Co-Delivery of IL-12 Cytokine Gene and Cisplatin Prodrug by Polymetformin-Conjugated Nanosystem for Chemo-Gene Cancer Treatment Through Chemotherapy Sensitization and Tumor Microenvironment Modulation

The dose-related toxicity has been one of the major limiting factors in cisplatin (CDDP)-based cancer therapy. Based on it, a novel strategy of combination of CDDP and interleukin-12 (IL-12) gene is an effective treatment, which resulted in synergistic antitumor effects while avoiding dose-limiting toxicity in a cancer mice model. However, efficient encapsulation and co-delivery of CDDP and IL-12 gene while retaining their active remains a significant challenge. In this study, a tumor-targeted micelleplexes (HC/pIL-12/polyMET) were developed for the co-delivery of the chemotherapeutic drug CDDP and plasmid encoding IL-12 gene (pIL-12). The polymetformin (polyMET) were synthesized as the cationic polymer for condensation of pIL-12 to form a cationic pIL-12/polyMET micelleplexes, and the anionic HC prodrug was then collaboratively assembled to pIL-12/polyMET to stabilize the micelleplexes and co-delivery of CDDP. The HC/pIL-12/polyMET micelleplexes exhibited desirable particle size, excellent stability and high pIL-12 loading capacity. More importantly, in vitro cell experiments verified that HC/pIL-12/polyMET micelleplexes could significantly improve the uptake by LLC tumor cells and promote the endosomal escape of CDDP and pIL-12, resulting in enhanced cytotoxicity and apoptosis induction. Besides, this strategy significantly enhanced the pIL-12 transfection efficiency in LLC cells. In vivo studies further revealed that HC/pIL-12/polyMET micelleplexes possessed the highest drug accumulation and excellent pIL-12 transfection efficiency in tumors of LLC tumor-bearing mice. Consequently, the HC/pIL-12/polyMET micelleplexes exhibit significantly tumor growth inhibition, and prolong the overall survival of lung cancer mice model. The underlying immune mechanism demonstrated that the combination of CDDP and pIL-12 activated immune effector cells to release IFN-γ and induced M1-type differentiation of tumor-related macrophages, thereby generating synergistic chemoimmunotherapy effect. Taken together, this study may provide an effective strategy for drug/gene co-delivery and cancer chemoimmunotherapy.