Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province 250012, People's Republic of China.
Nanoscale. 2019 Aug 7;11(29):13934-13946. doi: 10.1039/c9nr03374b. Epub 2019 Jul 15.
Tumor associated macrophage (TAM)-based immunotherapy has been presented as a promising strategy in cancer therapy. The combination of TAM-based immunotherapy with sorafenib (SF) could be conceivably quite more effective in hepatocellular carcinoma (HCC) treatment. A co-delivery system was superior in improving the co-accumulation of two drugs in tumor tissues for chemoimmunotherapy, while in the case of selective targeting of separated cells such as tumor cells and immune cells, a novel targeted co-delivery strategy was badly required. In this study, twin-like core-shell nanoparticles (TCN) were developed for synchronous biodistribution and separated cell targeting delivery of SF and TAM re-polarization agents IMD-0354 to cancer cells and TAM to enhance tumor-localized chemoimmunotherapy, respectively. First of all, SF loaded cationic lipid-based nanoparticles (SF-CLN) and mannose-modified IMD-0354 loaded cationic lipid-based nanoparticles (M-IMD-CLN) were prepared, respectively. SF on the surface of SF-CLN and mannose on the M-IMD-CLN were regarded as targeting ligands for selective targeting delivery of SF-CLN and M-IMD-CLN to cancer cells and TAM separately. Then, pH-responsive charge reversal polymer O-carboxymethyl-chitosan (CMCS) was coated on the SF-CLN and M-IMD-CLN to obtain twin-like CMCS/SF-CLN and CMCS/M-IMD-CLN, respectively. The results of cellular uptake assay on Hepa1-6 cells and RAW 264.7 cells in vitro, respectively, as well as the results of tumor tissue distribution of SF and IMD-0354 in vivo suggested that CMCS/SF-CLN and CMCS/M-IMD-CLN exhibited similar properties in vitro and synchronous biodistribution in vivo, and were efficient at separated cell targeting delivery. What's more, the results of antitumor efficiency in vivo and phenotype analysis of TAM in tumor tissues proved that CMCS/SF-CLN and CMCS/M-IMD-CLN exhibited superior synergistic antitumor efficacy and M2-type TAM polarization ability compared with SF treatment in Hepa1-6 tumor bearing mice. Consequently, TCN which was the combination of co-administration and nano-drug delivery systems has great potential to be used in tumor-localized chemoimmunotherapy in clinics.
肿瘤相关巨噬细胞（TAM）为基础的免疫疗法已被提出作为癌症治疗的一种很有前途的策略。TAM 为基础的免疫疗法与索拉非尼（SF）联合治疗肝癌（HCC）可能更有效。共递药系统在改善两种药物在肿瘤组织中的共积聚以进行化疗免疫治疗方面具有优势，而对于选择性靶向分离细胞（如肿瘤细胞和免疫细胞），则迫切需要新的靶向共递药策略。在这项研究中，开发了类双胞胎核壳纳米粒（TCN），用于索拉非尼和 TAM 再极化剂 IMD-0354 分别向癌细胞和 TAM 的同步生物分布和分离细胞靶向递药，以增强肿瘤局部化疗免疫治疗。首先，制备了负载索拉非尼的阳离子脂质纳米粒（SF-CLN）和甘露糖修饰的 IMD-0354 负载阳离子脂质纳米粒（M-IMD-CLN）。SF-CLN 表面上的 SF 和 M-IMD-CLN 表面上的甘露糖分别被视为 SF-CLN 和 M-IMD-CLN 选择性靶向递药至癌细胞和 TAM 的靶向配体。然后，将 pH 响应性电荷反转聚合物 O-羧甲基壳聚糖（CMCS）涂覆在 SF-CLN 和 M-IMD-CLN 上，分别得到类双胞胎 CMCS/SF-CLN 和 CMCS/M-IMD-CLN。体外 Hepa1-6 细胞和 RAW 264.7 细胞摄取实验以及体内 SF 和 IMD-0354 的肿瘤组织分布结果表明，CMCS/SF-CLN 和 CMCS/M-IMD-CLN 在体外具有相似的性质，体内同步生物分布，并能有效地进行分离细胞靶向递药。更重要的是，体内抗肿瘤效率和肿瘤组织中 TAM 表型分析的结果表明，与 SF 治疗相比，CMCS/SF-CLN 和 CMCS/M-IMD-CLN 在 Hepa1-6 荷瘤小鼠中表现出优越的协同抗肿瘤疗效和 M2 型 TAM 极化能力。因此，TCN 作为联合给药和纳米药物递送系统的结合，具有在临床肿瘤局部化疗免疫治疗中应用的巨大潜力。
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