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Reduction‐Sensitive Reversibly Crosslinked Biodegradable Micelles for Triggered Release of Doxorubicin
Author(s) -
Xu Yanmin,
Meng Fenghua,
Cheng Ru,
Zhong Zhiyuan
Publication year - 2009
Publication title -
macromolecular bioscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.924
H-Index - 105
eISSN - 1616-5195
pISSN - 1616-5187
DOI - 10.1002/mabi.200900233
Subject(s) - micelle , chemistry , dithiothreitol , ethylene glycol , copolymer , peg ratio , critical micelle concentration , gel permeation chromatography , polymer chemistry , amphiphile , nuclear chemistry , poloxamer , aqueous solution , organic chemistry , polymer , finance , economics , enzyme
Abstract Reduction‐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‐L 2 ‐PCL) has been synthesized. 1 H NMR spectroscopy and gel permeation chromatography (GPC) measurements show that the PEG‐L 2 ‐PCL block copolymer had a controlled composition (PEG 5 kDa and PCL 5.4 kDa) and a polydispersity index (PDI) of 1.36. PEG‐L 2 ‐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.