Cancer Chemother Pharmacol (1996) 39: 90—96  Springer-Verlag 1996 ORIGINAL ARTICLE Alessandro Olivi · Matthew G. Ewend Tadanobu Utsuki · Betty Tyler · Abraham J. Domb Daniel J. Brat · Henry Brem Interstitial delivery of carboplatin via biodegradable Polymers is effective against experimental glioma in the rat Received: 25 August 1995/Accepted: 21 February 1996 Abstract Purpose: Carboplatin has shown promise ex- perimentally as an antineoplastic agent against both primary central nervous system (CNS) tumors and sev- eral solid tumors that frequently metastasize to the brain. Unfortunately, carboplatin is limited in its clini- cal use for tumors in the CNS by systemic toxicity and poor penetration through the blood—brain barrier. Re- cent advances in polymer technology have made feas- ible the intracranial implantation of a biodegradable polymer capable of local sustained delivery of chemo- therapy for brain neoplasms. This study assessed the toxicity and efficacy of carboplatin delivered from in- tracranial sustained release polymers in the treatment of experimental gliomas in rodents. Methods: Two bio- degradable anhydride polymer systems were tested: a copolymer of 1,3-bis-(p-carboxyphenoxy propane) and sebacic acid, and a copolymer of fatty acid dimer and sebacic acid. The polymers were loaded with carbo- platin and dose escalation studies evaluating 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 containing the highest tolerated doses were implanted at the site of A. Olivi ( ) · M.G. Ewend · T. Utsuki · B. Tyler · H. Brem Department of Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA TEL (410) 614—0477; FAX (410) 614—0478 A. Olivi · H. Brem Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA A.J. Domb Department of Pharmaceutical Chemistry, School of Pharmacy-Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel 91120 D.J. Brat Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA tumor growth. The survival of animals receiving carbo- platin-loaded polymer was compared with that of ani- mals receiving intraperitoneal doses of the same agent. Results: Carboplatin-polymer was well tolerated at doses up to 5% loading in both polymer systems. Locally delivered carboplatin effectively prolonged sur- vival of rats with F98 gliomas. Maximal treatment effect was seen with 5% loading of either polymer, with median survival increased threefold over control (P(0.004). Systemic carboplatin also significantly prolonged survival, but the best intracranial polymer dose was significantly more effective than the best sys- temic dose tested. Conclusions: Carboplatin can be safely delivered intracranially by biodegradable sus- tained- release polymers. This treatment improves survival in rodents with experimental gliomas, with locally delivered carboplatin being more effective than systemic carboplatin. Key words Carboplatin · Glioma · Polymer · Drug delivery systems · Brain tumor Introduction Platinum drugs, which exert antitumor effects by bind- ing to DNA and producing interstrand crosslinks, have shown promise in the treatment of central nervous system (CNS) tumors including malignant glioma, medulloblastoma, optic pathway glioma, brainstem glioma and ependymoma [6, 14, 33, 41, 42]. These drugs are also active against a variety of solid tumors that frequently metastasize to brain, including breast and non-small-cell lung cancer [8, 16, 19, 28, 30, 34]. Unfortunately, the use of platinum-based drugs is limited by systemic toxicity. Cisplatin (cis-diamminedichloro- platinum) has significant neurotoxicity, nephrotoxicity, ototoxicity, and gastrointestinal toxicity [17]. To mini- mize these toxic effects, analogs of cisplatin including