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.

Liposomal, Nanoparticle, and Conjugated Formulations of Anticancer Agents

“…This new development has been attributed to the use of highermolecular-weight PEGs (>20,000) and especially with the use of PEG 40,000, which has an extended t 1/2 in plasma and potential selective distribution to solid tumors (59). Various PEG conjugates of anticancer agents, such as doxorubicin (60), methotrexate (61), IFN (62,63), and camptothecin analogues (64,65), are currently in development (60 -65). PEG-and 20-carbonate conjugates of camptothecin analogues are especially interesting as the conjugated prodrug forms highly water soluble agents and significantly extend the duration of exposure after a single dose (64 -66).…”

Effects of Different Carboxylic Ester Spacers on Chemical Stability, Release Characteristics, and Anticancer Activity of Mono-PEGylated Curcumin Conjugates

“…[31][32][33] The use of PEG as a promoiety to attach to drug molecules known as PEGylation is an accepted strategy for human therapy that takes advantage of the safety profile of PEG. 34,35 In addition to its application as a drug carrier, PEG is used clinically for its chemopreventive properties in colon carcinogenesis. 36,37 PEGylated bovine adenosine deaminase (ADAGEN R ), L-asparaginase (ONCASPAR R ), and "-interferon (PEG-INTRON R ) have been approved by the FDA for treatment of human disease.…”

Polyamidoamine Nanoparticles as Nanocarriers for the Drug Delivery to Malaria Parasite Stages in the Mosquito Vector

“…More recently, PAAs have been adopted as carriers for anticancer drugs such as mytomycin C [50], platinates [51] and doxorubicin. Conjugation of doxorubicin to polymers improves drug solubility, increases its blood half-life, decreases its toxicity, and mediates more efficient tumour targeting [52]. As the drug is inactive in its conjugated form and can be selectively released at the tumour site, doxorubicin can act primarily against cancer cells with minimal damage to healthy tissue.…”