title: Synthesis and in vivo antitumor efficacy of PEGylated poly(l-lysine) dendrimer-camptothecin conjugates.
abstract: Polymer conjugates of camptothecin (CPT) have been pursued as a solution to the difficulties present in treating cancers with CPT and its derivatives. Covalent attachment of CPT to a polymer can improve solubility, increase blood circulation time, enhance tumor uptake, and significantly improve efficacy of the drug. In this report, we describe a novel polymer conjugate of CPT using a core-functionalized, symmetrically PEGylated poly(l-lysine) (PLL) dendrimer. The PEGylated dendrimer consisted of a lysine dendrimer functionalized with aspartic acid, which was used as an attachment site for poly(ethylene glycol) (PEG) and CPT. The final conjugate had a molecular weight of 40 kDa and was loaded with 4-6 wt % CPT. Polymer-bound CPT was shown to have a long blood circulation half-life of 30.9 +/- 8.8 h and a tumor uptake of 4.2 +/- 2.3% of the injected dose/g of tissue, compared to free CPT in which less than 1% was retained in the blood after 30 min and had a tumor accumulation of 0.29 +/- 0.04% of the injected dose/g of tissue. The PEGylated PLL-CPT showed superior efficacy in murine (C26) and human colon carcinoma (HT-29) tumor models when compared with no treatment or treatment with irinotecan. In the C26 tumor model, treatment resulted in significantly prolonged survival (P < 0.05) for all mice treated with a single injection of PEGylated PLL-CPT. In the HT-29 tumor model, all mice treated with multiple injections of a low dose survived to the end of the study, with three mice of eight surviving tumor-free.
authors: College of Chemistry, University of California, Berkeley, California 94720-1460, USA.
authors: Megan E
authors: ME
authors: Fox
authors: Steve
authors: S
authors: Guillaudeu
authors: Jean M J
authors: JM
authors: Fréchet
authors: Katherine
authors: K
authors: Jerger
authors: Nichole
authors: N
authors: Macaraeg
authors: Francis C
authors: FC
authors: Szoka
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis; D004354:Drug Screening Assays, Antitumor; D005260:Female; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D050091:Dendrimers; D004337:Drug Carriers; C443714:polylysine-graft-(poly(ethylene glycol)); D011107:Polylysine; D011092:Polyethylene Glycols; D002166:Camptothecin