BIOMATERIALS
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2020
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IF 10.317
Jiayu Zhao,Sheng Ma,Yudi Xu,Xinghui Si,Haochen Yao,Zichao Huang,Yu Zhang,Haiyang Yu,Zhaohui Tang,Wantong Song,Xuesi Chen
STING (stimulator of interferon genes) signaling pathway has attracted considerable attention in cancer immunotherapy due to its capacity to boost vigorous antitumor immunity. However, the shortage of effective STING agonists limits the promotion of STING pathway in cancer treatment. Herein, we present an approach for in situ activation of STING pathway with nanoparticles delivered DNA-targeting chemo agents, based on the understanding that cytosol DNA is a pre-requisite for STING pathway activation. Through in vitro screening among several DNA-targeting chemo agents, we identified 7-ethyl-10-hydroxycamptothecin (SN38) as the most potent drug for stimulating interferon (IFN)-β secretion and proved that this process is mediated by the passage of DNA-containing exosomes from treated tumor cells to bone marrow-derived dendritic cells (BMDCs) and subsequent activation of the STING pathway. Furthermore, we designed a polymeric-SN38 conjugate that could self-assemble into nanoparticles (SN38-NPs) for in vivo application. The SN38-NPs formulation reduced toxicity of free SN38, effectively stimulated the activation of STING pathway in E0771 tumors, and resulted in a tumor suppression rate (TSR%) of 82.6%. Our results revealed a new mechanism of SN38 in cancer treatment and should inspire using more DNA-targeting agents, especially in nanoformulation, for activating STING pathway and cancer chemoimmunotherapy.
研究领域:
癌症免疫治疗
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药学
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纳米技术
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分子生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Inorganic Chemistry Frontiers
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2019
·Vol. 6
·期 4
·1040-1049
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IF 5.934
Yi-Gang Wu,Dong-Bo Wang,Juan-Juan Hu,Xue-Qing Song,Cheng-Zhi Xie,Zhong-Ying Ma,Jing-Yuan Xu
The design, synthesis, crystal structures and in vitro biological assessment of three iron(III) complexes, namely [Fe(L1)2]Cl (1), [Fe(L2)2]·FeCl4 (2) and [Fe(L3)(HL3)2]·(FeCl4)2·(CH3OH) (3) (HL1 = N’-(4-oxothiazolidin-2-ylidene)picolinohydrazonamide, HL2 = 2-(2-(1-(pyridin-2-yl)ethylidene)hydrazono)thiazolidin-4-one, HL3 = 3-ethyl-2-(2-(1-(pyridin-2-yl)ethylidene)hydrazono)thiazolidin-4-one, are reported in this article. Single crystal X-ray diffraction revealed that all three complexes were mononuclear molecules, approaching a coordination polyhedron of octahedral geometry, in which the 4-thiazolidinone derivative ligands exhibited different coordination modes and conformations. Their interactions with DNA were investigated by UV–visible and fluorescence spectrometries, and by agarose gel electrophoresis. Results indicated that they presented efficient DNA binding propensities and cleavage activities. In vitro, the iron(III) complexes caused cell cycle arrest at the G1 phase in response to DNA damage, effectively inhibited the cyclinD1 expression and decreased the migration of HeLa cells with a lower wound-healing rate than that of the control. Complex 3 was the most sensitive to HeLa cancer cells, followed by 2 and 1. Attractively, the tested complexes demonstrated significantly enhanced selectivity index values determined for HeLa vs. LO2 normal cells compared with cisplatin, especially for complex 3, which was up to 13.94-fold. Unlike cisplatin, more complex 3 would accumulate in HeLa cancer cells compared with LO2 normal cells.
研究领域:
无机化学
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药物化学
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肿瘤学
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分子生物学
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生物化学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Zhe Li,Xiao-Meng Liu,Fei Tan,Jia-Qian Wang,Xin Qiao,Yu-Kuan Feng,Jing-Yuan Xu,Ji-Hui Hao
Convincing evidence revealed that some platinum-based drugs could stimulate immunological recognition, thereby inducing immunogenic cell death (ICD). Indoleamine-2,3-dioxygenase (IDO) is overexpressed in tumors, which caused exhaustion of tryptophan (T-cell energy) and constructed an immunosuppressive tumor microenvironment. Herein, considering IDO inhibition to improve chemotherapy, a series of IDOi-Pt(IV) prodrugs were designed to not only target DNA and IDO but also facilitate tumor-antigen exposure and immunomodulation. The optimal IDOi-Pt(IV) prodrugs (named compound 10) significantly enhanced intracellular accumulation 22.4-fold and cytotoxicity 61.75-fold superior to cisplatin in HeLa cells. Moreover, immunofluorescence and enzyme-linked immunosorbent assays revealed that 10 induced reactive oxygen species-mediated endoplasmic reticulum stress and secretion of damage-associated molecular patterns, thereby presenting ICD effects. Molecular docking, enzyme inhibition, and Western blot assays demonstrated that 10 could effectively inhibit IDO1 and reverse immunosuppression, as further verified by mixed leukocyte reactions. In vivo tests showed that 10 exhibited high-efficiency and low-toxicity antitumor effects compared to cisplatin, presenting successful chemoimmunotherapy.
研究领域:
肿瘤学
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免疫学
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药理学
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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