Metal nanoparticles with customized shapes, sizes, and surface modification have demonstrated tremendous potential for cancer therapy. It is well recognized that physical radiation dose deposited within tumors can be enhanced by passive accumulation of gold nanoparticles in tumors due to the remarkable increase in the fluence of photoelectrons when photons interact with high atomic number elements such as gold. However, the requirements of less clinically relevant radiation quality (low energy kilovolt x-rays) and clinically unachievable (without direct injection) gold concentration reduce enthusiasm for this approach. This proposal seeks to surmount these challenges by achieving a more tumor cell-specific concentration of gold nanoparticles within tumors by adopting an active targeting strategy using gold nanorods (GNRs) and providing photon source options optimized for specific clinical scenarios under active targeting. In preliminary data, we demonstrate that an active targeting strategy results in remarkable in vivo radiosensitization despite a much lower concentration of GNRs within tumors than the concentration previously believed to be necessary for radiosensitization following passive accumulation of gold nanoparticles in tumors. Active targeting also leads to radiosensitization in vitro, reduced repair of radiation-induced DNA double-strand breaks, and overcomes the inherent treatment resistance of tumors to traditional targeted therapies. Our central hypothesis is that active targeting significantly improves the efficiency of GNR-mediated radiosensitization by directly modulating tumor radiation response as a result of substantial microscopic dose enhancement in the vicinity of GNRs that reside in close proximity to tumor cells and vascular endothelial cells in vivo. A corollary hypothesis is that the GNRs serve as vectors for optimal delivery of the targeting moiety to an otherwise resistant tumor, a feature that can be further exploited for therapeutic payload delivery. Critical unanswered questions relate to the molecular mechanism of radiosensitization, biodistribution and kinetics of GNRs, and their fate at the whole animal, tumor and cellular levels. We will test our hypotheses and provide answers to the questions posed above by pursuing three Specific Aims: (a) to determine the molecular mechanism of GNR-mediated radiosensitization in vitro and in vivo, (b) to quantify the radiation dose enhancement by GNRs on a nano-/cellular-scale for different clinical irradiation scenarios, and (c) to determine the intratumoral concentration of GNRs. We anticipate that this proposal will lead to development of a comprehensive physically, biologically and clinically characterized radiation response modulation strategy that can be widely applied as a class solution across multiple tumor types, laying the foundation for more effective clinical radiotherapy with less toxicity.

Public Health Relevance

This proposal builds upon strong preliminary data supporting a new paradigm in gold nanoparticle (GNP)-mediated radiosensitization of tumors using tumor-specific targeting of the GNP and optimized photon source options to develop a new paradigm for treatment of cancer. Using novel experimental and theoretical/computational techniques, this proposal seeks to understand the mechanistic underpinnings of the observed effect and define the operating constraints for maximal clinical impact of this paradigm. Eventually, this multidisciplinary collaborative effort seeks to develop a comprehensive physically, biologically and clinically characterized radiation response modulation strategy that can be widely applied as a class solution across multiple tumor types.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155446-03
Application #
8529471
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Prasanna, Pat G
Project Start
2011-09-19
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$291,334
Indirect Cost
$66,837
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Ahmed, Md Foiez; Yasar, Selcuk; Cho, Sang Hyun (2018) Development of an attenuation correction method for direct x-ray fluorescence (XRF) imaging utilizing gold L-shell XRF photons. Med Phys 45:5543-5554
Manohar, Nivedh; Reynoso, Francisco J; Cho, Sang Hyun (2018) Technical Note: A benchtop cone-beam x-ray fluorescence computed tomography (XFCT) system with a high-power x-ray source and transmission CT imaging capability. Med Phys 45:4652-4659
Ahmed, Md Foiez; Yasar, Selcuk; Cho, Sang Hyun (2018) A Monte Carlo Model of a Benchtop X-Ray Fluorescence Computed Tomography System and Its Application to Validate a Deconvolution-Based X-Ray Fluorescence Signal Extraction Method. IEEE Trans Med Imaging 37:2483-2492
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Venkatesulu, Bhanu P; Krishnan, Sunil (2017) Radiosensitization by inhibiting DNA repair: Turning the spotlight on homologous recombination. Hepatology :
Cho, Jongmin; Gonzalez-Lepera, Carlos; Manohar, Nivedh et al. (2016) Quantitative investigation of physical factors contributing to gold nanoparticle-mediated proton dose enhancement. Phys Med Biol 61:2562-81
Manohar, Nivedh; Reynoso, Francisco J; Diagaradjane, Parmeswaran et al. (2016) Quantitative imaging of gold nanoparticle distribution in a tumor-bearing mouse using benchtop x-ray fluorescence computed tomography. Sci Rep 6:22079
Cho, Jongmin; Wang, Min; Gonzalez-Lepera, Carlos et al. (2016) Development of bimetallic (Zn@Au) nanoparticles as potential PET-imageable radiosensitizers. Med Phys 43:4775

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