Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Sang Hyun Cho
R Jason Stafford
Less that 10% of pancreatic cancer patients are eligible for curative resection, and clinical trials evaluating chemoradiation in locally advanced patients with unresectable disease have been largely disappointing. New and creative therapeutic approaches are needed to address the unment need for treatment options. The objective of this thesis is to advance radiosensitization of treatment-resistant densely desmoplastic pancreatic cancer using nanoparticles to surmount biological barriers to effective particle distribution for DNA-targeting.
Clinical translation of radiosensitizing nanoparticles has stalled owing to technical challenges. Current strategies to use AuNPs for radiosensitization require large quantities of gold, kilovoltage x-rays, immediate irradiation after intravenous administration, and repetitive administrations of AuNPs prior to each radiation dose during a course of fractionated radiotherapy. To overcome these challenges, the next generation of AuNPs should be engineered with 2 design criteria: compatibility with multiple radiation platforms, and appropriate in vivobiodistribution for radiation dose enhancement at low gold quantities.
To address this, nuclear-targeted gold nanoparticles (nAuNPs) are developed as payloads for the thermosensitive liposomes (TSLs). The nAuNP-loaded liposomes are biocompatible carriers capable of penetrating the biophysical barriers and reach deep inside the tumor. Non-invasive thermal stimulation then releases the nanoparticle load at the intended of site of cellular uptake. The nuclear targeting of gold nanoparticles enhances the local effects of radiation via generation of short-range secondary electrons in the proximity of the DNA in aggressive cancer clones.
To test nAuNPs as a radiosensitizing payload of the TSLs, a three-phase plan is presented. Phase I focuses on AuNP cellular distribution, demonstrating signal specific nuclear localization. Phase II appraises radiosensitizing effects of nAuNPs in vitro. Finally, Phase III demonstrates in vivo biodistribution and anti-tumor efficacy of the nAuNPS with and without TLSs in xenograft models of human pancreatic adenocarcinoma. This 3-phase study advances triggered-release of nuclear-targeted nanoparticles as a radiosensitizing modality for localized cancer therapy. This work provides a framework for the development of a readily deployable class solution for radiosensitization in a variety of tumors.
pancreatic cancer, gold nanoparticles, nuclear-targeting, radiation, radiosensitization, liposomal delivery, hyperthermia
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