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.
Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Stem Cell Reports. 2023 Oct 10;18(10):1913-1924. doi: 10.1016/j.stemcr.2023.08.005. Epub 2023 Aug 31.
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.
化疗药物多柔比星（DOX）在癌症治疗过程中对心脏有不良影响。这就需要开发非心脏毒性的给药系统，以保持 DOX 的抗癌疗效。我们使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）、内皮细胞（hiPSC-ECs）、心脏成纤维细胞（hiPSC-CFs）、多能性心脏球体（hiPSC-CSs）、患者特异性 hiPSCs 和多种人癌细胞系，比较了单一蛋白包裹 DOX（SPEDOX-6）和标准未制剂（UF）DOX 的抗癌疗效和降低的心脏毒性。在人癌细胞、hiPSC-ECs 和 hiPSC-CFs 中的细胞活力测定和免疫染色显示 SPEDOX-6 的摄取能力很强，对这些增殖细胞类型具有杀伤作用。相比之下，SPEDOX-6 处理的 hiPSC-CMs 和 hiPSC-CSs 与 UF DOX 相比，细胞毒性明显降低。SPEDOX-6 处理的 hiPSC-CMs 和 hiPSC-CSs 保持了其功能，这可以通过肌节收缩性评估、钙成像、多电极阵列和 RNA 测序来证明。这项研究表明，SPEDOX-6 有可能减轻 UF DOX 相关的心脏毒性副作用，同时保持其抗癌效力。
