<br>酸响应纳米反应器破坏了中毒酸中毒和饥饿协同治疗的“瓦尔堡效应”,Small

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酸响应纳米反应器破坏了中毒酸中毒和饥饿协同治疗的“瓦尔堡效应”
Small ( IF 13.0 ) Pub Date : 2023-07-20 , DOI: 10.1002/smll.202304058
Jiawei Zhu ₁ , Hao Cai ₁ , Chengshuang Xu ₁ , Wenjun Wang ₂ , Xuejiao Song ₁ , Buhong Li ₃ , Yi Shen ₃ , Xiaochen Dong _{1,

4}

Affiliation

“瓦伯格效应”表明，大多数肿瘤细胞依赖有氧糖酵解来供能，导致恶性能量剥夺，形成“内碱外酸”的肿瘤微环境。破坏“瓦尔堡效应”是抑制肿瘤进展的有效途径。在此，制备了一种酸响应纳米反应器（Au@CaP-Flu@HA），用于中毒性酸中毒和饥饿的协同治疗。在纳米反应器中，氟伐他汀（Flu）可以通过抑制乳酸-质子转运蛋白（单羧酸转运蛋白，MCT4）来减少乳酸外流，导致细胞内乳酸积累。同时，模拟葡萄糖氧化酶的金纳米复合材料消耗葡萄糖诱导细胞饥饿，同时产生葡萄糖酸，与乳酸结合加剧中毒性酸中毒。此外，在能量剥夺和缺氧加剧的情况下，肿瘤细胞上调的自噬能量供应被自噬抑制剂CaP阻断。 pHi 酸化下的细胞功能障碍和饥饿下三磷酸腺苷 (ATP) 合成受损可协同促进肿瘤细胞凋亡。体外和体内研究均表明，这种中毒性酸中毒/饥饿治疗的组合方法可以有效破坏“瓦尔堡效应”，从而抑制肿瘤生长和抗转移作用。

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Acidity-Responsive Nanoreactors Destructed “Warburg Effect” for Toxic-Acidosis and Starvation Synergistic Therapy

“Warburg Effect” shows that most tumor cells rely on aerobic glycolysis for energy supply, leading to malignant energy deprivation and an “internal alkaline external acid” tumor microenvironment. Destructing the “Warburg Effect” is an effective approach to inhibit tumor progression. Herein, an acidity-responsive nanoreactor (Au@CaP-Flu@HA) is fabricated for toxic acidosis and starvation synergistic therapy. In the nanoreactor, the fluvastatin (Flu) could reduce lactate efflux by inhibiting the lactate-proton transporter (monocarboxylate transporters, MCT4), resulting in intracellular lactate accumulation. Meanwhile, the glucose oxidase-mimic Au-nanocomposite consumes glucose to induce cell starvation accompanied by gluconic acid production, coupling with lactate to exacerbate toxic acidosis. Also, the up-regulated autophagic energy supply of tumor cells under energy deprivation and hypoxia aggravation is blocked by autophagy inhibitor CaP. Cellular dysfunction under pHi acidification and impaired Adenosine Triphosphate (ATP) synthesis under starvation synergistically promote tumor cell apoptosis. Both in vitro and in vivo studies demonstrate that this combinational approach of toxic-acidosis/starvation therapy could effectively destruct the “Warburg Effect” to inhibit tumor growth and anti-metastatic effects.

更新日期：2023-07-20

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