Poster O13 - One-Step Ring-Opening Polymerization for the Preparation of Disulfide/Trisulfide Core-Crosslinked Polycarbonate Nanocarriers for Intracellular Reduction-Triggered Drug Release
Professor Wuhan University of Technology WuHan, United States
Introduction: Polymeric nanocarriers hold great potential for targeted anticancer drug delivery, but achieving both circulation stability and controlled intracellular release remains a significant hurdle. Herein, we developed star-shaped, reduction-sensitive polycarbonate nanocarriers for improved anticancer drug delivery. By incorporating disulfide or trisulfide linkages, we prepared stable nanoparticles that allowed controlled drug release in tumor cells. Trisulfide-based nanoparticles demonstrated superior drug release and enhanced inhibition of cancer cells compared to their disulfide counterparts. These findings highlight the potential of trisulfide cross-linked polycarbonates for effective cancer therapy.
Materials and
Methods: Two novel six-membered bicyclic carbonate monomers containing disulfide (DSBC) and trisulfide (TSBC) bonds were synthesized. Then, a series of reduction-sensitive polycarbonate copolymers (i.e., PEG-PDSBC and PEG-PTSBC) were synthesized through one-step ring-opening polymerization, using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) or diphenyl phosphate (DPP) as organic catalysts, and doxorubicin (DOX)-loaded nanoparticles were prepared using a nanoprecipitation method.
Results, Conclusions, and Discussions: Results and
Discussion: Novel six-membered bicyclic carbonate monomers containing disulfide (DSBC) and trisulfide (TSBC) bonds were synthesized. These monomers were then subjected to ring-opening polymerization initiated by hydroxyl-terminated PEG (PEG-OH) to prepare PEG-polycarbonate copolymers. The synthesized polymers were self-assembled into nanoparticles via nanoprecipitation. DLS measurements indicated that the sizes of blank PEG-PDSBC and PEG-PTSBC nanoparticles were ~95 nm and 112 nm, respectively, with PDIs of 0.18 and 0.19. After loading with DOX, the particle sizes increased to ~118 nm and 136 nm for the two types of nanoparticles, with PDIs of 0.14 and 0.12, respectively. Under varying GSH concentrations, DOX-loaded PEG-PTSBC nanoparticles exhibited faster and greater drug release compared to DOX-loaded PEG-PDSBC nanoparticles, indicating that trisulfide bonds have greater reduction sensitivity than disulfide bonds. Moreover, in the elevated-glutathione environment of 4T1 tumor cells, the trisulfide bonds in the drug-loaded nanoparticles resulted in greater DOX release and ultimately lower 4T1 cell survival rates compared to disulfide bonds.
Conclusions: In summary, a GSH-sensitive core-crosslinked PEG-polycarbonate drug delivery system for the tumor microenvironment was successfully constructed using a one-step ring-opening polymerization. Trisulfide cross-linked polycarbonate-based nanocarriers hold promise as an anticancer drug delivery system, combining stability in the bloodstream with specific intracellular drug release, compared to disulfide counterparts, providing new insights for developing novel, efficient, and safe anticancer nanomedicines
Acknowledgements (Optional): The research was supported by the National Natural Science Foundation of China (No. 52003211), Basic and Applied Basic Research Foundation of Guangdong Province (No. 2024A1515011550).
