Monday, March 31, 2025
3/31/2025
Expanding the therapeutic window of chemoradiation through radiation-responsive nanoparticle drug depots - Certain cancers have remained difficult to control locally, despite progress in multimodal treatments that combine X-ray radiation therapy (XRT), chemotherapy, and surgery. Although XRT can be delivered with ever- increasing anatomical precision, most drugs used in conjunction with XRT exhibit rapid and non-specific distribution throughout the body. High chemotherapy doses improve durable response rates in various indications when combined with XRT, but severe and sometimes deadly off-target toxicities are frequent. Even patients with durable remission can be left with debilitating side effects. Thus a major unmet challenge lies in expanding the therapeutic window of chemoradiation to improve local disease control while mitigating toxicities. We propose to address this issue by developing a nanoparticle-based strategy that uses XRT to control the sustained and local release of chemotherapy payloads within irradiated tissue. Nanomaterials have been extensively studied for their ability to enhance XRT effects. However, past strategies have often relied on short-lived radical species operating over nanometer length-scales, leaving them susceptible to spatially heterogeneous effects and variability from endogenous biochemical processes. To overcome this limitation, we build on our past research in drug-loaded nanomedicines, radiation physics, and prodrug chemistry to develop a Scintillating nanoparticle drug depot (SciDD) platform that operates by using nanoparticles to convert X-ray energy into light that releases potent and tumor-penetrating cytotoxic drug payloads into irradiated tissue. In preliminary studies, SciDD safely controls tumor progression in multiple mouse models of cancer while mitigating systemic toxicities. Nonetheless, major knowledge gaps remain in understanding how such radiation-activated drug delivery impacts the cascade of cellular and immunologic responses to XRT within the tumor microenvironment, and in understanding how such an approach compares with traditional drug delivery nanomedicines and radiosensitizers. We will therefore optimize SciDD as a platform for robust, sustained, XRT-activatable drug delivery (Specific Aim 1), study the spatial and single-cell impact of XRT and SciDD on the tumor microenvironment of orthotopic cancer models (Specific Aim 2), and test the ability to safely control disease progression while mitigating systemic toxicity (Specific Aim 3). This project brings together new highly multiplexed and in vivo imaging techniques to study the tumor microenvironment with molecular and spatial detail, and will produce rich datasets comparing radiation-activatable drug delivery with traditional radiosensitizing and drug-delivery nanoparticles. As a result, the project will advance radiation-responsive nanomaterials for therapy and will shed light on how XRT affects the structure and enhanced permeability and retention effects of the tumor microenvironment.
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