Nano Codelivery of Oxaliplatin and Folinic Acid Achieves Synergistic Chemo-Immunotherapy with 5-Fluorouracil for Colorectal Cancer and Liver Metastasis
Nano Codelivery of Oxaliplatin and Folinic Acid Achieves Synergistic Chemo-Immunotherapy with 5-Fluorouracil for Colorectal Cancer and Liver Metastasis
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DOI：
10.1021/acsnano.0c01676
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发表时间：
2020-04-28
期刊：
影响因子：
17.1
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
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作者：
Guo, Jianfeng;Yu, Zhuo;Huang, Leaf
FOLFOX是亚叶酸（FnA）、5-氟尿嘧啶（5-Fu）和奥沙利铂（OxP）的联合治疗策略，数十年来一直被用作结直肠癌（CRC）的标准治疗。尽管提高了生存率，但患者仍然遭受诸如低疗效、高毒性和长疗程的缺点。需要新的策略来解决这些问题，以进一步提高临床效益。在这项研究中，由OxP（[Pt（DACH）（H2O）（2）]（2+）和FnA的活性形式形成纳米沉淀物（C26 H35 N9 O 7 Pt），使用纳米沉淀技术将其配制成微乳液中的氨基乙基茴香酰胺靶向聚乙二醇化脂质纳米粒。所得制剂（即Nano-Folox）在原位CRC小鼠模型中显著促进了铂药物和FnA的血液循环和肿瘤蓄积。新出现的证据表明，OxP不仅可以提供抗癌细胞毒性作用，而且还可以诱导免疫原性细胞死亡（一种引发抗癌免疫应答的细胞凋亡）。因此，Nano-Folox在原位CRC小鼠中表现出有利的化学免疫抑制活性。此外，与FOLFOX相比，Nano-Folox和5-Fu联合使用可获得显著更强的化学免疫应答，且未显示毒性。此外，抗PD-L1单克隆抗体增强Nano-Folox/5-Fu减少小鼠肝转移。这些结果表明基于Nano-Folox的组合策略用于治疗CRC的潜力。
FOLFOX, the combinational strategy of folinic acid (FnA), 5-fluorouracil (5-Fu), and oxaliplatin (OxP), has been used as standard treatment of colorectal cancer (CRC) for decades. Despite the improved survival, patients still suffer from drawbacks such as low efficacy, high toxicity, and long course of treatment. New strategies to address these issues are needed to further clinical benefits. In this study, a nanoprecipitate (C26H35N9O7Pt) was formed by the active form of OxP ([Pt(DACH)(H2O)(2)](2+) and FnA, which was formulated into an aminoethyl anisamide targeted PEGylated lipid nanoparticle within microemulsions using nanoprecipitation technique. The resultant formulation (namely Nano-Folox) significantly promoted the blood circulation and tumor accumulation of platinum drug and FnA in an orthotopic CRC mouse model. Emerging evidence indicates that OxP can not only provide anticancer cytotoxic effects but also induce immunogenic cell death (a type of apoptosis that primes anticancer immune responses). Consequently, Nano-Folox demonstrated favorable chemo-immunotherapeutic activities in orthotopic CRC mice. In addition, when compared to FOLFOX the significantly stronger chemo-immunotherapeutic responses were achieved by the combination of Nano-Folox and 5-Fu without showing toxicity. Moreover, the anti-PD-L1 monoclonal antibody enhanced Nano-Folox/5-Fu for decreased liver metastases in mice. These results indicate the potential of Nano-Folox-based combination strategy for the treatment of CRC.