title: Poly(ethylene glycol)-poly(ester-carbonate) block copolymers carrying PEG-peptidyl-doxorubicin pendant side chains: synthesis and evaluation as anticancer conjugates.
abstract: Water soluble polymer anticancer conjugates can improve the pharmacokinetics of covalently bound drugs by limiting cellular uptake to the endocytic route, thus prolonging plasma circulation time and consequently facilitating tumor targeting by the enhanced permeability and retention (EPR) effect. Many of the first generation antitumor polymer conjugates used nonbiodegradable polymeric carriers which limits the molecular weight that can be safely used to <40,000 g/mol. The aim of this ambitious study was to synthesize and evaluate a novel, prototype biodegradable polymeric system based on high molecular weight, water-soluble functionalized polyesters. The main polymeric platform was prepared from bis(4-hydroxy)butyl maleate (DBM) and poly(ethylene glycol) (PEG4000) blocks to give the polymer DBM2-PEG4000 containing biodegradable carbonate bonds and having a M(w) of 100,000-190,000 g/mol; M(n) of 37,000-53,000 g/mol, and M(w)/M(n) of 3.0-3.7. Using thioether linkages, this polymer was then grafted with HS-PEG3000-Gly-Phe-Lue-Gly doxorubicin (HS-PEG3000-GFLG-Dox) pendant side chains ( approximately 30 per DBM2-PEG chain). The final construct, DBM2-PEG4000-S-PEG3000-GFLG-Dox had a total Dox content of 3-4 wt % and a free Dox content of < or = 0.7% total Dox. During incubation with isolated lysosomal enzymes, the rate of Dox release from the polymer backbone was relatively slow (<5% release over 5 h) compared to that seen for PEG5000-GFLG-Dox alone (>20% over 5 h). The in vitro cytotoxicity was assessed using B16F10 murine melanoma (MTT assay). DBM2-PEG4000-S-PEG3000-GFLG-Dox was 10-20-fold less toxic than free Dox. In vivo antitumor activity of the DBM2-PEG4000-S-PEG3000-GFLG-Dox conjugates was assessed using a subcutaneous (s.c.) B16F10 murine melanoma model, and an intraperitoneal (i.p.) L1210 leukaemia model. The increased toxicity (attributed to poor solubility) and low antitumor activity of DBM2-PEG4000-S-PEG3000-GFLG-Dox conjugates compared to PEG5000-GFLG-Dox and HPMA copolymer-Dox conjugates was attributed to the slow rate of Dox release. The DBM2-PEG4000-S-PEG3000-GFLG-Dox conjugates were considered unfavorable as candidates for further development. However, the successful scale-up synthesis of DBM2-PEG4000-S-PEG3000 constructs suggest that they are worthy of further investigation as carriers for controlled release and targeting of less hydrophobic agents.
authors.affiliation: PolyPeptide Laboratories (Sweden) AB, PO Box 30089, SE 20061 Limhamn, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Andersson
authors.forename: John
authors.initials: J
authors.lastname: Davies
authors.forename: Ruth
authors.initials: R
authors.lastname: Duncan
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferruti
authors.forename: Jayne
authors.initials: J
authors.lastname: Ford
authors.forename: Samantha
authors.initials: S
authors.lastname: Kneller
authors.forename: Raniero
authors.initials: R
authors.lastname: Mendichi
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pasut
authors.forename: Oddone
authors.initials: O
authors.lastname: Schiavon
authors.forename: Clive
authors.initials: C
authors.lastname: Summerford
authors.forename: Anders
authors.initials: A
authors.lastname: Tirk
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Veronese
authors.forename: Veronica
authors.initials: V
authors.lastname: Vincenzi
authors.forename: Gefei
authors.initials: G
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D001673:Biodegradation, Environmental; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000627:therapeutic use; D016503:Drug Delivery Systems; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011091:Polyesters; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000627:therapeutic use; D011108:Polymers / Q000138:chemical synthesis* / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis; D051381:Rats; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011091:Polyesters; D011108:Polymers; D011355:Prodrugs; D011092:Polyethylene Glycols; D004317:Doxorubicin