文献类型：期刊文献

英文题名：Diselenide-Containing Polymer Based on New Antitumor Mechanism as Efficient GSH Depletion Agent for Ferroptosis Therapy

作者：Zhou, Chen[1];Zhao, Yuhao[2,3];Yang, Mao[2,3];Yin, Wang[1];Li, Yongsheng[2,3];Xiao, Yan[1];Liu, Yingbin[2,3];Lang, Meidong[1]

机构：[1]East China Univ Sci & Technol, Sch Mat Sci & Engn, Shanghai 200237, Peoples R China;[2]Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Biliary Pancreat Surg, Shanghai 200127, Peoples R China;[3]Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes, Shanghai 200032, Peoples R China

年份：2024

卷号：13

期号：17

外文期刊名：ADVANCED HEALTHCARE MATERIALS

收录：;EI(收录号：20241515851560);WOS:【SCI-EXPANDED(收录号:WOS:001197478200001)】；

基金：C.Z., Y.Z., and M.Y. contributed equally to this work. This work was supported by The Key Laboratory of Advanced Polymeric Materials of Shanghai and Shanghai Jiao Tong University star of Jiao Tong University program medical and industrial cross-research fund (No. YG2022QN027). All animal procedures were performed in accordance with the guidelines for the Care and Use of Laboratory Animals of Shanghai Cancer Institute, and approved by the Animal Ethics Committee of Shanghai Cancer Institute. The assigned approval number is RJ2022-1014.

语种：英文

外文关键词：diselenide-containing polymers; ferroptosis; glutathione depletion; pancreatic cancers; self-delivery

摘要：Glutathione (GSH) depletion-induced ferroptosis has emerged as a promising treatment for malignant cancer. It works by inactivating glutathione peroxidase 4 (GPX4) and facilitating lipid peroxidation. However, effectively delivering inducers and depleting intracellular GSH remains challenging due to the short half-lives and high hydrophobicity of small-molecule ferroptosis inducers. These inducers often require additional carriers. Herein, diselenide-containing polymers can consume GSH to induce ferroptosis for pancreatic cancer therapy. The diselenide bonds are controllably built into the backbone of the polycarbonate with a targeting peptide CRGD (Cys-Arg-Gly-Asp), which allows for self-assembly into stable nanoparticles (denoted CRNSe) for self-delivery. Significantly, at a concentration of 12 mu g mL-1, CRNSe binds to the active site cysteine of GSH resulting in a thorough depletion of GSH. In contrast, the disulfide-containing analog only causes a slight decrease in GSH level. Moreover, the depletion of GSH inactivates GPX4, ultimately inducing ferroptosis due to the accumulation of lipid peroxide in BxPC-3 cells. Both in vitro and in vivo studies have demonstrated that CRNSe exhibits potent tumor suppressive ability with few side effects on normal tissue. This study validates the anti-tumor mechanism of diselenide-containing polymers in addition to apoptosis and also provides a new strategy for inherently inducing ferroptosis in cancer therapy. To circumvent the disadvantages of small molecule-based ferroptosis inducers, a diselenide-containing macromolecular inducer is proposed for self-delivery. It is demonstrated for the first time that a relatively low concentration of such diselenide-containing polymers efficiently induces ferroptosis via thorough depletion of glutathione (GSH), which is the new mechanism of tumor suppression by diselenide-containing polymers. image