A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy

IF 10.7 1区 医学 Q1 PHARMACOLOGY & PHARMACY Asian Journal of Pharmaceutical Sciences Pub Date : 2023-11-01 DOI:10.1016/j.ajps.2023.100872
Min Zhong , Peiqin Liang , Zhenzhen Feng , Xin Yang , Guang Li , Rui Sun , Lijuan He , Jinxiu Tan , Yangpengcheng Xiao , Zhiqiang Yu , Muhua Yi , Xuefeng Wang
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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.

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一种纳米复合材料能够通过线粒体功能障碍和NO气体协同治疗克服卵巢癌的级联耐药
卵巢癌(OC)是妇科最常见和复发的恶性肿瘤之一。复发性卵巢癌患者在反复化疗下往往会出现“级联耐药”(CDR),导致后续化疗失败。为了克服这一挑战,两亲体(P1)携带一氧化氮(NO)供体(ISMN)和高密度二硫化合物,用于包封线粒体靶向四价铂前药(TPt),构建纳米复合材料(INP@TPt)。机制研究表明,INP@TPt通过增加铂的细胞摄取和线粒体积累,消耗谷胱甘肽,并通过产生高毒性过氧亚硝酸盐阴离子(ONOO−)阻止细胞凋亡逃逸,从而显著抑制耐药细胞。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患者源性肿瘤异种移植(PDXOC)模型。INP@TPt对PDXOC模型的治疗效果最好。相应的肿瘤组织中ONOO−含量较高,这是由于肿瘤组织中O2•−和NO同时释放所致。综上所述,INP@TPt-based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,为卵巢治疗提供了实际应用。
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来源期刊
Asian Journal of Pharmaceutical Sciences
Asian Journal of Pharmaceutical Sciences Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
18.30
自引率
2.90%
发文量
11
审稿时长
14 days
期刊介绍: The Asian Journal of Pharmaceutical Sciences (AJPS) serves as the official journal of the Asian Federation for Pharmaceutical Sciences (AFPS). Recognized by the Science Citation Index Expanded (SCIE), AJPS offers a platform for the reporting of advancements, production methodologies, technologies, initiatives, and the practical application of scientific knowledge in the field of pharmaceutics. The journal covers a wide range of topics including but not limited to controlled drug release systems, drug targeting, physical pharmacy, pharmacodynamics, pharmacokinetics, pharmacogenomics, biopharmaceutics, drug and prodrug design, pharmaceutical analysis, drug stability, quality control, pharmaceutical engineering, and material sciences.
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