Journal
NANO LETTERS
Volume 21, Issue 18, Pages 7862-7869Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.1c03089
Keywords
GSH-responsive; dimeric prodrug; glycolysis; immunosuppression; cancer therapy
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Funding
- National Natural Science Foundation of China [21927811, 21874086, 21775094]
- Youth Innovation Science and Technology Program of Higher Education Institution of Shandong Province [2019KJC022]
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The study synthesized a nanoprodrug that can inhibit glycolysis of cancer cells and alleviate the immunosuppressive microenvironment by releasing two drugs, which increased intracellular oxidative stress and induced immunogenic cell death of cancer cells. This strategy opens up new possibilities for exploring dimeric prodrugs for synergistic cancer therapy.
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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