Preparation and Properties of Redox-Responsive Paclitaxel Micelles

A novel disulfide cross-linked redox-sensitive lipoic acid dendronized methoxy polyethylene glycol-polylactide block copolymer (mPEG-PLA-(LA)₄) was successfully prepared. Firstly, methoxy polyethylene glycol-polylactide (mPEG-PLA) was synthesized by a ring opening polymerization of D, L-lactide using methoxy polyethylene glycol (mPEG) as a macroinitiator and stannous octoate (Sn(Oct)₂) as the catalyst. Then, mPEG-PLA-(OH)₄ was obtained by reaction of mPEG-PLA with acetonide-2, 2-dimethylol propanoic anhydride (Ac-DMPA) and deprotection of the terminal acetonide groups. Finally, lipoic acid terminated methoxy polyethylene glycol-polylactide block copolymer (mPEG-PLA-(LA)₄) was synthesized and paclitaxel-loaded mPEG-PLA-(LA)₄ micelles were prepared by solid dispersion-thin film hydration method. The structures and molecular weights of the polymers were characterized by nuclear magnetic hydrogen spectrum (¹H-NMR) and gel permeation chromatography (GPC). Transmission electron microscope (TEM) and dynamic light scattering (DLS) were used to investigate the morphology and size distribution of the micelles. The results show that mPEG-PLA-(LA)₄ micelles have spherical structure with average diameter of 34.0 nm. Besides, the in vitro release behavior of paclitaxel-loaded mPEG-PLA-(LA)₄ micelles was determined by a modified dialysis method. Compared with mPEG-PLA micelles, mPEG-PLA-(LA)₄ micelles have better stability and redox-responsive. The in vivo results reveal that mPEG-PLA-(LA)₄ micelles reduce the acute toxicity in mice and show improved anti-tumor efficacy compared with mPEG-PLA micelles. All these indicate that mPEG-PLA-(LA)₄ micelles are highly promising drug delivery system for clinical application.