title: An adduct of cis-diamminedichloroplatinum(II) and poly(ethylene glycol)poly(L-lysine)-succinate: synthesis and cytotoxic properties.
abstract: A noncovalent adduct of the antineoplastic drug cis-diamminedichloroplatinum (cDDP) and a biocompatible graft copolymer of poly(L-lysine) and methylpoly(ethylene glycol) succinate is described. Upon incubation of cDDP with [O-methylpoly(ethylene glycol)-O'-succinyl]-N- epsilon-poly(L-lysine)n-N-epsilon-succinate, n = 250-270, highly soluble, long circulating adducts were formed which contained 4.3% of platinum by weight. Approximately 60% of the polymer-associated drug was released during dialysis against saline or serum albumin containing saline, with a half-time of release of 63 h. The adducts showed a pronounced antineoplastic effect in BT-20 human adenocarcinoma cell cultures. In cell proliferation assays, the concentration of half-inhibition of [3H]thymidine uptake was 0.9 +/- 0.2 microM for the drug-copolymer adduct compared to 0.3 +/- 0.1 microM for free cDDP. The adduct showed a long blood half-life (ca. 14 h in rats) and accumulated in experimental mammary adenocarcinomas at 2.5-3.5% injected dose per gram of tissue. A control adduct of cDDP with the backbone portion of the copolymer, poly(L-lysine)-N-epsilon-succinate, had a short half-life in the bloodstream (ca. 30 min) and low accumulation (0.5% injected dose per gram) in tumor. A dual therapeutical effect of methylpoly(ethylene glycol)succinylpoly(L-lysine)-succinate as a carrier of cDDP is suggested: (1) as a carrier for systemic release of the active drug from the macromolecule while it circulates in the bloodstream and (2) as a carrier for on-site delivery which results from the release of the drug in the tumor as a consequence of accumulation of the copolymer in the tumor.
authors: Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129.
authors: A A
authors: AA
authors: Bogdanov
authors: C
authors: C
authors: Martin
authors: A V
authors: AV
authors: Bogdanova
authors: T J
authors: TJ
authors: Brady
authors: R
authors: R
authors: Weissleder
mesh_terms: D000230:Adenocarcinoma; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D011092:Polyethylene Glycols; D011107:Polylysine; D051381:Rats; D011916:Rats, Inbred F344; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C099578:(O-methylpoly(ethylene glycol)-O'-succinyl)-N-epsilon-poly(L-lysine); D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004337:Drug Carriers; D007202:Indicators and Reagents; D011107:Polylysine; D011092:Polyethylene Glycols; D002945:Cisplatin; D013936:Thymidine