Advanced prostate cancer tends to be relatively refractory to standard chemotherapeutic agents, and this chemoresistance correlates with a lack of functional p53. Our preliminary data indicate that cancer cells can be sensitized to chemotherapy via p53 replacement using a tumor-targeting liposomal delivery system. In this proposal, a recombinant single-chain fragment (scFv) derived from a monoclonal antibody will be employed to target the transferrin receptor that is known to be elevated on the surface of cells from a variety of tumor types including prostate. In Phase I, the lipid composition of the immunoliposome will be optimized, the scFv expressed and purified, and the delivery system tested using human prostate cancer cells in culture. The impact of p53 gene restoration on the sensitivity of these cells to a variety of commonly used chemotherapeutic agents will be assessed. Finally, using a nude mouse model involving human prostate cancer xenografts, the ability of the immunoliposomes to target primary and metastatic prostate tumors will be tested. 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 chemotherapy.
|Yu, W; Pirollo, K F; Rait, A et al. (2004) A sterically stabilized immunolipoplex for systemic administration of a therapeutic gene. Gene Ther 11:1434-40|
|Xu, Liang; Huang, Cheng-Cheng; Huang, Weiqun et al. (2002) Systemic tumor-targeted gene delivery by anti-transferrin receptor scFv-immunoliposomes. Mol Cancer Ther 1:337-46|
|Xu, L; Tang, W H; Huang, C C et al. (2001) Systemic p53 gene therapy of cancer with immunolipoplexes targeted by anti-transferrin receptor scFv. Mol Med 7:723-34|