Core-crosslinked pH-sensitive degradable micelles: A promising approach to resolve the extracellular stability versus intracellular drug release dilemma

The extracellular stability versus intracellular drug release dilemma has been a long challenge for micellar drug delivery systems. Here, core-crosslinked pH-sensitive degradable micelles were developed based on poly(ethylene glycol)-b-poly(mono-2,4,6-trimethoxy benzylidene-pentaerythritol carbonate-co-acryloyl carbonate) (PEG-b-P(TMBPEC-co-AC)) diblock copolymer that contains acid-labile acetal and photo-crossslinkable acryloyl groups in the hydrophobic polycarbonate block for intracellular paclitaxel (PTX) release. The micelles following photo-crosslinking while displaying high stability at pH 7.4 were prone to rapid hydrolysis at mildly acidic pHs of 4.0 and 5.0, with half lives of ca. 12.5 and 38.5 h, respectively. Notably, these micelles showed high drug loading efficiencies of 76.0-93.2% at theoretical PTX loading contents of 5-15 wt.%. Depending on drug loading contents, PTX-loaded micelles had average sizes varying from 132.2 to 171.6 nm, which were decreased by 17-22 nm upon photo-crosslinking. The in vitro release studies showed that PTX release at pH 7.4 was greatly inhibited by crosslinking of micelles. Notably, rapid drug release was obtained under mildly acidic conditions, in which 90.0% and 78.1% PTX was released in 23 h at pH 4.0 and 5.0, respectively. MTT assays showed that PTX-loaded crosslinked micelles retained high anti-tumor activity with a cell viability of 9.2% observed for RAW 264.7 cells following 72 h incubation, which was comparable to PTX-loaded non-crosslinked counterparts (cell viability 7.5%) under otherwise the same conditions, supporting efficient drug release from PTX-loaded crosslinked micelles inside the tumor cells. These core-crosslinked pH-responsive biodegradable micelles with superior extracellular stability and rapid intracellular drug release provide a novel platform for tumor-targeting drug delivery. (c) 2012 Elsevier B.V. All rights reserved.