Mito-DCA: a mitochondria targeted molecular scaffold for efficacious delivery of metabolic modulator dichloroacetate.
Mito-DCA: a mitochondria targeted molecular scaffold for efficacious delivery of metabolic modulator dichloroacetate.
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DOI：
10.1021/cb400944y
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发表时间：
2014-05-16
影响因子：
4
通讯作者：
Dhar, Shanta
中科院分区：
文献类型：
--
作者：
Pathak, Rakesh K.;Marrache, Sean;Harn, Donald A.;Dhar, Shanta
肿瘤的生长是通过糖酵解来推动的，而正常细胞只在缺氧的情况下才使用糖酵解。糖酵解使肿瘤细胞抵抗正常的死亡过程。靶向这种独特的肿瘤代谢可以提供一种选择性破坏肿瘤的替代策略，使正常组织不受伤害。孤儿药二氯醋酸盐（DCA）是一种线粒体激酶抑制剂，具有显示这些特征的能力。然而，其分子形式显示出较差的吸收和生物利用度以及到达其靶向线粒体的有限能力。在这里，我们描述了一种用于构建多DCA负载化合物Mito-DCA的靶向分子支架，与DCA相比，Mito-DCA具有三个数量级的增强效力和癌细胞特异性。通过Mito-DCA中的可生物降解的接头将亲脂性三苯基鳞阳离子并入允许线粒体靶向。Mito-DCA对正常细胞没有表现出任何显著的代谢作用，但线粒体功能障碍的肿瘤细胞受到Mito-DCA的影响，这导致糖酵解转变为葡萄糖氧化，随后通过凋亡导致细胞死亡。将DCA有效递送至线粒体导致乳酸水平显著降低，并且在调节树突状细胞（DC）表型中发挥重要作用，这通过在用来自Mito-DCA处理的癌细胞的肿瘤抗原活化后DC分泌白细胞介素-12来证明。将线粒体代谢抑制剂靶向于线粒体可以诱导有效的抗肿瘤免疫应答，从而引入了将糖酵解抑制与免疫系统相结合来破坏肿瘤的概念。
Tumor growth is fueled by the use of glycolysis, which normal cells use only in the scarcity of oxygen. Glycolysis makes tumor cells resistant to normal death processes. Targeting this unique tumor metabolism can provide an alternative strategy to selectively destroy the tumor, leaving normal tissue unharmed. The orphan drug dichloroacetate (DCA) is a mitochondrial kinase inhibitor that has the ability to show such characteristics. However, its molecular form shows poor uptake and bioavailability and limited ability to reach its target mitochondria. Here, we describe a targeted molecular scaffold for construction of a multiple DCA loaded compound, Mito-DCA, with three orders of magnitude enhanced potency and cancer cell specificity compared to DCA. Incorporation of a lipophilic triphenylphosphonium cation through a biodegradable linker in Mito-DCA allowed for mitochondria targeting. Mito-DCA did not show any significant metabolic effects toward normal cells but tumor cells with dysfunctional mitochondria were affected by Mito-DCA, which caused a switch from glycolysis to glucose oxidation and subsequent cell death via apoptosis. Effective delivery of DCA to the mitochondria resulted in significant reduction in lactate levels and played important roles in modulating dendritic cell (DC) phenotype evidenced by secretion of interleukin-12 from DCs upon activation with tumor antigens from Mito-DCA treated cancer cells. Targeting mitochondrial metabolic inhibitors to the mitochondria could lead to induction of an efficient antitumor immune response, thus introducing the concept of combining glycolysis inhibition with immune system to destroy tumor.
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影响因子：
10.8
作者：
Boddapati, Sarathi V.;D'Souza, Gerard G. M.;Weissig, Volkmar
通讯作者：
Weissig, Volkmar
DOI：
10.1073/pnas.1301929110
发表时间：
2013-06-04
影响因子：
11.1
作者：
Marrache, Sean;Dhar, Shanta
通讯作者：
Dhar, Shanta
影响因子：
3.9
作者：
Murphy, MP
通讯作者：
Murphy, MP
DOI：
10.1002/anie.201308899
发表时间：
2014-02-10
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Pathak, Rakesh K;Marrache, Sean;Dhar, Shanta
通讯作者：
Dhar, Shanta
影响因子：
4.3
作者：
Higgins, L. H.;Withers, H. G.;Moyes, C. D.
通讯作者：
Moyes, C. D.