文章：

利用聚乙二醇化氧化石墨烯纳米颗粒通过RNAi靶向SOD1治疗铂耐药性卵巢癌

Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer 

原文发布日期：2023-08-15 

英文摘要：

Acquired platinum resistance poses a significant therapeutic impediment to ovarian cancer patient care, accounting for more than 200,000 deaths annually worldwide. We previously identified that overexpression of the antioxidant superoxide dismutase 1 (SOD1) in ovarian cancer is associated with a platinum-resistant phenotype via conferring oxidative stress resistance against platinum compounds. We further demonstrated that enzymatic inhibition using small-molecule inhibitors or silencing of SOD1 via RNA interference (RNAi) increased cisplatin sensitivity and potency in vitro. We launched this study to explore the potential therapeutic applications of SOD1 silencing in vivo in order to reverse cisplatin resistance using a graphene-based siRNA delivery platform. PEGylated graphene oxide (GO) polyethyleneimine (GOPEI-mPEG) nanoparticle was complexed with SOD1 siRNA. GOPEI-mPEG-siSOD1 exhibited high biocompatibility, siRNA loading capacity, and serum stability, and showed potent downregulation of SOD1 mRNA and protein levels. We further observed that cisplatin and PEI elicited mitochondrial dysfunction and transcriptionally activated the mitochondrial unfolded protein response (UPRmt) used as a reporter for their respective cytotoxicities. SOD1 silencing was found to augment cisplatin-induced cytotoxicity resulting in considerable tumour growth inhibition in cisplatin-sensitive A2780 and cisplatin-resistant A2780DDP subcutaneous mouse xenografts. Our study highlights the potential therapeutic applicability of RNAi-mediated targeting of SOD1 as a chemosensitizer for platinum-resistant ovarian cancers. 

摘要翻译： 

获得性铂类耐药对卵巢癌患者的治疗构成重大障碍，每年导致全球超过20万例死亡。我们先前发现卵巢癌中抗氧化酶超氧化物歧化酶1（SOD1）的过度表达通过赋予对铂类化合物的氧化应激抵抗能力，与铂类耐药表型相关。我们进一步证实，使用小分子抑制剂进行酶活性抑制或通过RNA干扰（RNAi）沉默SOD1，可在体外增加顺铂敏感性和效力。本研究旨在探索基于石墨烯的siRNA递送平台沉默SOD1在体内逆转顺铂耐药的治疗潜力。采用聚乙二醇化氧化石墨烯（GO）-聚乙烯亚胺（GOPEI-mPEG）纳米颗粒与SOD1 siRNA复合。GOPEI-mPEG-siSOD1表现出良好的生物相容性、siRNA负载能力和血清稳定性，并能有效下调SOD1 mRNA和蛋白水平。我们进一步观察到顺铂和PEI引发线粒体功能障碍，并转录激活线粒体未折叠蛋白反应（UPRmt），该反应可作为二者细胞毒性的报告指标。研究发现SOD1沉默可增强顺铂诱导的细胞毒性，在顺铂敏感型A2780和顺铂耐药型A2780DDP小鼠皮下移植瘤模型中显著抑制肿瘤生长。本研究凸显了RNAi介导的SOD1靶向作为铂类耐药卵巢癌化疗增敏剂的治疗应用潜力。

原文链接：

Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer