pH and ROS Dual-Responsive Core-Cross-Linked Micelles Based on Boronic Ester Linkage for Efficient PTX Delivery

Abstract

Micelle-based drug delivery systems (DDS) have emerged as a promising solution to address challenges associated with the in vivo delivery of hydrophobic anticancer chemotherapeutics. However, micelles still encounter issues such as drug pre-leakage and poor stability in physiological conditions. To overcome these limitations, we developed a core-cross-linking strategy utilizing amphiphilic copolymers, mPEG-b-P(AVL-co-LA) (mPPAL), functionalized with phenylboronic acid (PBA), and catechol by CuAAc “click” chemistry, respectively. These copolymers self-assembled into core-cross-linked micelles (CLMs), featuring boronic ester bonds, which were characterized through a series of evaluations. The CLMs exhibited a rational particle size, uniform morphology, low critical micelle concentration (CMC), high PTX loading capacity, and excellent stability. Two promising micelles, CLM1 and CLM3, were identified, and their responsiveness to acidic pH and elevated levels of ROS was confirmed to enable controlled PTX release. The results of MTT assay and hemolytic analysis demonstrated high biocompatibility and potential in vivo application of these selected CLMs. The anticancer efficacy of the selected PTX-CLMs was further validated through MTT assay and 3D tumor spheroid studies. Fluorescence microscopy and flow cytometry demonstrated rapid intracellular uptake of the CLMs. In vivo biodistribution studies demonstrated successful accumulation in the targeted tumor tissue. These findings suggest that the boronic ester-based CLMs developed in this study are a promising nanocarrier for effective PTX delivery.