Fabrication and reduction-sensitive behavior of polyion complex nano-micelles based on PEG-conjugated polymer containing disulfide bonds as a potential carrier of anti-tumor paclitaxel.

Huang, H., Zhang, X., Yu, J.H., Zeng, J., Chang, P.R., Xu, H., and Huang, J. (2013). "Fabrication and reduction-sensitive behavior of polyion complex nano-micelles based on PEG-conjugated polymer containing disulfide bonds as a potential carrier of anti-tumor paclitaxel.", Colloids and Surfaces B, Biointerfaces, 110, pp. 59-65. doi : 10.1016/j.colsurfb.2013.04.023  Access to full text

Abstract

This work is aimed at the development of a reduction-sensitive drug carrier for the delivery of the anti-cancer drug paclitaxel (PTX). N,N’-bis(acryloyl)cystamine (CBA) was reacted with ethanolamine (AEOL) via Michael addition to synthesize cationic poly(CBA-AEOL) (PCA) containing disulfide bonds. Subsequently, polycaprolactone (PCL) was grafted from PCA to form a novel reduction-sensitive copolymer (PCA-g-PCL). The PCA-g-PCL copolymer self-assembled as spherical micelles with a mean size of ca. 108 nm. The disulfide bonds in the PCA-g-PCL copolymer contributed to the reduction-sensitivity of the micelles, observed as stepwise aggregation under simulated reduction conditions. To improve the stability of PCA-g-PCL micelles in aqueous media, carboxyl-terminated poly(ethylene glycol) methyl ether (mPEG-COOH) was conjugated with the PCA-g-PCL copolymer via electrostatic interaction to produce polyion complex micelles with a hydrophilic PEG surface. The in vitro release of PTX from the mPEG@PCA-g-PCL micelle showed a reduction sensitive profile, namely the rate of drug release strongly depended upon the concentration of the reducing agent. Leakage of PTX was limited to below 30% under normal conditions while almost all the drug was released in 9 hours under reduction conditions with 40 mM DTT. In conclusion, the assembled mPEG@PCA-g-PCL micelle with reduction-sensitive controlled release shows great potential for improving the therapeutic effect of paclitaxel.

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