Enhanced anti-tumor efficacy of prNK-lysin delivered by injectable pH-responsive hydrogel in the treatment of orthotopic breast cancer.

Cancer metastasis often presents the main reason for mortality in cancer patients. As such, metastasis prevention may facilitate long-term survival of individuals affected by this disease. Previous studies carried out by our laboratory demonstrated that the prNK-lysin inhibits the growth and metastasis of cancer cells in vitro. However, the intrinsic properties of cationic oncolytic peptides severely limit prNK-lysin's clinical applicability, as no dedicated delivery system for it has been reported. In an effort to overcome these limitations and enhance the anticancer efficacy of prNK-lysin, we designed low-modulus soft hydrogels as a new strategy for prNK-lysin delivery. This pH-responsive, HA-modified dextran-based hydrogel achieves precise controlled release of prNK-lysin within solid tumors, offering an innovative approach for efficient local delivery of protein/peptide drugs. Our results demonstrated that the system features favorable injectability and biocompatibility, along with sustained drug release capability, while mitigating prNK-lysin's systemic adverse reactions. Moreover, prNK-lysin@DEX/HA Gel exhibits growth and metastasis inhibitory effects on breast cancer cells both in vitro and in vivo. Significantly, its inhibitory effects were augmented in vivo compared to free prNK-lysin, consistent with improved drug retention. Additionally, preliminary findings indicate the potential of prNK-lysin to stimulate anti-tumor immunity. Overall, this soft hydrogel system could enhance the inhibitory effect of prNK-lysin on orthotopic breast cancer growth and lung metastasis. Therefore, it may represent a valuable technology for future breast cancer treatment.