卵巢癌
过氧亚硝酸盐
药理学
前药
化学
药物输送
药品
癌症研究
抗药性
细胞凋亡
癌症
医学
内科学
生物
生物化学
超氧化物
酶
有机化学
微生物学
作者
Min Zhong,Peiqin Liang,Zhonglin Feng,Yang Xia,Guang Li,Rui Sun,He Li,Jinxiu Tan,Yi Xiao,Zhiqiang Yu,Muhua Yi,Xuefeng Wang
标识
DOI:10.1016/j.ajps.2023.100872
摘要
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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