Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives.
Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives.
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DOI：
10.1016/j.apsb.2018.05.006
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Kang HC
中科院分区：
文献类型：
--
作者：
Battogtokh G;Choi YS;Kang DS;Park SJ;Shim MS;Huh KM;Cho YY;Lee JY;Lee HS;Kang HC
线粒体靶向是解决目前临床化疗和疾病诊断中存在的问题的一种有前途的方法。在这里，我们讨论线粒体靶向部分与抗癌药物、抗氧化剂和传感器分子的直接缀合。其中，应用最广泛的线粒体靶向部分是三苯基鳞（TPP），其是一种离域阳离子脂质，由于高度负的线粒体膜电位，其容易积聚并穿透线粒体膜。其他部分，包括短肽，地喹铵，胍，罗丹明，和F16，也被认为是有前途的线粒体靶向剂。与它们的非靶向对应物相比，线粒体靶向部分与抗癌药物、抗氧化剂和传感器的直接缀合分别导致增加的细胞毒性、抗氧化活性和传感活性，特别是在耐药细胞中。虽然许多靶向抗癌药物偶联物已经在体外和体内进行了研究，但仍需要进一步的临床研究。另一方面，在I、II和III期临床试验中分析了几种靶向抗氧化剂，其中一种缀合物已在俄罗斯被批准用于治疗眼病。有许多正在进行中的研究，以神经元为目标的传感器。线粒体靶向的抗癌剂、抗氧化剂和传感剂可以选择性地在线粒体中积累，在线粒体中发生它们的作用模式。在大多数情况下，亲脂性分子通过亲脂性亲和力嵌入线粒体膜中，并由于膜电位差而进一步移动通过基质。
Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors. Mitochondria-targeted anticancer, antioxidant, and sensing agents can selectively accumulate in the mitochondria, where their modes of action occur. In most cases, lipophilic molecules intercalate into the mitochondrial membrane through lipophilic affinity and further move through the matrix owing to the membrane potential difference.
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