INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Haiying Xu,Zhongping Su,Hui Zhang,Ying Zhang,Yujun Bao,Huanli Zhang,Xiaodan Wu,Rui Yan,Zhiqiang Wang,Yingxue Jin
Photodynamic therapy (PDT) and chemodynamic therapy (CDT) can activate immunogenicity, so PDT and CDT combined immunotherapy is a promising treatment strategy. However, insufficient hydrogen peroxide activity, hypoxia, and overexpressed glutathione in the tumor microenvironment (TME) significantly impaired the ability to activate immunogenicity. Thus, in this paper, self-reinforcing conjugates Cu 2+ -Pyropheophorbide-a-Cysteine (CuPPaCC), combined synergetic NIR and pH triggered PDT/CDT with glutathione depletion ability was constructed. CuPPaCC was encapsulated in mesoporous silica, and spherical HSCuPPaCC nanoparticles were prepared by Hyaluronic acid (HA) on the silica surface by Schiff base modification. HSCuPPaCC has tumor-specific targeting via HA mediated. In acidic solution, the Schiff base of HSCuPPaCC is destroyed and CuPPaCC is released (>70%), with excellent pH response release function. The results of the MTT analysis showed that the PDT/CDT synergistic anti-tumor effect was significant. HSCuPPaCC was activated in TME, catalyzing the decomposition of hydrogen peroxide to generate hydroxyl radicals and oxygen, alleviating TME hypoxia, replenishing oxygen to PDT, and significantly down regulating hypoxia factor HIF-1α expression. HSCuPPaCC has an excellent dual ROS mechanism and a dual depleting GSH mechanism resulting in a surge in intracellular ROS levels to efficiently kill cancer cells, enhance the ability to induce immunogenicity, and make tumors more sensitive to checkpoint PD-L1 blockade therapy. With the CT26 mouse model, not only the primary tumor was eradicated, but also the distal tumor at the end of treatment was completely suppressed by HSCuPPaCC combined with anti-PD-L1 immune checkpoint blockade therapy.
研究领域:
纳米技术
·
癌症治疗
·
生物医学工程
·
药学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHINESE JOURNAL OF CHEMISTRY
·
2024
·
IF 5.5
Junfeng Ding,Tianran Wang,Yan Rong,Chaoliang He,Xuesi Chen
Comprehensive Summary Due to the immunosuppressive tumor microenvironment (TME), T cells are usually inactivated and tend to differentiate into regulatory T cells (Tregs) in the tumor tissues, which seriously hinders the anti-tumor efficiency of immunotherapy. In this study, an immune-stimulating polypeptide hydrogel conjugated with an indoleamine-2,3-dioxygenase (IDO) inhibitor, 1-methyl- D -tryptophan (D1MT), through a glutathione (GSH)-responsive spacer was developed as an immunotherapy platform capable of regulating the TME. A combined immunotherapy system was further constructed through encapsulating doxorubicin (Dox) and immune checkpoint blocking antibody targeting programmed cell death protein 1 (aPD-1) in the hydrogel. Dox released from the hydrogel could cause the immunogenic cell death (ICD) of tumor cells and induce the maturation of antigen presenting cells (APCs). After intratumoral injection, the multiple agent-loaded hydrogel elicited effective anti-tumor immunity in mice bearing B16F10 melanoma. Moreover, compared with the control hydrogel without D1MT, the immune-stimulating hydrogel showed better efficiency in improving the immunosuppressive TME with increased number of activated T cells and reduced number of Tregs. Therefore, the immune-stimulating hydrogel has great potential as a stimuli-responsive platform for regulating suppressive TME and enhanced anti-tumor chemo-immunotherapy.
研究领域:
癌症免疫疗法
·
药学
·
生物医学工程
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
Nanomaterials
·
2019
·Vol. 9
·期 1
·91
·
IF 4.034
Chuan Zhang,Yuzhuo Wang,Yue Zhao,Hou Liu,Yueqi Zhao,Xiangwei Li,Quan Lin
The chemotherapy of stimuli-responsive drug delivery systems (SDDSs) is a promising method to enhance cancer treatment effects. However, the low efficiency of chemotherapy drugs and poor degradation partly limit the application of SDDSs. Herein, we report doxorubicin (DOX)-loading mixed micelles for biotin-targeting drug delivery and enhanced photothermal/photodynamic therapy (PTT/PDT). Glutathione (GSH)-responsive mixed micelles were prepared by a dialysis method, proportionally mixing polycaprolactone-disulfide bond-biodegradable photoluminescent polymer (PCL-SS-BPLP) and biotin-polyethylene glycol-cypate (biotin-PEG-cypate). Chemically linking cypate into the mixed micelles greatly improved cypate solubility and PTT/PDT effect. The micelles also exhibited good monodispersity and stability in cell medium (~119.7 nm), low critical micelles concentration, good biodegradation, and photodecomposition. The high concentration of GSH in cancer cells and near-infrared light (NIR)-mediated cypate decomposition were able to achieve DOX centralized release. Meanwhile, the DOX-based chemotherapy combined with cypate-based NIR-triggered hyperthermia and reactive oxygen species could synergistically induce HepG2 cell death and apoptosis. The in vivo experiments confirmed that the micelles generated hyperthermia and achieved a desirable therapeutic effect. Therefore, the designed biodegradable micelles are promising safe nanovehicles for antitumor drug delivery and chemo/PTT/PDT combination therapy.Keywords:photothermal therapy;photodynamic therapy;biodegradable;stimuli-responsive drug delivery systems;cypate
研究领域:
癌症治疗
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药物递送系统
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生物医学工程
·
高分子化学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2026
·
IF 3.1
Hong Tang,Qing Rao,Ting Liu,Zixia Hu,Zhanhui Feng,Yu Chen,Yan He,Dongbing Cui,Ximei Li,Qing Zhang,Ying Peng,Weiwei Li,Jiang Zheng
Cantharidin (CTD) possesses potent anticancer activity, whereas its prominent hepatotoxicity severely limits its clinical application. Because the detailed molecular mechanisms responsible for CTD-triggered hepatotoxicity have not been fully elucidated, additional investigations are necessary to uncover its toxicological pathways. This study investigated the mechanism of CTD-triggered hepatotoxicity and the protective effects of exogenous glutathione (GSH) supplementation. In vitro results showed that CTD reduced the GSH/glutathione disulfide (GSSG) ratio and the activities of catalase (CAT) and glutathione peroxidase (GPX) in hepatocytes, induced a compensatory upregulation of superoxide dismutase (SOD), and promoted malondialdehyde (MDA) accumulation. Additionally, CTD downregulated glutamate-cysteine ligase modifier subunit (GCLM) expression, decreased mitochondrial membrane potential (MMP), suppressed B-cell lymphoma 2 (Bcl-2) expression, and upregulated Bcl-2-associated X protein (Bax), cysteine-dependent aspartate-directed protease (caspase-9), downstream caspase-3, and cytochrome c (Cyt c) levels, thereby triggering hepatocyte apoptosis, with no significant changes in cellular cysteine (Cys) content and glutamate-cysteine ligase catalytic subunit (GCLC) expression. In vivo experiments verified that CTD markedly decreased hepatic GSH and Cys levels and downregulated GCLC expression, whereas GCLM expression and hepatic Cyt c levels showed only a slight upward trend without statistical significance. Glutathione ethyl ester (GSH-OEt) pretreatment in vitro and GSH intervention in vivo effectively prevented CTD-caused oxidative damage. Collectively, CTD induces divergent expression patterns of glutamate-cysteine ligase (GCL) subunits in vitro and in vivo, disrupts GSH metabolic homeostasis, and provokes oxidative stress and mitochondrial dysfunction, ultimately leading to hepatocellular injury.
✓ 已验证
产品关联
DOI
高影响因子
ANALYST
·
2023
·
IF 4.2
Jia Chen,Shengrong Yu,Zhiling Qian,Kangdi He,Bingqian Li,Yuting Cao,Keqi Tang,Shengjia Yu,Yong-Xiang Wu
Rapid, simultaneous, and sensitive detection of biomolecules has important application prospects in disease diagnosis and biomedical research. However, because the content of intracellular endogenous target biomolecules is usually very low, traditional detection methods can't be used for effective detection and imaging, and to enhance the detection sensitivity, signal amplification strategies are frequently required. The hybridization chain reaction (HCR) has been used to detect many disease biomarkers because of its simple operation, good reproducibility, and no enzyme involvement. Although HCR signal amplification methods have been employed to detect and image intracellular biomolecules, there are still false positive signals. Therefore, a target-triggered enzyme-free amplification system (GHCR system) was developed, as a fluorescent AND-gated sensing platform for intracellular target probing. The false positive signals can be well avoided and the accuracy of detection and imaging can be improved by using the design of the AND gate. Two cancer markers, GSH and miR-1246, were used as two orthogonal inputs for the AND gated probe. The AND-gated probe only works when GSH and miR-1246 are the inputs at the same time, and FRET signals can be the output. In addition to the use of AND-gated imaging, FRET-based high-precision ratiometric fluorescence imaging was employed. FRET-based ratiometric fluorescent probes have a higher ability to resist interference from the intracellular environment, they can avoid false positive signals well, and they are expected to have good specificity. Due to the advantages of HCR, AND-gated, and FRET fluorescent probes, the GHCR system exhibited highly efficient AND-gated FRET bioimaging for intracellular endogenous miRNAs with a lower detection limit of 18 pM, which benefits the applications of ratiometric intracellular biosensing and bioimaging and offers a novel concept for advancing the diagnosis and therapeutic strategies in the field of cancer.
研究领域:
生物化学
·
分子生物学
·
医学诊断
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2019
·Vol. 30
·期 4
·1907954
·
IF 15.621
Xiaoyan Zhong,Xianwen Wang,Liang Cheng,Yong'an Tang,Guiting Zhan,Fei Gong,Rui Zhang,Jun Hu,Zhuang Liu,Xiangliang Yang
The ultrahigh concentration of glutathione (GSH) inside tumors destroys reactive oxygen species (ROS)-based therapy, improving the outcome of chemodynamic therapy (CDT)-enhanced sonodynamic therapy (SDT) by depleting GSH is full of great challenge. Herein, PtCu 3 nanocages are first reported as acting as a sonosensitizer with highly efficient ROS generation under ultrasound irradiation. In addition, PtCu 3 nanocages can act as horseradish peroxidase-like nanozymes, catalyzing the decomposition of H 2 O 2 into • OH under acidic conditions for CDT. Surprisingly, PtCu 3 nanocages can act as another kind of nanozyme, mimicking glutathione peroxidase (GSH-Px), which plays an important role in accelerating GSH depletion by oxidizing molecules, further weakening the capacity of tumor cells scavenging ROS by GSH. Both in vitro and in vivo studies demonstrate that PtCu 3 nanocages perform well in reducing GSH level for CDT-enhanced SDT. Moreover, utilizing the high absorption in the near-infrared region and strong X-ray attenuation ability, the PtCu 3 nanocages are able to conduct photoacoustic/computed tomography dual-modal imaging-guided combined cancer therapy. It is worth mentioning that PtCu 3 nanocages cause minimal toxicity to normal tissues at therapeutic doses. This work highlights the use of PtCu 3 nanocages for effective CDT-enhanced SDT via GSH depletion.
研究领域:
肿瘤学
·
纳米医学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
·
2021
·Vol. 99
·期 12
·
IF 2.273
Weimin Xu,Peng Wang,Dalong Wang,Ke Liu,Shuaishuai Zhang,Wei Zhao,Guoqing Liu
The aim of the present study was to investigate the protective effect of S-ketamine (S-KET) against carbon tetrachloride (CCl4) – induced liver damage and oxidative stress, as well as to elucidate the related underlying mechanisms. Blood was collected to measure biochemical parameters (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TB) and γ-glutamyltransferase (γ-GT)) and the liver was harvested for histopathological analysis of enzymes related to the antioxidant response (malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX)). Liver cell apoptosis was evaluated using the TUNEL assay. In addition, the expression levels of apoptosis-related proteins and the nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway were detected by Western blot analysis to explore potential mechanisms. S-KET protected the liver from CCl4-induced damage. The changes to the liver biochemical parameters (increased ALT, AST, ALP, TB, and γ-GT) and oxidative stress-related indicators (increased MDA; depleted SOD, GSH, and GSH-PX) induced by CCl4 were inhibited by S-KET. S-Ket also inhibited CCl4-induced cell apoptosis, the changes in expression of related proteins, and blocked CCl4-induced liver injury and oxidative stress via activation of the Nrf2/HO-1 signaling pathway. S-KET effectively protected the liver by inhibition of CCl4-induced damage via upregulation the Nrf2/HO-1 signaling pathway.
研究领域:
药理学
·
肝病学
·
分子生物学
·
毒理学
✓ 已验证
DOI
PubMed
高影响因子
Biosensors-Basel
·
2023
·Vol. 13
·期 8
·827
·
IF 5.4
Meixuan Liu,Chen Yan,Qianyun Ye,Xiaohuan Sun,Jie Han
Glutathione (GSH) is the most abundant low-molecular-weight biological thiol in vivo and has been linked to several diseases. The accurate quantification of GSH is therefore crucial for disease diagnosis and monitoring. In this study, we prepared self-assembled Cu(I)-Cys (cysteine) nanozymes through a two-step procedure. The Cu(I)-Cys nanoparticles exhibited peroxidase-mimicking activity. Upon the addition of H2O2, they were able to oxidize 3,3,5,5-tetramethylbenzidine (TMB) into oxTMB, resulting in a measurable increase in UV-Vis absorption at 655 nm. However, in the presence of GSH, oxTMB was reduced back to TMB, leading to a decrease in UV-Vis absorption at 655 nm. By utilizing these changes in the absorption intensity, we achieved the sensitive detection of GSH with a detection limit of 2.13 μM. Moreover, taking advantage of the different peroxidase-mimicking activities of Cu(I)-Cys nanoparticles at various pH values, a sensor array with Cu(I)-Cys nanoparticles at pH 4 and pH 5 was constructed. The discrimination of GSH among Cys and ascorbic acid was achieved and the practicability of the sensor array in human serum was validated. This novel approach holds significant promise for the precise discrimination and quantification of GSH and its potential applications in disease diagnosis and therapeutics.Keywords:nanozyme;GSH quantification;GSH discrimination
研究领域:
生物化学
·
分析化学
·
纳米技术
·
诊断学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Xiaojing Zhang,Yansong Chen,Jingwei Tang,Chen Chen,Yanfeng Sun,Hao Zhang,Mengxiang Qiao,Gongsheng Jin,Xianfu Liu
Combination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavailable. Herein, we designed and synthesized a glutathione (GSH)--responsive heterotrimeric prodrug and formulated it with an amphiphilic polymer to obtain nanoparticles (DSSC2 NPs) for precise synergistic chemotherapy of TNBC. The heterotrimeric prodrug was prepared using docetaxel (DTX) and curcumin (CUR) at the optimal synergistic ratio of 1: 2. DTX and CUR were covalently conjugated by disulfide linkers. Compared with control NPs, DSSC2 NPs had quantitative/ratiometric drug loading, high drug co-loading capacity, better colloidal stability, and less premature drug leakage. After systemic administration, DSSC2 NPs selectively accumulated in tumor tissues and released the encapsulated drugs triggered by high levels of GSH in cancer cells. In vitro and in vivo experiments validated that DSSC2 NPs released DTX and CUR at the predefined ratio and had a highly synergistic therapeutic effect on tumor suppression in TNBC, which can be attributed to ratiometric drug delivery and synchronous drug activation. Altogether, the heterotrimeric prodrug delivery system developed in this study represents an effective and novel approach for combination chemotherapy.
研究领域:
肿瘤学
·
药剂学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MATERIALS & DESIGN
·
2022
·
IF 9.417
Huaming He,Fang Zhao,Wukun Zhong,Yuling Yang,Yuhong Lin,Yihang Ding,Jiajia Yang,Chunhua Lu,Xiankun Tu
Mitochondria-targeting nanoparticles have proven to be promising platforms for cancer therapy. However, precise mitochondria targeting in the complex tumor environment is still challenging and requires more ingenious design. Herein, we developed the glutathione (GSH)-responsive nanoagents to target mitochondria in tumor cells precisely for photothermal-enhanced chemodynamic therapy (CDT). The nanoagents were designed by preparing the cubic shape of CuFeS2 nanoparticles that sequentially modified with mitochondrial-targeting peptide (KLAK) and integrin-targeting peptide (RGD), which KLAK and RGD were covalently conjugated via a disulfide bond. After being endocytosed into integrin-overexpressed tumor cells, disulfide bond was broken and RGD was separated from the nanoagents in the presence of overexpressed GSH. Then, the exposure of KLAK on the surface further aid the rustling nanoagents to target mitochondria. Under NIR laser irradiation, the surrounding temperature of the nanoagents would rise due to their excellent photothermal effect, resulting in the improvement of the Fenton reaction from the CuFeS2. It was well demonstrated that this photothermal-enhanced chemodynamic therapy nanoplatform could effectively damage the mitochondrial function and further induce the apoptosis of tumor cells. As a therapeutic platform with both tumor/mitochondria-targeting and PTT-enhanced CDT, our study has provided a new path in the field of cancer therapy.
研究领域:
肿瘤学
·
纳米医学
·
生物材料学
✓ 已验证
产品关联
DOI
高影响因子
Antioxidants
·
2023
·Vol. 12
·期 11
·1917
·
IF 7
Yutan Chu,Qiongli Bao,Yan Li,Hongyu Sun,Zewei Liu,Jiahao Shi,Yizong Huang
Antimony (Sb) is a hazardous metal element that is potentially toxic and carcinogenic. Melatonin (MT) is an indole compound with antioxidant properties that plays an essential role in plant growth and alleviates heavy metal stresses. Nevertheless, little is known about the effects and mechanisms of exogenous MT action on rice under Sb stress. The aim of this experiment was to explore the mechanism of MT reducing Sb toxicity in rice via hydroponics. The results showed that Sb stress significantly inhibited the growth of rice, including biomass, root parameters, and root viability. Exogenous MT obviously alleviated the inhibition of Sb stress on seedling growth and increased biomass, root parameters, and root viability by 15–55%. MT significantly reduced the total Sb content in rice and the subcellular Sb contents in roots by nearly 20–40% and 12.3–54.2% under Sb stress, respectively. MT significantly decreased the contents of malondialdehyde (MDA, by nearly 50%), ROS (H2O2and O2·−, by nearly 20–30%), and RNS (NO and ONOO−) in roots under Sb stress, thus reducing oxidative stress and cell membrane damage. Furthermore, MT reversed Sb-induced phytotoxicity by increasing the activities of antioxidant enzymes (SOD, POD, CAT, and APX) by nearly 15% to 50% and by regulating the AsA–GSH cycle. In conclusion, this study demonstrates the potential of MT to maintain redox homeostasis and reduce Sb toxicity in rice cells, decreasing the content of Sb in rice and thereby alleviating the inhibition of Sb on rice growth. The results provided a feasible strategy for mitigating Sb toxicity in rice.Keywords:antimony (Sb);melatonin (MT);rice;antioxidant;AsA–GSH cycle
研究领域:
植物生理学
·
环境毒理学
·
农学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2013
·
IF 7.604
Wei-Hai Chen,Xiao-Ding Xu,Hui-Zhen Jia,Qi Lei,Guo-Feng Luo,Si-Xue Cheng,Ren-Xi Zhuo,Xian-Zheng Zhang
A novel strategy to construct a therapeutic system based on functionalized AuNPs which can specifically respond to tumor microenvironment was reported. In the therapeutic system, doxorubicin was conjugated to AuNPs via thiol–Au bond by using a peptide substrate, CPLGLAGG, which can be specifically cleaved by the protease. In vivo study shows that after injection of the functionalized AuNPs to the tumor-bearing mice, the over-expressed protease of MMP-2 in tumor tissue and intracellular GSH can lead to the rapid release of the anti-tumor drug (doxorubicin) from the functionalized AuNPs to inhibit tumor growth and realize fluorescently imaging simultaneously. The functionalized AuNPs with tumor-triggered drug release property can further improve the efficacy and reduce side effects significantly.
研究领域:
纳米医学
·
肿瘤学
·
生物化学
✓ 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）