In situ fast gelling poloxamer 407/ poly(NIPAAm-co-MA) thermosensitive 0 0injectable hydrogels incorporating chitosan/ curcumin nanoparticles for dual drug delivery

In this study, an injectable composite hydrogel was developed for the co-delivery of curcumin (CUR) and methotrexate (MTX) to achieve synergistic cancer cell treatment. The hydrogel matrix was based on thermosensitive poloxamer 407, with a copolymer of maleic anhydride (MA) and N-isopropylacrylamide (NIPAAm) (poly(NIPAAm-co-MA)) incorporated to modulate the gelation temperature. Chitosan nanoparticles (CS NPs) loaded with CUR were introduced as sustained-release additives, prepared via ionic gelation using sodium tripolyphosphate (TPP). The CS NPs exhibited average diameters ranging from 48 to 87 nm, with polydispersity index (PDI) values between 0.04 and 0.07, depending on the CS:TPP ratio. The lower critical solution temperature (LCST, the transition point where the polymer shifts from a soluble to an insoluble state) of the gelling system was initially around 32 °C. Upon addition of the thermosensitive copolymer, the transition temperature increased to approximately 39 °C, aligning with the physiological temperature of tumor tissues. CUR, encapsulated within the CS NPs (CUR/CS NPs), showed a sustained release over 25 hours, with release at acidic pH (tumor-like conditions) reaching up to 20%, faster than at physiological pH. In contrast, the single-drug MTX formulation displayed a burst release within 4 hours. Within 150 hours, the dual drug delivery system released 77% of CUR and 69% of MTX, while the single drug formulation released 75% of CUR and 86% of MTX. These results indicate that incorporating both drugs together slowed the release process, thereby extending MTX availability.