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Published on: February 5, 2019
"Layer peeling" co-delivery system for enhanced RNA interference-based tumor associated macrophages-specific
Tianqi Wang1, Weiwei Mu1, Feifei Li1
1Department 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. zhangnancy9@sdu.edu.cn.
Abstract:
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.
