학술논문
Protein-encapsulated doxorubicin reduces cardiotoxicity in hiPSC-cardiomyocytes and cardiac spheroids while maintaining anticancer efficacy.
Document Type
Academic Journal
Author
Arzt M; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Gao B; Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Mozneb M; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Pohlman S; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; CIRM Bridges to Stem Cell Research Program, California State University, Channel Islands, CA, USA.; Cejas RB; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Liu Q; Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Huang F; Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS, USA.; Yu C; Division of Chemistry & Chemical Engineering, California Institute of Technology, Pasadena, CA, USA; Sunstate Biosciences LLC, Monrovia, CA, USA.; Zhang Y; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Fan X; Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Jenkins A; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Giuliano AE; Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Burridge PW; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Cui X; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: xiaojiang.cui@cshs.org.; Sharma A; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: arun.sharma@cshs.org.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 101611300 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-6711 (Electronic) Linking ISSN: 22136711 NLM ISO Abbreviation: Stem Cell Reports Subsets: MEDLINE
Subject
Language
English
Abstract
The chemotherapeutic doxorubicin (DOX) detrimentally impacts the heart during cancer treatment. This necessitates development of non-cardiotoxic delivery systems that retain DOX anticancer efficacy. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), endothelial cells (hiPSC-ECs), cardiac fibroblasts (hiPSC-CFs), multi-lineage cardiac spheroids (hiPSC-CSs), patient-specific hiPSCs, and multiple human cancer cell lines to compare the anticancer efficacy and reduced cardiotoxicity of single protein encapsulated DOX (SPEDOX-6), to standard unformulated (UF) DOX. Cell viability assays and immunostaining in human cancer cells, hiPSC-ECs, and hiPSC-CFs revealed robust uptake of SPEDOX-6 and efficacy in killing these proliferative cell types. In contrast, hiPSC-CMs and hiPSC-CSs exhibited substantially lower cytotoxicity during SPEDOX-6 treatment compared with UF DOX. SPEDOX-6-treated hiPSC-CMs and hiPSC-CSs maintained their functionality, as indicated by sarcomere contractility assessment, calcium imaging, multielectrode arrays, and RNA sequencing. This study demonstrates the potential of SPEDOX-6 to alleviate cardiotoxic side effects associated with UF DOX, while maintaining its anticancer potency.
Competing Interests: Conflict of interests C.Y. is a named inventor for patent applications regarding “Single Protein-Encapsulated Pharmaceutics for Enhancing Therapeutic Effects” and a shareholder of Sunstate Biosciences, LLC. The remaining authors have nothing to disclose.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Competing Interests: Conflict of interests C.Y. is a named inventor for patent applications regarding “Single Protein-Encapsulated Pharmaceutics for Enhancing Therapeutic Effects” and a shareholder of Sunstate Biosciences, LLC. The remaining authors have nothing to disclose.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)