恢复线粒体稳态的肽-药物偶联物与ros反应性NO释放能力用于心肌梗死的靶向治疗。

IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Zhaoyang Lu, Quanyou Chai, Wenbin Dai, Bo Yu, Qingbo Lv, Fuyu Qiu, Jing Gao, Juhong Zhang, Xiaohua Shen, Shengyu Chen, Zhida Shen, Min Shang, Wenbin Zhang, Guosheng Fu, Qiao Jin, Yanbo Zhao, Fan Jia
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引用次数: 0

摘要

心肌梗死(MI)是世界范围内导致死亡的主要原因。外源性一氧化氮(NO)在心肌梗死治疗中显示出巨大的潜力。然而,心肌缺血微环境中突发生成的活性氧(ROS)将NO氧化为有害的过氧亚硝酸盐(ONOO-)。它会对心肌细胞造成继发性损伤,导致NO基础治疗的失败。在此,我们提出了ROS响应肽-药物偶联物(PDCs)来克服基于NO的治疗困境。PDC中偶联的心脏损伤靶向肽(CTP)(命名为CTP- pba - isn)促进药物在心肌梗死部位的选择性积累。此外,一氧化氮前药单硝酸异山梨酯(ISN)通过病理性ROS触发的硼酸酯水解实现了控释。同时,抗氧化副产物4-羟基苄基醇进一步清除大量的ROS,减少RNS的产生,提高NO的生物利用度。CTP-PBA-ISN通过减轻氧化应激、促进血管生成和恢复线粒体稳态和功能,有效抑制心肌凋亡,改善心肌功能,改善心肌梗死后小鼠不良心脏重构。这些发现证明,ROS的协同调节对于最大化NO的治疗效果至关重要。我们的CTP-PBA-ISN可能为开发其他心肌梗死和其他缺血性疾病的治疗方法提供宝贵的灵感。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mitochondrial homeostasis restoring peptide-drug conjugates with ROS-responsive NO releasing ability for targeted therapy of myocardial infarction.

Myocardial infarction (MI) is the leading cause of death worldwide. Exogenous delivery of nitric oxide (NO) shows great potential in MI treatment. However, the burst generation of reactive oxygen species (ROS) in ischemic microenvironment of MI oxidize NO to harmful peroxynitrite (ONOO-). It renders secondary damage to cardiomyocyte, causing the failure of NO based therapies. Herein, we proposed an ROS responsive peptide-drug conjugates (PDCs) to overcome the dilemma of NO based therapy. The conjugated cardiac injury targeting peptide (CTP) in the PDC (named CTP-PBA-ISN) promoted selective accumulation of drugs in MI sites. Besides, controlled release of NO prodrug isosorbide mononitrate (ISN) was achieved by pathological ROS triggered hydrolysis of boronate ester. Meanwhile the antioxidant byproduct 4-hydroxybenzyl alcohol further scavenges the overwhelming ROS, reducing the production of RNS and improving the bioavailability of NO. The CTP-PBA-ISN efficiently inhibited myocardial apoptosis, improved myocardial function, and ameliorated adverse cardiac remodeling post-MI in mice by relief of oxidative stress, promotion of angiogenesis and restoration of mitochondrial homeostasis and function. These findings prove that the synergic ROS regulation is essential in maximizing therapeutic effects of NO. Our CTP-PBA-ISN may serve as a valuable inspiration for development of other treatments of myocardial infarction and other ischemic diseases.

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来源期刊
Journal of Nanobiotechnology
Journal of Nanobiotechnology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
13.90
自引率
4.90%
发文量
493
审稿时长
16 weeks
期刊介绍: Journal of Nanobiotechnology is an open access peer-reviewed journal communicating scientific and technological advances in the fields of medicine and biology, with an emphasis in their interface with nanoscale sciences. The journal provides biomedical scientists and the international biotechnology business community with the latest developments in the growing field of Nanobiotechnology.
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