PMID- 35926781 OWN - NLM STAT- MEDLINE DCOM- 20220929 LR - 20221222 IS - 1878-7568 (Electronic) IS - 1742-7061 (Linking) VI - 151 DP - 2022 Oct 1 TI - A reactive oxygen species-replenishing coordination polymer nanomedicine disrupts redox homeostasis and induces concurrent apoptosis-ferroptosis for combinational cancer therapy. PG - 480-490 LID - S1742-7061(22)00459-7 [pii] LID - 10.1016/j.actbio.2022.07.055 [doi] AB - Reactive oxygen species (ROS) are important signal molecules and imbalanced ROS level could lead to cell death. Elevated ROS levels in tumor tissues offer an opportunity to design ROS-responsive drug delivery systems (DDSs) or ROS-based cancer therapies such as chemodynamic therapy. However, their anticancer efficacies are hampered by the ROS-consuming nature of these DDSs as well as the high concentration of reductive agents like glutathione (GSH). Here we developed a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde (CA)-based ROS-replenishing organic ligand (TCA). TCA can ROS-responsively release CA to supplement intracellular ROS and deplete GSH by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe(3+)-enabled GSH depletion facilitated efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies revealed that ROS-replenishing PCFD exhibited much better anticancer effect than ROS-consuming control nanoparticle PAFD. The ingenious ROS-replenishing strategy could be expanded to construct versatile ROS-responsive DDSs and ROS-based nanomedicines with potentiated anticancer activity. STATEMENT OF SIGNIFICANCE: We develop a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde-based reactive oxygen species (ROS)-replenishing organic ligand. This functional ligand can ROS-responsively release cinnamaldehyde to supplement intracellular H(2)O(2) and deplete glutathione (GSH) by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe(3+)-enabled GSH depletion facilitates efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies reveal that ROS-replenishing PCFD exhibit much better anticancer effect than ROS consuming counterpart. This study provides a facile and straightforward strategy to design ROS amplifying nanoplatforms for cancer treatment. CI - Copyright (c) 2022. Published by Elsevier Ltd. FAU - Zhang, Zhuangzhuang AU - Zhang Z AD - National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China. FAU - Pan, Yang AU - Pan Y AD - National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China. FAU - Cun, Ju-E AU - Cun JE AD - National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China. FAU - Li, Junhua AU - Li J AD - National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China. FAU - Guo, Zhaoyuan AU - Guo Z AD - National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China. FAU - Pan, Qingqing AU - Pan Q AD - School of Preclinical Medicine, Chengdu University, Chengdu, 610106, China. FAU - Gao, Wenxia AU - Gao W AD - College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou, 325027, China. FAU - Pu, Yuji AU - Pu Y AD - National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China. Electronic address: yjpu@scu.edu.cn. FAU - Luo, Kui AU - Luo K AD - Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Functional and molecular imaging Key Laboratory of Sichuan Province, Sichuan University, China. FAU - He, Bin AU - He B AD - National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China. Electronic address: bhe@scu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220802 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 0 (Ligands) RN - 0 (Polymers) RN - 0 (Reactive Oxygen Species) RN - 0 (Sulfhydryl Compounds) RN - 7864XYD3JJ (Acrolein) RN - 80168379AG (Doxorubicin) RN - BBX060AN9V (Hydrogen Peroxide) RN - E1UOL152H7 (Iron) RN - GAN16C9B8O (Glutathione) RN - SR60A3XG0F (cinnamaldehyde) SB - IM MH - Acrolein/analogs & derivatives MH - Apoptosis MH - Cell Line, Tumor MH - Doxorubicin/pharmacology/therapeutic use MH - *Ferroptosis MH - Glutathione/pharmacology MH - Homeostasis MH - Hydrogen Peroxide/pharmacology MH - Iron/pharmacology MH - Ligands MH - Nanomedicine MH - *Nanoparticles MH - Oxidation-Reduction MH - Polymers/pharmacology MH - Reactive Oxygen Species/metabolism MH - Sulfhydryl Compounds/pharmacology OTO - NOTNLM OT - Chemodynamic therapy OT - Coordination polymer nanoparticle OT - Ferroptosis OT - Reactive oxygen species OT - Redox dyshomeostasis COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/08/05 06:00 MHDA- 2022/09/30 06:00 CRDT- 2022/08/04 19:26 PHST- 2022/05/11 00:00 [received] PHST- 2022/07/19 00:00 [revised] PHST- 2022/07/27 00:00 [accepted] PHST- 2022/08/05 06:00 [pubmed] PHST- 2022/09/30 06:00 [medline] PHST- 2022/08/04 19:26 [entrez] AID - S1742-7061(22)00459-7 [pii] AID - 10.1016/j.actbio.2022.07.055 [doi] PST - ppublish SO - Acta Biomater. 2022 Oct 1;151:480-490. doi: 10.1016/j.actbio.2022.07.055. Epub 2022 Aug 2.