PH/Reduction Dual-Stimuli-Responsive Cross-Linked Micelles Based on Multi-Functional Amphiphilic Star Copolymer: Synthesis and Controlled Anti-Cancer Drug Release.

Yunwei Huang,Zilun Tang,Shiyuan Peng,Guobin Yi,Wenjing Lin,Cuiying Tan,Xiaofeng Lin,Jingye Yan,Jiabao Ling,Xihong Zu

doi:10.3390/polym12010082

Yunwei Huang, Zilun Tang + Show 8 more

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https://doi.org/10.3390/polym12010082

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Abstract

Novel approach has been constructed for preparing the amphiphilic star copolymer pH/reduction stimuli-responsive cross-linked micelles (SCMs) as a smart drug delivery system for the well-controlled anti-tumor drug doxorubicin (DOX) release. The SCMs had a low CMC value of 5.3 mg/L. The blank and DOX-loaded SCMs both had a spherical shape with sizes around 100–180 nm. In addition, the good stability and well pH/reduction-sensitivity of the SCMs were determined by dynamic light scattering (DLS) as well. The SCMs owned a low release of DOX in bloodstream and normal tissues while it had a fast release in tumor higher glutathione (GSH) concentration and/or lower pH value conditions, which demonstrates their pH/reduction dual-responsiveness. Furthermore, we conducted the thermodynamic analysis to study the interactions between the DOX and polymer micelles in the DOX release process. The values of the thermodynamic parameters at pH 7.4 and at pH 5.0 conditions indicated that the DOX release was endothermic and controlled mainly by the forces of an electrostatic interaction. At pH 5.0 with 10 mM GSH condition, electrostatic interaction, chemical bond, and hydrophobic interactions contributed together on DOX release. With the low cytotoxicity of blank SCMs and well cytotoxicity of DOX-loaded SCMs, the results indicated that the SCMs could form a smart cancer microenvironment-responsive drug delivery system. The release kinetic and thermodynamic analysis offer a theoretical foundation for the interaction between drug molecules and polymer matrices, which helps provide a roadmap for the oriented design and control of anti-cancer drug release for cancer therapy.

Highlights

Polymer micelles have shown their attractive advantages as anti-cancer nanocarriers for anti-cancer drugs and attracted more attention in recent years [1,2,3,4]
The copolymer 4AS-PMAA-(PHEMA-SS~)-PPEGMA was synthesized using the combination of ARGET ATRP, Michael addition reaction, and hydrolysis method (Scheme 2)
The copolymer 4AS-PMAA-(PHEMA-SS~)-PPEGMA was synthesized by hydrolysis to remove the tertiary butyl groups from tBMA units

Summary

Introduction

Polymer micelles have shown their attractive advantages as anti-cancer nanocarriers for anti-cancer drugs and attracted more attention in recent years [1,2,3,4]. With the unique core-shell nanostructures, polymer micelles can enhance water solubility, raise drug-loaded capacity, reduce protein adsorption, prolong circulation duration, and increase drug accumulation at target sites and more [5,6,7,8,9]. One is the premature drug release in bloodstream and normal tissues, and the other is the slow and incomplete drug release within cancer cells. These two weaknesses increase side-effects, shorten drug effective time, and reduce therapeutic efficacy.

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