Wang Tianqi, Mu Weiwei, Li Feifei, Zhang Jing, Hou Teng, Pang Xiuping, Yin Xiaolan, Zhang Na
Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong Province 250012, China.
Nanoscale. 2020 Aug 20;12(32):16851-16863. doi: 10.1039/d0nr04025h.
RNA interference (RNAi)-based immunotherapy combined with chemotherapy has emerged as a promising therapeutic strategy for cancer treatment. The transport of siRNA and small molecular agents from the tumor vasculature to a separate therapeutic target has been impeded by multiple physiological barriers, which has restricted the development of RNAi-based chemoimmunotherapy. A nanotechnology-based co-delivery system was superior in improving the co-localization of gene and drug in the same tumor cell, while a co-delivery system for chemoimmunotherapy was expected to realize xenotype cell-targeting, which means delivering immunotherapy agents and chemotherapy drugs to immune cells and tumor cells, respectively. A multilayer structure co-delivery system was outstanding in crossing these barriers and targeting different cells in tumor tissue. Herein, a "layer peeling" co-delivery system (CDMPR) was developed with co-loaded IKKβ-siRNA and doxorubicin (DOX), in which IKKβ-siRNA was used for RNAi-based tumor associated macrophages (TAMs) polarization for immunotherapy and DOX was used for chemotherapy. A transwell assay in vitro and an immunofluorescence assay in Hepa1-6 tumor-bearing mice indicated that CDMPR exhibited a pH-sensitive disassembly ability in tumor tissue, IKKβ-siRNA was precisely delivered to M2-type TAMs and DOX was internalized into tumor cells. An M2-type TAMs polarization ability study of CDMPR demonstrated that M2-type TAMs could be polarized to M1-type TAMs by CDMPR in vitro and in vivo. In Hepa1-6 tumor-bearing mice, CDMPR exhibited improved antitumor efficiency with M2-type re-polarization ability by the precise delivery of IKKβ-siRNA and DOX to M2-type TAMs and tumor cells, respectively. Consequently, the combination of RNAi-based TAMs polarization and chemotherapy by the "layer peeling" co-delivery system would achieve an enhanced chemoimmunotherapy effect, which provides a novel strategy to improve cancer therapeutic effects.
基于RNA干扰（RNAi）的免疫疗法联合化疗已成为一种很有前景的癌症治疗策略。小干扰RNA（siRNA）和小分子药物从肿瘤脉管系统转运至单独的治疗靶点受到多种生理屏障的阻碍，这限制了基于RNAi的化学免疫疗法的发展。基于纳米技术的共递送系统在改善基因与药物在同一肿瘤细胞中的共定位方面具有优势，而化学免疫疗法的共递送系统有望实现异源型细胞靶向，即将免疫治疗药物和化疗药物分别递送至免疫细胞和肿瘤细胞。多层结构共递送系统在跨越这些屏障并靶向肿瘤组织中的不同细胞方面表现出色。在此，开发了一种共负载IKKβ-siRNA和阿霉素（DOX）的“逐层剥离”共递送系统（CDMPR），其中IKKβ-siRNA用于基于RNAi的肿瘤相关巨噬细胞（TAM）极化以进行免疫治疗，DOX用于化疗。体外Transwell实验和荷Hepa1-6肿瘤小鼠体内免疫荧光实验表明，CDMPR在肿瘤组织中表现出pH敏感的解离能力，IKKβ-siRNA被精确递送至M2型TAM，DOX被内化进入肿瘤细胞。对CDMPR的M2型TAM极化能力研究表明，在体外和体内CDMPR均可将M2型TAM极化为M1型TAM。在荷Hepa1-6肿瘤小鼠中，通过分别将IKKβ-siRNA和DOX精确递送至M2型TAM和肿瘤细胞，CDMPR表现出具有M2型再极化能力的更高抗肿瘤效率。因此，通过“逐层剥离”共递送系统将基于RNAi的TAM极化与化疗相结合可实现增强的化学免疫治疗效果，这为提高癌症治疗效果提供了一种新策略。
