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

作　　者：Min Zhong Peiqin Liang Zhenzhen Feng Xin Yang Guang Li Rui Sun Lijuan He Jinxiu Tan Yangpengcheng Xiao Zhiqiang Yu Muhua Yi Xuefeng Wang 

机构地区：[1]Department of Obstetrics and Gynecology,The Third Affiliated Hospital of Southern Medical University,Guangzhou 510632,China [2]School of Pharmaceutical Sciences,Guangdong Provincial Key Laboratory of New Drug Screening,Southern Medical University,Guangzhou 510515,China [3]Department of Laboratory Medicine,Dongguan Institute of Clinical Cancer Research,The Tenth Affiliated Hospital of Southern Medical University(Dongguan people’s hospital),Dongguan 523018,China [4]Department of Pathology,Affiliated Dongguan Hospital,Southern Medical University,Dongguan 523059,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2023年第6期144-156,共13页亚洲药物制剂科学（英文）

基　　金：supported by the Guangdong Basic and Applied Basic Research Foundation of China(No.2021A1515011050);President Foundation of The Third Affiliated Hospital of SouthernMedical University[grant number YM202202].

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 encapsulatingmitochondria-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 O_(2)^(·−)and NO in tumor tissues.Taken together,INP@TPtbased systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR,providing practical applications for ovarian therapy.

关 键 词：Cisplatin resistance Patient-derived xenograft model Mitochondrial dysfunction Nitric oxide Ovarian cancer 

分 类 号：R943[医药卫生—药剂学]