Systemic miRNA delivery by nontoxic nanoscale coordination polymers limits epithelial-to-mesenchymal transition and suppresses liver metastases of colorectal cancer
Systemic miRNA delivery by nontoxic nanoscale coordination polymers limits epithelial-to-mesenchymal transition and suppresses liver metastases of colorectal cancer
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DOI：
10.1016/j.biomaterials.2019.04.028
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发表时间：
2019-07-01
期刊：
影响因子：
14
通讯作者：
Lin, Wenbin
中科院分区：
文献类型：
--
作者：
Chan, Christina;Guo, Nining;Lin, Wenbin
尽管近年来原发性肿瘤的早期检测和治疗有了显着改善，但转移性疾病仍然是癌症治疗中最重大的挑战之一。癌细胞可以在检测到原发肿瘤形成微小或大体转移之前扩散，需要有毒的全身治疗。为了预防和抑制转移，我们开发了一种无毒、长循环的纳米级配位聚合物（NCP），可以保护循环中的微小RNA（miRNA）并将其释放到肿瘤中。含有 NCP (PtEN) 的 Pt-IV(en)(2) [en = 乙二胺] 可以释放无毒、动力学惰性的 Pt-II(en)(2) 化合物和二氧化碳，有助于其 miRNA 货物 miR-655-3p 的内体逃逸。在没有 PtEN 核心的情况下，miRNA 显示出细胞摄取但没有效果。当通过 NCP 转染人结直肠 HCT116 细胞时，这种寡转移 miRNA 通过阻止 β-catenin 核易位和肿瘤细胞侵袭来限制增殖和上皮间质转化。在 HCT116 异种肝转移模型中，全身施用 PtEN/miR-655-3p 可以持续有效转染，减少肝脏定植和肿瘤负荷，且没有任何可观察到的毒性。
Though early detection and treatment of primary tumors has significantly improved in recent years, metastatic disease remains among the most significant challenges in cancer therapy. Cancer cells can disseminate before the primary tumor is detected to form micro or gross metastases, requiring toxic systemic therapies. To prevent and suppress metastases, we have developed a nontoxic, long-circulating nanoscale coordination polymer (NCP) protecting microRNA (miRNA) in circulation and releasing it in tumors. Pt-IV(en)(2) [en = ethylenediamine] containing NCPs (PtEN) can release a nontoxic, kinetically inert Pt-II(en)(2) compound and carbon dioxide which aids the endosomal escape of its miRNA cargo, miR-655-3p. Without the presence of the PtEN core, the miRNA showed cellular uptake but no effect. When transfected into human colorectal HCT116 cells by NCPs, this oligometastatic miRNA limited proliferation and epithelial-to-mesenchymal transition by preventing beta-catenin nuclear translocation and tumor cell invasion. Systemic administrations of PtEN/miR-655-3p sustained effective transfection to reduce liver colonization and tumor burden in a xenogenic hepatic metastatic model of HCT116 without any observable toxicity.