Elastin-like polypeptides (ELP) present a promising novel mechanism for delivering brachytherapy for cancer treatment. We present a genetically encoded polymer solution, composed of a novel radiolabeled-ELP design that self-assembles upon intratumoral injection. Our preliminary results of small animal studies demonstrate 100% tumor response, effective radionuclide retention rates, strong in vivo depot stability, and no polymer- induced toxicities. While highly promising for improved brachytherapy, the current ELP workflow lacks a dosimetry framework. Without this essential clinical analog, the feasibility of an ELP brachytherapy approach remains indefinitely limited to a pre-clinical environment. The overall objective of this proposal is therefore to provide this critical infrastructure by developing, validating, and evaluating a methodology for determining optimal image-guided dosimetry for ELP-based injectable brachytherapy. This includes implementing modern diagnostic imaging capabilities into the current workflow, developing new dose calculation and optimization schemes that account for the unique nature of ELP dynamics, and designing novel dosimetry verification experiments to validate the process.
Aim 1 is to develop a method for image-guided dosimetric planning for injectable ELP brachytherapy.
Aim 2 is to evaluate the performance of the developed dosimetric planning methodology. Outcome of the proposed study will provide initial treatment planning, optimization, and verification capabilities for ELP-based procedures. We will fundamentally improve our understanding of ELP dynamics in tissue and its impact on dosimetry. This will transform the way in which ELP procedures are performed in the pre-clinical setting, forming a stronger translational relationship between basic polymer science and clinical radiation oncology. The fully developed methodology will serve as the technical foundation for the biopolymer approach, a necessary component if the technique is to someday be implemented into clinical practice.
Radiation oncology is contingent upon the notion of delivering ionizing radiation to cancerous tissue, while sparing non-cancerous tissues. A successful prognosis therefore largely depends not only on how much dose was deposited to the target volume, but also how much normal tissue was spared in the process. Localized therapies that maximize this ratio are therefore well suited to minimize normal tissue toxicities and long term, chronic side effects. Recent advances in polymer science and genetics engineering have invited the idea of using thermally responsive elastin-like polypeptides (ELPs) as a means for delivering such localized therapy. The novelty of these biopolymers is their ability to exhibit inverse temperature phase transitions; i.e., ELPs remain highly soluble in aqueous solution below a tunable threshold temperature, but will aggregate to form a hydrophobic structure in response to a slight temperature increase. Therefore, if ELPs are chemically tagged with radioactive payloads, their unique behavior results in a targeted dose of radiation, exclusively at the site of protein aggregation. We present a genetically encoded polymer solution, composed of a novel radiolabeled- ELP design that self-assembles upon intratumoral injection. Although ELPs are a particularly attractive new mechanism for delivering brachytherapy, a dosimetry framework currently does not exist to plan for such a procedure, and therefore the therapeutic ratio cannot be determined. This study will result in a robust framework with which to plan ELP-based radiation therapy procedures in a pre-clinical environment. The fully developed system will serve as the technical foundation for the biopolymer approach, a necessary component if the technique is to someday be implemented into clinical practice as a new form of localized radiation therapy.
