Poly(ethylene glycol)-Poly(ester-carbonate) Block Copolymers Carrying PEG-Peptidyl-Doxorubicin Pendant Side Chains: Synthesis and Evaluation as Anticancer Conjugates
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- 作者：Lars Andersson ; John Davies ; Ruth Duncan ; Paolo Ferruti ; Jayne Ford ; Samantha Kneller ; Raniero Mendichi ; Gianfranco Pasut ; Oddone Schiavon ; Clive Summerford ; Anders Tirk ; Francesco M. Veronese ; Veroni
- 刊名：Biomacromolecules
- 出版年：2005
- 出版时间：March 2005
- 年：2005
- 卷：6
- 期：2
- 页码：914 - 926
- 全文大小：425K
- 年卷期：v.6,no.2(March 2005)
- ISSN：1526-4602
文摘
Water soluble polymer anticancer conjugates can improve the pharmacokinetics of covalently bound drugsby limiting cellular uptake to the endocytic route, thus prolonging plasma circulation time and consequentlyfacilitating tumor targeting by the enhanced permeability and retention (EPR) effect. Many of the firstgeneration antitumor polymer conjugates used nonbiodegradable polymeric carriers which limits the molecularweight that can be safely used to <40 000 g/mol. The aim of this ambitious study was to synthesize andevaluate a novel, prototype biodegradable polymeric system based on high molecular weight, water-solublefunctionalized 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 containingbiodegradable carbonate bonds and having a Mw of 100 000-190 000 g/mol; Mn of 37 000-53 000 g/mol,and Mw/Mn 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 (~ 30 per DBM2-PEG chain). Thefinal construct, DBM2-PEG4000-S-PEG3000-GFLG-Dox had a total Dox content of 3-4 wt % and a free Doxcontent of 
0.7% total Dox. During incubation with isolated lysosomal enzymes, the rate of Dox releasefrom 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 vivoantitumor 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 increasedtoxicity (attributed to poor solubility) and low antitumor activity of DBM2-PEG4000-S-PEG3000-GFLG-Doxconjugates compared to PEG5000-GFLG-Dox and HPMA copolymer-Dox conjugates was attributed to theslow rate of Dox release. The DBM2-PEG4000-S-PEG3000-GFLG-Dox conjugates were considered unfavorableas 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 releaseand targeting of less hydrophobic agents.
0.7% total Dox. During incubation with isolated lysosomal enzymes, the rate of Dox releasefrom 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 vivoantitumor 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 increasedtoxicity (attributed to poor solubility) and low antitumor activity of DBM2-PEG4000-S-PEG3000-GFLG-Doxconjugates compared to PEG5000-GFLG-Dox and HPMA copolymer-Dox conjugates was attributed to theslow rate of Dox release. The DBM2-PEG4000-S-PEG3000-GFLG-Dox conjugates were considered unfavorableas 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 releaseand targeting of less hydrophobic agents.