INTERSTITIAL DELIVERY OF CARBOPLATIN VIA BIODEGRADABLE POLYMERS IS EFFECTIVE AGAINST EXPERIMENTAL GLIOMA IN THE RAT

Purpose: Carboplatin has shown promise experimentally as an antineopla stic agent against both primary central nervous system (CNS) tumors an d several solid tumors that frequently metastasize to the brain. Unfor tunately, carboplatin is limited in its clinical use for tumors in the CNS by systemic toxicity and poor penetration through the blood-brain barrier. Recent advances in polymer technology have made feasible the intracranial implantation of a biodegradable polymer capable of local sustained delivery of chemotherapy for brain neoplasms. This study as sessed the toxicity and efficacy of carboplatin delivered from intracr anial sustained release polymers in the treatment of experimental glio mas in rodents. Methods: Two biodegradable anhydride polymer systems w ere tested: a copolymer of 1,3-bis-(p-carboxyphenoxy propane) and seba cic acid, and a copolymer of fatty acid dimer and sebacic acid. The po lymers were loaded with carboplatin and dose escalation studies evalua ting toxicity were performed by implanting carboplatin-loaded polymers into the brains of rats. Next, efficacy was tested. F-98 glioma cells were injected intracranially into rats, and 5 days later polymers con taining the highest tolerated doses were implanted at the site of tumo r growth. The survival of animals receiving carboplatin-loaded polymer was compared with that of animals receiving intraperitoneal doses of the same agent. Results: Carboplatin-polymer was well tolerated at dos es up to 5% loading in both polymer systems. Locally delivered carbopl atin effectively prolonged survival of rats with F98 gliomas. Maximal treatment effect was seen with 5% loading of either polymer, with medi an survival increased threefold over control (P < 0.004). Systemic car boplatin also significantly prolonged survival, but the best intracran ial polymer dose was significantly more effective than the best system ic dose tested. Conclusions: Carboplatin can be safely delivered intra cranially by biodegradable sustained- release polymers. This treatment improves survival in rodents with experimental gliomas, with locally delivered carboplatin being more effective than systemic carboplatin.