Self-assembly of micelles with pH/ROS dual-responsiveness and mitochondrial targeting for potential anti-tumor applications

Abstract

Nano-drug carriers have been widely used in chemotherapy to improve the efficacy of chemotherapeutic drugs. Polymer nano-carriers have greater potential for the enrichment of chemotherapeutic drugs at the target tumor site and controlled release. Herein, a series of amphiphilic copolymers (ITT) was synthesized via melt polymerization with a ROS-cleavable thioketal cross-linker, imidazole groups, and polyethylene glycol-conjugated triphenylphosphonium (PEG-TPP) segments; the actual proportions of the imidazole groups to the PEG-TPP segments were 5.2 : 1, 2.6 : 1, and 1.8 : 1, respectively. The amphiphilic copolymers could self-assemble into cationic micelles with hydrophobic imidazole groups as the core and hydrophilic PEG-TPP segments as the shell in deionized water. The cationic micelles with an average particle size of 124.6–187.3 nm showed a drug loading content (DLC) of 5.65–6.10%. In vitro release studies revealed the pH/ROS dual-responsiveness of the DOX-loaded ITT micelles, and the release behavior of DOX from the micelles strongly depended on the content of imidazole groups in the ITT micelles. Typically, the release of the encapsulated DOX was 27.2%, 30.0%, and 34.1% from DOX-loaded ITT-1 micelles in PBS (pH 6.5) containing 0, 100, and 500 μM H₂O₂, respectively. The release of the encapsulated DOX was 20.3%, 27.2%, and 42.5% from DOX-loaded ITT-1 micelles in PBS (pH 7.4), PBS (pH 6.5), and PBS (pH 5.0), respectively. The DOX-loaded micelles effectively inhibited the growth of 4T1 cells through being internalized into the 4T1 cells and releasing DOX into the mitochondria, with a cell viability of less than 65% when the DOX concentration was 2.5 μg mL⁻¹. This work presents a novel mitochondria-targeting and pH/ROS-responsive polymer nanocarrier for potential chemotherapy applications.