@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

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 = {},

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 = {},

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 = {},

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{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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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 = {},

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{barlow2017high,

title = {High throughput microencapsulation of Bacillus subtilis in semi-permeable biodegradable polymersomes for selenium remediation},

author = {Jacob Barlow and Kevin Gozzi and Chase P Kelley and Benjamin M Geilich and Thomas J Webster and Yunrong Chai and Srinivas Sridhar and Anne L van de Ven},

year  = {2017},

date = {2017-01-01},

journal = {Applied microbiology and biotechnology},

volume = {101},

number = {1},

pages = {455--464},

publisher = {Springer Berlin Heidelberg},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{geilich2017superparamagnetic,

title = {Superparamagnetic iron oxide-encapsulating polymersome nanocarriers for biofilm eradication},

author = {Benjamin M Geilich and Ilia Gelfat and Srinivas Sridhar and Anne L van de Ven and Thomas J Webster},

year  = {2017},

date = {2017-01-01},

journal = {Biomaterials},

volume = {119},

pages = {78--85},

publisher = {Elsevier},

abstract = {The rising prevalence and severity of antibiotic-resistant biofilm infections poses an alarming threat to public health worldwide. Here, biocompatible multi-compartment nanocarriers were synthesized to contain both hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) and the hydrophilic antibiotic methicillin for the treatment of medical device-associated infections. SPION co-encapsulation was found to confer unique properties, enhancing both nanocarrier relaxivity and magneticity compared to individual SPIONs. These iron oxide-encapsulating polymersomes (IOPs) penetrated 20 μm thick Staphylococcus epidermidis biofilms with high efficiency following the application of an external magnetic field. Three-dimensional laser scanning confocal microscopy revealed differential bacteria death as a function of drug and SPION loading. Complete eradication of all bacteria throughout the biofilm thickness was achieved using an optimized IOP formulation containing 40 μg/mL SPION and 20 μg/mL of methicillin. Importantly, this formulation was selectively toxic towards methicillin-resistant biofilm cells but not towards mammalian cells. These novel iron oxide-encapsulating polymersomes demonstrate that it is possible to overcome antibiotic-resistant biofilms by controlling the positioning of nanocarriers containing two or more therapeutics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{guthier2017focal,

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

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

year  = {2017},

date = {2017-01-01},

journal = {Brachytherapy},

volume = {16},

number = {3},

pages = {S115},

publisher = {Elsevier},

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

Materials and Methods

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{van2017nanoformulation,

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

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

year  = {2017},

date = {2017-01-01},

journal = {Molecular cancer therapeutics},

volume = {16},

number = {7},

pages = {1279--1289},

publisher = {American Association for Cancer Research},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

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 = {},

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 = {},

pubstate = {published},

tppubtype = {article}

}

@article{schuemann2016roadmap,

title = {Roadmap to clinical use of gold nanoparticles for radiation sensitization},

author = {Jan Schuemann and Ross Berbeco and Devika B Chithrani and Sang Hyun Cho and Rajiv Kumar and Stephen J McMahon and Srinivas Sridhar and Sunil Krishnan},

year  = {2016},

date = {2016-01-01},

journal = {International Journal of Radiation Oncology* Biology* Physics},

volume = {94},

number = {1},

pages = {189--205},

publisher = {Elsevier},

abstract = {The past decade has seen a dramatic increase in interest in the use of gold nanoparticles (GNPs) as radiation sensitizers for radiation therapy. This interest was initially driven by their strong absorption of ionizing radiation and the resulting ability to increase dose deposited within target volumes even at relatively low concentrations. These early observations are supported by extensive experimental validation, showing GNPs' efficacy at sensitizing tumors in both in vitro and in vivo systems to a range of types of ionizing radiation, including kilovoltage and megavoltage X rays as well as charged particles. Despite this experimental validation, there has been limited translation of GNP-mediated radiation sensitization to a clinical setting. One of the key challenges in this area is the wide range of experimental systems that have been investigated, spanning a range of particle sizes, shapes, and preparations. As a result, mechanisms of uptake and radiation sensitization have remained difficult to clearly identify. This has proven a significant impediment to the identification of optimal GNP formulations which strike a balance among their radiation sensitizing properties, their specificity to the tumors, their biocompatibility, and their imageability in vivo. This white paper reviews the current state of knowledge in each of the areas concerning the use of GNPs as radiosensitizers, and outlines the steps which will be required to advance GNP-enhanced radiation therapy from their current pre-clinical setting to clinical trials and eventual routine usage.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{markovic2016near,

title = {Near-infrared fluorescence imaging platform for quantifying in vivo nanoparticle diffusion from drug loaded implants},

author = {Stacey Markovic and Jodi Belz and Rajiv Kumar and Robert A Cormack and Srinivas Sridhar and Mark Niedre},

year  = {2016},

date = {2016-01-01},

journal = {International journal of nanomedicine},

volume = {11},

pages = {1213},

publisher = {Dove Press},

abstract = {Drug loaded implants are a new, versatile technology platform to deliver a localized payload of drugs for various disease models. One example is the implantable nanoplatform for chemo-radiation therapy where inert brachytherapy spacers are replaced by spacers doped with nanoparticles (NPs) loaded with chemotherapeutics and placed directly at the disease site for long-term localized drug delivery. However, it is difficult to directly validate and optimize the diffusion of these doped NPs in in vivo systems. To better study this drug release and diffusion, we developed a custom macroscopic fluorescence imaging system to visualize and quantify fluorescent NP diffusion from spacers in vivo. To validate the platform, we studied the release of free fluorophores, and 30 nm and 200 nm NPs conjugated with the same fluorophores as a model drug, in agar gel phantoms in vitro and in mice in vivo. Our data verified that the diffusion volume was NP size-dependent in all cases. Our near-infrared imaging system provides a method by which NP diffusion from implantable nanoplatform for chemo-radiation therapy spacers can be systematically optimized (eg, particle size or charge) thereby improving treatment efficacy of the platform.



Keywords: optical imaging, fluorescence, drug delivery, brachytherapy, treatment monitoring},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{hau2016dose,

title = {Dose enhancement and cytotoxicity of gold nanoparticles in colon cancer cells when irradiated with kilo-and mega-voltage radiation},

author = {Herman Hau and Dipesh Khanal and Linda Rogers and Natalka Suchowerska and Rajiv Kumar and Srinivas Sridhar and David McKenzie and Wojciech Chrzanowski},

year  = {2016},

date = {2016-01-01},

journal = {Bioengineering & translational medicine},

volume = {1},

number = {1},

pages = {94--102},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cormack2016localized,

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

author = {Robert A Cormack and Paul N Nguyen and Anthony V D'Amico and Srinivas Sridhar and Gerassimos Makrigiorgos},

year  = {2016},

date = {2016-01-01},

journal = {Brachytherapy},

volume = {15},

pages = {S161--S162},

publisher = {Elsevier},

abstract = {Purpose

In-situ drug release concurrent with radiation therapy may 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. The drug distributions are expected to have a comparable, or greater spatial gradient than brachytherapy radiation distributions. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine whether drug eluting sources or spacers produce greater effect.

Methods and Materials

The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Prostate geometry, source and spacer positions were extracted from treatment plans of 125I permanent prostate implants. Radiation doses were calculated according to AAPM TG 43 point source formalism. Drug concentrations were calculated using a steady state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (φb). Radiosensitization was assumed to be dependent on drug concentration up to a saturation concentration (csat). Effective dose, taken to be the product of dose and sensitization, was used as an objective function to determine the optimal configuration of drug eluters for a range of φb, csat and number of eluters (ne). The locations of ne eluters were determined by a genetic optimization algorithm maximizing effective dose. The drug eluter that produced the greatest effective dose were tallied for points in parameter space [φb, csat,ne] to determine the conditions where one approach is preferable.

Results

The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration released from the surface of the eluter and ne from 10 to 60 drug eluters. For the region of [φb, csat] space that results in a large fraction of the gland being maximally sensitized, drug eluting spacers or sources produce equal increase in biologic effect. In the majority of the remaining [φb, csat] space, drug eluting spacers result in a greater biologic effect than sources even where sources often produce greater maximal radio-sensitization. Placing drug eluting implants in planned locations throughout the prostate results in even greater sensitization than using only source or spacer locations.

Conclusions

Drug eluting brachytherapy spacers offer a means to increase the biologic effect of brachytherapy implants with no change in treatment process. Incorporating additional needles allows the freedom to place spacers independently of sources and increases effective dose with minor modifications of the implant process. Further work is needed to understand the in-vivo spatial distribution of drug around drug eluters, and to incorporate time dependence of both drug release and radiation dose.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{belz2016we,

title = {WE-FG-BRA-02: Docetaxel Eluting Brachytherapy Spacers for Local Chemo-Radiation Therapy in Prostate Cancer},

author = {J Belz and R Kumar and G Makrigiorgos and A D'Amico and P Nguyen and R Cormack and S Sridhar},

year  = {2016},

date = {2016-01-01},

journal = {Medical physics},

volume = {43},

number = {6Part41},

pages = {3823--3823},

publisher = {American Association of Physicists in Medicine},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cheng2016endothelial,

title = {Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting},

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

year  = {2016},

date = {2016-01-01},

journal = {International journal of nanomedicine},

volume = {11},

pages = {3305},

publisher = {Dove Press},

abstract = {Cardiovascular diseases are facilitated by endothelial cell (EC) dysfunction and coincide with EC glycocalyx coat shedding. These diseases may be prevented by delivering medications to affected vascular regions using circulating nanoparticle (NP) drug carriers. The objective of the present study was to observe how the delivery of 10 nm polyethylene glycol-coated gold NPs (PEG-AuNP) to ECs is impacted by glycocalyx structure on the EC surface. Rat fat pad endothelial cells were chosen for their robust glycocalyx, verified by fluorescent immunolabeling of adsorbed albumin and integrated heparan sulfate (HS) chains. Confocal fluorescent imaging revealed a ~3 µm thick glycocalyx layer, covering 75% of the ECs and containing abundant HS. This healthy glycocalyx hindered the uptake of PEG-AuNP as expected because glycocalyx pores are typically 7 nm wide. Additional glycocalyx models tested included: a collapsed glycocalyx obtained by culturing cells in reduced protein media, a degraded glycocalyx obtained by applying heparinase III enzyme to specifically cleave HS, and a recovered glycocalyx obtained by supplementing exogenous HS into the media after enzyme degradation. The collapsed glycocalyx waŝ2 µm thick with unchanged EC coverage and sustained HS content. The degraded glycocalyx showed similar changes in EC thickness and coverage but its HS thickness was reduced to 0.7 µm and spanned only 10% of the original EC surface. Both dysfunctional models retained six- to sevenfold more PEG-AuNP compared to the healthy glycocalyx. The collapsed glycocalyx permitted NPs to cross the glycocalyx into intracellular spaces, whereas the degraded glycocalyx trapped the PEG-AuNP within the glycocalyx. The repaired glycocalyx model partially restored HS thickness to 1.2 µm and 44% coverage of the ECs, but it was able to reverse the NP uptake back to baseline levels. In summary, this study showed that the glycocalyx structure is critical for NP uptake by ECs and may serve as a passive pathway for delivering NPs to dysfunctional ECs.



Keywords: glycocalyx, heparan sulfate, endothelial cells, NP, gold},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{kunjachan2016po,

title = {PO-0983: Nanoparticle mediated tumor vascular disruption: A novel strategy in radiation therapy},

author = {S Kunjachan and A Detappe and R Kumar and S Sridhar and GM Makrigiorgos and R Berbeco},

year  = {2016},

date = {2016-01-01},

journal = {Radiotherapy and Oncology},

volume = {119},

pages = {S477--S478},

publisher = {Elsevier},

abstract = {Purpose or Objective: More than 50% all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation doses is strictly

restricted by the proximal healthy tissues. Chemical/biological agents to augment the radiosensitization of cancer cells are limited by severe off-target toxicity concerns. We propose a dual-targeting strategy using tumor vasculartargeted gold nanoparticles (which amplify radiosensitization) combined with the conformal imageguided radiation therapy to induce tumor vascular disruption. This is a unique concept with a clear translational path. S478 ESTRO 35 2016

_____________________________________________________________________________________________________

Material and Methods: Chemically synthesized, RGD-/PEGfunctionalized gold nanoparticles (RGD:AuNP; ≈2 -3 nm) were characterized using STEM, TEM, and LIBS imaging. Following clonogenic assay, radiation damage was induced in Panc1 xenografts with 10 Gy and 220 kVp (Xtrahl, Inc). γ-H2AX, 3D-(confocal) vessel imaging and IHC were performed. Results: Tumor vessel-targeted gold nanoparticles were subjected to conformal image-guided irradiation in Panc-1 tumor xenograft to induce tumor vascular disruption. By specifically targeting the early angiogenic tumor endothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limits the penetration and permeation of anti-cancer drugs/ nanoparticles to the cancer cells - a limitation of current radiosensitization approaches. In vitro testing in HUVEC displayed ≥3 -fold difference (***P<0.0001) in radiation damage in the +RGD:AuNP/+IR compared to the controls. More to it, the sub-millimeter accuracy of image guided radiation therapy facilitated improved therapeutic efficacy (95%-100% tumor dose distribution) and less off-target toxicities. Quantification of the DNA-strand breaks (by γH2AX) showed ≈3 -fold increase (P<0.001) in the radiation specific DNA damage in the 'nanoparticle-radiation' cohort (+RGD:AuNP/+IR: 57%) compared to the 'radiation' group (−RGD:AuNP/+IR:19%) and almost ≈10 -fold difference (P<0.001) compared to (+RGD:AuNP/−IR: 6% and −RGD:AuNP/−IR: 6%). Conclusion: This dual-targeting strategy holds great translational potential in radiation oncology. The resulting vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/ nanoparticle toxicity, extending its utility to intransigent/ non-resectable tumors that barely respond to standard therapies. This abstract presents the first in-depth experimental investigation of tumor vascular disruption with nanoparticles, a novel strategy in radiation therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cormack2016situ,

title = {In Situ Radiosensitization of Brachytherapy: Image Guided Planned Biologic Enhancement of Brachytherapy},

author = {RA Cormack and PL Nguyen and AV D'Amico and S Sridhar and M Makrigiorgos},

year  = {2016},

date = {2016-01-01},

journal = {International Journal of Radiation Oncology• Biology• Physics},

volume = {96},

number = {2},

pages = {E649},

publisher = {Elsevier},

abstract = {Purpose/Objective(s)

In situ radiosensitizer release concurrent with image guided brachytherapy has been proposed as a means to enhance the therapeutic ratio while avoiding toxicity associated with systemic delivery. Drug-eluting implants have been developed that release radio-sensitizer on time scales comparable to the half-life of isotopes used in brachytherapy procedures. This work presents a means of calculating the combined effect of eluter-source configurations and to optimize source positions for maximal biologic effect.

Materials/Methods

The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Implant geometries were extracted from treatment plans of 125I permanent prostate implants. Drug concentrations were simulated using a steady-state solution to the diffusion-elimination equation. Radiosensitization was modeled as dependent on drug concentration up to a saturation concentration. Effective dose was used as a metric to optimize eluter locations. The maximal effective dose was calculated for 3 types of implants across parameter space (diffusion-elimination modulus [φb], saturation concentration [csat], number of eluters [ ne]).

Results

Three types of eluter configurations were evaluated: drug-eluting brachytherapy sources, drug-eluting brachytherapy spacers, and planned eluter positioning. The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45 cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration at the surface of the eluter, and ne from 10 to 60 drug eluters. For the region of (φb, csat) space that results in a large fraction of the gland being maximally sensitized (low values of φb and csat), planned eluter locations do not increase the effective dose of the drug-radiation system more than either eluting spacers or sources. In the majority of the remaining (φb, csat) space (large φb and or csat ), planning the location of drug-eluting spacers will result in a greater biologic effect than sources even where sources often produce greater maximal radiosensitization.

Conclusion

Freely positioned drug-eluting implants offer the best means to increase the biologic effect of brachytherapy implants with minimal change in treatment process. Imaging, already in use for guidance of brachytherapy source placement, can be used to guide placement of radiosensitizing implants. A better understanding of in vivo drug distributions will allow brachytherapy planning systems to be adapted to incorporate the effects of in situ drug delivery.

Acknowledgment: DOD PC 110722, Mazzone 2012PD164.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{baldwin2016nanoformulationb,

title = {Nanoformulation of the PARP inhibitor olaparib enables radiosensitization of a radiation-resistant prostate cancer model},

author = {P Baldwin and AL Van De Ven and N Seitzer and S Clohessy and RA Cormack and M Makrigiorgos and PP Pandolfi and S Sridhar},

year  = {2016},

date = {2016-01-01},

journal = {International Journal of Radiation Oncology• Biology• Physics},

volume = {96},

number = {2},

pages = {E595},

publisher = {Elsevier},

abstract = {Purpose/Objective(s)

Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents, such as radiation. We hypothesized that delivery of a PARP inhibitor via a nanoformulation would increase the bioavailability and accumulation of the drug at the tumor site thereby leading to greater radiosensitization. Here we report the development and testing of this novel nanoformulation of Olaparib to allow intravenous delivery.

Materials/Methods

Nanoparticle formulations of Olaparib were synthesized and tested in vitro and in vivo. In vitro experiments include a comparison of free Olaparib and NanoOlaparib in prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. FK01 is a highly radio-resistant cell line and provided the ideal model to test the relationship between NanoOlaparib and radiation therapy via clonogenic assays. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.

Results

Strong radiosensitization was observed in FK01 cells with NanoOlaparib. As expected, there was little difference between free drug and the nanoformulation in vitro because it is formulated to enhance in vivo delivery. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib alone was shown to delay tumor growth, while the combination of radiation and NanoOlaparib clearly shrank the tumors.

Conclusion

Robust nanoparticle formulations of NanoOlaparib have been successfully demonstrated for in vitro and in vivo studies. These results show that NanoOlaparib can sensitize tumors which are normally highly resistant to radiation therapy to this mode of treatment. This implies a very promising potential for NanoOlaparib in the clinic for the treatment of both radiation sensitive and radiation resistant tumors. This work was supported by the IGERT grant NSF-DGE- 0965843 and the Mazzone Foundation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{belz2016docetaxel,

title = {Docetaxel-Loaded Brachytherapy Spacers for Combined Chemoradiation Therapy in Prostate Cancer},

author = {J Belz and Castilla N Ojo and R Kumar and RA Cormack and M Makrigiorgos and S Sridhar and AV D'Amico and PL Nguyen},

year  = {2016},

date = {2016-01-01},

journal = {International Journal of Radiation Oncology• Biology• Physics},

volume = {96},

number = {2},

pages = {S109},

publisher = {Elsevier},

abstract = {Purpose/Objective(s)

Combined chemo-radiation therapy (CRT) with Docetaxel (DTX) has been shown in several trials to improve survival in multiple cancers. We have developed an innovative combinatorial treatment strategy of local chemoradiation therapy (LCRT) using a sustained drug delivery platform in the form of a spacer loaded with DTX to locally radio-sensitize the prostate enabling a synergistic cure with the use of lower radiation doses. InCeRT spacers are physically similar to the inert spacers routinely used in prostate brachytherapy but are biodegradable releasing DTX over many weeks.

Materials/Methods

Biodegradable spacers of 1-2 mm length and 0.8 mm diameter were loaded with ∼500 μg Docetaxel (DTX) per spacer for prostate cancer studies. The spacers 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 IC50s were determined using an MTS assay in PC3 cells. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded spacers were injected once intratumorally using an 18G brachytherapy needle. Radiation was given using SARRP at 5 Gy, 10 Gy, and 15 Gy.

Results

The release profile of the drug from the spacer in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for DTX loaded spacers. The monotherapy with local DTX spacer showed sustained tumor inhibition compared to empty spacers and an equivalent DTX dose given systemically. At 40 days, 89% survival was observed for mice treated with localized DTX spacers compared with 0% in all other treatment groups. As hypothesized, the combined treatment with local DTX spacer and radiation (10 Gy) showed the highest degree of tumor suppression (significant tumor growth inhibition by day 90). The control mice which received no treatment showed continuous tumor growth and were scarified by day 56. Groups of mice treated with DTX-spacer or radiation alone showed initial tumor suppression but tumor growth continued after day 60. A larger experiment to further this study is ongoing.

Conclusion

This approach provides localized in-situ delivery of the chemotherapeutic sensitizer directly to the tumor and avoids the toxicities associated with current systemic delivery of docetaxel. Therapeutic-loaded spacers represent a novel delivery route that is well-tolerated. Sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. DTX loaded spacers would proffer a new treatment option for substantially enhancing therapeutic ratio and boosting cure rate for the hundreds of thousands of Americans diagnosed with prostate cancer each year. This work was supported by the Army W81XWH-14-1-0092, NSF-DGE 0965843, and HHS 1R25CA174650-02.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{kunjachan2016nanoparticle,

title = {Nanoparticle-Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy},

author = {S Kunjachan and A Detappe and R Kumar and S Sridhar and M Makrigiorgos and RI Berbeco},

year  = {2016},

date = {2016-01-01},

journal = {International Journal of Radiation Oncology• Biology• Physics},

volume = {96},

number = {2},

pages = {S97},

publisher = {Elsevier},

abstract = {Purpose/Objective(s)

More than half of all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation dose is severely restricted by proximal healthy tissues. Chemical and biological agents to augment the radiosensitization of cancer cells exhibit high off-target toxicity. 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. Subsequent tumor vascular damage considerably improved the therapeutic outcome and subsidized the radiation and/or nanoparticle toxicity. This is a unique concept with clear translational path.

Materials/Methods

(Arg-Gly-Asp)- and (PEG)-functionalized gold nanoparticles (RGD:AuNP) were designed and administered to mice pancreatic tumor xenografts (1.25 mg/mL equiv. Au) and angiogenic tumor blood vessels (expressing integrins) were targeted. In 24 h- post-administration, the mice were subjected to targeted irradiation (IR) to induce tumor vascular disruption.

Results

RGD:AuNP formulation (∼3 nm) is non-toxic and stable for more than 6 months. High-res.-TEM, LIBS/STEM imaging confirmed its preferential tumor endothelial uptake. By specifically targeting the early angiogenic neoendothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limit the penetration and permeation of anti-cancer drugs and nanoparticles to the tumor cells - a limitation of current radiosensitization approaches. The sub- mm accuracy of image-guided radiation therapy facilitated increased radio-therapeutic efficacy (95-100% tumor-dose distribution) and less off-target toxicity. More than 2.5-fold differences in the specific tumor vascular damage was observed in +RGD:AuNP/+IR (compared to controls) when assessed by γH2AX, 3D-(confocal) vessel imaging, and IHC analysis. Targeted irradiation at 24 h following RGD:AuNP administration showed significant reduction in the tumor size and improved overall animal survival by >140 days (P< 0.0001, Mantel-Cox test), compared to non-treated IR controls (∼95 days).

Conclusion

For the first time, our study demonstrates a catastrophic in vivo induction of “tumor vascular disruption” using targeted-gold nanoparticles and targeted-irradiation. The study was structured based on current clinical practices optimized for high therapeutic efficacy and minimal patient risk. This strategy may also be extended to other intransigent or non-resectable tumors for which radiation delivery is limited by adjacent organs, augmenting its potential clinical impact.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{reyes2016advancing,

title = {Advancing Bio-Inspired Rosette Nanotubes as a Novel and Effective siRNA Delivery Vehicle for the Treatment of Pancreatic Cancer},

author = {Gino Karlo Lapitan Delos Reyes and Anne Van de Ven and Rasam Soheilian and Srinivas Sridhar and Randall Erb and Hicham Fenniri},

year  = {2016},

date = {2016-01-01},

abstract = {Advancing Bio-Inspired Rosette Nanotubes as a Novel and Effective siRNA Delivery Vehicle for the

Treatment of Pancreatic Cancer

Gino Karlo Lapitan Delos Reyes1

, Anne Van de Ven2

, Rasam Soheilian3

, Srinivas Sridhar2

, Randall Erb3

,

Hicham Fenniri2

1

Dept. of Chemical Engineering, 2

Dept. of Physics, 3

Dept. of Mechanical and Industrial Engineering,

Northeastern University, Boston, MA

October 28, 2016

11:45 AM, 105 Shillman Hall

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year survival rate of less than 7% and

a median survival rate of merely six months following diagnosis1

. State-of-the-art therapies involve

subjecting patients to a cocktail of anti-cancer drugs, many of which have a host of undesirable side

effects. Implicated in 95% of PDAC patients is a mutated KRAS gene, which functions to enhance the

cancer phenotype2

. It is demonstrated through this work that Rosette Nanotubes (RNTs), developed in the

Supramolecular Nanomaterials Lab, can effectively deliver therapeutic small interfering RNA (siRNA)

targeted against the KRAS gene to pancreatic cancer cells and silence the gene.

RNTs are a biocompatible and tunable nanocarrier that can effectively carry a therapeutic RNA payload

to pancreatic cancer cells3

. A defining characteristic and strength of the RNTs as a drug delivery vehicle

is the ability to display various functional groups on their surface during self-assembly, conferring to

them tunable physical (stability, dimensions), chemical (surface charge and channel properties), and

biological (targeting peptides, bioactive molecules) properties. This works demonstrates the effectiveness

of RNTs to silence oncogenes in an in vitro PDAC cell model. Using fluorescently tagged siRNA (si555)

and siRNA targeted against the oncogene KRAS, we are able to demonstrate effective delivery and

function of using the RNT delivery system.

Methods

In order to determine the efficiency of delivery, Panc1 pancreatic cancer cells were seeded in microtiter

plates according to standard protocols. Groups of cells were then administered the following treatments:

untreated control, naked si555, K1 + si555, and Lipofectamine + si555. The RNTs used in this study are

routinely synthesized in our laboratory. Lipofectamine, a commercially available transfection reagent,

functions as a positive control. Post-treatment, the cells were then separated into single cell formations

and their total internal fluorescence subsequently analyzed on a benchtop flow cytometer.

Furthermore, the function of the siRNA delivered within the cells was evaluated through the assessment

of the expression of the the KRAS gene. In order to assess the function of the siRNA delivered within the

cells, anti-KRAS siRNA (siKRAS) was purchased (Invitrogen). The Panc1 cells were then separated into

replicate groups and administered the following: untreated control, naked siKRAS, K1 + siKRAS, K3 +

siKRAS, or Lipofectamine + siKRAS. Once again, Lipofectamine was utilized as a positive control. The

cells were incubated with the treatments for 48 hours, followed by cell lysis and harvesting of the total

mRNA. The expression of the KRAS gene was then determined using quantitative reverse transcription

polymerase chain reaction (RT-qPCR). 

Results and Discussion

In regards to the in vitro studies, the RNTs functioned significantly more effectively than the cells treated

with naked siRNA or the Lipofectamine-treated cells. For example, the cells treated with naked tagged

siRNA showed a total internal fluorescence, signifying intracellular delivery of the siRNA, that is roughly

75% less than the cells treated with the RNTs (Figure 1A). This clearly illustrates the benefit of using

RNTs as a gene delivery vehicle. The results in Figure 1B illustrated that the cells treated with naked

siRNA exhibited little to no knockdown of the KRAS gene, as reported by RT-qPCR. However, the cells

transfected using the K1 and K3 exhibited a remarkably greater knockdown levels (54% and 55% KRAS

expression, respectively) as compared to the naked siRNA control (96%) sample. These results are also

comparable to the cells transfected with the Lipofectamine. This result is significant because

Lipofectamine, although effective at gene delivery in vitro, is well documented to have cytotoxic effects

and is not viable in vivo. Overall, the results of this work demonstrate that RNTs are a viable and effective

gene delivery vehicle for the treatment of pancreatic cancer.

Funding Acknowledgements

NSF IGERT Nanomedicine Science and Technology program at Northeastern University, NSF/DGE096843

NSF CPS-1329649

Northeastern University Chemical Engineering Department

References:

1) P. Michl, T. M. Gress, Gut 2012, 317.

2) C. V Pecot, S. Y. Wu, S. Bellister, J. Filant, R. Rupaimoole, T. Hisamatsu, R. Bhattacharya, A.

Maharaj, S. Azam, C. Rodriguez-aguayo, et al., Small Mol. Ther. 2014, 13, DOI 10.1158/1535-

7163.MCT-14-0074.

3) H. Fenniri, P. Mathivanan, K. L. Vidale, D. M. Sherman, K. Hallenga, K. V. Wood, J. G. Stowell, J.

Am. Chem. Soc. 2001, 123, 3854–3855.

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{van2015essential,

title = {Essential components of a successful doctoral program in nanomedicine},

author = {Anne L van de Ven and Mary H Shann and Srinivas Sridhar},

year  = {2015},

date = {2015-01-01},

journal = {International journal of nanomedicine},

volume = {10},

pages = {23},

publisher = {Dove Press},

abstract = {The Nanomedicine program at Northeastern University provides a unique interdisciplinary graduate education that combines experiential research, didactic learning, networking, and outreach. Students are taught how to apply nanoscience and nanotechnology to problems in medicine, translate basic research to the development of marketable products, negotiate ethical and social issues related to nanomedicine, and develop a strong sense of community involvement within a global perspective. Since 2006, the program has recruited 50 doctoral students from ten traditional science, technology, and engineering disciplines to participate in the 2-year specialization program. Each trainee received mentoring from two or more individuals, including faculty members outside the student’s home department and faculty members at other academic institutions, and/or clinicians. Both students and faculty members reported a significant increase in interdisciplinary scholarly activities, including publications, presentations, and funded research proposals, as a direct result of the program. Nearly 90% of students graduating with a specialization in nanomedicine have continued on to careers in the health care sector. Currently, 43% of graduates are performing research or developing products that directly involve nanomedicine. This article identifies some key elements of the Nanomedicine program, describes how they were implemented, and reports on the metrics of success.



Keywords: nanomedicine, IGERT, nanotechnology, nanoscience, education, graduate training},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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},

journal = {Medical physics},

volume = {42},

number = {6Part29},

pages = {3565--3565},

publisher = {American Association of Physicists in Medicine},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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},

journal = {Science advances},

volume = {1},

number = {6},

pages = {e1500094},

publisher = {American Association for the Advancement of Science},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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 = {},

pubstate = {published},

tppubtype = {article}

}

@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},

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 = {},

pubstate = {published},

tppubtype = {article}

}

@article{chapman2013nanoparticles,

title = {Nanoparticles for cancer imaging: The good, the bad, and the promise},

author = {Sandra Chapman and Marina Dobrovolskaia and Keyvan Farahani and Andrew Goodwin and Amit Joshi and Hakho Lee and Thomas Meade and Martin Pomper and Krzysztof Ptak and Jianghong Rao and others},

year  = {2013},

date = {2013-01-01},

journal = {Nano today},

volume = {8},

number = {5},

pages = {454--460},

publisher = {Elsevier},

abstract = {Recent advances in molecular imaging and nanotechnology are providing new opportunities for biomedical imaging with great promise for the development of novel imaging agents. The unique optical, magnetic, and chemical properties of materials at the scale of nanometers allow the creation of imaging probes with better contrast enhancement, increased sensitivity, controlled biodistribution, better spatial and temporal information, multi-functionality and multi-modal imaging across MRI, PET, SPECT, and ultrasound. These features could ultimately translate to clinical advantages such as earlier detection, real time assessment of disease progression and personalized medicine. However, several years of investigation into the application of these materials to cancer research has revealed challenges that have delayed the successful application of these agents to the field of biomedical imaging. Understanding these challenges is critical to take full advantage of the benefits offered by nano-sized imaging agents. Therefore, this article presents the lessons learned and challenges encountered by a group of leading researchers in this field, and suggests ways forward to develop nanoparticle probes for cancer imaging.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{kumar2013third,

title = {Third generation gold nanoplatform optimized for radiation therapy},

author = {Rajiv Kumar and Houari Korideck and Wilfred Ngwa and Ross I Berbeco and Mike G Makrigiorgos and Srinivas Sridhar},

year  = {2013},

date = {2013-01-01},

journal = {Translational cancer research},

volume = {2},

number = {4},

publisher = {NIH Public Access},

abstract = {We report the design and fabrication of third generation ultrasmall PEGylated gold nanoparticles based platform (AuRad™) optimized for applications in radiation therapy. The AuRad™ nanoplatform has the following key features: (I) surface coating of hetero-bifunctional-PEG with amine, carboxyl, methoxy functional groups, which make this a versatile nanoplatform to conjugate various moieties like fluorophores, peptides, drugs, radiolabels; (II) size that is optimized for longer circulation, higher tumor uptake and modulated clearance; (III) high radiation enhancement. We have synthesized ultrasmall 2–3 nm gold nanoparticles, followed by attachment of hetero-bifunctional PEG and further conjugation of fluorophore AlexaFlour 647 for optical imaging, with a stability of more than 6 months. Confocal bioimaging with HeLa cells showed robust uptake of biocompatible nanoparticles in cells. Irradiation experiments X-rays showed greater than 2.8-fold cell kill enhancement as demonstrated by clonogenic survival assays. The results indicate that AuRad nanoplatform can act as potential theranostic agent in radiation therapy.



Keywords: Gold nanoparticles, PEGylation, multifunctional nanoparticles, clonogenic assay, radiation therapy},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{petrov2013electric,

title = {Electric field encephalography as a tool for functional brain research: a modeling study},

author = {Yury Petrov and Srinivas Sridhar},

year  = {2013},

date = {2013-01-01},

journal = {PloS one},

volume = {8},

number = {7},

publisher = {Public Library of Science},

abstract = {We introduce the notion of Electric Field Encephalography (EFEG) based on measuring electric fields of the brain and demonstrate, using computer modeling, that given the appropriate electric field sensors this technique may have significant advantages over the current EEG technique. Unlike EEG, EFEG can be used to measure brain activity in a contactless and reference-free manner at significant distances from the head surface. Principal component analysis using simulated cortical sources demonstrated that electric field sensors positioned 3 cm away from the scalp and characterized by the same signal-to-noise ratio as EEG sensors provided the same number of uncorrelated signals as scalp EEG. When positioned on the scalp, EFEG sensors provided 2–3 times more uncorrelated signals. This significant increase in the number of uncorrelated signals can be used for more accurate assessment of brain states for non-invasive brain-computer interfaces and neurofeedback applications. It also may lead to major improvements in source localization precision. Source localization simulations for the spherical and Boundary Element Method (BEM) head models demonstrated that the localization errors are reduced two-fold when using electric fields instead of electric potentials. We have identified several techniques that could be adapted for the measurement of the electric field vector required for EFEG and anticipate that this study will stimulate new experimental approaches to utilize this new tool for functional brain research.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{faegh2013cost,

title = {A cost-effective self-sensing biosensor for detection of biological species at ultralow concentrations},

author = {Samira Faegh and Nader Jalili and Ozgur Yavuzcetin and Dattatri Nagesha and Rajiv Kumar and Srinivas Sridhar},

year  = {2013},

date = {2013-01-01},

journal = {Journal of Applied Physics},

volume = {113},

number = {22},

pages = {224905},

publisher = {American Institute of Physics},

abstract = {Detection of ultrasmall masses and identification of biological molecules have been made possible as a result of advances in nanotechnology. Development of biosensing tools has significantly contributed to high-throughput diagnosis and analytical sensing exploiting high affinity of biomolecules. MicroCantilever (MC)-based detection has emerged as a promising biosensing tool for offering label-free and cost-effective sensing capabilities. One of the main criteria determining the success of each biosensor is the capability of the sensing platform to operate in aqueous media. Although being characterized with high sensitivity and simplicity, MCs do not provide an effective tool for measurement of marker proteins in liquid media due to large hydrodynamic damping and losses in the surrounding liquid. In this study, we describe two approaches to high sensitivity biomolecular detection using piezoelectric microcantilevers. (i) Immobilized Mass Detection in Air using electro-mechanical resonance: a unique self-sensing measurement technique is reported utilizing a self-sensing circuit consisting of a piezoelectric MC to address the mentioned limitation. The capability of the self-sensing measurement technique was first verified by detecting ultrasmall biological masses immobilized over the surface of MC by monitoring the shift in fundamental mechanical resonance frequency of the system in air and comparing it with optical-based measurement. This was further utilized for calibration of mass detection in liquid media. (ii) Immobilized Mass Detection in Liquid using the electrical self-sensing circuit's resonance: Once the capability to detect adsorbed mass was verified, the self-sensing platform was implemented to detect different concentrations of target molecule (glucose in this study) in liquid media by adopting the highly sensitive resonance frequency of the whole circuit instead of the mechanical response of MC. Molecular binding occurring over the surface of MC changes the capacitance of the total interface thus changing the resonance frequency of the circuit. The amount of shift in the measured circuit's resonance frequency provides qualitative and quantitative insight into the amount of target protein concentration. The reported diagnostic platform offers a simple, cost-effective, all-electronics method of detection where the need for any bulky, expensive optical based measurement is eliminated. Utilizing this technique, physiological concentration of glucose as low as 500 nM was measured in liquid media. This sensitivity is significantly higher than what has been previously reported using other mechanical resonance techniques.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ngwa2013toward,

title = {Toward Customizable Radiation Therapy Enhancement (CuRE) With Gold Nanoparticles Released, In Situ, From Gold-Loaded Brachytherapy Spacers},

author = {W Ngwa and H Korideck and R Kumar and S Sridhar and K David and N Paul and R Berbeco and R Cormack and G Makrigiorgos},

year  = {2013},

date = {2013-01-01},

journal = {International Journal of Radiation Oncology• Biology• Physics},

volume = {87},

number = {2},

pages = {S151},

publisher = {Elsevier},

abstract = {Purpose/Objective(s)

Loading routinely used brachytherapy spacers with non-toxic/biocompatible gold nanoparticles (AuNP), which can be released in situ to serve as radiosensitizers is a novel potential strategy for prostate tumor sub-volume boosting or dose-painting. This study investigates the release and diffusion of the AuNP from the brachytherapy spacer in vivo using CT imaging.

Materials/Methods

Gold-loaded brachytherapy spacers (GBS) (ca. 0.8 mm x 5 mm) were produced using AuNP and biodegradable PLGA copolymer. The GBS was implanted in mice using a brachytherapy needle and CBCT-imaged over time using the small animal radiation research platform (SARRP). The CT images were exported to imageJ and the intensity of the implanted spacer evaluated at different time points. Also, to simulate a burst release of the AuNP from an implanted spacer, 20 mg Au/mL concentration of 15 nm polymer coated AuNP suspended in 20 μL phosphate-buffered saline at pH 7.4, was injected intratumorally, and the AuNP diffusion monitored via serial CT imaging over 5 time points in hours: 0.5, 48, 120, 144, and 160. The CT images were then exported to imageJ and the pixel intensities for 5 sample tumor regions of interest (at: left, right, center, anterior, posterior) extracted to assess AuNP diffusion.

Results

Results for the implanted GBS showed that the CT intensity of the spacer decreased over time, indicating the release of the AuNP as the PLGA degrades in vivo. Meanwhile, the CBCT images from the AuNP burst release study showed clear evidence of AuNP diffusion. For example, at the site of AuNP release, the CT image intensity decreased by over 160% during the investigated time range (0.5 h – 160 h). During the same time, the intensity in the tumor subvolume or ROI on the opposite side of the release site increased by over 140%. The diffusion results also showed that for the 15 nm AuNP size, potent AuNP concentrations can reside within the tumor sub-volume for a sustained period of time.

Conclusions

The results provide the first in vivo evidence of AuNP release from gold loaded brachytherapy spacers. The sustained residence of potent AuNP concentrations in the tumor sub-volume could allow for significant dose boosting during brachytherapy. Such boosting could be further customized (e.g., by varying AuNP size, functionalization, spacer degradation time, etc.) since the intra-tumor biodistribution depends on such parameters. Overall, the results provide a useful basis for future R&D towards the development of Customizable Radiation therapy Enhancement (CuRE) with AuNP for prostate cancer. Potential clinical applications for such a new approach are anticipated in salvage brachytherapy, and sub-volume radiation boosting during initial treatment to help prevent prostate cancer recurrence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{kumar2013facile,

title = {Facile synthesis of PEGylated PLGA nanoparticles encapsulating doxorubicin and its in vitro evaluation as potent drug delivery vehicle},

author = {Rajiv Kumar and Apurva Kulkarni and Jude Nabulsi and Dattatri K Nagesha and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},

year  = {2013},

date = {2013-01-01},

journal = {Drug delivery and translational research},

volume = {3},

number = {4},

pages = {299--308},

publisher = {Springer US},

abstract = {The advent of nanotechnology has bolstered a variety of nanoparticle-based platforms for different biomedical applications. A better understanding for engineering novel nanoparticles for applications in cancer staging and therapy requires careful assessment of the nanoparticle’s physico-chemical properties. Herein we report a facile synthesis method for PEGylated PLGA nanoparticles encapsulating anti-cancer drug doxorubicin for cancer imaging and therapy. The simple nanoprecipitation method reported here resulted in very robust PEGylated PLGA nanoparticles with close to 95 % drug encapsulation efficiency. The nanoparticles showed a size of ~110 nm as characterized by TEM and DLS. The nanoparticles were further characterized by optical UV–Visible and fluorescence spectroscopy. The encapsulated doxorubicin showed a sustained release (>80 %) from the nanoparticles matrix over a period of 8 days. The drug delivery efficiency of the nanoparticles was confirmed in vitro confocal imaging with PC3 and HeLa cell lines. In vitro quantitative estimation of drug accumulation in PC3 cell line showed a 22 times higher concentration of drug in case of nanoparticle-based formulation in comparison to free drug and this was further reflected in the in vitro cytotoxicity assays. Overall the synthesis method reported here provides a simple and robust PLGA-based platform for efficient drug delivery and imaging of cancer cells in vitro and in vivo.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{andersonour,

title = {Our thanks to all those who have helped with this issue of Nanomedicine. Listed below are authors, referees and others who have kindly given their time, effort and expertise; their generosity has helped establish this publication.},

author = {D Anderson and A Archakov and K Avgoustakis and A Baumgartner and R Bawa and M Bernardo and V Biricova and R Brayner and MW Brechbiel and J Buse and others},

year  = {2012},

date = {2012-12-20},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{kumar2012vitro,

title = {In vitro evaluation of theranostic polymeric micelles for imaging and drug delivery in cancer},

author = {Rajiv Kumar and Apurva Kulkarni and Dattatri K Nagesha and Srinivas Sridhar},

year  = {2012},

date = {2012-01-01},

journal = {Theranostics},

volume = {2},

number = {7},

pages = {714},

publisher = {Ivyspring International Publisher},

abstract = {We describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.



For the past decade engineered nanoplatforms have seen a momentous progress in developing a multimodal theranostic formulation which can be simultaneously used for imaging and therapy. In this report we describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. CdSe quantum dots (QDs) and anti-cancer drug, doxorubicin (Dox), were co-encapsulated into the hydrophobic core of the micelles. The micelles are characterized using optical spectroscopy for characteristic absorbance and fluorescence features of QDs and Dox. TEM and DLS studies yielded a size of <50 nm for the micellar formulations with very narrow size distribution. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.



Keywords: Theranostic Polymeric Micelles, Imaging, Drug Delivery, Cancer

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{berbeco2012dna,

title = {DNA damage enhancement from gold nanoparticles for clinical MV photon beams},

author = {Ross I Berbeco and Houari Korideck and Wilfred Ngwa and Rajiv Kumar and Janki Patel and Srinivas Sridhar and Sarah Johnson and Brendan D Price and Alec Kimmelman and Mike G Makrigiorgos},

year  = {2012},

date = {2012-01-01},

journal = {Radiation research},

volume = {178},

number = {6},

pages = {604--608},

publisher = {The Radiation Research Society},

abstract = {OTHER| NOVEMBER 13 2012

DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams 

Ross I. Berbeco; Houari Korideck; Wilfred Ngwa; Rajiv Kumar; Janki Patel; Srinivas Sridhar; Sarah Johnson; Brendan D. Price; Alec Kimmelman; G. Mike Makrigiorgos

Radiat Res (2012) 178 (6): 604–608.

https://doi.org/10.1667/RR3001.1

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In this study, we quantify the relative damage enhancement due to the presence of gold nanoparticles (GNP) in vitro in a clinical 6 MV beam for various delivery parameters and depths. It is expected that depths and delivery modes that produce a larger proportions of low-energy photons will have a larger effect on the cell samples containing GNP. HeLa cells with and without 50 nm GNP were irradiated at depths of 1.5, 5, 10, 15 and 20 cm. Conventional beams with square aperture sizes 5, 10 and 15 cm at isocenter, and flattening filter free (FFF) beams were used. Relative DNA damage enhancement with GNP was evaluated by γ-H2AX staining. Statistically significant increases in DNA damage with GNP, compared to the absence of GNP, were observed for all depths and delivery modes. Relative to the shallowest depth, damage enhancement was observed to increase as a function of increasing depth for all deliveries. For the conventional (open field) delivery, DNA damage enhancement with GNP was seen to increase as a function of field size. For FFF delivery, a substantial increase in enhancement was found relative to the conventional field delivery. The measured relative DNA damage enhancement validates the theoretically predicted trends as a function of depth and delivery mode for clinical MV photon beams. The results of this study open new possibilities for the clinical development of gold nanoparticle-aided radiation therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{yavuzcetin2012photonic,

title = {Photonic crystal fabrication in lithium niobate via pattern transfer through wet and dry etched chromium mask},

author = {Ozgur Yavuzcetin and Herman P Novikov and Rebecca L Dally and Sean T Malley and Nicholas R Perry and Birol Ozturk and Srinivas Sridhar},

year  = {2012},

date = {2012-01-01},

journal = {Journal of Applied Physics},

volume = {112},

number = {7},

pages = {074303},

publisher = {American Institute of Physics},

abstract = {The need to fabricate photonic crystals from lithium niobate (LN) with accurate feature sizes is important to the development of optoelectronic devices. This paper reports a fabrication process to dry etch X-cut LN at a submicron scale using electron beam lithography and chromium as a hard mask. The chromium mask was used for both dry-etching and wet-etching in a unique method. Problems and solutions found during fabrication are presented. Arrays consisting of 400 nm diameter holes with a high aspect ratio were etched in LN, creating photonic crystals modeled to transmit light in the infrared spectrum.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{berbeco2012tu,

title = {TU-C-BRB-11: In Vitro Dose Enhancement from Gold Nanoparticles under Different Clinical MV Photon Beam Configurations},

author = {R Berbeco and H Korideck and W Ngwa and R Kumar and J Patel and S Sridhar and S Johnson and B Price and A Kimmelman and M Makrigiorgos},

year  = {2012},

date = {2012-01-01},

journal = {Medical Physics},

volume = {39},

number = {6Part23},

pages = {3900--3901},

publisher = {American Association of Physicists in Medicine},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ngwa2012vitro,

title = {In vitro dose enhancement from gold nanoparticles during low-dose-rate gamma irradiation with I-125 brachytherapy seeds},

author = {W Ngwa and H Korideck and A Kimmelman and AI Kassis and R Kumar and S Sridhar and M Makrigiorgos and RA Cormack},

year  = {2012},

date = {2012-01-01},

journal = {International Journal of Radiation Oncology• Biology• Physics},

volume = {84},

number = {3},

pages = {S134},

publisher = {Elsevier},

abstract = {Purpose/Objective(s)

Recent studies have predicted substantial dose enhancement to tumors when gold nanoparticles (AuNP) are employed as adjuvants to radiation therapy at kV energies. Because the enhancement results from processes at kV energies, some studies proposed gold nanoparticle-aided brachytherapy as a radiation therapy approach with potential to meet technical and clinical requirements for implementation. To the best of our knowledge, there has been no study providing clear experimental evidence to corroborate the substantial dose enhancement predictions when irradiating with low dose rate gamma photons from brachytherapy sources. This study investigates the in vitro dose enhancement of AuNP during irradiation of cancer cells by I-125 low dose rate brachytherapy sources.

Materials/Methods

HeLa cell cultures were incubated with and without gold nanoparticles (AuNP) in alternate wells of an 8 well-chamber slide; 4 wells on each slide had cell cultures with AuNP while 4 wells contained cell cultures with no AuNP. Two slides were prepared for each experiment: one slide to be irradiated while the other serves as sham-irradiation control. The cells were irradiated with gamma photons from I-125 brachytherapy seeds in a plaque contained in a custom-built irradiation jig. The plaque was designed to achieve a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at 370C at dose rates ranging from 2.1 cGy/hr to 4.5 cGy/hr. The dose rates were varied by varying the height of the cell culture slide above the plaque containing the I-125 seeds. Residual gammaH2AX was measured 24 hours after irradiation and used to compare the dose response of the cells with and without AuNP. In addition, the relative dose enhancement factor (DEF), representing the ratio of the dose to the cells with and without the presence of AuNP, was estimated from the data.

Results

From the dose response behavior, the results show that the biologic effect when irradiating with 0.2 mg/mL concentration of AuNP is up to 2.3 times greater than without AuNP. This major increase in radiation damage to cancer cells incubated with AuNP corresponds to an estimated DEF of over 3.5.

Conclusions

Our findings provide the first experimental evidence of substantial dose enhancement from gold nanoparticles during low dose rate gamma irradiation from brachytherapy sources. These in vitro study results provide impetus for further preclinical and clinical investigations in the development of gold nanoparticle-aided brachytherapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cormack2012locally,

title = {Locally Drug Enhanced Brachytherapy: A Comparison of 2 Approaches Based on Biologically Effective Dose},

author = {R Cormack and P Nguyen and AV D'Amico and S Sridhar and GM Makrigiorgos},

year  = {2012},

date = {2012-01-01},

journal = {International Journal of Radiation Oncology• Biology• Physics},

volume = {84},

number = {3},

pages = {S854--S855},

publisher = {Elsevier},

abstract = {Purpose/Objective(s)

Permanent prostate brachytherapy may be enhanced by delivering radiosensitizer to the target during the implant process. Nanoparticles released from a substrate can deliver drug over an extended period of time and can be engineered to adjust their diffusion parameters. Nanoparticle eluting polymers have been proposed to coat radioactive sources or to form brachytherapy spacers as a way of delivering drug to the prostate. This work determines whether it is preferable to deliver radiosensitizer from sources or spacers.

Materials/Methods

The relative effectiveness of spacers or sources as sources of sensitizer was evaluated by comparing biologic effective dose (BED) of the combined effect of radiation and drug distributions within the prostate. Treatment plans of six patients receiving 125I prostate implants were analyzed under an IRB approved protocol. Target contours were extracted as were the locations of radioactive sources and spacers. Radiation dose was calculated according to AAPM TG43 methodology. Drug distributions were calculated from a solution of the diffusion equation, relative to the steady state concentration at the eluter's surface, for a range of diffusion-elimination modulus (φb) values and concentration needed for maximum sensitization (Cs). φb is viewed as a variable because the properties of the nanoparticles can be adjusted to affect diffusion and time of residence. Cs is treated as a variable because the amplitude of the drug distribution depends on the capacity of the implanted object and the time frame of release. BED calculations of the composite effect were done. The calculations were compared to an approach where the location of the spacers was allowed to be adjusted.

Results

The ratio of the BED for the two delivery approaches is presented in the 2D parameter space of φb and Cs. A full sensitization region, corresponding to low values of φb and Cs, shows no difference between approaches. The majority of the remaining parameter space, showed that using spacers to radiosensitize results in a greater BED. Changing the spacer locations from fixed by the treatment plan to adjustable allowed further increase of BED.

Conclusions

Using brachytherapy spacers as a vehicle to deliver radiosensitizing nanoparticles offers a greater potential to increase the effectiveness of prostate brachytherapy by in-situ radiosensitization. Further increase was achieved by treating spacer location as planning parameter. Using implanted non-radioactive devices for local radiosensitization suggests the potential of planned chemical distributions in conjunction with radiation planning to produce an optimal combined result.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{H.Lewisa2011,

title = {Thermomagnetic determination of Fe3O4 magnetic nanoparticle diameters for biomedical applications},

author = {Brian D.Plouffea and Dattatri K.Nagesha and Robert S.DiPietro and Srinvas Sridhar and Don Heimand and Shashi K.Murthya and Lewis H.Lewisa

},

doi = {S0304885311002423},

year  = {2011},

date = {2011-09-01},

journal = {Journal of Magnetism and Magnetic Materials},

volume = {323},

number = {17},

pages = {2310-2317},

abstract = {The utility and promise of magnetic nanoparticles (MagNPs) for biomedicine rely heavily on accurate determination of the particle diameter attributes. While the average functional size and size distribution of the magnetic nanoparticles directly impact the implementation and optimization of nanobiotechnology applications in which they are employed, the determination of these attributes using electron microscopy techniques can be time-consuming and misrepresentative of the full nanoparticle population. In this work the average particle diameter and distribution of an ensemble of Fe3O4 ferrimagnetic nanoparticles are determined solely from temperature-dependent magnetization measurements; the results compare favorably to those obtained from extensive electron microscopy observations. The attributes of a population of biocompatible Fe3O4 nanoparticles synthesized by a thermal decomposition method are obtained from quantitative evaluation of a model that incorporates the distribution of superparamagnetic blocking temperatures represented through thermomagnetization data. The average size and size distributions are determined from magnetization data via temperature-dependent zero-field-cooled magnetization. The current work is unique from existing approaches based on magnetic measurement for the characterization of a nanoparticle ensemble as it provides both the average particle size as well as the particle size distribution.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Makrigiorgos2011,

title = {Optimal drug release schedule for in-situ radiosensitization of image guided permanent prostate implants},

author = {Robert A. Cormack; Paul L. Nguyen; Anthony V. D'Amico; Sri Sridhar; Mike Makrigiorgos

},

doi = {10.1117/12.878139},

year  = {2011},

date = {2011-03-03},

journal = {Proceedings Volume 7964, Medical Imaging 2011: Visualization, Image-Guided Procedures, and Modeling},

volume = {7964},

number = {2011},

abstract = {Planned in-situ radiosensitization may improve the therapeutic ratio of image guided 125I prostate brachytherapy. Spacers used in permanent implants may be manufactured from a radiosensitizer-releasing polymer to deliver protracted localized sensitization of the prostate. Such devices will have a limited drug-loading capacity, and the drug release schedule that optimizes outcome, under such a constraint, is not known. This work determines the optimal elution schedules for 125I prostate brachytherapy. The interaction between brachytherapy dose distributions and drug distribution around drug eluting spacers is modeled using a linear-quadratic (LQ) model of cell kill. Clinical brachytherapy plans were used to calculate the biologic effective dose (BED) for planned radiation dose distributions while adding the spatial distributions of radiosensitizer while varying the temporal release schedule subject to a constraint on the drug capacity of the eluting spacers. Results: The greatest increase in BED is achieved by schedules with the greatest sensitization early in the implant. Making brachytherapy spacers from radiosensitizer eluting polymer transforms inert parts of the implant process into a means of enhancing the effect of the brachytherapy radiation. Such an approach may increase the therapeutic ratio of prostate brachytherapy or offer a means of locally boosting the radiation effect without increasing the radiation dose to surrounding tissues.

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{savo2011observation,

title = {Observation of slow-light in a metamaterials waveguide at microwave frequencies},

author = {Salvatore Savo and BDF Casse and Wentao Lu and Srinivas Sridhar},

year  = {2011},

date = {2011-01-01},

journal = {Applied Physics Letters},

volume = {98},

number = {17},

pages = {171907},

publisher = {American Institute of Physics},

abstract = {We report an experimental observation of slow-light in the GHz microwave regime utilizing the mechanism of the degeneracy of forward and backward waves in a planar waveguide consisting of a dielectric core cladded by single-negative metamaterial.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ye2011tuning,

title = {Tuning the optical properties of metamaterials based on gold nanowire arrays embedded in alumina},

author = {Yong-Hong Ye and YJ Huang and WT Lu and BDF Casse and D Xiao and SP Bennett and D Heiman and L Menon and S Sridhar},

year  = {2011},

date = {2011-01-01},

journal = {Optical Materials},

volume = {33},

number = {11},

pages = {1667--1670},

publisher = {North-Holland},

abstract = {We fabricated a series of gold nanowires/alumina composite films with different wire lengths. Optical transmission measurements confirmed that the composite films exhibit transverse and longitudinal surface plasmon resonances. We show that the wavelength of the longitudinal resonance is sensitive to nanowire length, while that of the transverse resonance is not. The experimental results are in agreement with the modeled results based on the Maxwell Garnett effective medium theory. Moreover, the window for negative refraction of the samples can be tuned in synchronism with the longitudinal resonance by the nanowire length.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{yavuzcetin2011conicity,

title = {Conicity and depth effects on the optical transmission of lithium niobate photonic crystals patterned by focused ion beam},

author = {Ozgur Yavuzcetin and Birol Ozturk and Dong Xiao and Srinivas Sridhar},

year  = {2011},

date = {2011-01-01},

journal = {Optical Materials Express},

volume = {1},

number = {7},

pages = {1262--1271},

publisher = {Optical Society of America},

abstract = {We report on novel focused ion beam fabrication techniques that can greatly improve the optical performance of photonic crystal structures. The finite depth and conicity effects of holes and trenches in Lithium Niobate (LN) photonic crystals have been theoretically analyzed, showing that the conicity causes refraction into the bulk sample, resulting in high transmission loss and no useful spectral features. The techniques for reducing the conicity angle from 25° to 5° were explained for the focused ion beam (FIB) milled structures.



©2011 Optical Society of America},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{casse2011robust,

title = {Robust method to determine the resolution of a superlens by analyzing the near-field image of a two-slit object},

author = {BDF Casse and WT Lu and YJ Huang and S Sridhar},

year  = {2011},

date = {2011-01-01},

journal = {arXiv preprint arXiv:1105.0182},

abstract = {In the last decade, metamaterials-based superlenses, with a resolution below Abbe's diffraction limit, have emerged. To obtain a rough estimate of the resolution of such superlenses, imaging of two subwavelength slits, separated by a subwavelength gap textit{d} is typically performed. The resolution Δ of the lens corresponds to the minimum possible gap dmin for which a distinct image of the two slits can be resolved (Δ∼dmin). In this letter, we present a more quantitative estimate of the resolution of manufactured lenses by fitting analytical near-field image profiles, obtained from imaging a two-slit object with a theoretical negative-index lens of known resolution, to experimental data. We conclude the discussion by applying our analytical method to 3 case examples of superlensing from the literature. As shown, this method is particularly attractive for rapidly assessing the performance of fabricated superresolution lenses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cassesuperresolution,

title = {Superresolution imaging and superfocusing with negative-index metamaterials},

author = {Bernard Didier F Casse and Srinivas Sridhar},

year  = {2010},

date = {2010-03-19},

abstract = {Developments in higher-resolution optics have often led to rapid scientific and technological progress in the life sciences and engineering. In 1873, Ernst Abbe showed1 that the spatial resolution of optical-imaging instruments is limited by diffraction because of the finite wavelength of light. Abbe’s diffraction-limit theory implies that the resolving power of optical components cannot be smaller than half the wavelength of the incident light. Nanoscale optical elements that can mold the flow of light offer the potential of entirely new modalities of superresolution imaging. With a vision to build superlenses capable of resolving subwavelength details, in the last decade the photonics community has focused on fabricating tiny metallic inclusions (or, closely related, plasmonic architectures) characterized by a negative index of refraction. 2 Unfortunately, such metamaterials suffer from material losses enhanced by resonances, leading to a degradation of functionality. Instead, our group has demonstrated successful performance of highly functional nanostructured metamaterials in ‘low-loss’ dielectric platforms such as metal-dielectric composites and III-V semiconductors (composed of indium phosphide/indium gallium arsenide phosphide: InP/InGaAsP). We recently reported the experimental realization of superresolution imaging with a low-loss 3D nanolens, 3 comprised of gold nanowires embedded in nanoporous alumina: see Figure 1 (right). This 3D nanolens, manufactured using a combination of bottom-up self-assembly and electrochemical process, transmits subwavelength details down to= 4 (: Wavelength) and over a significant distance of more than …},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gultepe2010nanoporous,

title = {Nanoporous inorganic membranes or coatings for sustained drug delivery in implantable devices},

author = {Evin Gultepe and Dattatri Nagesha and Srinivas Sridhar and Mansoor Amiji},

year  = {2010},

date = {2010-01-01},

journal = {Advanced drug delivery reviews},

volume = {62},

number = {3},

pages = {305--315},

publisher = {Elsevier},

abstract = {The characteristics of nanoporous inorganic coatings on implants or on implantable devices are reviewed. The commonly used nanoporous materials, such as aluminum oxide (Al2O3), titanium oxide (TiO2) and porous silicon are highlighted with illustrative examples. The critical issues for sustained release systems are examined and the elution pro?les of nanoporous coatings are discussed. The available data shows that these systems can be used effectively for sustained release applications. They satisfy the basic biocompatibility tests, meet the requirements of drug loading and sustained release pro?les extending to several weeks and also are compatible with current implant technologies. Nanoporous inorganic coatings are well suited to provide improved ef?cacy and integration of implants in a variety of therapeutic situations.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{casse2010super,

title = {Super-resolution imaging using a three-dimensional metamaterials nanolens},

author = {BDF Casse and WT Lu and YJ Huang and E Gultepe and L Menon and S Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Applied Physics Letters},

volume = {96},

number = {2},

pages = {023114},

publisher = {American Institute of Physics},

abstract = {Super-resolution imaging beyond Abbe’s diffraction limit can be achieved by utilizing an optical medium or “metamaterial” that can either amplify or transport the decaying near-field evanescent waves that carry subwavelength features of objects. Earlier approaches at optical frequencies mostly utilized the amplification of evanescent waves in thin metallic films or metal-dielectric multilayers, but were restricted to very small thicknesses (⪡λ, wavelength) and accordingly short object-image distances, due to losses in the material. Here, we present an experimental demonstration of super-resolution imaging by a low-loss three-dimensional metamaterial nanolens consisting of aligned gold nanowires embedded in a porous alumina matrix. This composite medium possesses strongly anisotropic optical properties with negative permittivity in the nanowire axis direction, which enables the transport of both far-field and near-field components with low-loss over significant distances (>6λ), and over a broad spectral range. We demonstrate the imaging of large objects, having subwavelength features, with a resolution of at least λ/4 at near-infrared wavelengths. The results are in good agreement with a theoretical model of wave propagation in anisotropic media.

The authors would like to thank M. G. Silveirinha, D. Heiman, J. Sokoloff, and F. Camino for useful discussions and comments. This work was financially supported by the Air Force Research Laboratories, Hanscom through Grant No. FA8718-06-C-0045 and NSF through Grant No. PHY-0457002. The work was also performed in part at the Kostas Center at Northeastern University and the Center for Nanoscale Systems, a member of NNIN, which is supported by the National Science Foundation under NSF Award No. ECS-0335765. Research carried out in part at the Center for Functional Nanomaterials, Brookhaven National Laboratory, which is supported by the U.S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{stambaugh2010we,

title = {WE-E-204B-02: Release Kinetics of Radio-Sensitizers from Nanoporous Coatings on Gold Fiducials: Biological In-Situ Dose-Painting for IGRT},

author = {C Stambaugh and D Tada and D Nagesha and E Jost and C Levy and RA Cormack and M Makrigiorgos and S Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Medical Physics},

volume = {37},

number = {6Part13},

pages = {3437--3438},

publisher = {American Association of Physicists in Medicine},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cormack2010drug,

title = {Drug Eluting Brachytherapy Spacers: A Potential for Biologically-Enhanced Brachytherapy},

author = {Robert A Cormack and Dattatri Nagesha and Evin Gultepe and Paul Nguyen and Anthony V D'Amico and Srinivas Sridhar and Mike Makrigiorgos},

year  = {2010},

date = {2010-01-01},

journal = {Brachytherapy},

volume = {9},

pages = {S48--S49},

publisher = {Elsevier},

abstract = {Purpose: Ultrasound-guided prostate brachytherapy routinely implants spacers between the 125I radiation sources, that provide no therapeutic benefit although they are essential to the technical completion of the implant. The spacers offer a vehicle for in-situ delivery of radio-sensitizer, or other agents, which could increase the biologic effective dose of the radiation. This work studies the achievable drug coverage as a function of the chemical and physical properties of the drugs and devices.

Materials and Methods: Fluorescent doxorubicin in a polymer suspension and gold substrate were used to evaluate the ability to create a radio-opaque drug eluter. Elution kinetics from polymer coating of gold substrate was measured via fluorescence spectrometry. An analytic solution to the diffusion elimination equation was used to perform computer modeling of drug distributions produced by configurations of eluters placed within ultrasound guided prostate implants. Measures of tumor coverage and normal tissue involvement are evaluated for multiple combinations of eluter sizes and diffusion elimination moduli φb.

Results: Timed-release of doxorubicin from a polymer coating on a gold substrate, as shown in the top half of the figure, is technically possible. The many spacers used in prostate brachytherapy are sufficient to sensitize a portion of the prostate with values of φb close to the calculated ones. The use of drug-eluting brachytherapy spacers would enable a more localized enhancement in biologic effective dose than what can be delivered by a local brachytherapy boost. The bottom half of the figure shows a prostate implant at treated at our institution and and how it could be locally enhanced with the addition of a small number of drug eluting spacers.

Conclusions: IGRT techniques, such as ultrasound-guided brachytherapy, already implant devices within tumors as part of the standard of care. These devices may be enhanced with drug-eluting coatings to provide an in-situ increase in biologic effective dose without increasing the physical dose involved in the therapy. Generalization of this biologically in-situ enhanced IGRT (BIS-IGRT) to other agents in combination with advances in biologic imaging may provide an opportunity for personalized biologically in-situ enhanced brachytherapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lu2010storing,

title = {Storing light in active optical waveguides with single-negative materials},

author = {WT Lu and YJ Huang and BDF Casse and RK Banyal and S Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Applied Physics Letters},

volume = {96},

number = {21},

pages = {211112},

publisher = {American Institute of Physics},

abstract = {We show that a nonresonant planar waveguide consisting of conventional dielectric cladded with single-negative materials supports degenerate propagating modes for which the group velocity and total energy flow can be zero if the media are lossless. Absorptive losses will destroy the zero-group velocity condition for real frequency/complex wave vector modes.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gultepe2010monitoring,

title = {Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution},

author = {Evin Gultepe and Francisco J Reynoso and Aditi Jhaveri and Praveen Kulkarni and Dattatri Nagesha and Craig Ferris and Mukesh Harisinghani and Robert B Campbell and Srinivas Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Nanomedicine},

volume = {5},

number = {8},

pages = {1173--1182},

publisher = {Future Medicine Ltd London, UK},

abstract = {The development of noninvasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. The aim of the present study is to show that magnetic cationic liposomes (MCLs), incorporating superparamagnetic iron oxide nanoparticles (SPIONs), are a versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. We have shown that tumor signal intensities in T2-weighted MR images decreased by an average of 20 ± 5% and T2* relaxation times decreased by 14 ± 7 ms 24 h after intravenous administration of our MCL formulation. This compares to an average decrease in tumor signal intensity of 57 ± 12% and a T2* relaxation time decrease of 27 ± 8 ms after the same time period with the aid of magnetic guidance. MR and biodistribution analysis clearly show the ef?cacy of MCLs as MRI contrast agents, prove the use of magnetic guidance, and demonstrate the potential of MCLs as agents for imaging, guidance and therapeutic delivery.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{makrigiorgos201040,

title = {40 poster: Biological In-Situ Dose Painting for IGRT (BIS-IGRT) by Use of Drug-Loaded Implantable Fiducials and Spacers},

author = {M Makrigiorgos and S Sridhar and A D’Amico and P Nguyen and R Cormack},

year  = {2010},

date = {2010-01-01},

journal = {Radiotherapy and Oncology},

volume = {94},

pages = {S18},

publisher = {Elsevier},

abstract = {Conclusions: 18F-ML-10 holds promise for early detection of tumor response to radiation. Generating" Delta image" for mapping response is feasible, and these images may potentially be employed for planning a non-uniform dose administration and adjustment, conforming to differential radio-sensitivity of various regions within the tumor. Multi-center studies are ongoing to evaluate performance of 18F-ML-10 in predicting response of different tumors to radiation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gultepe2010sustained,

title = {Sustained Drug Release from Non-eroding Nanoporous Templates},

author = {Evin Gultepe and Dattatri Nagesha and Bernard DF Casse and Ravinder Banyal and Trifon Fitchorov and Alain Karma and Mansoor Amiji and Srinivas Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Small},

volume = {6},

number = {2},

pages = {213--216},

publisher = {WILEY-VCH Verlag Weinheim},

abstract = {We present the results for the release of a model drug, doxorubicin (Dox), fromdifferent non-eroding nanopor- ous coatings. Detailed studies of drug release from these platforms in the form of anodic aluminum oxide (AAO) and anodic titaniumoxide (ATO)were carried out. We show that nanoporous surfaces can achieve a sustained release rate over periods of several weeks, similar to polymeric platforms but without the risk of delamination or leaching since they are not degradable. We show that the kinetics of the sustained release from these nanoporous platforms is well described by an activated surface-density-dependent desorptionmodel,which appears to be universal for non-eroding platforms.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nagesha2010radiosensitizer,

title = {Radiosensitizer-eluting nanocoatings on gold fiducials for biological in-situ image-guided radio therapy (BIS-IGRT)},

author = {DK Nagesha and DB Tada and CKK Stambaugh and E Gultepe and E Jost and CO Levy and R Cormack and GM Makrigiorgos and S Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Physics in Medicine & Biology},

volume = {55},

number = {20},

pages = {6039},

publisher = {IOP Publishing},

abstract = {The therapeutic efficiency of IGRT can be further enhanced by biological in-situ dose painting (BIS-IGRT) of radiosensitizers through localized delivery within the tumor using gold fiducial markers that have been coated with nanoporous polymer matrices loaded with nanoparticles (NPs) . In this work, two approaches were studied: (i) a free drug release system consisting of Doxorubicin (Dox), a hydrophilic drug, loaded into a non-degradable polymer Poly(methyl methacrylate) (PMMA) coating and (ii) Poly(D,L-lactic-co-glycolic acid) (PLGA) NPs loaded with fluorescent Coumarin-6, serving as a model for a hydrophobic drug, in a biodegradable chitosan matrix. The results show that dosage and rate of release of these radiosensitizers coated on gold fiducials for IGRT can be precisely tailored to achieve the desired release profile for radiation therapy of cancer.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{tada2010chitosan,

title = {Chitosan film containing poly (D, L-lactic-co-glycolic acid) nanoparticles: a platform for localized dual-drug release},

author = {Dayane B Tada and Surinder Singh and Dattatri Nagesha and Evan Jost and Craig O Levy and Evin Gultepe and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Pharmaceutical research},

volume = {27},

number = {8},

pages = {1738--1745},

publisher = {Springer US},

abstract = {The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.



Purpose

To characterize and evaluate chitosan film containing PLGA nanoparticles (NPs) as a platform for localized dual-drug release.



Methods

Fluorescent Paclitaxel (FPTX), a hydrophobic drug, was incorporated into PLGA NPs. FPTX-loaded PLGA NPs and Carboxyfluorescein (CF), a hydrophilic model drug, were embedded into chitosan films. Release of CF and NPs from chitosan and release of FPTX from PLGA NPs were monitored by fluorescence. The stability of the platform was observed through SEM and dynamic light scattering (DLS).



Results

Chitosan films containing CF and FPTX-loaded PLGA NPs showed a biphasic release profile. In the first phase, 78% of CF and 34% of NPs were released within few days. In the second phase, the release was slower, showing an additional release of 22% of CF and 18% of NPs after 3 weeks. SEM images and DLS measurements showed that NP release depends on film degradation rate. FPTX-loaded PLGA NPs showed the release of 19.8% of total drug in 2 days, and no additional release was detected in the next 26 days.



Conclusions

The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lu2010slow,

title = {Slow light, open-cavity formation, and large longitudinal electric field on a slab waveguide made of indefinite permittivity metamaterials},

author = {WT Lu and S Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Physical Review A},

volume = {82},

number = {1},

pages = {013811},

publisher = {APS},

abstract = {The optical properties of slab waveguides made of indefinite permittivity (

ɛ

) materials (IEMs) are considered. In this medium, the real part of the transverse permittivity is negative while that of the longitudinal permittivity is positive. At any given frequency, the IEM waveguide supports an infinite number of transverse magnetic (TM) eigenmodes. For a slab waveguide with a fixed thickness, at most only one TM mode is forward wave. The remainder are backward waves which can have a very large phase index. At a critical thickness, the waveguide supports degenerate forward- and backward-wave modes with zero group velocity if loss is absent. Above the critical thickness, the waveguide supports complex-conjugate decay modes instead of propagating modes. The presence of loss in IEMs will lift the TM mode degeneracy, resulting in modes with finite group velocity. A feasible realization is proposed. The performance of the IEM waveguide is analyzed and possible applications are discussed, which are supported by numerical calculations. These slab waveguides can be used to make optical delay lines in optical buffers to slow down and trap light, to form open cavities, to generate strong longitudinal electric fields, and as phase shifters in optical integrated circuits. Although the presence of loss will hinder these applications, gain can be introduced to compensate the loss and enhance the performance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cormack2010biological,

title = {Biological in situ dose painting for image-guided radiation therapy using drug-loaded implantable devices},

author = {Robert A Cormack and Srinivas Sridhar and Warren W Suh and Anthony V D'Amico and Mike G Makrigiorgos},

year  = {2010},

date = {2010-01-01},

journal = {International Journal of Radiation Oncology* Biology* Physics},

volume = {76},

number = {2},

pages = {615--623},

publisher = {Elsevier},

abstract = {Implantable devices routinely used for increasing spatial accuracy in modern image-guided radiation treatments (IGRT), such as fiducials or brachytherapy spacers, encompass the potential for in situ release of biologically active drugs, providing an opportunity to enhance the therapeutic ratio.We model this new approach for two types of treatment. Drug distributions from three-dimensional arrangements of drug eluters versus eluter size and drug prop- erties were tabulated. Four radiosensitizer-loaded fiducials provide adequate radiosensitization for 4-cm-diameter lung tumors, thus potentially boosting biologically equivalent doses in centrally located stereotactic body treated lesions. Similarly, multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of biologi- cally equivalent doses to fit requirements difficult to meet by using radiation alone, e.g., boosting a high-risk region juxtaposed to the urethra while respecting normal tissue tolerance of both the urethra and the rectum. Drug loading of implantable devices routinely used in IGRT provides new opportunities for therapy modulation via biological in situ dose painting.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cormack2010mo,

title = {MO-FF-A1-01: Optimal Schedule for Localized Radio-Sensitization of 125I Prostate Implants},

author = {R Cormack and P Nguyen and A D” Amico and S Sridhar and M Makrigiorgos},

year  = {2010},

date = {2010-01-01},

journal = {Medical Physics},

volume = {37},

number = {6Part26},

pages = {3361--3361},

publisher = {American Association of Physicists in Medicine},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{reynoso2010th,

title = {TH-D-201C-08: Multi-Modal MRI SPECT and CT Imaging of Theranostic Nanoplatforms},

author = {F Reynoso and E Gultepe and A Jhaveri and P Kulkarni and B Gershman and C Ferris and R Campbell and M Harisinghani and S Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Medical Physics},

volume = {37},

number = {6Part8},

pages = {3470--3470},

publisher = {American Association of Physicists in Medicine},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{casse2010superresolution,

title = {Superresolution Imaging Using a 3D Nanolens Made Up of Bulk Nanowires Metamaterials},

author = {Bernard Didier Frederic Casse and Wentao Lu and Yongjian Huang and Evin Gultepe and Latika Menon and Srinivas Sridhar},

year  = {2010},

date = {2010-01-01},

journal = {Bulletin of the American Physical Society},

volume = {55},

publisher = {APS},

abstract = {Superresolution Imaging Using a 3D Nanolens Made Up of Bulk

Nanowires Metamaterials1 BERNARD DIDIER FREDERIC CASSE, WENTAO LU, YONGJIAN HUANG, EVIN GULTEPE, LATIKA MENON, SRINIVAS

SRIDHAR, Northeastern University — We report superresolution imaging of large

objects, having sub-λ features, over significant distances (>> λ, wavelength) with

a resolution well below the diffraction limit in optics, using a metallic nanolens.

The metallic nanolens is composed of high aspect ratio gold nanowires embedded

in disordered porous alumina template matrix. This composite medium possesses

strongly anisotropic optical properties with negative permittivity in the nanowire

axis direction, which enables negative refraction, and transports both far-field and

near-field components with minimal distortions and with very lowattenuations. The

long-distance image transport mechanism is not based on resonances of materials parameters and thus the subwavelength imaging occurs with low loss (Figure-of-merit

(FOM) = Re(n)/Im(n) ∼ 12 (much higher than existing metamaterials)) and in

a broad spectral range. This nanolens not only exhibits superior optical properties

over existing metamaterials-based lenses, but can also be manufactured in large scale

(mm size), thereby offering significant potential for applications in optical storage

devices, nanolithography and biomedical imaging.

1This work was financially supported by the AFRL, Hanscom through grant no.

FA8718-06-C-0045 and the NSF through grant no. PHY-0457002.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{casse2009imaging,

title = {Imaging with subwavelength resolution by a generalized superlens at infrared wavelengths},

author = {BDF Casse and WT Lu and RK Banyal and YJ Huang and S Selvarasah and MR Dokmeci and CH Perry and S Sridhar},

year  = {2009},

date = {2009-01-01},

journal = {Optics letters},

volume = {34},

number = {13},

pages = {1994--1996},

publisher = {Optical Society of America},

abstract = {We demonstrate experimentally negative refraction by a photonic crystal prism and imaging of a point source by a photonic crystal slab at 1.5 μm wavelength. The photonic crystal structures were nanofabricated in a InGaAsP/InP heterostructure platform, and optical characterization was performed using a near-field scanning optical microscope. By designing a suitable lens surface termination, an image spot size of 0.12λ^2 was achieved, demonstrating superlens imaging with subwavelength resolution well below Abbe's diffraction limit (0.5λ^2).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lu2009slow,

title = {Slow microwave waveguide made of negative permeability metamaterials},

author = {Wentao T Lu and Savatore Savo and Didier B F Casse and Srinivas Sridhar},

year  = {2009},

date = {2009-01-01},

journal = {Microwave and Optical Technology Letters},

volume = {51},

number = {11},

pages = {2705--2709},

publisher = {Wiley Subscription Services, Inc., A Wiley Company Hoboken},

abstract = {The framework for designing a slow light waveguide structure which operates in the GHz and up to THz frequencies is outlined. The design for the structure consists of a dielectric core layer cladded with negative permeability metamaterials. The parameter space for the metamaterial has been identified for the waveguide to stop light and the negative permeability is achieved by split‐ring resonator (SRR) metallic elements. A prototype structure operating at 8.5 GHz is proposed. Numerical simulations of electromagnetic waves interacting with SRRs have been performed to extract scattering parameters and a parameter retrieval method has been used to verify the designed window for negative permeability. © 2009 Wiley Periodicals, Inc. Microwave Opt Technol Lett 51: 2705–2709, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.24727},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nagesha2009functionalization,

title = {Functionalization-induced improvement in magnetic properties of Fe 3 O 4 nanoparticles for biomedical applications},

author = {Dattatri K Nagesha and Brian D Plouffe and Minh Phan and Laura H Lewis and Srinivas Sridhar and Shashi K Murthy},

year  = {2009},

date = {2009-01-01},

journal = {Journal of Applied Physics},

volume = {105},

number = {7},

pages = {07B317},

publisher = {American Institute of Physics},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{sawant2009nanosized,

title = {Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles},

author = {Rishikesh M Sawant and Rupa R Sawant and Evin Gultepe and Dattatri Nagesha and Brigitte Papahadjopoulos-Sternberg and Srinivas Sridhar and Vladimir P Torchilin},

year  = {2009},

date = {2009-01-01},

journal = {Journal of Nanoparticle Research},

volume = {11},

number = {7},

pages = {1777},

publisher = {Springer Netherlands},

abstract = {Stable 30-50 nm polymeric polyethylene glycol-phosphatidylethanolamine (PEG-PE)-based micelles entrapping superparamagnetic iron oxide nanoparticles (SPION) have been prepared. At similar concentrations of SPION, the SPION-micelles had significantly better magnetic resonance imaging (MRI) T2 relaxation signal compared to ‘plain’ SPION. Freeze-fracture electron microscopy confirmed SPION entrapment in the lipid core of the PEG-PE micelles. To enhance the targeting capability of these micelles, their surface was modified with the cancer cell-specific anti-nucleosome monoclonal antibody 2C5 (mAb 2C5). Such mAb 2C5-SPION immunomicelles demonstrated specific binding with cancer cells in vitro and were able to bring more SPION to the cancer cells thus demonstrating the potential to be used as targeted MRI contrast agents for tumor imaging.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lu2009slowb,

title = {Slow light, open cavity formation, and large longitudinal electric field on slab waveguide made of indefinite-index metamaterials},

author = {WT Lu and S Sridhar},

year  = {2009},

date = {2009-01-01},

journal = {arXiv preprint arXiv:0902.4482},

abstract = {There is a strong interest in slow light structures and devices [1–10]. This is driven by the need for optical buffers and optical memory in optical integrated circuits and other applications. In order to have small group velocity, various methods have been exploited to engineer material and structural dispersions, such as electromagnetic induced transparency [11], coupled resonant structures [5, 12], and optical nonlinearity [3]. Tsakmakidis et al [6] proposed a new scheme to realize trapped rainbow by using negative-index metamaterials. This slow light waveguide requires its core layer to be made of double negative metamaterial (DNM) whose permittivity and permeability are both negative. It is quite a challenge to realize DNMs with very low loss [13] since even moderate loss will destroy the zero group velocity mode [14, 15]. Strictly speaking, when loss is present as is inevitable in passive systems, stop light is impossible. However, gain may be introduced to compensate loss and makes zero group velocity possible [16]. In this paper we consider planar waveguide made of the so-called indefinite-index media [17–20] whose permittivity and/or the permeability tensors are indefinite matrices. For an indefinite-index metamaterial (IIM), the dispersion is hyperbolic for one polarization and elliptical for the other. Negative refraction, superlens imaging, and hyperlens focusing [21, 22] can be realized by using IIMs. Nanowire waveguide made of IIM has been considered by Huang et al [23]. These indefinite-index waveguides can support both forward-and backwardwave modes. High phase index can be obtained for these guided modes. These waveguides …},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{sridhar2009nanoplatforms,

title = {Nanoplatforms for Nanomedicine},

author = {S Sridhar},

year  = {2009},

date = {2009-01-01},

abstract = {Biocompatible nanomaterials are key components of novel approaches to addressing the major problems of modern medicine. A variety of nanoplatforms have emerged that have resulted in dramatic developments in imaging, early diagnosis and targeted delivery of therapeutics. Several varieties of nanoplatforms: metal, semiconducting polymeric and magnetic nanoparticles, liposomes, micelles, and nanoassemblies, have been developed that can enable efficacious delivery of drugs, DNA or energy to localized sites such as tumors, using targeting agents such as antibodies or guided navigation using magnetic fields. The optical properties of these nanoparticles offer an attractive alternative to the fluorophore-based staining and labeling of biological samples, and have potential use in a wide range of biological and physical applications. Magnetic nanoplatforms for theranostics combine multiple functionalities including imaging, magnetic guidance to the disease site, delivery of the drug payload through sustained as well as triggered drug release. Nanoporous coatings have been developed for implants, cardiovascular stents and fiducials used in image guided radio therapy. The non-erodable coatings show sustained release profiles that are comparable to those from erodible polymer platforms, but without the problems of delamination. A new doctoral program has also been established incorporating new courses and interdisciplinary research in nanomedicine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{makrigiorgos2009biological,

title = {Biological In Situ Dose-painting for Image-guided Radiation Therapy using Drug-loaded Implantable Devices},

author = {M Makrigiorgos and S Sridhar and W Suh and A D'Amico and R Cormack},

year  = {2009},

date = {2009-01-01},

journal = {International Journal of Radiation Oncology• Biology• Physics},

volume = {75},

number = {3},

pages = {S711--S712},

publisher = {Elsevier},

abstract = {Drug distributions from three-dimensional arrangements of drug eluters versus eluter size and drug properties were tabulated. Drug loading of implantable devices routinely used in IGRT provides new opportunities for therapy modulation via biological in situ dose painting.



Drug distributions from three-dimensional arrangements of drug-eluters were tabulated versus eluter size (0.5-2 mm) and drug properties (effective diffusion in tissue). Four regularly-spaced taxotere-loaded fiducials may provide a 50% radio-sensitization in 80-100% of the volume of up to 4 cm diameter lung tumors. The 50% increase in therapeutic ratio provides a boost of biologically-equivalent doses in centrally-located SBRT-treated lesions difficult to treat with radiation alone. Similarly, three-dimensionally planned placement of multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of ‘biologically-equivalent doses’ to fit requirements that are difficult to meet by using radiation alone, eg boosting biologically-effective dose by 25-50% to a 5 mm high-risk region juxtaposed to the urethra, while respecting the normal tissue tolerance of both urethra and rectum. Further, it is …



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cormack2009th,

title = {TH-D-210A-06: Drug Eluting Implanted Devices to Increase Biologic Effective Dose in Image Guided Radiation Therapy},

author = {RA Cormack and S Sridhar and D Nagesha and E Gultepe and W Suh and AV D'Amico and M Makrigiorgos},

year  = {2009},

date = {2009-01-01},

journal = {Medical Physics},

volume = {36},

number = {6Part28},

pages = {2819--2819},

publisher = {American Association of Physicists in Medicine},

keywords = {},

pubstate = {published},

tppubtype = {article}

}