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

Szenasi, Attila, Sivasudhan, Enakshi, Du, Hong, Zhang, Peizhuo, Huang, Jie, Zhang, Zhijun, Rocha, Sonia and Wang, Mu (2023) Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer. CANCER GENE THERAPY, 30 (11). pp. 1554-1568.

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Abstract

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 (GO^PEI-mPEG) nanoparticle was complexed with SOD1 siRNA. GO^PEI-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 (UPR^mt) 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 A2780^DDP subcutaneous mouse xenografts. Our study highlights the potential therapeutic applicability of RNAi-mediated targeting of SOD1 as a chemosensitizer for platinum-resistant ovarian cancers.

Item Type:	Article
Uncontrolled Keywords:	Cell Line, Tumor, Animals, Humans, Mice, Ovarian Neoplasms, Cisplatin, Graphite, Polyethylene Glycols, RNA, Small Interfering, Antineoplastic Agents, RNA Interference, Drug Resistance, Neoplasm, Female, Nanoparticles, Superoxide Dismutase-1, Carcinoma, Ovarian Epithelial
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	29 Sep 2023 09:47
Last Modified:	02 Dec 2023 02:08
DOI:	10.1038/s41417-023-00659-2
Open Access URL:	https://www.nature.com/articles/s41417-023-00659-2
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3173197