Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study & School of Pharmaceutical Science, Hengyang Medical School, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China.
Adv Healthc Mater. 2022 Oct;11(19):e2200990. doi: 10.1002/adhm.202200990. Epub 2022 Jul 27.
Mitochondrial dysfunction of cardiomyocytes (CMs) has been identified as a significant pathogenesis of early myocardial infarction (MI). However, only a few agents or strategies have been developed to improve mitochondrial dysfunction for the effective MI treatment. Herein, a reactive oxygen species (ROS)-responsive PAMB-G-TK/4-arm-PEG-SG hydrogel is developed for localized drug-loaded liposome delivery. Notably, the liposomes contain both elamipretide (SS-31) and sphingosine-1-phosphate (S1P), where SS-31 acts as an inhibitor of mitochondrial oxidative damage and S1P as a signaling molecule for activating angiogenesis. Liposome-encapsulated PAMB-G-TK/4-arm-PEG-SG hydrogels demonstrate myocardium-like mechanical strength and electrical conductivity, and ROS-sensitive release of SS-31 and S1P-loaded liposomes. Further liposomal release of SS-31, which can target cytochrome c in the mitochondrial inner membrane of damaged CMs, inhibits pathological ROS production, improving mitochondrial dysfunction. Meanwhile, S1P released from the liposome induces endothelial cell angiogenesis by activating the S1PR1/PI3K/Akt pathway. In a rat MI model, the resulting liposomal composite hydrogel improves cardiac function by scavenging excess ROS, improving mitochondrial dysfunction, and promoting angiogenesis. This study reports for the first time a liposomal composite hydrogel that can directly target mitochondria of damaged CMs for a feedback-regulated release of encapsulated liposomes to consume the overproduced pathological ROS for improved CM activity and enhanced MI treatment.
心肌细胞 (CMs) 的线粒体功能障碍已被确定为早期心肌梗死 (MI) 的重要发病机制。然而，目前仅有少数药物或策略被开发出来以改善线粒体功能障碍，从而实现有效的 MI 治疗。在此，我们开发了一种活性氧 (ROS) 响应性 PAMB-G-TK/4-臂-PEG-SG 水凝胶，用于局部载药脂质体递送。值得注意的是，脂质体同时包含了 Elamipretide (SS-31) 和 1-磷酸鞘氨醇 (S1P)，其中 SS-31 作为线粒体氧化损伤抑制剂，S1P 作为激活血管生成的信号分子。包载脂质体的 PAMB-G-TK/4-臂-PEG-SG 水凝胶具有类似于心肌的机械强度和导电性，以及 ROS 敏感的 SS-31 和 S1P 载脂质体释放。进一步释放的 SS-31 可以靶向损伤的 CMs 线粒体内膜中的细胞色素 c，抑制病理性 ROS 的产生，从而改善线粒体功能障碍。同时，脂质体释放的 S1P 通过激活 S1PR1/PI3K/Akt 通路诱导内皮细胞血管生成。在大鼠 MI 模型中，所得的脂质体复合水凝胶通过清除过量的 ROS、改善线粒体功能障碍和促进血管生成来改善心脏功能。本研究首次报道了一种脂质体复合水凝胶，它可以直接靶向损伤的 CMs 的线粒体，实现包封脂质体的反馈调节释放，以消耗过度产生的病理性 ROS，从而改善 CM 活性并增强 MI 治疗效果。
