Publications

@article{guthier2017focal,
title = {Focal Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants},
author = {Christian V Guthier and Anthony V D'Amico and Martin T King and Paul L Nguyen and Peter F Orio and Srinivas Sridhar and Mike G Makrigiorgos and Robert A Cormack},
year = {2017},
date = {2017-01-01},
journal = {Brachytherapy},
volume = {16},
number = {3},
pages = {S115},
publisher = {Elsevier},
abstract = {In-situ drug release concurrent with radiation therapy has been proposed as a means to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine which of the proposed methods is the preferred delivery approach.
Materials and Methods
The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}

@article{van2017nanoformulation,
title = {Nanoformulation of olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation},
author = {Anne L van de Ven and Shifalika Tangutoori and Paige Baldwin and Ju Qiao and Codi Gharagouzloo and Nina Seitzer and John G Clohessy and Mike G Makrigiorgos and Robert Cormack and Pier Paolo Pandolfi and others},
year = {2017},
date = {2017-01-01},
journal = {Molecular cancer therapeutics},
volume = {16},
number = {7},
pages = {1279--1289},
publisher = {American Association for Cancer Research},
abstract = {The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279–89. ©2017 AACR.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}

@article{hachani2017assessing,
title = {Assessing cell-nanoparticle interactions by high content imaging of biocompatible iron oxide nanoparticles as potential contrast agents for magnetic resonance imaging},
author = {Roxanne Hachani and Martin A Birchall and Mark W Lowdell and Georgios Kasparis and Le D Tung and Bella B Manshian and Stefaan J Soenen and Willy Gsell and Uwe Himmelreich and Codi A Gharagouzloo and others},
year = {2017},
date = {2017-01-01},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {1--14},
publisher = {Nature Publishing Group},
abstract = {Stem cell tracking in cellular therapy and regenerative medicine is an urgent need, superparamagnetic iron oxide nanoparticles (IONPs) could be used as contrast agents in magnetic resonance imaging (MRI) that allows visualization of the implanted cells ensuring they reach the desired sites in vivo. Herein, we report the study of the interaction of 3,4-dihydroxyhydrocinnamic acid (DHCA) functionalized IONPs that have desirable properties for T2 - weighted MRI, with bone marrow-derived primary human mesenchymal stem cells (hMSCs). Using the multiparametric high-content imaging method, we evaluate cell viability, formation of reactive oxygen species, mitochondrial health, as well as cell morphology and determine that the hMSCs are minimally affected after labelling with IONPs. Their cellular uptake is visualized by transmission electron microscopy (TEM) and Prussian Blue staining, and quantified using an iron specific colourimetric method. In vitro and in vivo studies demonstrate that these IONPs are biocompatible and can produce significant contrast enhancement in T2-weighted MRI. Iron oxide nanoparticles are detected in vivo as hypointense regions in the liver up to two weeks post injection using 9.4 T MRI. These DHCA functionalized IONPs are promising contrast agents for stem cell tracking by T2-weighted MRI as they are biocompatible and show no evidence of cytotoxic effects on hMSCs.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}

@article{gharagouzloo2017quantitative,
title = {Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function},
author = {Codi A Gharagouzloo and Liam Timms and Ju Qiao and Zihang Fang and Joseph Nneji and Aniket Pandya and Praveen Kulkarni and Anne L van de Ven and Craig Ferris and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
journal = {Neuroimage},
volume = {163},
pages = {24--33},
publisher = {Academic Press},
abstract = {A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.},
keywords = {MRI},
pubstate = {published},
tppubtype = {article}
}

@article{belz2017sustained,
title = {Sustained release talazoparib implants for localized treatment of BRCA1-deficient breast cancer},
author = {Jodi E Belz and Rajiv Kumar and Paige Baldwin and Noelle Castilla Ojo and Ana S Leal and Darlene B Royce and Di Zhang and Anne L van de Ven and Karen T Liby and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
journal = {Theranostics},
volume = {7},
number = {17},
pages = {4340},
publisher = {Ivyspring International Publisher},
abstract = {Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}

@article{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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Education},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine, Sensors},
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 = {Nanomedicine},
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 = {MRI, Nanomedicine},
pubstate = {published},
tppubtype = {article}
}