Research Project
6444919
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 sensitize to chemotherapy via p53 replacement using a tumor-targeting liposomal delivery system. The low stability and rapid clearance from circulation of these ligand-liposomes are significant drawbacks for their clinical use. The addition of polyethylene glycol (PEG) to cationic liposomes can improve these two parameters. However, in most cases PEG coating can result in large size complexes and/or can impede the ligand-targeting potential of the complex. We have developed a novel method to prepare a ligand-directed, PEG stabilized complex as a gene delivery system for targeted gene therapy. Due to the presence of PEG these novel complexes have longer circulating times than conventional ligand-liposome complexes and reduced toxicities. In addition, due to the presence of the ligand in the complex with PEG, these complexes are tissue targeting. Furthermore, they retain their small size making them very desirable for in vivo use. This Phase I project we propose to optimize this ligand-PEG-liposome-DNA complex for use as a systemic therapy for prostate cancer, and demonstrate as Proof-of-Principle, its tumor and metastases targeting potential in nude mouse models. The longer-term aim of this project is development and marketing of a more effective treatment for prostate cancer using ligand-PEG stabilized, liposome-mediated gene therapy in combination with chemotherapy. PROPOSED COMMERCIAL APPLICATIONS: Prostate cancer is the most common cancer among American men. Over one million American men are now living with a diagnosis of prostate cancer and thus constitute a substantial marker for new prostate cancer therapies. Four of the world's eight top-selling anti-cancer drugs are prostate drugs (Casodex, Eulixin, Lupron, and Zoladex). These agents have combined annual sales of $1.7 billion, despite the fact that they are merely palliative.
