pH/Reduction Dual-Responsive Diselenide-Containing Mixed Cross-Linked Micelles for Folic Acid-Targeted Doxorubicin Delivery

To improve the stability and drug-controlled release capability of folic acid-modified pH-responsive polymeric mixed micelles FA-PEG-PHEMA-PDEAEMA (FA-P1)/PCL-PHEMA-PPEGMA (P2), the hydroxyl termini of the PHEMA blocks in polymers FA-P1 and P2 were esterified with selenooctanoic acid (SA) to produce FA-P1-SA and P2-SA, which were capable of self-cross-linking and exhibited reduction responsiveness. Thus, folic acid-modified dual-responsive diselenide-containing mixed cross-linked micelles composed of FA-P1-SA and P2-SA were constructed and employed for the delivery of doxorubicin (DOX). Structural characterization by ¹H NMR, FT-IR, Raman spectroscopy, and GPC confirmed successful SA conjugation at an esterification degree of approximately 70%. Experimental and dissipative particle dynamics (DPD) analyses showed that the DOX loading content and encapsulation efficiency of the FA-containing mixed cross-linked micelles (MCLM@DOX) (1:1 mass ratio of FA-P1-SA/P2-SA) were slightly lower than those of non-cross-linked micelles (MMSA@DOX), yet afforded superior retention under physiological conditions (16.11% vs 22.49% release at 120 h) and rapid, stimuli-triggered release (75.20% vs 83.32%) in reductive, acidic conditions. Cytotoxicity assays indicated minimal polymer toxicity after SA modification. Furthermore, FA-containing MCLM@DOX exhibited relatively good tumor-targeting and anticancer efficacy compared with FA-free counterparts (MCLM1@DOX).