Dual Pseudo and Chemical Crosslinked Polymer Micelles for Effective Paclitaxel Delivery and Release

The fabrication of polymer micelles, both with ample intracorporeal circulation stability and fast release within cancerous cells, is still facing challenges. Herein, we fabricated a strategy to improve the stability of polymer micelles using pseudo- and chemical crosslinking jointly. To be specific, a star-shaped polymer (TMP-PGMA-g-PEG) with trimethylolpropane (TMP) as the inner core was synthesized with glycidyl methacrylate (GMA), followed by the graft reaction with amine-terminated poly(ethylene glycol) (mPEG-NH₂). Star polymer micelle-based nanomedicines (TPP/paclitaxel (PTX)) were obtained using paclitaxel (PTX) as a model drug and polymer micelles (TPP) as carriers, which were constructed by TMP-PGMA-g-PEG. The star core and arms behaved as pseudo crosslinkers, which reduced their critical micelle concentration (CMC) values and improved their stability; profoundly, cystamine was used as a chemical crosslinker to react with the rest of the epoxy groups of TPP or TPP/PTX and further improve their stability. Finally, dual pseudo and chemical crosslinked star polymer micelles (CTPP) and micelle-based nanomedicines (CTPP/PTX) were obtained. The results demonstrated that CTPP/PTX with combined stability design presented excellent stability both in vitro and in vivo physiological conditions. Notably, cystamine not only served as a crosslinker but also had a reduction-responsive disulfide bond to achieve fast release inside cancer cells with a high level of glutathione (GSH). This smart design effectively resolved the antinomy that the polymer micelle delivery system could not cause rapid release in tumor sites when it possesses extreme stability resulted from chemical crosslinking. Both in vitro and in vivo experiments clearly stated the advantages of CTPP/PTX, including excellent stability, fast reduction-responsive release, and remarkable antitumor efficacy.