An ATP-Responsive Codelivery System of Doxorubicin and MiR-34a To Synergistically Inhibit Cell Proliferation and Migration.
An ATP-Responsive Codelivery System of Doxorubicin and MiR-34a To Synergistically Inhibit Cell Proliferation and Migration.
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DOI：
10.1021/acs.molpharmaceut.7b00184
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发表时间：
2017-06
影响因子：
4.9
通讯作者：
Yudi Wang;Jiawen Chen;X. Liang;Haobo Han;Hao Wang;Yan Yang;Quanshun Li
中科院分区：
文献类型：
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作者：
Yudi Wang;Jiawen Chen;X. Liang;Haobo Han;Hao Wang;Yan Yang;Quanshun Li
由于化疗和基因治疗的协同作用，建立用于抗癌药物和寡核苷酸共递送的刺激响应性纳米系统是一种很有前途的癌症治疗策略。本文中，首先将ATP适体与其cDNA序列杂交以产生双链体，化疗剂阿霉素（DOX）通过双链体的富含GC的基序与所述双链体相互作用，然后使用PEI 25 K作为载体以使装载DOX的双链体和miR-34 a缩合以构建三元纳米复合物PEI/DOX-Duplex/miR-34 a。该纳米复合物通过对胞液中高浓度ATP的响应而表现出良好的药物释放特性。ATP响应性递送系统被证明具有比单一货物递送更高的抗增殖作用（细胞活力<40%），这可以归因于DOX和miR-34 a协同诱导细胞凋亡和细胞周期阻滞。此外，伤口愈合和Transwell测定阐明了三元纳米复合物比DOX-Duplex或miR-34 a递送更高的抗迁移作用。总体而言，通过ATP响应方式组合递送DOX和miR-34 a可以触发胞质溶胶中货物的快速释放，并通过这两种组分的协同方式增强对细胞增殖和迁移的抑制。
Establishing stimulus-responsive nanosystems for the codelivery of anticancer drug and oligonucleotide is a promising strategy in cancer treatment owing to the combination of chemotherapy and gene therapy in a synergistic manner. Herein, an ATP aptamer and its cDNA sequence were first hybridized to produce the duplex, into which chemotherapeutic agent doxorubicin (DOX) interacted through the GC-rich motif of duplex, and PEI25K was then employed as a carrier to condense the DOX-loading duplex and miR-34a to construct the ternary nanocomplex PEI/DOX-Duplex/miR-34a. The nanocomplex exhibited a favorable drug release profile through the response to high concentration of ATP in the cytosol. The ATP-responsive delivery system was demonstrated to possess higher antiproliferative effect (cell viability of <40%) than the single cargo delivery, which could be attributed to the synergistic induction of cell apoptosis and cell cycle arrest from DOX and miR-34a. Furthermore, wound healing and Transwell assay elucidated the higher antimigration effect of ternary nanocomplex than DOX-Duplex or miR-34a delivery. Overall, the combinatorial delivery of DOX and miR-34a through an ATP-responsive manner could trigger the rapid release of cargoes in the cytosol and enhance the inhibition of cell proliferation and migration through the synergistic manner of these two components.