Abstract

Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma. However, its clinical applications have been hindered due to low efficacy and bioavailability, and particularly frequent emergence of reactive oxygen species (ROS)-decrease induced drug resistance. The transcription factor NF-E2-related factor 2 (Nrf2) is increased in cancer patients and induces poor outcome in osteosarcoma treatment, making it a novel target to improve the efficacy of chemotherapy. Herein, a hyaluronidase-responsive multi-layer liposome (HLCN) for co-delivery of cisplatin and Nrf2 siRNA (siNrf2) is developed. It is composed of Vpr_52-96 modified liposome covered with hyaluronic acid (HA). HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44, and can be degraded by endosomal hyaluronidase to generate cationic liposome, which promotes the endosomal escape of Vpr_52-96, cisplatin and siNrf2. HLCN can effectively decrease Nrf2 level, promote ROS generation, activate itochondrial apoptotic pathway, and consequently enhance anticancer efficacy of cisplatin. Particularly, HLCN shows high cytotoxicity to osteosarcoma cells with an IC₅₀ value of about 1 µM, which is four-fold lower than liposomal cisplatin (IC₅₀ 4 µM), indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells. Importantly, HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects. Therefore, this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.

中文翻译：

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顺铂和Nrf2 siRNA的刺激反应联合疗法改善骨肉瘤的抗肿瘤治疗

摘要

顺铂是一种广泛应用于骨肉瘤治疗的疗法。然而，由于其低功效和生物利用度，特别是频繁出现的活性氧（ROS）降低引起的耐药性，阻碍了其临床应用。转录因子NF-E2相关因子2（Nrf2）在癌症患者中增加，并在骨肉瘤治疗中导致不良预后，使其成为提高化疗疗效的新靶标。本文中，开发了用于顺铂和Nrf2 siRNA（siNrf2）共递送的透明质酸酶响应多层脂质体（HLCN）。由Vpr _52-96组成透明质酸（HA）覆盖的修饰脂质体。HLCN通过靶向肿瘤特异性CD44选择性地在骨肉瘤中蓄积，并可以被内体透明质酸酶降解以产生阳离子脂质体，从而促进Vpr _52-96，顺铂和siNrf2的内体逸出。HLCN可以有效降低Nrf2水平，促进ROS生成，激活线粒体凋亡途径，从而增强顺铂的抗癌功效。特别是，HLCN对骨肉瘤细胞显示高细胞毒性，IC ₅₀值约为1 µM，比顺铂脂质体（IC _50）低四倍。4 µM），表明Nrf2沉默可以显着提高癌细胞中顺铂的敏感性。重要的是，HLCN可以显着抑制异种移植骨肉瘤小鼠的肿瘤生长，且全身性不良反应极小。因此，这种新颖的顺铂和siNrf2刺激反应联合疗法为骨肉瘤的治疗提供了有希望的策略。