Anexelekto (AXL) is an attractive molecular target for ovarian cancer therapy because of its important role in ovarian cancer initiation and progression. To date, several AXL inhibitors have entered clinical trials for the treatment of ovarian cancer. However, the disadvantages of low AXL affinity and severe off-target toxicity of these inhibitors limit their further clinical applications. Herein, by rational design of a nonapeptide derivative Nap-Phe-Phe-Glu-Ile-Arg-Leu-Arg-Phe-Lys (Nap-IR), a strategy of in situ nanofiber formation is proposed to suppress ovarian cancer growth. After administration, Nap-IR specifically targets overexpressed AXL on ovarian cancer cell membranes and undergoes a receptor-instructed nanoparticle-to-nanofiber transition. In vivo and in vitro experiments demonstrate that in situ formed Nap-IR nanofibers efficiently induce apoptosis of ovarian cancer cells by blocking AXL activation and disrupting subsequent downstream signaling events. Remarkably, Nap-IR can synergistically enhance the anticancer effect of cisplatin against HO8910 ovarian tumors. It is anticipated that the Nap-IR can be applied in clinical ovarian cancer therapy in the near future.

中文翻译：

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原位纳米纤维形成阻止 AXL 和 GAS6 结合，抑制卵巢癌的发展

Anexelekto (AXL) 是卵巢癌治疗的一个有吸引力的分子靶点，因为它在卵巢癌的发生和进展中发挥着重要作用。迄今为止，多种AXL抑制剂已进入治疗卵巢癌的临床试验。然而，这些抑制剂的AXL亲和力低和脱靶毒性严重的缺点限制了它们的进一步临床应用。在此，通过合理设计九肽衍生物Nap-Phe-Phe-Glu-Ile-Arg-Leu-Arg-Phe-Lys（Nap-IR），提出了一种原位纳米纤维形成策略来抑制卵巢癌的生长。给药后，Nap-IR特异性靶向卵巢癌细胞膜上过度表达的 AXL，并经历受体指导的纳米颗粒到纳米纤维的转变。体内和体外实验表明，原位形成的Nap-IR纳米纤维通过阻断 AXL 激活并破坏后续下游信号传导事件，有效诱导卵巢癌细胞凋亡。值得注意的是，Nap-IR可以协同增强顺铂对HO8910卵巢肿瘤的抗癌作用。预计Nap-IR在不久的将来可以应用于临床卵巢癌治疗。