Design and evaluation of mPEG-PLA micelles functionalized with drug-interactive domains as improved drug carriers for docetaxel delivery

Abstract

Polymeric micelles are very attractive drug delivery systems for hydrophobic agents, owing to their readily tailorable chemical structure and ease for scale-up preparation. However, the intrinsic poor stability of drug-loaded micelles presents one of the major challenges for most micellar systems in the translation to clinical applications. In this study, a simple, well-defined, and easy-to-scale up 9-Fluorenylmethoxycarbonyl (Fmoc) and tert-butoxycarbonyl (Boc) containing lysine dendronized mPEG-PLA (mPEG-PLA-Lys(FB)) micellar formulation was designed and prepared for docetaxel (DTX) delivery, in an effort to improve the stability of the micelles, and its physicochemical properties, pharmacokinetics, and anti-tumor efficacy against SKOV-3 ovarian cancer were evaluated. MPEG-PLA-Lys(FB) was synthesized via a three-step synthetic route, and it actively interacted with DTX in aqueous media to form stable micelles with small particle sizes (~17-19 nm) and narrow size distribution (PI < 0.1), which can be lyophilized and easily reconstituted in saline without significant change in particle size distribution. In vitro drug-release study demonstrated that mPEG-PLA-Lys(FB) micelles achieved delayed and sustained release manner of DTX in comparison with mPEG-PLA micelles. Further in vivo xenograft tumor model in nude mice DTX/mPEG-PLA-Lys(FB) micelles demonstrated significantly higher inhibitory effect on tumor growth than the marketed formulation Taxotere. Thus, our system may hold promise as a simple and effective delivery system for DTX with a potential for translation into clinical study.

Development of a docetaxel micellar formulation using poly(ethylene glycol)–polylactide–poly(ethylene glycol) (PEG–PLA–PEG) with successful reconstitution for tumor targeted drug delivery

“…Based on these results, the loading capacity of DTBM for DTX is shown to be approximately 7.4 wt%. High DTX loading capacity in the micelles may be due to the hydrophobic PLA block that enabled the physical entrapment of hydrophobic drug in polymeric micelles by hydrophobic interaction between the drug molecule and the hydrophobic core of micelles (Shuai et al., 2004 ; Gao et al., 2012 ; Zhang et al., 2014 ; Hoang et al., 2017a ; Qi et al., 2017 ). DTBM prepared with 10% DTX loading exhibited particles of 125 nm in size with a spherical structure and narrow size distribution in DW ( Figure 2 ).…”