Polymer Delivery of Camptothecin against 9L Gliosarcoma: Release,Distribution, and Efficacy |
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Authors: | Storm Phillip B. Moriarity John L. Tyler Betty Burger Peter C. Brem Henry Weingart Jon |
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Affiliation: | (1) Department of Neurological Surgery, Hunterian Brain Tumor Research Laboratory, Baltimore, MD, USA;(2) Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA |
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Abstract: | Camptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro; unfortunately, systemic toxicity has limited its in vivo efficacy. This is the first study to investigate the release, biodistribution, and efficacy of camptothecin from a biodegradable polyanhydride polymer. Tritiated camptothecin was incorporated into biodegradable polymers that were implanted intracranially in 16 male Fischer 344 rats and the animals were followed up to 21 days post-implant. A concentration of 11–45g of camptothecin-sodium/mg brain tissue was within a 3mm radius of the polymer disc, with levels of 0.1g at the outermost margin of the rat brain, 7mm from the site of implantation. These tissue concentrations are within the therapeutic ranges for human and rat glioma lines tested against camptothecin-sodium in vitro. The in vivo efficacy of camptothecin-sodium was evaluated with male Fischer 344 rats implanted intracranially with 9L gliosarcoma and compared with the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The animals were divided into four groups. Group 1 (control) had a median survival of 17 days. Group 2 (3.8% BCNU polymer) had a median survival of 23 days (P=0.006). Group 3 (20% camptothecin polymer) had a median survival of 25 days (P=0.023). Group 4 (50% camptothecin polymer) had a median survival of 69 days (P<0.001). Drug loadings of 20% and 50% camptothecin released intact camptothecin for up to 1000h in vitro. We conclude that the biodegradable polymer p(CPP:SA) releases camptothecin-sodium, produces tumoricidal tissue levels, results in little or no systemic toxicity, and prolongs survival in a rat glioma model. |
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Keywords: | camptothecin glioma polymer distribution blood– brain barrier |
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