Preparation\nof Disulfide/Trisulfide Core-Cross-Linked\nPolycarbonate Nanocarriers for Intracellular Reduction-Triggered Drug\nRelease

Polymeric\nnanocarriers have attracted significant attention\nin\nthe field of anticancer drug delivery due to their unique advantages.\nHowever, designing nanocarriers that can maintain stability in the\nbloodstream while achieving specific drug release within tumor cells\nremains a major challenge. To address this issue, constructing reversible\ncross-linked polymeric nanocarriers that are sensitive to the intracellular\nreducible glutathione (GSH) characteristic of the tumor microenvironment\nis a promising strategy. Based on this, we designed and synthesized\ntwo novel six-membered bicyclic carbonate monomers containing disulfide\n(DSBC) and trisulfide (TSBC) bonds. Through a one-step ring-opening\npolymerization, a series of reduction-sensitive polycarbonate copolymers\n(i.e., PEG–PDSBC and PEG–PTSBC) were prepared, and doxorubicin\n(DOX)-loaded nanoparticles were fabricated using a nanoprecipitation\nmethod. The <i>in vitro</i> drug release behaviors of these\nnanoparticles were systematically investigated. The results showed\nthat these polymers, due to the cross-linked structure formed by the\nring-opening polymerization of their bicyclic monomers, could self-assemble\ninto stable nanoparticles. Under different concentrations of glutathione,\nDOX-loaded PEG–PTSBC nanoparticles demonstrated faster drug\nrelease, indicating more optimized intracellular drug release properties.\nFurther cytotoxicity experiments revealed that both types of blank\nnanoparticles exhibited good biocompatibility with the 4T1 and NIH-3T3\ncells. Fluorescence microscopy and flow cytometry results further\nindicated that DOX-loaded PEG–PTSBC nanoparticles released\nmore drugs in 4T1 cells, significantly inhibiting tumor cell growth\ncompared with DOX-loaded PEG–PDSBC nanoparticles, with no noticeable\ndifference in NIH-3T3 normal cells. In conclusion, this study suggests\nthat trisulfide cross-linked polycarbonate-based nanocarriers hold\npromise as an anticancer drug delivery system that combines stability\nin the bloodstream with specific intracellular drug release, offering\nnew insights for the development of novel, efficient, and safe anticancer\nnanomedicines.