Poly(1,4,5-oxadithiepan-2-one)-Based Redox and pH Dual-Responsive Polyzwitterionic Micelles for Tumor Cell-Targeted Drug Delivery

Stimuli-responsive polymeric nanoparticles that respond to distinct microenvironments around tumor cells, such as low extracellular pH and high levels of glutathione (GSH), can provide precise and targeted release of drugs and minimize their nonspecific accumulation in healthy organs. A pH and redox dual-responsive diblock copolymer POD-b-PDMAEMA-Q was prepared based on poly(1,4,5-oxadithiepan-2-one) (POD) and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA). First, the POD–OH block was prepared by the ring-opening polymerization (ROP) of 1,4,5-oxadithiepan-2-one which was subsequently converted to POD-Br. Using this as the macroinitiator, POD-b-PDMAEMA was synthesized by atom transfer radical polymerization (ATRP) of DMAEMA. This was then quaternized by reaction with bromoacetic acid to prepare POD-b-PDMAEMA-Q. The particle size of the resulting self-assembled block copolymeric micelles was found to be in the 137–182 nm range with spherical morphology in aqueous solution. The POD-b-PDMAEMA-Q was converted to its polyzwitterionic form POD-b-PDMAEMA-ZIP in phosphate-buffered saline (PBS) (pH = 7.4) buffer, and then DOX was loaded within the polyzwitterionic micelle. The drug loading efficiency of all three copolymeric micelles was in the 32–51% range and showed 93–99% cumulative drug release in the presence of 2 mM dithiothreitol (DTT) at pH 6.5. The DOX-loaded copolymeric micelles effectively increased selective cellular uptake and cytotoxicity in 4T1 breast cancer cells while maintaining cytocompatibility in NIH-3T3 fibroblasts with lower cellular uptake. The bovine serum albumin (BSA) protein adsorption on the polyzwitterionic micelles was very low. Our results show that these disulfide-based dual-responsive polyzwitterionic nanoparticles show promise for targeted delivery of antitumor drugs while simultaneously reducing adverse effects on normal tissues and warrant further investigation.