The objective of the proposed research is to selectively deliver systemically injected radionuclides to solid tumors by a thermal targeting strategy. This objective will be achieved by conjugating radionuclides (131I and 211 At) to thermally sensitive polypeptide carriers, which will be targeted to solid tumors by focused hyperthermia of the tumor. The thermally responsive macromolecular carriers used for thermal targeting are polypeptides derived from mammalian elastin, composed of Val-Pro- Gly-Xaa-Gly (VPGXG) repeats, which undergo an inverse phase transition; below their inverse transition temperature (Tt), ELPs are highly soluble, but when the temperature is raised above their Tt, they undergo a phase transition within a 2-3 degrees Celsius range, leading to desolvation and aggregation of the polypeptide. The underlying hypothesis of the proposed research is that intravenously injected radionuclides, conjugated to a temperature-responsive ELP, can be designed such that they will selectively accumulate in the tumor, maintained at 42 degrees Celsius by local hyperthermia due to aggregation of the ELP in response to its phase transition. In preliminary research, we have demonstrated that thermal targeting provides a 2-3 fold increase in tumor localization versus non-heated controls and a approximately 2 fold enhancement with respect to a thermally insensitive control ELP in heated human tumor xenografts implanted in athymic mice. We propose the following specific aims to achieve the objectives of this proposal: (1) to synthesize ELPs with a Tt of 40 degrees Celsius by recombinant DNA methods; (2) to conjugate radionuclides to the ELPs; (3) to optimize the thermally targeted delivery of ELPs to human tumor xenografts implanted in athymic mice; (4) to carry out systemic radionuclide therapy with 211 At-labeled ELPs using the optimized protocols and external hyperthermia of solid tumors. The development of thermally responsive radionuclide-ELP conjugates that can be targeted to solid tumors by externally-induced local hyperthermia is a new paradigm for targeted delivery which directly targets the tumor microvasculature and circumvents the barriers associated with the interstitium and antibody-tumor cell surface antigen/receptor binding that are intrinsic to affinity targeting approaches for radionuclide therapy.
Showing the most recent 10 out of 42 publications
