Polymer delivery of camptothecin against 9L gliosarcoma: release, distribution, and efficacy.
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 11-45 microg of camptothecin-sodium/mg brain tissue was within a 3 mm radius of the polymer disc, with levels of 0.1 microg at the outermost margin of the rat brain, 7 mm 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 1000 h 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.
Storm
Phillip B
PB
Department of Neurological Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Moriarity
John L
JL
Tyler
Betty
B
Burger
Peter C
PC
Brem
Henry
H
Weingart
Jon
J
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004343:Drug Implants; D018316:Gliosarcoma / Q000188:drug therapy* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D016019:Survival Analysis; D013997:Time Factors; D014018:Tissue Distribution
D000972:Antineoplastic Agents, Phytogenic; D004343:Drug Implants; D002166:Camptothecin