Advanced prostate cancer tends to be relatively refractory to standard chemotherapeutic agents and radiation treatment, and this resistance correlates with a lack of functional p53. Our previous data indicate that cancer cells can be sensitized to radiation and chemotherapy via p53 replacement using a tumor-targeting liposomal delivery system. In the STTR Phase I proposal, we constructed a recombinant singlechain fragment (scFv) derived from a monoclonal antibody against the transferrin receptor that is known to be elevated on the surface of cells from a variety of tumor types including prostate. The scFv was expressed and purified, and the delivery and transfection efficiency assessed in culture. Using a nude mouse model, the ability of the immunoliposomes to target primary and metastatic tumors was demonstrated. After achieving above and beyond what was proposed in Phase I, in this Phase II application we will test the efficacy of the scFv-targeted liposome delivered p53 to sensitize several prostate cancer cell lines to radio-/chemo-therapy in vitro and in vivo. We will also perform the requisite pre-clinical animal studies leading to performance of human clinical trials. The longer-term aim of this project is development and marketing of a more effective treatment for prostate cancer using immunoliposome-mediated p53 gene therapy plus radiation/chemotherapy.