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
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肿瘤学
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分析化学
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生物技术
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Qingfei Zhang,Gaizhen Kuang,Yunru Yu,Xiaoya Ding,Haozhen Ren,Weijian Sun,Yuanjin Zhao
Chemo-immunotherapy shows promising antitumor therapeutic outcomes for many primary cancers. Research in this area has been focusing on developing an ideal formula that enables the potent efficacy of chemo-immunotherapy in combating various cancers with reduced systemic toxicity. Herein, we present novel hierarchical hydrogel microparticles (MDDP) delivering oxaliplatin and NLG919 nanoprodrugs for local chemo-immunotherapy with desired features. The oxaliplatin prodrug and NLG919 were efficiently loaded in the dual-drug polymeric nanoparticles (DDP NPs), which were further encapsulated into a MDDP by using microfluidic technology. When delivered to the tumor site, the DDP NPs will be sustainedly released from the MDDP and retained locally to reduce systemic toxicity. After being endocytosed by cancer cells, the cytotoxic oxaliplatin and NLG919 could be successfully triggered to release from DDP NPs in a chain-shattering manner, leading to the immunogenic cell death (ICD) of tumor cells and the suppression of intratumoral immunosuppressive Tregs, respectively. With the assistance of an immune modulator, the chemotherapeutics-induced ICD could trigger robust systemic antitumor immune responses, presenting superior synergistic antitumor efficacies. Thus, the hierarchical microparticles could substantially inhibit the growth of mouse subcutaneous colorectal tumors, breast tumors, and colorectal tumors with large initial sizes via synergized chemo-immunotherapy, showing great potential in the practical clinical application of oncotherapy.
研究领域:
肿瘤学
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药学
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免疫学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
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
Advanced Science
·
2024
·
IF 14.3
Hangyi Wu,Xiaoyu Lu,Yuhan Hu,J. Baatarbolat,Zhihao Zhang,Yiping Liang,Youwen Zhang,Ye Liu,Huixia Lv,Xin Jin
Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and disrupt intracellular Cu homeostasis. Extra intracellular Cu induces cuproptosis and chemodynamic therapy (CDT), which further cascades immunogenic cell death (ICD) and activates antitumor immune responses. However, the tumor immunosuppressive microenvironment (TIM) attenuates the efficiency of the immune response. Herein, a biomimic nanodrug (ECNM) is fabricated, of which ES, Cu 2+ and NLG919 (an IDO1 inhibitor) are integrated via a self-assembly process and subsequently coated with 4T1 cell membrane. ECNM can overcome the typical drawbacks of ES, ameliorating the stability and half-life of ES by membrane-coating and enhancing its tumor accumulation and internalization via homotypic targeting. It is worth mentioning that, the addition of NLG919 is also beneficial to the system circulation stability of ES and reduces the non-specific ES release. After internalization, ECNM dissociates via the glutathione-responsive process and exhibits comprehensive antitumor capabilities, including cuproptosis, CDT and TIM reversing, thereby eliciting ICD and optimizing the antitumor immune response. Furthermore, ECNM not only accelerates tumor regression but also gains a strong abscopal effect and displays the potential of tumor vaccination. Overall, ECNM can activate antitumor immunity via cuproptosis and CDT, together with TIM reversing, for cancer treatment.
研究领域:
肿瘤学
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纳米医学
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免疫治疗
✓ 已验证
DOI
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
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药学
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纳米技术
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Xun Wang,Bin Yan,Hugang Li,Jianlan Yuan,Jingyi Guo,Siyao Wang,Penggao Dai,Xiaoli Liu
Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.
研究领域:
癌症生物学
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纳米技术
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免疫疗法
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分子生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Liangliang Dai,Xiang Li,Mengjiao Yao,Peiyun Niu,Xichen Yuan,Ke Li,Maowen Chen,Zengxiang Fu,Xianglong Duan,Haibin Liu,Kaiyong Cai,Hui Yang
IDO blockade-based immunotherapy has been impeded by the activation of antitumor immune response and low delivery efficiency of immunotherapeutic, resulting from natural biological barriers and immune resistance. Herein, a programmable drug delivery nanosystem with enhanced tumor penetration and endocytosis is constructed for chemotherapy-enhanced immunotherapy by loading immune checkpoint IDO inhibitor NLG919 in pH/redox cascade-responsive prodrug micelle . The nanosystem shrinked micelles sizes and converted charge from negative to positive for enhanced tumor penetration and endocytosis in responding to the weakly acidic tumor microenvironment . The endocytosed nanosystem dramatically disassembled and released curcumin and NLG919 in redox-rich cytoplasm. In vitro and in vivo studies demonstrate that the nanosystem not only effectively overcame biological barriers, but also significantly boosted antitumor immune response and reduced immune resistance. It was realized by the combined effects of chemotherapy-enhanced immunogenicity , and NLG919-induced IDO-blockade immunotherapy, consequently inhibiting tumor growth, metastasis and recurrence with high efficiency in vivo . The study offers a nanoplatform with deep tumor penetration, high cellular uptake and effective antitumor immune response for the advance of chemo-immunotherapy.
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
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2019
·
IF 8.063
Zeqian Huang,Gaofei Wei,Zishan Zeng,Yanjuan Huang,Liangfeng Huang,Yifeng Shen,Xiaoqi Sun,Congjun Xu,Chunshun Zhao
Cancer metastases is still a hurdle for good prognosis and live quality of breast cancer patients. Treatment strategies that can inhibit metastatic cancer while treating primary cancer are needed to improve the therapeutic effect of breast cancer. Methods: In this study, a dual functional drug conjugate comprised of protoporphyrin IX and NLG919, a potent indoleamine-2,3-dioxygenase (IDO) inhibitor, is designed to combine photodynamic therapy and immune checkpoint blockade to achieve both primary tumor and distant metastases inhibition. Liposomal delivery is applied to improve the biocompatibility and tumor accumulation of the drug conjugate (PpIX-NLG@Lipo). A series of in vitro and in vivo experiments were carried out to examine the PDT effect and IDO inhibition activity of PpIX-NLG@Lipo, and subsequently evaluate its anti-tumor capability in the bilateral 4T1 tumor-bearing mice. Results: The in vitro and in vivo experiments demonstrated that PpIX-NLG@Lipo possess strong ability of ROS generation to damage cancer cells directly through PDT. Meanwhile, PpIX-NLG@ Lipo can induce immunogenic cell death to elicit the host immune system. Furthermore, PpIX-NLG@Lipo interferes the activity of IDO, which can amplify PDT-induced immune responses, leading to an increasing amount of CD8 + T lymphocytes infiltrated into tumor site, finally achieve both primary and distant tumor inhibition. Conclusion: This work presents a novel conjugate approach to synergize photodynamic therapy and IDO blockade for enhanced cancer therapy through simultaneously inhibiting both primary and distant metastatic tumor.
研究领域:
肿瘤学
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药学
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免疫疗法
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2022
·Vol. 10
·期 22
·4261-4273
·
IF 7.571
Hui Guo,Fangzhe Liu,Enqi Liu,Shanshan Wei,Wenbo Sun,Baoqiang Liu,Guoying Sun,Lehui Lu
Micelles as nanocarriers not only offer new opportunities for early diagnosis and treatment of malignant cancers but also encounter numerous barriers in the path of efficient delivery of drugs to diseased areas in the body. To address these issues, we developed a pH/GSH responsive nano-prodrug micelle (NLG919/PGA–Cys–PPA@Gd) with a high drug-loading ratio and controlled drug release performance for MRI-guided tumor photodynamic therapy (PDT) and immune synergistic therapy. Under normal conditions, theranostic nanomicelles remained stable and in a photo-quenched state. Upon accumulation in the tumor site, however, the micelles demonstrated tumor microenvironment (TME) triggered photoactive formed-PPA (a photosensitizer) and NLG919 (an indoleamine 2,3-dioxygenase (IDO) inhibitor) release because the amide bonds of PGA–Cys–PPA and the disulfide linkage of Cys were sensitive to pH and GSH, respectively. More importantly, these micelles could avoid the undesired PPA leakage in blood circulation due to the conjugation between PPA and polymers. Furthermore, the obtained micelles could also enhance the contrast of T1-weighted MRI of tumors by virtue of their high relaxivity (r1 = 29.85 mM−1 s−1). In vitro and in vivo results illustrated that the micelles had good biocompatibility and biosafety. On the basis of the efficient drug delivery strategies in PDT and IDO pathway inhibition, this intelligent dual-drug delivery system could serve as an effective approach for MRI guided combination therapy of cancer.
研究领域:
纳米技术
·
癌症治疗
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磁共振成像（MRI）
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药物递送系统
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光动力疗法
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免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2021
·Vol. 10
·期 21
·2100683
·
IF 9.933
Tiantian Zuo,Tianxu Fang,Jun Zhang,Jie Yang,Rui Xu,Zhihua Wang,Huizi Deng,Qi Shen
Ferritin internalized into tumor cells is degraded and releases iron ions via ferritinophagy. Iron ions participate in Fenton reaction to produce reactive oxygen species for lipid peroxidation and ferroptosis. Inhibition of indoleamine-2,3-dioxygenase (IDO) decreases tryptophan elimination to induce T cells activation for tumor immunosuppression relief. The active tumor targeting nanoparticles containing ferritin and a pH-sensitive molecular-switch (FPBC@SN) are developed to utilize ferritinophagy-cascade ferroptosis and tumor immunity activation for cancer therapy. FPBC@SN disintegrates in acidic cytoplasm and releases sorafenib (SRF) and IDO inhibitor (NLG919). SRF upregulates nuclear receptor coactivator 4 (NCOA4) to induce ferritin and endogenous iron pool degradation by ferritinophagy, then obtained iron ions participate in the Fenton reaction to produce lipid peroxide (LPO). Meanwhile, SRF blocks glutathione synthesis to downregulate glutathione peroxidase 4 (GPX4) which can scavenge LPO as a different pathway from ferritinophagy to promote ferroptosis in tumor cells. NLG919 inhibits IDO to reduce tryptophan metabolism, so immunity in tumors is aroused to anti-tumor. In vitro and in vivo experiments prove FPBC@SN inhibits tumor cell growth and metastasis, indicating the potential of FPBC@SN for breast cancer therapy based on the combination of ferritinophagy-cascade ferroptosis and tumor immunity activation.
研究领域:
癌症生物学
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纳米技术
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药学
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免疫学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Xiaoxiao Hu,Qingqing Dou,Peixiao Jiang,Mo Zhang,Jing Wang
The dense extracellular matrix (ECM) and immunosuppressive tumor microenvironment represent two major challenges in the treatment of triple-negative breast cancer (TNBC). To address these obstacles, this study has developed a polymer micelle (NTP) for ECM remodeling and mitigation the immune microenvironment, based on activating endogenous matrix metalloproteinases (MMP) and suppression indoleamine 2,3-dioxygenase (IDO). Through self-assembly technology, this micelle effectively incorporates chemotherapy drugs (camptothecin (CPT) and cinnamaldehyde (CA)), reactive oxygen species (ROS) stimulants, nitric oxide (NO) donor and IDO inhibitor (NLG919), where CPT and CA have been reported to help generating ROS mainly in the mitochondrion. The guanidine group of poly-L-arginine (PArg), as an NO donor, can react with ROS to generate NO. The micelles aim to achieve significant therapeutic outcomes through robust drug penetration and anti-tumor immunity in multimodal therapy. They exhibit remarkable tumor tissue penetration ability, facilitating precise targeting of mitochondria and ROS production stimulation. Building upon this therapeutic foundation, the micellar system achieves in situ NO release, which effectively degrades the primary ECM through the activation of MMPs, while simultaneously promoting tumor cell apoptosis. Furthermore, the encapsulated NLG919 can be released and effectively mitigating the immunosuppressive milieu and triggering anti-tumor immune responses. Experimental results demonstrate that the micelles exhibit significant anti-tumor effects both in vitro and in vivo , accompanied by favorable biocompatibility. This study provides new insights into the application of subcellular targeting drug delivery systems in TNBC treatment, potentially heralding a new breakthrough in TNBC therapy.
研究领域:
肿瘤学
·
药剂学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）