The energy blocker inside the power house: Mitochondria targeted delivery of 3-bromopyruvate.
The energy blocker inside the power house: Mitochondria targeted delivery of 3-bromopyruvate.
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DOI：
10.1039/c4sc01963f
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发表时间：
2015-03
期刊：
影响因子：
8.4
通讯作者：
Dhar S
中科院分区：
文献类型：
--
作者：
Marrache S;Dhar S
线粒体递送3-溴丙酮酸用于癌细胞的代谢重编程。许多侵袭性癌症的一个关键特征是葡萄糖代谢加速。催化葡萄糖代谢第一步的酶是己糖激酶。己糖激酶2 （HK2）水平升高是在癌细胞中发现的，但只在少数正常组织中发现。利用抑制HK2的能量阻阻剂3-溴丙酮酸（3-BP）对癌细胞进行代谢重编程，有可能提供肿瘤特异性抗癌药物。然而，线粒体独特的结构和功能特征禁止选择性亚细胞靶向3-BP来调节该细胞器的功能以获得治疗效果。一种线粒体靶向金纳米粒子（T-3-BP-AuNP）被3-BP和离域亲脂性三苯基磷阳离子修饰，靶向线粒体膜电位（Δψ m），利用癌细胞中比正常细胞更高的Δψ m，将3-BP输送到癌细胞线粒体。体外研究表明，与非靶向构建体NT-3-BP-AuNP或游离3-BP相比，t -3-BP- aunp具有更强的抗癌活性。在激光照射下，T-3-BP-AuNPs的抗癌活性通过激发AuNP的表面等离子体共振带进一步增强，从而利用3-BP化疗和AuNP光热效应的结合。T-3-BP-NPs对正常间充质干细胞的毒性较低，表明这些NPs优先杀死癌细胞。T-3-BP-AuNPs显示出通过抑制糖酵解和破坏线粒体氧化磷酸化来调节癌细胞代谢的增强能力。我们的研究结果表明，利用能够靶向线粒体的单一NP，介导糖酵解抑制剂的同时释放和光热消融，协同化疗-光热治疗糖酵解癌细胞，可能有希望成为一种新的抗癌治疗方法。
Mitochondrial delivery of 3-bromopyruvate for metabolic reprogramming of cancer cells. A key hallmark of many aggressive cancers is accelerated glucose metabolism. The enzymes that catalyze the first step of glucose metabolism are hexokinases. Elevated levels of hexokinase 2 (HK2) are found in cancer cells, but only in a limited number of normal tissues. Metabolic reprogramming of cancer cells using the energy blocker 3-bromopyruvate (3-BP), which inhibits HK2, has the potential to provide tumor-specific anticancer agents. However, the unique structural and functional characteristics of mitochondria prohibit selective subcellular targeting of 3-BP to modulate the function of this organelle for therapeutic gain. A mitochondria-targeted gold nanoparticle (T-3-BP-AuNP), decorated with 3-BP and delocalized lipophilic triphenylphosphonium cations to target the mitochondrial membrane potential (Δψ m), was developed for delivery of 3-BP to cancer cell mitochondria by taking advantage of the higher Δψ m in cancer cells compared to normal cells. In vitro studies demonstrated an enhanced anticancer activity of T-3-BP-AuNPs compared to the non-targeted construct NT-3-BP-AuNP or free 3-BP. The anticancer activity of T-3-BP-AuNPs was further enhanced upon laser irradiation by exciting the surface plasmon resonance band of AuNP and thereby utilizing a combination of 3-BP chemotherapeutic and AuNP photothermal effects. The lower toxicity of T-3-BP-NPs in normal mesenchymal stem cells indicated that these NPs preferentially kill cancer cells. T-3-BP-AuNPs showed an enhanced ability to modulate cancer cell metabolism by inhibiting glycolysis as well as demolishing mitochondrial oxidative phosphorylation. Our findings demonstrate that concerted chemo-photothermal treatment of glycolytic cancer cells with a single NP capable of targeting mitochondria, mediating simultaneous release of a glycolytic inhibitor and photothermal ablation, may have promise as a new anticancer therapy.