Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China.
Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China; Key Laboratory of Hui Ethnic Medicine Modernization, Ningxia Medical University, Yinchuan, 750004, China.
Acta Biomater. 2021 Jul 1;128:447-461. doi: 10.1016/j.actbio.2021.04.034. Epub 2021 Apr 22.
The combination of chemotherapy and gene therapy has been indicated as a promising approach for cancer therapy. However, this combination strategy is still faced a challenge by the lack of suitable carriers to co-loaded chemotherapeutic drug and gene into one single nanoplatform. In this study, a tumor-targeted HC/pIL-12/polyMET micelleplexes were developed for the co-loading and co-delivery of cisplatin (CDDP) and plasmid encoding interleukin-12 gene (pIL-12), which would be utilized to generate synergistic actions through chemotherapy sensitization and microenvironment modulation. The HC/pIL-12/polyMET exhibited desirable particle size, superior serum stability, effective intracellular CDDP release and pIL-12 transfection efficiency. More important, the HC/pIL-12/polyMET generated the enhanced LLC cell proliferation inhibition and apoptosis induction efficiency. The long-circulating HC/pIL-12/polyMET micelleplexes promoted the accumulation of CDDP and pIL-12 in tumor site, which resulted in significantly inhibiting the growth of lung cancer, and prolonging the overall survival of tumor-bearing mice. The underlying immune mechanism demonstrated 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. STATEMENT OF SIGNIFICANCE: Chemoimmunotherapy has been indicated as an approach to improve efficacy of cancer therapy. Herein, a tumor-targeted micelleplexes (HC/pIL-12/polyMET) were developed for the co-delivery of cisplatin (CDDP) and plasmid encoding IL-12 gene (pIL-12), which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. The HC/pIL-12/polyMET exhibited desirable particle size, superior serum stability, high gene transfection efficiency and antitumor activity on tumor cell proliferation inhibition and apoptosis induction. More importantly, the long-circulating HC/pIL-12/polyMET micelleplexes could effectively accumulate in tumor sites and then rapidly release the CDDP and pIL-12, significantly inhibit the growth of lung cancer. This strategy provides a new concept for chemo-gene combination with a strengthened overall therapeutic efficacy of chemoimmunotherapy.
化疗和基因治疗的联合已被证明是癌症治疗的一种有前途的方法。然而，这种联合策略仍然面临着缺乏合适载体的挑战，无法将化疗药物和基因共同装载到单个纳米平台中。在这项研究中，开发了一种肿瘤靶向的 HC/pIL-12/polyMET 胶束复合物，用于共载和共递顺铂 (CDDP) 和编码白细胞介素 12 基因的质粒 (pIL-12)，通过化疗增敏和微环境调节产生协同作用。HC/pIL-12/polyMET 表现出理想的粒径、优异的血清稳定性、有效的细胞内 CDDP 释放和 pIL-12 转染效率。更重要的是，HC/pIL-12/polyMET 产生了增强的 LLC 细胞增殖抑制和凋亡诱导效率。长循环的 HC/pIL-12/polyMET 胶束复合物促进了 CDDP 和 pIL-12 在肿瘤部位的积累，从而显著抑制肺癌的生长，并延长荷瘤小鼠的总生存期。潜在的免疫机制表明，CDDP 和 pIL-12 的联合激活了免疫效应细胞释放 IFN-γ，并诱导肿瘤相关巨噬细胞向 M1 型分化，从而产生协同的化疗免疫治疗效果。综上所述，本研究可为药物/基因共递药和癌症化疗免疫治疗提供一种有效的策略。
声明：化疗免疫治疗已被证明是提高癌症治疗效果的一种方法。本文开发了一种肿瘤靶向的胶束复合物 (HC/pIL-12/polyMET)，用于共递顺铂 (CDDP) 和编码白细胞介素 12 基因 (pIL-12) 的质粒，通过化疗增敏和微环境调节产生协同作用。HC/pIL-12/polyMET 表现出理想的粒径、优异的血清稳定性、高基因转染效率和对肿瘤细胞增殖抑制和凋亡诱导的抗肿瘤活性。更重要的是，长循环的 HC/pIL-12/polyMET 胶束复合物可以有效地在肿瘤部位积累，然后迅速释放 CDDP 和 pIL-12，显著抑制肺癌的生长。该策略为化疗-基因联合治疗提供了一个新概念，增强了化疗免疫治疗的整体疗效。
