Many aspects of medical imaging and treatment rely on the use of high-energy radiation. For example, X-ray and ?-ray therapies are common for the treatment of tumors. While effective, healthy tissues are also exposed to radiation during this type of treatment. Current research efforts to reduce total radiation doses to patients are focused on delivering radiosensitization materials to cancerous sites. These materials, such as metal nanoparticles, adsorb more of the radiation locally and spare heathy tissue. Intriguingly, the results of these experiments indicate that the efficacies of these nanoparticles are higher than would be expected theoretically from just an increase in radiation adsorption. One attractive, but unproven, explanation is that low-energy electrons (LEEs) are generated by the radiosensitization materials and most of the local tissue damage is caused by these LEEs. In this project, we directly measure LEE emission from known radiosensitizers, which we will correlate to cell damage. This will be the first-ever direct assessment of the roles of LEEs in radiotherapy, and is enabled by a new instrument we have developed that can measure both the flux and energy of LEEs induced by X-ray irradiation or radioactive decay of radioisotope-nanoparticle conjugates. Because LEEs readily cause chemical reactions such as DNA strand breaks but have an extremely short range in solution, we hypothesize that targeting LEE-emitting nanoparticles to specific compartments in tumor cells will maximize their effectiveness while minimizing damage to healthy tissues. Our LEE emission measurements and in vitro experiments will inform the design of a new generation of targeted nanomaterials with high LEE emission. The best-performing nanomaterials will subsequently be tested in a mouse model of lung cancer to evaluate in vivo efficacy. Overall, this project represents the first rational design strategy for maximizing the therapeutic effect of radiosensitizing nanomaterials.
Radiosensitization is a promising way to decrease the side effects of radiotherapy to healthy tissue, but so far nanoparticle radiosensitizers are developed using a slow trial-and-error approach that hinders their pathway to application in the clinic. This project will directly probe the physical, chemical, and biological properties of these nanoparticles and enable a new and data-driven approach to understand their performance in vivo. The project will then leverage these measurements to rationally design a new generation of nanoparticle radiosensitizers for maximal clinical performance, and test them in animal models of cancer.
