Reverting chemoresistance of targeted agents by a ultrasoluble dendritic nanocapsule
Reverting chemoresistance of targeted agents by a ultrasoluble dendritic nanocapsule
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DOI：
10.1016/j.jconrel.2019.11.020
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发表时间：
2020-01-10
影响因子：
10.8
通讯作者：
Liang, Tingbo
中科院分区：
文献类型：
--
作者：
Hu, Qida;Wu, Wangteng;Liang, Tingbo
用不溶的靶向药物治疗的恶性肿瘤具有低剂量暴露和治疗反应，因此容易产生耐药性。纳米颗粒修饰的药物可能通过增加剂量暴露和改变耐药途径来破坏化疗耐药性，如通过静脉途径给药以最大化疗效。在这里，我们提出了一种自组装纳米胶囊策略来构建由多臂聚合物和新型树枝状大分子系列(MAP-MG3)组成的纳米复合体，用于通过核苷酸锁定来包裹不溶性缓蚀剂。以雷帕霉素(MTOR)抑制剂OSI-027为靶点的MAP-MG3(MAP-MG3/OSI-027)具有更高的载药量、更好的溶解性、控释性和更高的细胞内肿瘤蓄积。MAP-MG3/OSI-027比游离靶向药物更有效地减弱mTOR的磷酸化，抑制胰腺癌细胞的生长。此外，MAP-MG3/OSI-027通过增加细胞内剂量暴露，以及调节ABCB1的表达和代偿途径，逆转了耐药胰腺癌对OSI-027的耐药性。优化的纳米胶囊设计提供了一种有效的策略来设计和重新激活不溶于水的靶向试剂，用于抗化疗应用。
Malignancies treated by insoluble targeted agents show low dose exposure and therapeutic responses, therefore easily develop drug resistance. Nanoparticle-modified drugs might disrupt chemoresistance by increasing dose exposure and altering resistance pathways, as administrated via the intravenous route to maximize efficacy. Herein, we proposed a self-assembled nanocapsulation strategy to construct a nanocomplex with multiarm polymer and novel dendrimer series (MAP-mG3) for encapsulating insoluble inhibitors by nucleotide lock. MAP-mG3 delivering the mammalian target of rapamycin (mTOR) inhibitor OSI-027 (MAP-mG3/OSI-027) showed higher loading capacity, enhanced solubility, controlled release, and increased intracellular tumoral accumulation. MAP-mG3/OSI-027, more efficiently than the free targeted agents, attenuated mTOR phosphorylation and inhibited growth of pancreatic cancer cells. In addition, MAP-mG3/OSI-027 reverted chemoresistance to OSI-027 in drug resistance pancreatic cancer by increasing intracellular dose exposure, as well as regulating ABCB1 expression and compensatory pathways. The optimized nanocapsulation design provides an effective strategy to engineer and reactivate insoluble targeted agents for chemoresistant applications.