Nanoscale
·
2025
·
IF 5.1
Wentao Lei,Yinghui Wang,Tangyue Zheng,Qihang Wu,Hui Wen,Tingting Sun,Jun Liu,Zhigang Xie
It remains a clinical challenge to treat triple-negative breast cancer due to its aggressiveness and metastasis. Photothermal therapy (PTT) in combination with checkpoint blockade immunotherapy offers a promising strategy for such intractable tumors. In this study, a second near-infrared (NIR-II) photothermal agent (PCD NPs) and a tumor microenvironment-activatable nanoprodrug (NLG NPs) for indoleamine 2,3-dioxygenase 1 (IDO-1) blockade have been designed for the therapy of orthotopic triple-negative breast cancer. The NIR-II absorption of PCD NPs can guarantee the high penetration depth of the laser during PTT. At the same time, NLG NPs can be decomposed into the NLG919 monomer in the tumor microenvironment, which can effectively strengthen the immunogenic cell death-induced immune response. NIR-II PTT in synergy with IDO-1 blockade can effectively inhibit tumor growth and prevent tumor recurrence and metastasis. This work thus provides a safe, efficient and feasible method for the treatment of malignant tumors.
研究领域:
肿瘤学
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生物医学工程
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免疫学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2019
·
IF 2.431
Ning Wang,Jie Zhang,Qiao Li,Hui Xu,Geng Chen,Zhiyong Li,Difa Liu,Xin Yang
Indoleamine 2,3-dioxygenase (IDO) is one of the important targets for cancer immunotherapy through tryptophan pathway. Recently it has being paid great attention to search potent and safe IDO inhibitor from small-molecule compounds. Picrasma quassioides is a kind of medicinal plant abundant with tryptophan-derived indole alkaloids . By virtual screening and kinetic method for enzymatic analysis, lead compounds with potential IDO inhibitory activity were discovered for the first time from PQAs, the natural alkaloids in Picrasma quassioides . The results based on molecular docking analysis and structure-activity relationship (SAR) study demonstrated that coordinating with ferrous ion on the active site of IDO has a great impact on the inhibition potency, and β -carboline with carboxyl substituted on C-1 is the key pharmacophore for IDO inhibition of PQAs. Enzymatic assay provided further evidence for the effectiveness of β -carboline-1-carboxylic acid, which displayed as the most potent competitive inhibitor of IDO among these PQAs, and is even more potent than the recognized positive control 1-methyl tryptophan. This natural tryptophan-derived alkaloid thus deserved further deep research as a promising IDO modulator for cancer immunotherapy.
研究领域:
药理学
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肿瘤学
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植物化学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2021
·
IF 13.273
Kaipei Luo,Yunfei Lian,Min Zhang,Hua Yu,Guangji Wang,Juan Li
Immunotherapy is demonstrating great potential for cancer therapy nowadays. However, its therapeutic efficacy has been impeded by the natural biological barriers, poor immunogenicity, and highly immunosuppressive tumor microenvironment (ITM). In this study, a charge convertible biomimetic micellar nanoparticle co-encapsulated with chemotherapeutic drug paclitaxel (PTX) and indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 is developed for combined chemoimmunotherapy. The resulting nanoparticle presents prolonged blood circulation as well as specific uptake in both B16F10 melanoma cells and M2-type tumor-associated macrophages (TAM2) via folate receptor-mediated endocytosis. Moreover, rapid drug release could be elegantly triggered by the charge conversion from negative to positive in response to the acidic environment in the lysosomes. PTX can lead to immunogenic cell death to provoke antitumor immunogenicity and intratumoral infiltration of effector T cells, while the ITM is reversed by simultaneous NLG919-mediated IDO inhibition and PTX-induced TAM2 elimination. Such a biomimetic nanomedicine efficiently boosts the synergistic antitumor treatment and minimizes systemic side effects in a mouse melanoma model. Hence, this strategy demonstrates high drug delivery efficiency and provides a potential application for the combined chemoimmunotherapy of melanoma.
研究领域:
癌症治疗
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纳米技术
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药学
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免疫学
✓ 已验证
DOI
高影响因子
ACS Nano
·
2024
·
IF 15.8
Jingnan Li,Chengyan Luo,Tingyu Sun,Yinglin Zhou,Xinchang Huang,Dezhou Wu,Xirui Luo,Chao Zeng,Huanan Li
As a noninvasive treatment modality, high-intensity focused ultrasound (HIFU)-induced antitumor immune responses play a vital role in surgery prognosis. However, limited response intensity largely hinders postoperative immunotherapy. Herein, a hypoxia-specific metal–organic framework (MOF) nanosystem, coordinated by Fe3+, hypoxic-activated prodrug AQ4N, and IDO-1 signaling pathway inhibitor NLG919, is developed for the potentiating immunotherapy of HIFU surgery. The loaded AQ4N enhances the photoacoustic imaging effects to achieve accurate intraoperative navigation. Within the HIFU-established severe hypoxic environment, AQ4N is activated sequentially, following which it cooperates with Fe3+ to effectively provoke immunogenic cell death. In addition, potent NLG919 suppresses IDO-1 activity and degrades the immunosuppressive tumor microenvironment aggravated by postoperative hypoxia. In vivo studies demonstrate that the MOF-mediated immunotherapy greatly inhibits the growth of primary/distant tumors and eliminates lung metastasis. This work establishes a robust delivery platform to improve immunotherapy and the overall prognosis of HIFU surgery with high specificity and potency.
研究领域:
肿瘤学
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生物医学工程
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诊疗学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioanalysis
·
2023
·Vol. 15
·期 6
·
IF 1.8
Juan Li,Yongjing Cao,Xiaojie Zhang,Min An,Juntao Zhang,Yanhua Liu
Background: Indocyanine2,3-dioxygenase (IDO) is an enzyme that can catalyze the metabolism of tryptophan (Trp) into kynurenine (Kyn), thus inhibiting the tumor immune microenvironment. Method: Based on its inhibitor, NLG919 (NLG), the authors developed a new immunomodulatory polymer micelle and established and verified an ultrahigh performance liquid chromatography–mass spectrometry method for the simultaneous determination of NLG, Trp and Kyn in mouse tumors through the ratio determination of Trp/Kyn tissue distribution and pharmacokinetics. The linear range of the method was 0.001–10 μg/ml. Results: Compared with NLG solution, the immunomodulatory polymeric drug-loaded micelles based on polystyrene-arginine showed higher Trp/Kyn ratio, more tumor aggregation and good pharmacokinetics. Conclusion: This method has been successfully applied to the simultaneous determination of Trp/Kyn and NLG in tumor tissues of mice.
研究领域:
药理学
·
肿瘤学
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分析化学
·
生物技术
✓ 已验证
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2024
·
IF 9.3
Kai Wang,Shufen Zhang,Yunxia Wang,Xiaomei Wu,Lijuan Wen,Tingting Meng,Xiangyu Jin,Sufen Li,Yiling Hong,Jia Ke,Yichong Xu,Hong Yuan,Fuqiang Hu
Background and purpose Neurodevelopmental disorders (NDDs) are characterized by abnormalities in brain development and neurobehaviors, including autism. The maternal–fetal interface (MFI) is a highly specialized tissue through which maternal factors affect fetal brain development. However, limited research exists on restoring and maintaining MFI homeostasis and its potential impact on NDDs. This study explores the role of placental indoleamine 2,3-dioxygenase (IDO-1) in MFI homeostasis and fetal brain development. Experimental Approach The maternal-fetal barrier was disrupted by sodium valproate (VPA) in pregnant mice, whose offspring show typical autism-like behaviors. Ultrastructural analysis and flow cytometric analysis were conducted to observe the morphological and immune system changes. Behavioral tests and immunofluorescence staining was used to investigate the ability and mechanism of taprenepag to alleviate the abnormal behaviors of VPA-exposed offspring and normalize the development of serotonergic neurons. Key results In VPA-exposed pregnant mice, the downregulation of IDO-1 led to maternal immune overactivation and disruption of maternal-fetal barrier, resulting in excessive 5-HT synthesis in the placenta. This process disrupted the development of the serotonergic neuronal system in the offspring, resulting in impaired development of serotonergic neurons, thalamocortical axons, and NDDs in the progeny. However, a single injection of taprenepag at E13.5 ultimately upregulated placental IDO-1 through amplifying the positive feedback loop COX-2/PGE 2 /PTGER-2/IDO-1 and abolished these alterations. Conclusion Taprenepag improved autism-like behaviors in the offspring of VPA-exposed mice by addressing placental IDO-1 downregulation. This study highlights the potential of targeting IDO-1 to mitigate MFI disruption and NDD development. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-024-03300-7.
研究领域:
神经科学
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免疫学
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发育生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2022
·Vol. 10
·期 5
·1292-1303
·
IF 7.59
Zian Wang,Xuan Wang,Hua Yu,Meiwan Chen
Camptothecin (CPT) is a potent broad-spectrum antitumor agent with efficient therapeutic effect for various cancers. However, its application in glioma therapy has been impeded by the tumor immunosuppressive environment and blood–brain barrier (BBB)-associated drug delivery challenges. Herein, neurotransmitter analogs-modified liposomes (NTs-LIP) were prepared by doping lipidized tryptamine (Tryp) to co-deliver CPT and curcumin (CUR) for improved chemo-immunotherapy in glioma. The introduction of Tryp promotes the delivery efficiency of CPT and CUR across the BBB. CPT inhibits cell proliferation after cellular uptake of NTs-LIP, the combination of which with CUR downregulates the elevated expression of the programmed cell death 1 ligand 1 (PD-L1) caused by CPT to prevent the inactivation of T-cells and synergistically enhance chemo-immunotherapy efficacy. Furthermore, both Tryp and CUR interfere with the indoleamine 2,3-dioxygenase (IDO) pathway to reduce regulatory T cell (Treg)-mediated immunosuppression, exhibiting the potential to combine with PD-L1 inhibition for synergistic antitumor immunity. Taken together, this platform contributes towards targeted delivery and alleviation of the immunosuppressive environment in glioma therapy.
研究领域:
药理学
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神经科学
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肿瘤学
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纳米技术
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免疫疗法
✓ 已验证
DOI
PubMed
高影响因子
Nanoscale Horizons
·
2020
·Vol. 6
·期 2
·120-131
·
IF 9.927
Yaxin Zhou,Xiaomeng Ren,Zhaosheng Hou,Ningning Wang,Yue Jiang,Yuxia Luan
Photosensitizer-based photodynamic therapy (PDT) can not only kill tumor cells by the generated cytotoxic reactive oxygen species (ROS), but also trigger immunogenic cell death (ICD) and activate an immune response for immunotherapy. However, such photodynamic immunotherapy suffers from major obstacles in the tumor microenvironment. The hypoxic microenvironment greatly weakens PDT, while the immunosuppressive tumor microenvironment caused by aberrant tumor blood vessels and indoleamine 2,3-dioxygenase (IDO) leads to a significant reduction in immunotherapy. To overcome these obstacles, herein, an engineered photosensitizer nanoplatform is designed for amplified photodynamic immunotherapy by integrating chlorin e6 (Ce6, a photosensitizer), axitinib (AXT, a tyrosine kinase inhibitor) and dextro-1-methyl tryptophan (1MT, an IDO inhibitor). In our nanoplatform, AXT improves the tumor microenvironment by normalizing tumor blood vessels, which not only promotes PDT by reducing the level of hypoxia of the tumor microenvironment, but also promotes immunotherapy through facilitating infiltration of immune effector cells into the tumor and reversing the immunosuppressive effect of vascular endothelial growth factor (VEGF). Moreover, 1MT effectively inhibits the activity of IDO, further reducing the immunosuppressive nature of the tumor microenvironment. Therefore, this nanoplatform demonstrates an amplified photodynamic immunotherapy via tumor microenvironment modulation, exhibiting outstanding therapeutic efficacy against tumor growth and metastasis with negligible side toxicity. The current concept of engineering photosensitizer nanoplatforms for overcoming photodynamic immunotherapy obstacles provides a promising strategy against tumors.
研究领域:
肿瘤学
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免疫学
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纳米医学
·
癌症治疗
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2018
·Vol. 41
·期 8
·1243-1250
·
IF 1.694
Yunpeng Qi,Renping Wang,Liang Zhao,Lei Lv,Fan Zhou,Tian Zhang,Feng Lu,Hongli Yan,Gengli Duan
Celastrol is well known for its anti-cancer effects, yet its specific mechanisms against colon cancer are still not fully elucidated. In this study, cytotoxic effect of celastrol against HCT116 colon cancer cells was investigated based on cell viability assay and flow cytometry assay, and the possible mechanism was explored using a strategy combining metabolic profiling and targeted metabolite analysis based on ultra performance liquid chromatography (UPLC)/MS. Celastrol was found to inhibit the growth of colon cancer cells and induce apoptosis. Metabolomics analysis revealed characteristic changes in metabolic profiles of the colon cancer cells, revealing altered levels of amino acids, carnitine, and lipid markers. Most interestingly, with the assistance of targeted metabolite analysis, tryptophan (Trp) level was significantly increased whereas kynurenine (Kyn) level was decreased in colon cancer cells after celastrol treatment, together with markedly declined Kyn/Trp ratios. Western blot analysis revealed that expression of indoleamine 2,3-dioxygenase (IDO), the enzyme catalyzing Trp to generate Kyn, was dramatically inhibited in colon cancer cells after celastrol treatment, with a dose-dependent manner. These results suggest that suppression of IDO expression and tryptophan catabolism may be part of the mechanisms of celastrol in its cytotoxic effect against HCT116 colon cancer cells. This study provided scientific basis for further development of celastrol on treating colon cancer.
研究领域:
肿瘤学
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药理学
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代谢组学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-18
·
IF 10.6
Zou Ting,Huang Yun,Zhou Zongtao,He Shuangyan,Liu Jia,Chen Yalan,Liu Hongdu,Luo Zhonghui,Liu Miaoxin,Wei Hua,Yu CuiYun
Clinical treatment of hepatocellular carcinoma (HCC) with 5-fluorouracil (5-FU), the primary anticancer agent, remains unsatisfactory due to the glutathione (GSH)-associated drug resistance and immunosuppressive microenvironment of HCC. To develop a facile yet robust strategy to overcome 5-FU resistance for enhanced immunotherapy treatment of HCC via all dimensional GSH exhaustion, we report in this study construction of a minimalist prodrug consisting of 5-FU linked to an indoleamine-(2,3)-dioxygenase (IDO) inhibitor (IND) via a disulfide bridge, FU-SS-IND that can further self-assemble into stabilized nanoparticles, FU-SS-IND NPs. Specifically, besides the disulfide linker-induced GSH exhaustion, IND inhibits GSH biosynthesis and enhances the effector function of T cells for turning a “cold” tumor to a “hot” one, which synergistically achieving a tumor inhibition rate (TIR) of 92.5% in a 5-FU resistant mice model. Most importantly, FU-SS-IND NPs could upregulate programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, which enables facile combination with immune checkpoint blockade (ICB) for a ultimate prolonged survival lifetime of 5-FU-resistant tumors-bearing mice. Overall, the minimalist bioreducible nano-prodrug developed herein demonstrates great translatable potential for efficiently reversing drug resistance and enhancing immunotherapy of HCC.
研究领域:
肿瘤学
·
药理学
·
免疫疗法
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Endocrinology
·
2024
·
IF 3.9
Chen Si-Ting,Ran Feng,Shi Wen-Wen,Liu Cheng-Kan,Wang Peng-Chao,Luo Hui-Na,Yang Zeng-Ming
Nutritional deficiency occurs frequently during pregnancy and breastfeeding. Tryptophan (Trp), an essential amino acid which is critical for protein synthesis, serves as the precursor for serotonin, melatonin, and kynurenine (Kyn). The imbalance between serotonin and kynurenine pathways in Trp metabolism is closely related to inflammation and depression. This study assessed the effects of Trp deficiency on mouse early pregnancy. Embryo implantation and decidualization were analysed after female mice had been fed diets containing 0.2% Trp (for the control group), 0.062% Trp (for the low Trp group) and 0% Trp (for the Trp-free group) for two months. The uteri of the mice were collected on days 4, 5, and 8 of pregnancy. On day 8 of pregnancy, the number of implantation sites were found to be similar between the control and the low Trp groups. However, no implantation sites were detected in the Trp-free group. On day 5 of pregnancy, plane polarity- and decidualization-related molecules showed abnormal expression pattern in the Trp-free group. On day 4 of pregnancy, there was no significant difference in uterine receptivity molecules between the low-Trp group and the control group, but uterine receptivity was abnormal in the Trp-free group. At implantation sites of the Trp-free group, IDO and AHR levels were markedly elevated. This potentially increased levels of Kyn, 2-hydroxy estradiol, and 4-hydroxy estradiol to affect decidualization. Hence, Trp-free diet may impair decidualization via the IDO-KYN-AHR pathway.
研究领域:
营养学
·
生殖生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Deteng Zhang,Jinxiao Song,Zhenghui Jing,Huan Qin,You Wu,Jingyi Zhou,Xinlong Zang
Background Hepatocellular carcinoma (HCC) is a serious global health concern, accounting for about 90% of all liver cancer instances. Surgical treatment is a fundamental aspect of HCC management; however, the challenge of postoperative recurrence significantly impacts mortality rates.Methods We have developed a pH and reactive oxygen species (ROS) dual stimulus-responsive drug delivery system (PN@GPB-PEG NPs) loaded with chemotherapeutic paclitaxel (PTX) and indoleamine 2.3-dioxygenase (IDO) inhibitor NLG919, for HCC chemoimmunotherapy. The physiochemical properties, such as particle size, zeta potential, morphology, and encapsulation efficiency, were characterized. Furthermore, we investigated in vitro cytotoxicity, cellular uptake and immunogenic cell death in tumor cells treated with our nanoparticles. In vivo biodistribution, antitumor effects and immune responses were assessed in an HCC mice model.Results PN@GPB-PEG NPs display pH-responsive properties with improved targeting abilities toward tumors and improved uptake by HCC cells. Upon exposure to oxygen peroxide (H2O2), the sophisticated design allows for rapid release of therapeutic agents. In this process, PTX induces immunogenic cell death (ICD), which activates the immune system to generate an antitumor response. Simultaneously, NLG919 works to inhibit IDO, mitigating the immunosuppressive environment. This combination strategy leverages the advantages of both chemotherapy and immunotherapy, resulting in a powerful synergistic antitumor effect. In a mouse model of HCC, our nanoparticles effectively inhibited the growth of primary and recurrent tumors.Conclusion These encouraging results highlight the potential of our nanocarrier system as an innovative therapeutic approach to address HCC primary tumor and postsurgical recurrence, providing hope for enhanced patient outcomes.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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