‐state compound concentration released from the surface of the eluter. The number of used eluters (ne) was simulated from 10 to 60 eluters. For the region of (c sat , Φ)‐space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (c sat , Φ)‐space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations.



Conclusions

Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.



},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{versek2018electric,

title = {Electric field encephalography for brain activity monitoring},

author = {C Versek and T Frasca and J Zhou and K Chowdhury and S Sridhar},

year  = {2018},

date = {2018-01-01},

journal = {Journal of neural engineering},

volume = {15},

number = {4},

pages = {046027},

publisher = {IOP Publishing},

abstract = {Objective. We describe an early-stage prototype of a new wireless electrophysiological sensor system, called NeuroDot, which can measure neuroelectric potentials and fields at the scalp in a new modality called Electric Field Encephalography (EFEG). We aim to establish the physical validity of the EFEG modality, and examine some of its properties and relative merits compared to EEG. Approach. We designed a wireless neuroelectric measurement device based on the Texas Instrument ADS1299 Analog Front End platform and a sensor montage, using custom electrodes, to simultaneously measure EFEG and spatially averaged EEG over a localized patch of the scalp (2 cm  ×  2 cm). The signal properties of each modality were compared across tests of noise floor, Berger effect, steady-state visually evoked potential (ssVEP), signal-to-noise ratio (SNR), and others. In order to compare EFEG to EEG modalities in the frequency domain, we use a novel technique to compute spectral power densities and derive narrow-band SNR estimates for ssVEP signals. A simple binary choice brain–computer-interface (BCI) concept based on ssVEP is evaluated. Also, we present examples of high quality recording of transient Visually Evoked Potentials and Fields (tVEPF) that could be used for neurological studies. Main results. We demonstrate the capability of the NeuroDot system to record high quality EEG signals comparable to some recent clinical and research grade systems on the market. We show that the locally-referenced EFEG metric is resistant to certain types of movement artifacts. In some ssVEP based measurements, the EFEG modality shows promising results, demonstrating superior signal to noise ratios than the same recording processed as an analogous EEG signal. We show that by using EFEG based ssVEP SNR estimates to perform a binary classification in a model BCI, the optimal information transfer rate (ITR) can be raised from 15 to 30 bits per minute—though these preliminary results are likely sensitive to inter-subject variations and choice of scalp locations, so require further investigation. Significance. Enhancement of ssVEP SNR using EFEG has the potential to improve visually based BCIs and diagnostic paradigms. The time domain analysis of tVEPF signals shows robust features in the electric field components that might have clinical relevance beyond classical VEP approaches.},

keywords = {Nanomedicine, Opthalmology},

pubstate = {published},

tppubtype = {article}

}

@article{upponi2018polymeric,

title = {Polymeric micelles: Theranostic co-delivery system for poorly water-soluble drugs and contrast agents},

author = {Jaydev R Upponi and Kaushal Jerajani and Dattatri K Nagesha and Praveen Kulkarni and Srinivas Sridhar and Craig Ferris and Vladimir P Torchilin},

year  = {2018},

date = {2018-01-01},

journal = {Biomaterials},

volume = {170},

pages = {26--36},

publisher = {Elsevier},

abstract = {Interest in theranostic agents has continued to grow because of their promise for simultaneous cancer detection and therapy. A platform-based nanosized combination agent suitable for the enhanced diagnosis and treatment of cancer was prepared using polymeric polyethylene glycol-phosphatidylethanolamine-based micelles loaded with both, poorly soluble chemotherapeutic agent paclitaxel and hydrophobic superparamagnetic iron oxide nanoparticles (SPION), a Magnetic Resonance Imaging contrast agent. The co-loaded paclitaxel and SPION did not affect each other's functional properties in vitro. In vivo, the resulting paclitaxel-SPION-co-loaded PEG-PE micelles retained their Magnetic Resonance contrast properties and apoptotic activity in breast and melanoma tumor mouse models. Such theranostic systems are likely to play a significant role in the combined diagnosis and therapy that leads to a more personalized and effective form of treatment.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{baldwin2018vitro,

title = {In vitro analysis of pArp inhibitor nanoformulations},

author = {Paige Baldwin and Shifalika Tangutoori and Srinivas Sridhar},

year  = {2018},

date = {2018-01-01},

journal = {International journal of nanomedicine},

volume = {13},

number = {T-NANO 2014 Abstracts},

pages = {59},

publisher = {Dove Press},

abstract = {PARP-l is a DNA repair protein that plays a role in a number of repair pathways and also helps in transcriptional regulation; thus PARP inhibitors (PARPi), such as olaparib and BMN-673, act by inhibiting DNA damage repair. This leads to an accumulation of deleterious mutations leading to genetic instability as a result of a number of cell replications. Currently, olaparib is only available in an oral form and has poor bioavailability, consequently leading to poor accumulation in the tumor due to first-pass metabolism. Therefore, in the present study, an injectable nanoparticle formulation of olaparib was created that offers a delivery route in which the drug would be fully bioavailable in the vasculature, suggesting greater tumor accumulation. Our results illustrated that injectable nanoformulations of olaparib and BMN-673, a next generation PARPi, could be developed, and an efficacy test indicated that BMN-673 is a much more potent PARPi than olaparib. The success of these molecular inhibitors as a monotherapy in inhibiting colony formation suggests enhanced efficacy of these treatments in combination with other therapies, even in tumors which have developed resistance.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{baronia2018synthesis,

title = {Synthesis and characterization of multifunctional gold nanoclusters for application in radiation therapy},

author = {Richa Baronia and Manjri Singh and Rajat B Gupta and Stalin Karuppiah and Rajiv Kumar and Jodi Belz and Rishi Shanker and Srinivas Sridhar and Surinder P Singh},

year  = {2018},

date = {2018-01-01},

journal = {International journal of nanomedicine},

volume = {13},

number = {T-NANO 2014 Abstracts},

pages = {113},

publisher = {Dove Press},

abstract = {Gold nanoparticles, because of their high radiation absorption coefficient and efficient generation of secondary photoelectrons, have been predicted to enhance therapeutic efficacy in radiation therapy. However, high dose for effective treatment limits their use. We have synthesized multifunctional gold nanoclusters (GNCs) that can be used for imaging and radiation therapy. The designed GNCs have been characterized for their physicochemical properties, biocompatibility, and their radiation dose enhancement potential on PC3 cell lines.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{gupta2018synthesis,

title = {Synthesis and in vitro studies of PLGA-DTX nanoconjugate as potential drug delivery vehicle for oral cancer},

author = {Parul Gupta and Manjri Singh and Rajiv Kumar and Jodi Belz and Rishi Shanker and Premendra D Dwivedi and Srinivas Sridhar and Surinder P Singh},

year  = {2018},

date = {2018-01-01},

journal = {International journal of nanomedicine},

volume = {13},

number = {T-NANO 2014 Abstracts},

pages = {67},

publisher = {Dove Press},

abstract = {Advances in nanotechnology have led to the design of multifunctional nanoparticles capable of cellular imaging, targeted drug delivery, and diagnostics for early cancer detection. We synthesized poly(lactic-co-glycolic acid) nanoparticles encapsulating a model radiosensitizing drug docetaxel accomplishing localized in situ delivery of the sensitizer to the tumor site. The synthesized nanoparticles have been characterized for their physicochemical properties. The in vitro cytotoxicity of drug-loaded nanoparticles has been studied on human tongue carcinoma cell line SCC-9 (ATCC-CRL-1629).},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{celluzzi2018biophysical,

title = {Biophysical and biological contributions of polyamine-coated carbon nanotubes and bidimensional buckypapers in the delivery of miRNAs to human cells},

author = {Antonella Celluzzi and Alessandro Paolini and Valentina D’Oria and Roberta Risoluti and Stefano Materazzi and Marco Pezzullo and Stefano Casciardi and Simona Sennato and Federico Bordi and Andrea Masotti},

year  = {2018},

date = {2018-01-01},

journal = {International journal of nanomedicine},

volume = {13},

pages = {1},

publisher = {Dove Press},

abstract = {Recent findings in nanomedicine have revealed that carbon nanotubes (CNTs) can be used as potential drug carriers, therapeutic agents and diagnostics tools. Moreover, due to their ability to cross cellular membranes, their nanosize dimension, high surface area and relatively good biocompatibility, CNTs have also been employed as a novel gene delivery vector system. In our previous work, we functionalized CNTs with two polyamine polymers, polyethyleneimine (PEI) and polyamidoamine dendrimer (PAMAM). These compounds have low cytotoxicity, ability to conjugate microRNAs (such as miR-503) and, at the same time, transfect efficiently endothelial cells. The parameters contributing to the good efficiency of transfection that we observed were not investigated in detail. In fact, the diameter and length of CNTs are important parameters to be taken into account when evaluating the effects on drug delivery efficiency. In order to investigate the biophysical and biological contributions of polymer-coated CNTs in delivery of miRNAs to human cells, we decided to investigate three different preparations, characterized by different dimensions and aspect ratios. In particular, we took into account very small CNTs, a suspension of CNTs starting from the commercial product and a 2D material based on CNTs (ie, buckypapers [BPs]) to examine the transfection efficiency of a rigid scaffold. In conclusion, we extensively investigated the biophysical and biological contributions of polyamine-coated CNTs and bidimensional BPs in the delivery of miRNAs to human cells, in order to optimize the transfection efficiency of these compounds to be employed as efficient drug delivery vectors in biomedical applications.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{kunjachan2018targeted,

title = {Targeted Drug Delivery by Radiation-Induced Tumor Vascular Modulation},

author = {Sijumon Kunjachan and Shady Kotb and Rajiv Kumar and Robert Pola and Michal Pechar and Felix Gremse and Reza Taleeli and Florian Trichard and Vincent Motto-Ros and Lucie Sancey and others},

year  = {2018},

date = {2018-01-01},

journal = {bioRxiv},

pages = {268714},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Effective drug delivery is severely restricted by the presence of complex pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, mature and hypopermeable tumor blood vessels limit the permeation and penetration of chemo or nanotherapeutics to cancer cells and substantially reduce the treatment efficacy. New, clinically-viable strategies are therefore sought to breach the neoplastic barriers that prevent optimal tumor-specific drug delivery. Here, we present an original idea to boost targeted drug delivery by selectively knocking down the tumor vascular barrier in a poorly permeable human pancreatic cancer model. For the first time, we demonstrate that clinical irradiation (10 Gy, 6 MV) can induce tumor vascular modulation when combined with tumor endothelial-targeting gold nanoparticles. Active disruption of tumor blood vessels by nanoparticle-combined radiotherapy led to increased vessel permeability and improved tumor uptake of two prototypical model nanodrugs: i) a short-circulating nanocarrier with MR-sensitive gadolinium (Gad-NC; 8 kDa; t1/2=1.5 h) and ii) a long-circulating nanocarrier with fluorescence-sensitive NIR dye (FL-NC; 30 kDa; t1/2=25 h). Functional changes in the altered tumor vessel dynamics, measured by relative changes in permeability (Ktrans), flux rate (Kep) and extracellular interstitial volume (Ve) were consistent with the concomitant increase in nanodrug delivery. This combination of radiation-induced antivascular and nanodrug-mediated anti-tumor treatment offers high therapeutic benefit for tumors with pathophysiology that restricts efficient drug delivery},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{gharagouzloo2018dataset,

title = {Dataset on a 173 region awake resting state quantitative cerebral blood volume rat brain atlas and regional changes to cerebral blood volume under isoflurane anesthetization and CO2 challenge},

author = {Codi A Gharagouzloo and Liam Timms and Ju Qiao and Zihang Fang and Joseph Nneji and Aniket Pandya and Praveen Kulkarni and Anne L van de Ven and Craig Ferris and Srinivas Sridhar},

year  = {2018},

date = {2018-01-01},

journal = {Data in brief},

volume = {17},

pages = {393--396},

publisher = {Elsevier},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{cheng2018synthesis,

title = {Synthesis of functionalized 10-nm polymer-coated gold particles for endothelium targeting and drug delivery},

author = {Ming J Cheng and Priya Prabakaran and Rajiv Kumar and Srinivas Sridhar and Eno E Ebong},

year  = {2018},

date = {2018-01-01},

journal = {JoVE (Journal of Visualized Experiments)},

number = {131},

pages = {e56760},

abstract = {Gold nanoparticles (AuNPs) have been used extensively in medical research due to their size, biocompatibility, and modifiable surface. Specific targeting and drug delivery are some of the applications of these AuNPs, but endothelial extracellular matrices' defensive properties hamper particle uptake. To address this issue, we describe a synthesis method for ultrasmall gold nanoparticles to improve vascular delivery, with customizable functional groups and polymer lengths for further adjustments. The protocol yields 2.5 nm AuNPs that are capped with tetrakis(hydroxymethyl)phosphonium chloride (THPC). The replacement of THPC with hetero-functional polyethylene glycol (PEG) on the surface of the AuNP increases the hydrodynamic radius to 10.5 nm while providing various functional groups on the surface. The last part of the protocol includes an optional addition of a fluorophore to allow the AuNPs to be visualized under fluorescence to track nanoparticle uptake. Dialysis and lyophilization were used to purify and isolate the AuNPs. These fluorescent nanoparticles can be visualized in both in vitro and in vivo experiments due to the biocompatible PEG coating and fluorescent probes. Additionally, the size range of these nanoparticles render them an ideal candidate for probing the glycocalyx without disrupting normal vasculature function, which may lead to improved delivery and therapeutics.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{belz2017sustained,

title = {Sustained release talazoparib implants for localized treatment of BRCA1-deficient breast cancer},

author = {Jodi E Belz and Rajiv Kumar and Paige Baldwin and Noelle Castilla Ojo and Ana S Leal and Darlene B Royce and Di Zhang and Anne L van de Ven and Karen T Liby and Srinivas Sridhar},

year  = {2017},

date = {2017-01-01},

journal = {Theranostics},

volume = {7},

number = {17},

pages = {4340},

publisher = {Ivyspring International Publisher},

abstract = {Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{gharagouzloo2017quantitative,

title = {Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function},

author = {Codi A Gharagouzloo and Liam Timms and Ju Qiao and Zihang Fang and Joseph Nneji and Aniket Pandya and Praveen Kulkarni and Anne L van de Ven and Craig Ferris and Srinivas Sridhar},

year  = {2017},

date = {2017-01-01},

journal = {Neuroimage},

volume = {163},

pages = {24--33},

publisher = {Academic Press},

abstract = {A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.},

keywords = {MRI},

pubstate = {published},

tppubtype = {article}

}

@article{hachani2017assessing,

title = {Assessing cell-nanoparticle interactions by high content imaging of biocompatible iron oxide nanoparticles as potential contrast agents for magnetic resonance imaging},

author = {Roxanne Hachani and Martin A Birchall and Mark W Lowdell and Georgios Kasparis and Le D Tung and Bella B Manshian and Stefaan J Soenen and Willy Gsell and Uwe Himmelreich and Codi A Gharagouzloo and others},

year  = {2017},

date = {2017-01-01},

journal = {Scientific reports},

volume = {7},

number = {1},

pages = {1--14},

publisher = {Nature Publishing Group},

abstract = {Stem cell tracking in cellular therapy and regenerative medicine is an urgent need, superparamagnetic iron oxide nanoparticles (IONPs) could be used as contrast agents in magnetic resonance imaging (MRI) that allows visualization of the implanted cells ensuring they reach the desired sites in vivo. Herein, we report the study of the interaction of 3,4-dihydroxyhydrocinnamic acid (DHCA) functionalized IONPs that have desirable properties for T2 - weighted MRI, with bone marrow-derived primary human mesenchymal stem cells (hMSCs). Using the multiparametric high-content imaging method, we evaluate cell viability, formation of reactive oxygen species, mitochondrial health, as well as cell morphology and determine that the hMSCs are minimally affected after labelling with IONPs. Their cellular uptake is visualized by transmission electron microscopy (TEM) and Prussian Blue staining, and quantified using an iron specific colourimetric method. In vitro and in vivo studies demonstrate that these IONPs are biocompatible and can produce significant contrast enhancement in T2-weighted MRI. Iron oxide nanoparticles are detected in vivo as hypointense regions in the liver up to two weeks post injection using 9.4 T MRI. These DHCA functionalized IONPs are promising contrast agents for stem cell tracking by T2-weighted MRI as they are biocompatible and show no evidence of cytotoxic effects on hMSCs.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{van2017nanoformulation,

title = {Nanoformulation of olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation},

author = {Anne L van de Ven and Shifalika Tangutoori and Paige Baldwin and Ju Qiao and Codi Gharagouzloo and Nina Seitzer and John G Clohessy and Mike G Makrigiorgos and Robert Cormack and Pier Paolo Pandolfi and others},

year  = {2017},

date = {2017-01-01},

journal = {Molecular cancer therapeutics},

volume = {16},

number = {7},

pages = {1279--1289},

publisher = {American Association for Cancer Research},

abstract = {The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279–89. ©2017 AACR.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{guthier2017focal,

title = {Focal Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants},

author = {Christian V Guthier and Anthony V D'Amico and Martin T King and Paul L Nguyen and Peter F Orio and Srinivas Sridhar and Mike G Makrigiorgos and Robert A Cormack},

year  = {2017},

date = {2017-01-01},

journal = {Brachytherapy},

volume = {16},

number = {3},

pages = {S115},

publisher = {Elsevier},

abstract = {In-situ drug release concurrent with radiation therapy has been proposed as a means to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine which of the proposed methods is the preferred delivery approach.

Materials and Methods

The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}