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

Yue Sun, Tong Yang, Yifan Li, Jiayu Yang, Rongyue Zhu, Yanhui Hou, Yanhua Liu
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Abstract

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.
聚二甲双胍缀合纳米系统共递送IL-12细胞因子基因和顺铂前药,通过化疗增敏和肿瘤微环境调节治疗肿瘤
剂量相关毒性一直是以顺铂(CDDP)为基础的癌症治疗的主要限制因素之一。基于此,在肿瘤小鼠模型中,CDDP与IL-12 (interleukin-12, IL-12)基因联合治疗是一种有效的治疗策略,可产生协同抗肿瘤作用,同时避免剂量限制性毒性。然而,如何在保持CDDP和IL-12基因活性的同时有效地包封和共递送仍然是一个重大的挑战。本研究开发了一种肿瘤靶向胶束复合物(HC/ IL-12/polyMET),用于化疗药物CDDP和编码IL-12基因的质粒(IL-12)的共同递送。以聚二甲双胍(polyMET)为阳离子聚合物,与pIL-12缩合形成阳离子的pIL-12/polyMET胶束复合物,再将阴离子HC前药协同组装到pIL-12/polyMET上,稳定胶束复合物并共递送CDDP。HC/pIL-12/polyMET胶束复合物具有理想的粒径、优异的稳定性和高的pIL-12负载能力。更重要的是,体外细胞实验证实,HC/pIL-12/polyMET胶束复合物可以显著提高LLC肿瘤细胞对CDDP和pIL-12的摄取,促进CDDP和pIL-12的内体逃逸,从而增强细胞毒性和诱导凋亡。此外,该策略显著提高了LLC细胞中il -12的转染效率。体内研究进一步表明,HC/pIL-12/polyMET胶束复合物在LLC荷瘤小鼠的肿瘤中具有最高的药物积累和良好的il -12转染效率。因此,HC/pIL-12/polyMET胶束复合物具有明显的肿瘤生长抑制作用,并延长肺癌小鼠模型的总生存期。潜在的免疫机制表明,CDDP和pIL-12联合激活免疫效应细胞释放IFN-γ,诱导肿瘤相关巨噬细胞向m1型分化,从而产生协同的化学免疫治疗作用。综上所述,本研究可能为药物/基因共递送和癌症化学免疫治疗提供有效的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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