Advanced staged high-grade serous ovarian cancer (HGSOC) is the leading cause of gynecological cancer death in the developed world, with 5-year survival rates of only 25-30% due to late-stage diagnosis and the shortcomings of platinum-based therapies. A Phase I clinical trial of a combination of free cisplatin and poly(ADP-ribose) polymerase inhibitors (PARPis) showed therapeutic benefit for HGSOC. In this study, we address the challenge of resistance to platinum-based therapy by developing a targeted delivery approach. Novel electrostatic layer-by-layer (LbL) liposomal nanoparticles (NPs) with a terminal hyaluronic acid layer that facilitates CD44 receptor targeting are designed for selective targeting of HGSOC cells; the liposomes can be formulated to contain both cisplatin and the PARPi drug within the liposomal core and bilayer. The therapeutic effectiveness of LbL NP-encapsulated cisplatin and PARPi alone and in combination was compared with the corresponding free drugs in luciferase and CD44-expressing OVCAR8 orthotopic xenografts in female nude mice. The NPs exhibited prolonged blood circulation half-life, mechanistic staged drug release and targeted codelivery of the therapeutic agents to HGSOC cells. Moreover, compared to the free drugs, the NPs resulted in significantly reduced tumor metastasis, extended survival, and moderated systemic toxicity.

中文翻译：

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用于新型顺铂和PARP抑制剂递送的层状纳米颗粒，用于卵巢癌中铂类药物耐药性治疗。

晚期高级别浆液性卵巢癌（HGSOC）是发达国家妇科癌症死亡的主要原因，由于晚期诊断和铂类疗法的缺点，其5年生存率仅为25-30％ 。游离顺铂和聚（ADP-核糖）聚合酶抑制剂（PARPis）组合的I期临床试验显示了对HGSOC的治疗益处。在这项研究中，我们通过开发靶向递送方法来应对对铂类疗法耐药的挑战。具有可促进CD44受体靶向的末端透明质酸层的新型静电逐层（LbL）脂质体纳米颗粒（NPs）设计用于HGSOC细胞的选择性靶向；脂质体可以被配制为在脂质体核心和双层中同时包含顺铂和PARPi药物。将LbL NP封装的顺铂和PARPi单独使用或联合使用与相应的游离药物在雌性裸鼠体内的荧光素酶和表达CD44的OVCAR8原位异种移植物中的治疗效果进行了比较。NPs表现出延长的血液循环半衰期，阶段性的药物释放和靶向治疗剂向HGSOC细胞的代码传递。而且，与游离药物相比，NPs显着减少了肿瘤转移，延长了生存期，并减轻了全身毒性。机械化阶段性药物释放和靶向治疗剂向HGSOC细胞的代码传递。而且，与游离药物相比，NPs显着减少了肿瘤转移，延长了生存期，并减轻了全身毒性。机械化阶段性药物释放和靶向治疗剂向HGSOC细胞的代码传递。而且，与游离药物相比，NPs显着减少了肿瘤转移，延长了生存期，并减轻了全身毒性。