EFFECTIVENESS AND SAFETY OF CONTROLLED-RELEASE DRUG DELIVERY FOR BRAIN TUMORS

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We are proposing a new approach to treating brain tumors utilizing local controlled delivery via biodegradable polymers of effective agents directly to the site of the tumor. During the prior granting period we tested the hypothesis that local sustained treatment by delivery of such agents directly at the tumor site via biodegradable controlled release polymers would be more effective than systemic therapy. We developed polymer/drug complexes; and, after extensive preclinical studies in animal models that established their biocompatibility, safety, and effectiveness, we conducted Phase l - 3 clinical trials with a BCNU-polymer implant devised through the collaborative efforts of this NCDDG. We have, in collaboration with the other programs of this NCDDG, developed new polymers with new effective agents and demonstrated their safety and improved efficacy for treating brain tumors. We are now in a position to build on the gains made in the past 4 years to test our hypotheses that the optimal direct tumor delivery of an effective agent will improve outcome without the side effects of systemic therapy and that combinations of agents and/or biological approaches will be more effective than single agents. Our specific aims are: Aim l: To test the effectiveness of new biodegradable polymers by (a) evaluating their safety in the brain; and (b) assessing their effectiveness when utilized with established drugs against rat brain tumors. Aim 2: To test the effectiveness of newly developed antitumor drugs by (a) determining their release kinetics from various polymers and their efficacy in vitro; (b) evaluating the new drug polymer combination for neurotoxicity and establishing the maximum tolerated dose; (c) evaluating the effectiveness in the rat 9L glioma model; and (d) efficacy against human xenografts in the nude rat. Aim 3: To explore combinations of drugs and other treatments, including (a) investigating radiosensitizers in combination with external radiation; (b) utilizing antiangiogenic agents, immunotoxins, and cytokines, with chemotherapeutic and other biological agents.