Doxorubicin (DOX) is a widely used and effective anticancer drug. However, it shows high cardiotoxicity in several patients. The exact biological mechanisms of DOX-induced cardiotoxicity remain unclear. In the present study, we developed and assessed novel injectable hydrogel matrices combined with nanoparticles and secretome biomolecules to reduce DOXinduced cytotoxicity in human stem cell-derived cardiomyocytes. A Fe₂O₃ nanoparticle-loaded biocompatible silk sericin nanocomposite form was fabricated and used as an injectable carrier for secretome for in vivo cardiomyocyte metabolism. The formulated hydrogels carrying secretome were analyzed in vitro for proliferation, migration, and tube formation of human stem cell-derived cardiomyocytes. Biological analyses revealed that the secretome-encapsulated florescent Fe₃O₂ Silk sericin (Sec@MSS) hydrogel markedly reduced calcein-PI dual staining in cardiomyocytes, revealing significantly induced apoptosis. Furthermore, we evaluated the mitochondrial membrane potential for DOX and Sec@MSS hydrogel, and demonstrated apoptosis of the cardiomyocytes in the DOX-alone and Sec@MSS groups. However, the cardiotoxicity of Sec@MSS sericin was much lower than that in the DOX group, and was further evaluated via VEGFR and TUNEL analyses. The results indicate that Sec@MSS hydrogel might serve as an effective treatment agent in cardiac diseases in the future.

中文翻译：

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荧光磁性氧化铁纳米颗粒包裹的蛋白水凝胶，对抗阿霉素相关的心脏毒性和增强的心肌细胞存活率。

阿霉素（DOX）是一种广泛使用且有效的抗癌药物。但是，它在几位患者中显示出很高的心脏毒性。DOX诱导的心脏毒性的确切生物学机制仍不清楚。在本研究中，我们开发和评估了新型可注射水凝胶基质，与纳米颗粒和分泌组生物分子结合，以降低DOX诱导的人干细胞来源的心肌细胞毒性。制备了负载有Fe 2 O 3纳米颗粒的生物相容性丝胶蛋白纳米复合物形式，并用作体内心肌细胞代谢的分泌蛋白的可注射载体。体外分析配制的带有分泌蛋白的水凝胶用于人类干细胞衍生的心肌细胞的增殖，迁移和管形成。生物学分析表明，被分泌蛋白包裹的荧光Fe 3 O 2丝胶（Sec @ MSS）水凝胶显着降低了心肌细胞中钙黄绿素-PI双重染色，显示出明显的诱导凋亡。此外，我们评估了DOX和Sec @ MSS水凝胶的线粒体膜电位，并证明了仅DOX和Sec @ MSS组中心肌细胞的凋亡。然而，Sec @ MSS丝胶的心脏毒性远低于DOX组，并通过VEGFR和TUNEL分析进行了进一步评估。结果表明，Sec @ MSS水凝胶有望在将来成为心脏病的有效治疗剂。