Although surgery and radiation are typically used in the treatment of malignant gliomas, the prognosis and 5-year survival rate for these patents is very poor. Gliomas are typically radioresistant and represent 1 of the most difficult tumors to treat by noninvasive methods. Gemcitabine is a potent radiosensitizer whose clinical utility is limited by its inherent toxicity to normal tissues (low therapeutic index) and short plasma half-life. The specific objective of this research proposal is to develop a novel biocompatible, biodegradable polyester nanoparticle (NP) platform for tumor specific (targeted) systemic delivery of gemcitabine to brain tumors to increase the efficacy of ionizing radiation (IR). Use of an actively targeted systemic NP delivery system for gemcitabine is unprecedented and is expected to overcome the usual limitations of systemic drug delivery by minimizing exposure of normal tissues to the drug while simultaneously penetrating the blood brain barrier to deliver therapeutic concentrations to the tumor. Phase I of the project will focus on 4 objectives: (1) the synthesis and physicochemical characterization of biodegradable polyester NPs, including in vitro degradation half-life; (2) in vitro demonstration of cell line specific NP targeting to tumor cells and neovasculature; (3) encapsulation of gemcitabine; and (4) in vivo demonstration of an acceptable elimination half-life in rats after a single IV injection. Phase II research will include in vivo F3 targeting studies and in vivo radiosensitization and efficacy studies in the 9L rat glioma and other brain tumor models for optimization of dose and schedule dependency (for both the NP and IR). The overall goals of the proposed research plans are (1) to validate a new targeted, biodegradable polyester NP drug carrier for tumor specific delivery of therapeutics to brain tumors and (2) to demonstrate radiosensitization and efficacy with the combination of targeted gemcitabine NP with IR in preclinical models of human brain tumors, thereby addressing the current lack of efficacious treatment for gliomas. Project Narrative: Gliomas are typically radioresistant and represent 1 of the most difficult tumors to treat by noninvasive methods. The overall goals of the proposed research plans are to demonstrate radiosensitization and efficacy with the combination of targeted gemcitabine containing nanoparticles with radiotherapy in preclinical models of human brain tumors, thereby addressing the current lack of efficacious treatment for gliomas. ? ? ?
