PDF(Pubmed)
Abstract：
Ovarian cancer (OC) is one of the most common and recurring malignancies in gynecology. Patients with relapsed OC always develop \"cascade drug resistance\" (CDR) under repeated chemotherapy, leading to subsequent failure of chemotherapy. To overcome this challenge, amphiphiles (P1) carrying a nitric oxide (NO) donor (Isosorbide 5-mononitrate, ISMN) and high-density disulfide are synthesized for encapsulating mitochondria-targeted tetravalent platinum prodrug (TPt) to construct a nanocomposite (INP@TPt). Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum, depleting glutathione, and preventing apoptosis escape through generating highly toxic peroxynitrite anion (ONOO-). To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor, an OC patient-derived tumor xenograft (PDXOC) model in BALB/c nude mice was established. INP@TPt showed the best therapeutic effects in the PDXOC model. The corresponding tumor tissues contained high ONOO- levels, which were attributed to the simultaneous release of O2•- and NO in tumor tissues. Taken together, INP@TPt-based systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR, providing practical applications for ovarian therapy.
摘要：
卵巢癌（OC）是妇科最常见和复发的恶性肿瘤之一。复发性OC患者在反复化疗下总是出现“级联耐药”(CDR)，导致随后的化疗失败。为了克服这一挑战，携带一氧化氮（NO）供体（5-单硝酸异山梨酯，合成了ISMN）和高密度二硫化物，用于包封线粒体靶向的四价铂前药（TPt），以构建纳米复合材料（INP@TPt）。机制研究表明，INP@TPt通过增加细胞摄取和线粒体积累铂显著抑制耐药细胞，消耗谷胱甘肽，并通过产生高毒性的过氧亚硝酸盐阴离子（ONOO-）来防止凋亡逃逸。为了更好地复制耐药原发肿瘤的微环境和组织学特征,在BALB/c裸鼠中建立OC患者来源的肿瘤异种移植（PDXOC）模型。INP@TPt在PDXOC模型中显示出最佳的治疗效果。相应的肿瘤组织含有高ONOO-水平，这归因于肿瘤组织中O2·-和NO的同时释放。一起来看,基于INP@TPt的系统策略在克服铂CDR方面显示出相当大的潜力和令人满意的生物相容性，为卵巢治疗提供实际应用。
