PMID- 37797662 OWN - NLM STAT- MEDLINE DCOM- 20231121 LR - 20231121 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 197 DP - 2023 Nov TI - Lysosomal-targeted doxorubicin delivery using RBC-derived vesicles to overcome drug-resistant cancer through mitochondrial-dependent cell death. PG - 106945 LID - S1043-6618(23)00301-8 [pii] LID - 10.1016/j.phrs.2023.106945 [doi] AB - Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However, current DDSs require sophisticated design and construction based on xenogeneic nanomaterials, evoking feasibility and biocompatibility concerns. Herein, a simple but versatile biological DDS (bDDS) composed of human red blood cell (RBC)-derived vesicles (RDVs) with excellent biocompatibility was surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs that remarkably suppressed MDR in uterine sarcoma through a lysosomal-mitochondrial axis-dependent cell death mechanism. Dox-gluRDVs can efficiently deliver and accumulate Dox in lysosomes, bypassing drug efflux transporters and facilitating cellular uptake and retention of Dox in drug-resistant MES-SA/Dx5 cells. The transfer of lysosomal calcium to the mitochondria during mitochondria-lysosome contact due to lysosomal Dox accumulation may result in mitochondrial ROS overproduction, mitochondrial membrane potential loss, and activation of apoptotic signaling for the superior anti-MDR activity of Dox-gluRDVs in vitro and in vivo. This work highlights the great promise of RDVs to serve as a bDDS of Dox to overcome MDR cancers but also opens up a reliable strategy for lysosomal-mitochondrial axis-dependent cell death for fighting against other inoperable cancers. CI - Copyright (c) 2023 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Lin, Chih-Peng AU - Lin CP AD - Department of Anesthesiology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100225, Taiwan. FAU - Wu, Shu-Hui AU - Wu SH AD - Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 30503, Taiwan. FAU - Lin, Tzu-Yin AU - Lin TY AD - Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 30503, Taiwan. FAU - Chu, Chia-Hui AU - Chu CH AD - Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 30503, Taiwan. FAU - Lo, Leu-Wei AU - Lo LW AD - Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 30503, Taiwan. FAU - Kuo, Ching-Chuan AU - Kuo CC AD - Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan. FAU - Chang, Jang-Yang AU - Chang JY AD - Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan; Taipei Cancer Center, Taipei Medical University Hospital, Taipei 110, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan. FAU - Hsu, Szu-Chun AU - Hsu SC AD - Department of Laboratory Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100225, Taiwan. FAU - Ko, Bor-Sheng AU - Ko BS AD - Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100225, Taiwan; Department of Hematological Oncology, National Taiwan University Cancer Center, Taipei 106037, Taiwan. FAU - Yao, Ming AU - Yao M AD - Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100225, Taiwan. FAU - Hsiao, Jong-Kai AU - Hsiao JK AD - Department of Medical Imaging, Taipei Tzu Chi General Hospital, Buddhist Tzu-Chi Medical Foundation, New Taipei City 23142, Taiwan; School of Medicine, Tzu Chi University, Hualien 97004, Taiwan. FAU - Wang, Shih-Wei AU - Wang SW AD - Institute of Biomedical Sciences, Mackay Medical College, New Taipei City 252005, Taiwan; Department of Medicine, Mackay Medical College, New Taipei City 252005, Taiwan; School of Pharmacy, College of Pharmacy, Kaohsiung 807378, Taiwan. FAU - Huang, Dong-Ming AU - Huang DM AD - Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 30503, Taiwan. Electronic address: dmhuang@nhri.edu.tw. LA - eng PT - Journal Article DEP - 20231004 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Pharmaceutical Preparations) RN - 80168379AG (Doxorubicin) SB - IM MH - Humans MH - Pharmaceutical Preparations MH - *Neoplasms MH - Cell Death MH - Lysosomes MH - Mitochondria MH - Erythrocytes MH - Doxorubicin/pharmacology OTO - NOTNLM OT - Cancer chemotherapy OT - Doxorubicin OT - Drug delivery OT - Multidrug resistance OT - Nanoparticle OT - RBC COIS- Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dong-Ming Huang has patent #Red blood cell-derived vesicles as a nanoparticle drug delivery system (US8,329,161 B2) issued to National Health Research Institutes. EDAT- 2023/10/06 00:43 MHDA- 2023/11/21 06:42 CRDT- 2023/10/05 19:29 PHST- 2023/06/15 00:00 [received] PHST- 2023/09/30 00:00 [revised] PHST- 2023/10/02 00:00 [accepted] PHST- 2023/11/21 06:42 [medline] PHST- 2023/10/06 00:43 [pubmed] PHST- 2023/10/05 19:29 [entrez] AID - S1043-6618(23)00301-8 [pii] AID - 10.1016/j.phrs.2023.106945 [doi] PST - ppublish SO - Pharmacol Res. 2023 Nov;197:106945. doi: 10.1016/j.phrs.2023.106945. Epub 2023 Oct 4.