Publications

@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},

urldate = {2015-01-01},

journal = {Medical physics},

volume = {42},

number = {6Part29},

pages = {3565--3565},

publisher = {American Association of Physicists in Medicine},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{ozturk2015atomically,

title = {Atomically thin layers of B--N--C--O with tunable composition},

author = {Birol Ozturk and Andres de-Luna-Bugallo and Eugen Panaitescu and Ann N Chiaramonti and Fangze Liu and Anthony Vargas and Xueping Jiang and Neerav Kharche and Ozgur Yavuzcetin and Majed Alnaji and others},

year  = {2015},

date = {2015-01-01},

urldate = {2015-01-01},

journal = {Science advances},

volume = {1},

number = {6},

pages = {e1500094},

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

keywords = {Metamaterials and Nanophotonics, Nanomaterials},

pubstate = {published},

tppubtype = {article}

}

@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}

}

@article{gharagouzloo2015quantitative,

title = {Quantitative contrast-enhanced MRI with superparamagnetic nanoparticles using ultrashort time-to-echo pulse sequences},

author = {Codi Amir Gharagouzloo and Patrick N McMahon and Srinivas Sridhar},

year  = {2015},

date = {2015-01-01},

journal = {Magnetic resonance in medicine},

volume = {74},

number = {2},

pages = {431--441},

keywords = {MRI, Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{sinha2015brachytherapy,

title = {Brachytherapy application with in situ dose painting administered by gold nanoparticle eluters},

author = {Neeharika Sinha and Gizem Cifter and Erno Sajo and Rajiv Kumar and Srinivas Sridhar and Paul L Nguyen and Robert A Cormack and Mike G Makrigiorgos and Wilfred Ngwa},

year  = {2015},

date = {2015-01-01},

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

volume = {91},

number = {2},

pages = {385--392},

publisher = {Elsevier},

abstract = {Purpose

Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS).



Method and Materials

An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using the Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131).



Results

Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125.



Conclusions

Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy application with in situ dose painting administered via gold nanoparticle eluters for prostate cancer.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{cifter2015next,

title = {Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles: MO-FG-BRA-05},

author = {G Cifter and E Sajo and H Korideck and R Kumar and S Sridhar and R Cormack and G Makrigiorgos and W Ngwa},

year  = {2015},

date = {2015-01-01},

journal = {Medical Physics},

volume = {42},

number = {6},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{geilich2015silver,

title = {Silver nanoparticle-embedded polymersome nanocarriers for the treatment of antibiotic-resistant infections},

author = {Benjamin M Geilich and Anne L van de Ven and Gloria L Singleton and Liuda J Sepulveda and Srinivas Sridhar and Thomas J Webster},

year  = {2015},

date = {2015-01-01},

journal = {Nanoscale},

volume = {7},

number = {8},

pages = {3511--3519},

publisher = {Royal Society of Chemistry},

abstract = {The rapidly diminishing number of effective antibiotics that can be used to treat infectious diseases and associated complications in a physician's arsenal is having a drastic impact on human health today. This study explored the development and optimization of a polymersome nanocarrier formed from a biodegradable diblock copolymer to overcome bacterial antibiotic resistance. Here, polymersomes were synthesized containing silver nanoparticles embedded in the hydrophobic compartment, and ampicillin in the hydrophilic compartment. Results showed for the first time that these silver nanoparticle-embedded polymersomes (AgPs) inhibited the growth of Escherichia coli transformed with a gene for ampicillin resistance (bla) in a dose-dependent fashion. Free ampicillin, AgPs without ampicillin, and ampicillin polymersomes without silver nanoparticles had no effect on bacterial growth. The relationship between the silver nanoparticles and ampicillin was determined to be synergistic and produced complete growth inhibition at a silver-to-ampicillin ratio of 1 : 0.64. In this manner, this study introduces a novel nanomaterial that can effectively treat problematic, antibiotic-resistant infections in an improved capacity which should be further examined for a wide range of medical applications.



},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{tangutoori2014we,

title = {WE-G-BRE-08: Radiosensitization by Olaparib Eluting Nanospheres},

author = {S Tangutoori and H Korideck and R Kumar and S Sridhar and G Makrigiorgos and R Cormack},

year  = {2014},

date = {2014-01-01},

journal = {Medical Physics},

volume = {41},

number = {6Part30},

pages = {518--518},

publisher = {American Association of Physicists in Medicine},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{petrov2014ultra,

title = {Ultra-dense EEG sampling results in two-fold increase of functional brain information},

author = {Yury Petrov and Jeffrey Nador and Christopher Hughes and Stanley Tran and Ozgur Yavuzcetin and Srinivas Sridhar},

year  = {2014},

date = {2014-01-01},

journal = {Neuroimage},

volume = {90},

pages = {140--145},

publisher = {Academic Press},

abstract = {We used an ultra-density electroencephalography (ud-EEG) sensor array with improved electrical characteristics to reveal unexpected strong potential variation at 1 cm scale. A new classification paradigm demonstrates that ud-EEG provides twice the signal to noise ratio for data classification compared with contemporary hd-EEG. These results suggest a paradigm shift from current thinking by showing that higher spatial resolution sampling of EEG is required and leads to increased functional brain information that is useful for diverse neurological applications. Contemporary high-density electroencephalographic systems (hd-EEG) comprising up to 256 electrodes have inter-electrode separations of 2–4 cm. Because electric currents of the brain are believed to strongly diffuse before reaching the scalp surface, higher-density electrode coverage is often deemed unnecessary. We used an ultra-dense electroencephalography (ud-EEG) sensor array to reveal strong potential variation at 1 cm scale and discovered that it reflects functional brain activity. A new classification paradigm demonstrates that ud-EEG provides twice the signal to noise ratio for brain-response classification compared with contemporary hd-EEG. These results suggest a paradigm shift from current thinking by showing that higher spatial resolution sampling of EEG is required and leads to increased functional brain information that is useful for diverse neurological applications.},

keywords = {Neurotechnology},

pubstate = {published},

tppubtype = {article}

}

@article{sridhar2014361,

title = {361 Nanoformulations of the PARP inhibitors olaparib and BMN 673 for cancer nanotherapy},

author = {S Sridhar and S Tangutoori and P Baldwin},

year  = {2014},

date = {2014-01-01},

journal = {European Journal of Cancer},

volume = {50},

pages = {116},

publisher = {Elsevier},

abstract = {Background: Intensive investigations are ongoing to identify and validate predictive molecular markers for anti-angiogenic agents in metastatic renal cell carcinoma (mRCC) and other solid tumour types. However, this proves to be challenging due to multiple resistance mechanisms. Maturing understanding of immuno-oncology functions, including tumour-infiltrating lymphocytes (TIL) and tumour-associated macrophages (TAM), and their influence on mRCC biology provides the opportunity for new insights into sensitivity to anti-angiogenic agents.

Materials and Methods: Archival tumour samples were collected on an optional basis and prior to axitinib dosing from 52 patients with mRCC treated with axitinib following 1 prior systemic first-line regimen in the phase III AXIS trial (NCT00678392). Samples were assessed for macrophage (CD68+) and lymphocyte (CD3+) infiltration using immunohistochemistry. Potential associations between these tumourassociated immune cells and clinical efficacy following axitinib treatment were investigated by Kaplan–Meier analysis using median CD68+(0.08 cells/mm2) and CD3+(399.5 cells/mm2) levels as thresholds and by receiver operating characteristics (ROC) analysis. Results: Higher CD68+ levels were associated with longer median progression-free survival (PFS) of 12.0 months for⩾ median CD68+ cells/mm2 vs 3.7 months for< median CD68+ cells/mm2 (hazard ratio= 0.42, log-rank P< 0.01; not subjected to multivariate analysis accounting for clinical variables). Multivariate analysis is ongoing. ROC analysis of PFS at 2, 4, 6, and 8 months generated optimised cut-points for CD68+ cells/mm2; the …},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{berbeco2014targeted,

title = {Targeted gold nanoparticles as vascular disrupting agents during radiation therapy},

author = {RI Berbeco and H Korideck and R Kumar and S Sridhar and A Detappe and W Ngwa and M Makrigiorgos},

year  = {2014},

date = {2014-01-01},

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

volume = {90},

number = {1},

pages = {S198},

publisher = {Elsevier},

abstract = {Purpose/Objective(s)

Recent developments in anti-angiogenic and vascular-disrupting therapies have shown the great potential of tumor vasculature as a therapeutic target for cancer medicine. We have an original idea for using targeted gold nanoparticles as vascular disruptive agents in conjunction with clinical megavoltage (MV) photon beams. Unlike competing approaches, we recognize that gold nanoparticles tend to accumulate in, and can even be targeted for, tumor blood vessels and that these structures may be more important for anti-cancer therapy than clonogenic cell death alone. Due to the short distance traveled by x-ray induced photoelectrons, the endothelial cells of the tumor will receive a sizable boost in dose, even for MV irradiation.

Materials/Methods

We have developed and characterized a novel 4th generation gold nanoparticle platform which includes PEGylation for long circulation, Arginylglycylaspartic acid (RGD) for neovascular targeting and AF647 for fluorescence imaging. Theoretical studies were performed using a combination of Monte Carlo and analytical methods. In vitro experiments were performed using a clinical 6 MV photon beam with the HeLa cell line. In vivo imaging experiments were performed in an orthotopic pancreatic cancer model.

Results

The targeted gold nanoparticle platform is non-toxic and stable over six months. TEM imaging demonstrated consistent gold nanoparticle size of 2-3 nm and confocal microscopy showed robust in vitro cell uptake. Theoretical studies predict a 50% dose enhancement to adjacent tumor endothelial cells. Experimental studies in a 6 MV beam found 40-60% damage enhancement with the effect greatest for deeper targets and with the linear accelerator operating in flattening filter free mode. Fluorescence and TEM imaging studies 24 hours post IV injection confirmed (1) preferential uptake in the tumor, (2) low uptake in normal tissue, (3) infiltration of the tumor endothelial cells, and (4) renal clearing of the gold nanoparticles.

Conclusions

Our studies have demonstrated that a substantial therapy enhancement is expected when gold nanoparticles are targeted to tumor endothelial cells prior to clinical radiation therapy. Our concept is compatible with current clinical practice and could offer an important clinical benefit with minimal patient risk.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{berbeco201420,

title = {20: Targeted Gold Nanoparticles as Vascular Disrupting Agents during Radiotherapy},

author = {R Berbeco and H Korideck and R Kumar and S Sridhar and M Makrigiorgos},

year  = {2014},

date = {2014-01-01},

journal = {Radiotherapy and Oncology},

volume = {110},

pages = {S10--S11},

publisher = {Elsevier},

abstract = {Results: More than 100 patients with various indications within the broad therapeutic spectrum covered at HIT received one or more post-therapeutic PET/CT measurements. Especially for proton induced activity, we could considerably improve the predictive power of the activity calculation by the refinement of the used crosssections for radionuclide production and, for brain tumour subjects, a refinement of tissue classification based on a novel multi-modal patient model. The initial clinical experience allows identifying the anatomical locations which benefit most from PET-based verification, as well as the shortcomings of the offline data acquisition. Conclusions: Post-therapeutic PET/CT-based treatment verification is fully integrated into the clinical workflow at HIT. Despite the comparatively low signal due to decay and washout during the transfer time distinct to the offline workflow, valuable treatment quality …},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{navarro2014phospholipid,

title = {Phospholipid-modified polyethylenimine-based nanopreparations for siRNA--mediated gene silencing: Implications for transfection and the role of lipid components},

author = {Gemma Navarro and Sean Essex and Rupa R Sawant and Swati Biswas and Dattatri Nagesha and Srinivas Sridhar and Conchita Tros de ILarduya and Vladimir P Torchilin},

year  = {2014},

date = {2014-01-01},

journal = {Nanomedicine: Nanotechnology, Biology and Medicine},

volume = {10},

number = {2},

pages = {411--419},

publisher = {Elsevier},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{ngwa2014targeted,

title = {Targeted radiotherapy with gold nanoparticles: current status and future perspectives},

author = {Wilfred Ngwa and Rajiv Kumar and Srinivas Sridhar and Houari Korideck and Piotr Zygmanski and Robert A Cormack and Ross Berbeco and Mike G Makrigiorgos},

year  = {2014},

date = {2014-01-01},

journal = {Nanomedicine},

volume = {9},

number = {7},

pages = {1063--1082},

publisher = {Future Medicine},

abstract = {Radiation therapy (RT) is the treatment of cancer and other diseases with ionizing radiation. The ultimate goal of RT is to destroy all the disease cells while sparing healthy tissue. Towards this goal, RT has advanced significantly over the past few decades in part due to new technologies including: multileaf collimator-assisted modulation of radiation beams, improved computer-assisted inverse treatment planning, image guidance, robotics with more precision, better motion management strategies, stereotactic treatments and hypofractionation. With recent advances in nanotechnology, targeted RT with gold nanoparticles (GNPs) is actively being investigated as a means to further increase the RT therapeutic ratio. In this review, we summarize the current status of research and development towards the use of GNPs to enhance RT. We highlight the promising emerging modalities for targeted RT with GNPs and the corresponding preclinical evidence supporting such promise towards potential clinical translation. Future prospects and perspectives are discussed.},

keywords = {Nanomedicine},

pubstate = {published},

tppubtype = {article}

}

@article{faegh2014ultrasensitive,

title = {Ultrasensitive piezoelectric-based microcantilever biosensor: Theory and experiment},

author = {Samira Faegh and Nader Jalili and Srinivas Sridhar},

year  = {2014},

date = {2014-01-01},

journal = {IEEE/ASME Transactions on Mechatronics},

volume = {20},

number = {1},

pages = {308--312},

publisher = {IEEE},

abstract = {Microcantilever (MC)-based sensors have become an advantageous tool for detection of ultrasmall masses and biological species. Exploiting high affinity of biomolecules, MCs offer a simple, inexpensive, and highly sensitive platform for high throughput diagnosis and analytical sensing. A number of methods have been reported targeting sensitivity enhancement of MC-based systems including geometry modification, employing nanoparticle-enhanced MCs, and operating MCs in lateral and torsional modes. High mode resonating MCs have been reported as a promising sensitivity enhancement method. Although being investigated, there have not been enough analytical high fidelity models describing all dynamics and behavior of MCs operating in high modes with experimental proof. In this study, experimental results of a piezoelectric self-sensing MC operating as a biological sensor at ultrahigh mode along with theoretical verification are presented. Effect of absorbed mass on the frequency shift was investigated using self-sensing and optical measurement methodologies. Mode convergence theory was adopted in order to get the best estimation of resonance frequencies at different modes. Amino groups of aminothenethaiol solution are immobilized over MC. Shift in resonance frequencies in higher modes are measured and the quality factor is calculated proving the fact that sensitivity of MC to detect absorbed masses enhances as the number of modes increases.},

keywords = {Sensors},

pubstate = {published},

tppubtype = {article}

}

@article{sridhar2014wavelet,

title = {Wavelet Transform Techniques for Image Compression-An Evaluation},

author = {S Sridhar and Rajesh P Kumar and KV Ramanaiah},

year  = {2014},

date = {2014-01-01},

journal = {International journal of image, graphics and signal processing},

volume = {6},

number = {2},

pages = {54},

publisher = {Modern Education and Computer Science Press},

abstract = {A vital problem in evaluating the picture quality of an image compression system is the difficulty in describing the amount of degradation in reconstructed image, Wavelet transforms are set of mathematical functions that have established their viability in image compression applications owing to the computational simplicity that comes in the form of filter bank implementation. The choice of wavelet family depends on the application and the content of image. Proposed work is carried out by the application of different hand designed wavelet families like Haar, Daubechies, Biorthogonal, Coiflets and Symlets etc on a variety of bench mark images. Selected benchmark images of choice are decomposed twice using appropriate family of wavelets to produce the approximation and detail coefficients. The highly accurate approximation coefficients so produced are further quantized and later Huffman encoded to eliminate the psychovisual and coding redundancies. However the less accurate detailed coefficients are neglected. In this paper the relative merits of different Wavelet transform techniques are evaluated using objective fidelity measures- PSNR and MSE, results obtained provide a basis for application developers to choose the right family of wavelet for image compression matching their application.},

keywords = {MRI},

pubstate = {published},

tppubtype = {article}

}