Reduction‐Sensitive Reversibly Crosslinked Biodegradable Micelles for Triggered Release of Doxorubicin

Abstract

AbstractReduction‐responsive reversibly crosslinked biodegradable micelles were developed and applied for triggered release of doxorubicin (DOX). An amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly(ε‐caprolactone) (PCL) that contains two lipoyl functional groups at their interface (PEG‐L2‐PCL) has been synthesized. 1H NMR spectroscopy and gel permeation chromatography (GPC) measurements show that the PEG‐L2‐PCL block copolymer had a controlled composition (PEG 5 kDa and PCL 5.4 kDa) and a polydispersity index (PDI) of 1.36. PEG‐L2‐PCL formed micelles with sizes that ranged from 20 to 150 nm in aqueous solutions, wherein a critical micelle concentration (CMC) of 16 mg·L−1 was determined. The micelles were readily crosslinked by adding 7.6 mol % of dithiothreitol (DTT) relative to the lipoyl groups. Notably, micelles after crosslinking demonstrated a markedly enhanced stability against dilution, physiological salt concentration, and organic solvent. In the presence of 10 × 10−3 M DTT, however, micelles were subject to rapid de‐crosslinking. In vitro release studies showed minimal release of DOX from crosslinked micelles at a concentration of 10 mg L−1 (C < CMC, analogous to intravenous injection), wherein less than 15% of the DOX was released in 10 h. In contrast, rapid release of DOX was observed for DOX‐loaded non‐crosslinked micelles under otherwise the same conditions (≈80% release in 0.5 h). In the presence of 10 × 10−3 M DTT mimicking an intracellular reductive environment, sustained release of DOX from crosslinked micelles was achieved, in which 75% of the DOX was released in 9 h. These novel reduction‐sensitive reversibly crosslinked biodegradable micelles are highly promising for targeted intracellular delivery of anticancer drugs.magnified image