Folate and lipoic acid functionalized pH/reductive dual-responsive mixed crosslinked micelles for paclitaxel delivery

To address the challenges of poor stability and weak targeting capability in polymeric micelles, which negatively impact controlled drug release performance, pH-responsive polymers PCL-PDEAEMA-PHEMA-PPEGMA (P1, P2, and P3) with distinct block lengths were designed and synthesized in this work. These copolymers were rigorously characterized using 1 H NMR, FT-IR, and GPC. Subsequently, polymer P3 was selected for modification based on comparative analyses of critical micelle concentrations (CMC) and drug-loading performance. Polymer P3 underwent esterification with lipoic acid (LA) and folic acid (FA) to yield LA-P3 and FA-P3, respectively. These derivatives were blended at a mass ratio of 1:1 (LA-P3:FA-P3), and dithiothreitol was employed to initiate self-crosslinking, resulting in the preparation of actively targeted crosslinked mixed micelles (C-MIX). The results revealed that C-MIX@PTX drug-loaded micelles prepared at a feeding ratio of 15 mg PTX/30 mg polymer exhibited a smaller size (134.7 nm) compared to non-crosslinked micelles, with a drug-loading content of 15.31 ± 1.79% and an encapsulation efficiency of 38.42 ± 5.22%. In vitro release studies demonstrated that under neutral conditions, C-MIX@PTX achieved a cumulative drug release of 16.8% at 120 h, significantly lower than non-crosslinked micelles. Under acidic/reductive conditions, C-MIX@PTX showed a cumulative drug release of 77.1% at 120 h, slightly lower compared to non-crosslinked micelles. Cytotoxicity assays confirmed that both MIX and C-MIX were biocompatible low-toxicity carrier materials, while LA-P3@PTX, FA-P3@PTX, MIX@PTX, and C-MIX@PTX exhibited inhibitory effects on HepG2 cells, FA-P3@PTX with folate-modified demonstrated enhanced efficacy.