Protein-encapsulated doxorubicin reduces cardiotoxicity in hiPSC-cardiomyocytes and cardiac spheroids while maintaining anticancer efficacy

Madelyn Arzt; Bowen Gao; Maedeh Mozneb; Stephany Pohlman; Romina B Cejas; Qizhi Liu; Faqing Huang; Changjun Yu; Yi Zhang; Xuemo Fan; Amelia Jenkins; Armando E Giuliano; Paul W Burridge; Xiaojiang Cui; Arun Sharma

doi:10.1016/j.stemcr.2023.08.005

Protein-encapsulated doxorubicin reduces cardiotoxicity in hiPSC-cardiomyocytes and cardiac spheroids while maintaining anticancer efficacy

Stem Cell Reports. 2023 Oct 10;18(10):1913-1924. doi: 10.1016/j.stemcr.2023.08.005. Epub 2023 Aug 31.

Authors

Madelyn Arzt¹, Bowen Gao², Maedeh Mozneb¹, Stephany Pohlman³, Romina B Cejas⁴, Qizhi Liu², Faqing Huang⁵, Changjun Yu⁶, Yi Zhang⁷, Xuemo Fan⁸, Amelia Jenkins¹, Armando E Giuliano², Paul W Burridge⁴, Xiaojiang Cui⁹, Arun Sharma¹⁰

Affiliations

¹ 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.
² Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ 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.
⁴ Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁵ Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS, USA.
⁶ Division of Chemistry & Chemical Engineering, California Institute of Technology, Pasadena, CA, USA; Sunstate Biosciences LLC, Monrovia, CA, USA.
⁷ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁹ 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.
¹⁰ 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.

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.

Keywords: cancer; cardiomyocyte; cardiotoxicity; chemotherapy; doxorubicin; iPSC; organoids; single protein encapsulation; spheroids; stem cell.

MeSH terms

Cardiotoxicity
Cells, Cultured
Doxorubicin / adverse effects
Endothelial Cells
Humans
Induced Pluripotent Stem Cells* / metabolism
Myocytes, Cardiac*

Substances

Doxorubicin

Abstract

MeSH terms

Substances

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