Co-Delivery of siNRF2 and Sorafenib by a "Click" Dual Functioned Hyperbranched Nanocarrier for Synergistically Inducing Ferroptosis in Hepatocellular Carcinoma

Rongliang Tong; Xiaode Feng; Jingqi Sun; Zhenan Ling; Jun Wang; Shun Li; Beng Yang; Junfang Deng; Guijin He; Jian Wu

doi:10.1002/smll.202307273

Co-Delivery of siNRF2 and Sorafenib by a "Click" Dual Functioned Hyperbranched Nanocarrier for Synergistically Inducing Ferroptosis in Hepatocellular Carcinoma

Small. 2023 Dec 15:e2307273. doi: 10.1002/smll.202307273. Online ahead of print.

Authors

Rongliang Tong^{1

2}, Xiaode Feng³, Jingqi Sun^{1

2}, Zhenan Ling^{1

2}, Jun Wang¹, Shun Li⁴, Beng Yang^{1

2}, Junfang Deng^{1

2}, Guijin He⁴, Jian Wu^{1

2

5

6}

Affiliations

¹ Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
² NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China.
³ Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
⁴ Department of Chemistry, Zhejiang University, Hangzhou, 310027, China.
⁵ Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China.
⁶ Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, 310003, China.

PMID: 38102096
DOI: 10.1002/smll.202307273

Abstract

In the course of antitumor therapy, the complex tumor microenvironment and drug-mediated changes in cell signaling and biological processes lead to drug resistance. The effect of sorafenib is greatly limited by the specific tumor microenvironment induced by antiangiogenic therapy and ferroptosis resistance induced by the upregulation of nuclear factor erythroid-2 related factor 2 (NRF2). In this study, a pH responsive and amphiphilic hyperbranched polyglycerol, HDP, is synthesized based on a co-graft click chemistry pathway. This nano-scale carrier provides excellent drug-loading capacity, storing stability and pH responsibility, and effectively co-delivery of sorafenib and siRNA. Sorafenib and siNRF2 plays a greatly synergistic effect in inducing reactive oxygen species (ROS), iron overloading, depleting glutathione (GSH), and promoting lipid peroxidation. Importantly, verified in two different animal experiments, HDP-ss (HDP loaded with both siNRF2 and sorafenib) presents a superior anti-tumor effect, by achieving a tumor inhibition rate of ≈94%. Thus, HDP can serve as an excellent targeted delivery nanocarrier with good biocompatibility in antitumor therapy, and combined application of siNRF2 effectively improves the antitumor effect of sorafenib by overcoming NRF2-mediated ferroptosis resistance. Taken together, this study provides a novel therapeutic strategy to combat the drug resistance in antiangiogenic therapy and ferroptosis.

Keywords: RNAi therapy; drug resistance; ferroptosis; hyperbranched polyglycerol; synergistic therapy.

Abstract

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