Synthesis of a H2O2-responsive thioether-containing alternating copolymer for drug delivery
Abstract
In this work, an amphiphilic alternating copolymer, P(EG-a-BDT), containing thioether functionalities in the main chain was synthesized via thiol–epoxy click polymerization of 1,4-butanedithiol (BDT) and ethylene glycol diglycidyl ether (EGDE) under mild conditions. The chemical structure, molecular weight, and thermal properties of the polymer were characterized by nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), consistent with the formation of the target copolymer. Owing to its amphiphilic structure, P(EG-a-BDT) self-assembled into spherical micelles with an average diameter of approximately 81.3 nm. Upon exposure to hydrogen peroxide (H2O2), the micelles underwent rapid disassembly, which is attributed to the oxidation of hydrophobic thioether groups into hydrophilic sulfoxide moieties. This process was investigated by dynamic light scattering (DLS), transmission electron microscopy (TEM), and 1H NMR analyses. MTT assays using NIH/3T3 cells indicated good cytocompatibility of the copolymer. Using doxorubicin (DOX) as a model drug, the drug-loading content (DLC) and drug-loading efficiency (DLE) were determined to be 3.67% and 8.52%, respectively. In vitro release studies revealed that DOX was rapidly released under H2O2 stimulation, while minimal release was observed in the absence of H2O2. Flow cytometry and confocal laser scanning microscopy (CLSM) further confirmed efficient cellular uptake of DOX-loaded P(EG-a-BDT) micelles by HeLa cells as a model cancer cell line. Furthermore, MTT assays demonstrated that DOX-loaded P(EG-a-BDT) micelles exhibited cytotoxicity toward HeLa cells comparable to that of free DOX. These results demonstrate that P(EG-a-BDT) is an oxidation-responsive amphiphilic alternating copolymer capable of H2O2-triggered micellar disassembly and controlled drug release, providing a useful platform for the development of oxidation-responsive drug delivery systems.