College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
Nano Lett. 2021 Sep 22;21(18):7862-7869. doi: 10.1021/acs.nanolett.1c03089. Epub 2021 Sep 8.
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.
阻断癌细胞的能量代谢并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，如何有效地输送具有这些功能的不同药物仍然是一个挑战。在这里，我们合成了一种由 F127 包裹的药物二聚体形成的纳米药物，以抑制癌细胞的糖酵解并减轻免疫抑制微环境。该二聚体通过二硫键将 lonidamine（LND）和 NLG919 连接起来，二硫键可以被过量的 GSH 切割，从而释放两种药物。LND 可以降低己糖激酶 II 的表达并破坏线粒体，从而抑制糖酵解以提供能量。NLG919 可以减少犬尿氨酸的积累和调节性 T 细胞的数量，从而减轻免疫抑制微环境。值得注意的是，二硫键消耗 GSH 会增加细胞内氧化应激并引发癌细胞的免疫原性细胞死亡。这种策略为探索用于协同癌症治疗的二聚体前药提供了更多可能性。
