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Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer
Attila Szénási1,2,3, Enakshi Sivasudhan2,4, Hong Du5
1Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, 215123, China.
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 (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.
Insights
Targeting superoxide dismutase 1 (SOD1) with RNA interference (RNAi) can overcome platinum resistance in ovarian cancer. This approach enhances cisplatin sensitivity and inhibits tumor growth in preclinical models.
Area of Science:
- Oncology
- Biotechnology
- Nanomedicine
Background:
- Acquired platinum resistance is a major challenge in ovarian cancer treatment, leading to over 200,000 deaths annually.
- Overexpression of superoxide dismutase 1 (SOD1) confers oxidative stress resistance, contributing to platinum resistance in ovarian cancer.
- Previous in vitro studies showed SOD1 inhibition increases sensitivity to platinum compounds.
Purpose of the Study:
- To investigate the in vivo therapeutic potential of silencing SOD1 using a graphene-based siRNA delivery system to reverse cisplatin resistance in ovarian cancer.
- To evaluate the efficacy of SOD1 silencing as a chemosensitizer in platinum-resistant ovarian cancer models.
Main Methods:
- Development of a PEGylated graphene oxide-polyethyleneimine nanoparticle (GOPEI-mPEG) for SOD1 siRNA delivery.
- Characterization of the nanoparticle's biocompatibility, siRNA loading, and serum stability.
- Assessment of SOD1 mRNA and protein downregulation in vitro and in vivo.
- Evaluation of cisplatin-induced cytotoxicity, mitochondrial dysfunction, and the mitochondrial unfolded protein response (UPRmt).
- Testing the therapeutic effect in cisplatin-sensitive and resistant ovarian cancer xenograft mouse models.
Main Results:
- The GOPEI-mPEG-siSOD1 nanoparticle demonstrated high biocompatibility, siRNA loading, and stability.
- Effective downregulation of SOD1 mRNA and protein levels was achieved.
- SOD1 silencing potentiated cisplatin-induced cytotoxicity and mitochondrial dysfunction.
- Significant tumor growth inhibition was observed in both cisplatin-sensitive and resistant ovarian cancer xenografts.
Conclusions:
- RNAi-mediated targeting of SOD1 holds promise as a therapeutic strategy to chemosensitize platinum-resistant ovarian cancers.
- The developed graphene-based siRNA delivery platform is effective for in vivo SOD1 silencing.
- This approach offers a potential new avenue for improving treatment outcomes in ovarian cancer patients with platinum resistance.
