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遗传学和分子生物学方面的研究表明,线粒体在生理功能的内稳态(包括电子传递、凋亡调节和钙稳态调节等)方面发挥着重要的作用,这些生理功能对人体健康来说至关重要。如果这些生理功能出现了障碍,会引起多种疾病,例如:糖尿病、癌症及遗传线粒体疾病分别由能量转运系统的功能障碍、细胞凋亡调节的缺失以及线粒体DNA(mitochondrial DNA,mtDNA)的突变引起[1]。线粒体功能障碍会引起多种线粒体疾病,因此,线粒体是一个重要的药物靶点[2]。研究表明,补充线粒体缺失的功能可以治疗线粒体疾病,但是由于缺乏合适的药物靶向系统,导致药物进入体内后,分布广泛,不能有效地浓集在靶点,导致治疗效果不佳。因此,发展针对药物小分子(电子传递系统的辅酶和抗氧化剂,如维生素E)和大分子(包括线粒体蛋白和mtDNA)的靶向药物是非常必要的[3]。
电离辐射诱发自由基及活性氧(reactive oxygen species,ROS)的产生,是辐射损伤的主要因素。线粒体呼吸链是ROS的主要来源,因此,减少辐射后ROS的产生,以及加快照射后组织细胞内ROS的清除成为辐射防护药物的研发重点,线粒体靶向抗氧化剂成为辐射防护药研究的新方向。Rwigema等[4]通过研究提出了两条发展线粒体靶向小分子辐射防护药的新策略,他们合成了线粒体靶向小分子辐射防护药JP4-039(氮氧自由基)和P53/MDM2/MDM4(P53:肿瘤转化相关蛋白53;MDM2:鼠双微体2;MDM4:鼠双微体4,MDM2和MDM4是P53的主要负调控蛋白)等抑制剂,体内、体外实验均验证其具有辐射防护作用[4]。Jiang等[5]也报道了一种新型的线粒体靶向辐射防护药,他们通过三苯基膦和氮氧自由基连接形成新化合物TPEY-Tempo(mitochondria-targeted triphenylphosphonium-conjugated nitroxide),三苯基膦可以把氮氧自由基靶向到线粒体中清除电离辐射产生的自由基,从而保护细胞免受损伤,达到辐射防护的作用。近些年,线粒体靶向技术发展迅速,线粒体靶向抗氧化剂在辐射防护方面具有自己独特的优势,因此,笔者综述最近几年发展较为成熟的线粒体靶向技术和方法,着重分析线粒体靶向给药系统的研究进展,讨论各个系统的优缺点及线粒体的靶向治疗策略。
线粒体靶向药物的研究进展
Progress in mitochondrial targeting drug delivery systems
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摘要: 电离辐射产生的活性氧(ROS)和自由基攻击DNA、脂质、蛋白质等生物大分子,造成机体细胞和组织的损伤。体内ROS主要来自线粒体,辐射造成线粒体损伤,使细胞内ROS持续增加。线粒体靶向抗氧化剂由于靶向在线粒体释放,能够高效地消除辐射导致的线粒体内过量ROS,保护线粒体,降低电离辐射对细胞的损伤,被认为是一类有前景的辐射损伤防护药。近年来,文献报道了多种线粒体靶向给药系统,笔者主要分析了线粒体靶向给药系统的方法及其发展趋势以及在辐射防护上的应用潜能。Abstract: Free radicals and reactive oxygen species(ROS) generated by ionizing radiation attack vital macromolecules, such as DNA, lipids and Proteins, thus causing cell and tissue damage. The major source of radiation-induced ROS production is believed to be associated with mitochondria. Removal of excessive mitochondrial reactive oxygen species by electron scavengers and antioxidants is a promising therapeutic strategy to reduce the detrimental effects of radiation exposure. Mitochondrial targeting antioxidants and electron scavengers have been suggested as promising radioprotectors due to their well ability to remove of excessive mitochondrial reactive oxygen species. Papers about mitochondrial targeting drug delivery systems have been publicated in recent years. Technique of mitochondrial targeting drug delivery system, potential application in radiation protection and its development trend are discussed in this review.
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