Abstract：
Disruption of the symbiosis of extra/intratumoral metabolism is a good strategy for treating tumors that shuttle resources from the tumor microenvironment. Here, we report a precision treatment strategy for enhancing pyruvic acid and intratumoral acidosis to destroy tumoral metabolic symbiosis to eliminate tumors; this approach is based on PEGylated gold and lactate oxidase-modified aminated dendritic mesoporous silica with lonidamine and ferrous sulfide loading (PEG-Au@DMSNs/FeS/LND@LOX). In the tumor microenvironment, LOX oxidizes lactic acid to produce pyruvate, which represses tumor cell proliferation by inhibiting histone gene expression and induces ferroptosis by partial histone monoubiquitination. In acidic tumor conditions, the nanoparticles release H2S gas and Fe2+ ions, which can inhibit catalase activity to promote the Fenton reaction of Fe2+, resulting in massive ·OH production and ferroptosis via Fe3+. More interestingly, the combination of H2S and LND (a monocarboxylic acid transporter inhibitor) can cause intracellular acidosis by lactate, and protons overaccumulate in cells. Multiple intracellular acidosis is caused by lactate-pyruvate axis disorders. Moreover, H2S provides motive power to intensify the shuttling of nanoparticles in the tumor region. The findings confirm that this nanomedicine system can enable precise antitumor effects by disrupting extra/intratumoral metabolic symbiosis and inducing ferroptosis and represents a promising active drug delivery system candidate for tumor treatment.
摘要：
破坏肿瘤外/肿瘤内代谢的共生是治疗从肿瘤微环境中穿梭资源的肿瘤的良好策略。这里,我们报道了一种提高丙酮酸和肿瘤内酸中毒以破坏肿瘤代谢共生以消除肿瘤的精准治疗策略;该方法基于聚乙二醇化金和乳酸氧化酶修饰的胺化树突状介孔二氧化硅,负载有隆尼胺和硫化亚铁(PEG-Au@DMSNs/FeS/LND@LOX).在肿瘤微环境中，LOX氧化乳酸产生丙酮酸，它通过抑制组蛋白基因表达来抑制肿瘤细胞的增殖，并通过部分组蛋白单氮化来诱导铁凋亡。在酸性肿瘤条件下，纳米粒子释放H2S气体和Fe2+离子，抑制过氧化氢酶活性促进Fe2+的Fenton反应,通过Fe3+产生大量的·OH和铁中毒。更有趣的是，H2S和LND（单羧酸转运蛋白抑制剂）的组合可以通过乳酸引起细胞内酸中毒，质子在细胞中过度积累。多种细胞内酸中毒是由乳酸-丙酮酸轴紊乱引起的。此外，H2S提供动力以增强纳米颗粒在肿瘤区域中的穿梭。研究结果证实，这种纳米医疗系统可以通过破坏肿瘤外/肿瘤内代谢共生和诱导铁凋亡来实现精确的抗肿瘤作用，并代表了一种有前途的活性药物递送系统候选肿瘤治疗。
