心肌靶向脂质体递送抗氧化肽 8P，对抗阿霉素诱导的心肌损伤。
Myocardium-targeted liposomal delivery of the antioxidant peptide 8P against doxorubicin-induced myocardial injury.
发表日期：2024 Aug 08
作者：
Meijun Zhao, Chang Liu, Zhenye Liu, Yuanyuan Zuo, Chen Chen, Shuai Shi, Xinlin Shi, Yining Xie, Huiying Yang, Yutong Chen
来源：
INTERNATIONAL JOURNAL OF PHARMACEUTICS
摘要：
阿霉素（Dox）是一种临床使用的广谱抗肿瘤化疗药物，但它具有显着的心脏毒性，严重时可导致心力衰竭。研究表明，氧化应激在阿霉素诱导的心肌细胞损伤中起着关键作用。因此，抗氧化剂的应用是减轻阿霉素心脏毒性作用的有效策略。在初步研究中，我们分离出一种抗氧化肽，PHWWEYRR (8P)。本研究利用PCM心肌细胞靶向肽修饰脂质体作为载体，将8P递送至心肌细胞内，旨在通过其抗氧化机制预防Dox诱导的心脏损伤。结果表明，我们制备的负载8P、PCM靶向的肽修饰脂质体（P-P-8P）具有良好的分散性、包封率、载药量、体外释放性以及心肌靶向能力。体外实验表明，P-P-8P可以通过线粒体依赖性途径预防H9C2细胞的氧化应激损伤，保护线粒体功能，抑制细胞凋亡。体内实验表明，P-P-8P可以预防小鼠血清生化指标异常、心功能障碍和心肌病理改变。总之，P-P-8P 有效地将 8P 递送至心肌细胞，提供针对 Dox 心脏毒性作用的保护，并具有作为药物诱发的心肌病的未来预防或治疗剂的潜力。版权所有 © 2024 Elsevier B.V. 保留所有权利。
Doxorubicin (Dox) is a broad-spectrum antineoplastic chemotherapeutic agent used in clinical settings, yet it exhibits significant cardiotoxicity, which in severe cases can lead to heart failure. Research indicates that oxidative stress plays a pivotal role in Dox -induced cardiomyocyte injury. Therefore, the application of antioxidants represents an effective strategy to mitigate the cardiotoxic effects of doxorubicin. In preliminary studies, we isolated an antioxidative peptide, PHWWEYRR (8P). This study utilizes a PCM cardiomyocyte-targeting peptide-modified liposome as a carrier to deliver 8P into cardiomyocytes, aiming to prevent Dox-induced cardiac injury through its antioxidative mechanism. The results demonstrated that we prepared the 8P-loaded and PCM-targeting peptide-modified liposome (P-P-8P), which exhibited good dispersibility, encapsulation efficiency, drug loading capacity, and in vitro release, along with myocardial targeting capability. In vitro experiments showed that P-P-8P could prevent oxidative stress injury in H9C2 cells, protect mitochondrial functions, and inhibit cell apoptosis through a mitochondria-dependent pathway. In vivo experiments indicated that P-P-8P could prevent abnormalities in serum biochemical indicators, cardiac dysfunction, and myocardial pathological changes in mice. In conclusion, P-P-8P effectively delivers 8P to cardiomyocytes, offering protection against the cardiotoxic effects of Dox, and holds potential as a future preventative or therapeutic agent for drug-induced cardiomyopathy.Copyright © 2024 Elsevier B.V. All rights reserved.