治疗癌症的化疗药物多柔比星（DOX）会对心脏造成不良影响。这需要开发非心脏毒性的给药系统，以保留DOX的抗癌疗效。我们使用人诱导多能干细胞衍生心肌细胞（hiPSC-CMs）、内皮细胞（hiPSC-ECs）、心脏成纤维细胞（hiPSC-CFs）、多系心肌球体（hiPSC-CSs）、患者特异性hiPSCs以及多种人类癌细胞株来比较单蛋白封装DOX（SPEDOX-6）与标准未配制（UF）DOX的抗癌疗效和降低心脏毒性。细胞存活率测定和免疫染色在人类癌细胞、hiPSC-ECs和hiPSC-CFs中显示SPEDOX-6能够更好地摄取并杀死这些增殖型细胞。相反，与UF DOX相比，SPEDOX-6处理的hiPSC-CMs和hiPSC-CSs表现出较低的细胞毒性。通过肌节收缩能力评估、钙成像、多电极阵列和RNA测序，证明SPEDOX-6处理的hiPSC-CMs和hiPSC-CSs保持了其功能。本研究证明了SPEDOX-6减轻UF DOX相关心脏毒性副作用的潜力，同时保持其抗癌效力。版权所有© 2023 作者。由Elsevier Inc.出版。保留所有权利。

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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.