GSH-Responsive Nanoprodrug to Inhibit Glycolysis and Alleviate Immunosuppression for Cancer Therapy

IF 9.1 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Letters Pub Date : 2021-09-08 DOI:10.1021/acs.nanolett.1c03089

Xiaohan Liu, Yanhua Li, Kaiye Wang, Yuanyuan Chen, Mingwan Shi, Xia Zhang, Wei Pan*, Na Li*, Bo Tang*

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引用次数: 65

Abstract

Blocking energy metabolism of cancer cells and simultaneously stimulating the immune system to perform immune attack are significant for cancer treatment. However, how to potently deliver different drugs with these functions remains a challenge. Herein, we synthesized a nanoprodrug formed by a F127-coated drug dimer to inhibit glycolysis of cancer cells and alleviate the immunosuppressive microenvironment. The dimer was delicately constructed to connect lonidamine (LND) and NLG919 by a disulfide bond which can be cleaved by excess GSH to release two drugs. LND can decrease the expression of hexokinase II and destroy mitochondria to restrain glycolysis for energy supply. NLG919 can reduce the accumulation of kynurenine and the number of regulatory T cells, thus alleviating the immunosuppressive microenvironment. Notably, the consumption of GSH by disulfide bond increased the intracellular oxidative stress and triggered immunogenic cell death of cancer cells. This strategy can offer more possibilities to explore dimeric prodrugs for synergistic cancer therapy.

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抑制糖酵解和减轻肿瘤免疫抑制的谷胱甘肽反应性纳米前药

阻断癌细胞的能量代谢，同时刺激免疫系统进行免疫攻击，对癌症治疗具有重要意义。然而，如何有效地递送具有这些功能的不同药物仍然是一个挑战。本文合成了一种由f127包被的药物二聚体形成的纳米前药，以抑制癌细胞的糖酵解，缓解免疫抑制微环境。该二聚体通过二硫键连接lonidamine (LND)和NLG919，该二硫键可被过量的谷胱甘肽裂解以释放两种药物。LND可降低己糖激酶II的表达，破坏线粒体，抑制糖酵解以供能量。NLG919可以减少犬尿氨酸的积累和调节性T细胞的数量，从而缓解免疫抑制微环境。值得注意的是，通过二硫键消耗谷胱甘肽增加了细胞内氧化应激，引发了癌细胞的免疫原性细胞死亡。这一策略为探索二聚体前药协同治疗癌症提供了更多的可能性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nano Letters 工程技术-材料科学：综合

CiteScore

16.80

自引率

2.80%

发文量

1182

审稿时长

1.4 months

期刊介绍： Nano Letters serves as a dynamic platform for promptly disseminating original results in fundamental, applied, and emerging research across all facets of nanoscience and nanotechnology. A pivotal criterion for inclusion within Nano Letters is the convergence of at least two different areas or disciplines, ensuring a rich interdisciplinary scope. The journal is dedicated to fostering exploration in diverse areas, including: - Experimental and theoretical findings on physical, chemical, and biological phenomena at the nanoscale - Synthesis, characterization, and processing of organic, inorganic, polymer, and hybrid nanomaterials through physical, chemical, and biological methodologies - Modeling and simulation of synthetic, assembly, and interaction processes - Realization of integrated nanostructures and nano-engineered devices exhibiting advanced performance - Applications of nanoscale materials in living and environmental systems Nano Letters is committed to advancing and showcasing groundbreaking research that intersects various domains, fostering innovation and collaboration in the ever-evolving field of nanoscience and nanotechnology.