Acta Pharmaceutica Sinica B
·
2024
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IF 14.7
Xueming Xu,Yuanfeng Han,Jiali Deng,Shengfeng Wang,Shijie Zhuo,Kai Zhao,Wenhu Zhou
Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing drugs. Recently, disulfiram (DSF), a drug primarily used for alcohol addiction treatment, has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis, a form of programmed cell death. The therapeutic activity of DSF can be further enhanced by the presence of Cu 2+ , although the underlying mechanism of this enhancement remains unclear. In this study, we investigated the mechanistic basis of Cu 2+ -induced enhancement and discovered that it is attributed to the formation of a novel copper ethylthiocarbamate (CuET) complex. CuET exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of action. However, despite its potent activity, CuET suffered from poor solubility and limited permeability, as revealed by our druggability studies. To overcome these intrinsic limitations, we developed a scalable method to prepare CuET nanocrystals (CuET NCs) using a metal coordination-driven self-assembly approach. Pharmacokinetic studies demonstrated that CuET NCs exhibited a 6-fold improvement in bioavailability. Notably, CuET NCs exhibited high biodistribution in the intestine, suggesting their potential application for the treatment of inflammatory bowel diseases (IBDs). To evaluate their therapeutic efficacy in vivo , we employed a murine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis symptoms. Our findings highlight the discovery of CuET as a potent anti-pyroptotic agent, and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.
研究领域:
药理学
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纳米技术
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炎症
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胃肠病学
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JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-17
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IF 12.6
Bai Ge,Liu Hongwen,Li Wei,Chen Sijia,Wang Lishan,Wang Zhangding,Zhou Yue,Pan Yani,Liu Yu,Chen Qi,Zhang Nannan,Wei Jingjing,Fu Xueni,Zhou Yaru,Zhu Yun,Xu Lei,Wang Lei
Background The remodeling of extracellular matrix often fails chemotherapeutic agents to fight intrahepatic cholangiocarcinoma (ICC). The cGAS/STING pathway can trigger the innate immune response to obtain better immunotherapeutic outcomes. Results A cLipG/CuET nanocomposite was designed and synthesized based on glycyrrhizic acid (GA) and copper diethyldithiocarbamate (CuET). GA can open mitochondrial permeability transition pores (MPTPs), allowing Cu (II) to interrupt mitochondrial function through copper toxicity. By activating the cGAS-STING signaling pathway in macrophages, this mitochondrial-targeting polymer (cLipG/CuET) significantly boosted the production of mitochondrial reactive oxygen species (mtROS), and promoted the escape of damaged mitochondrial DNA (mtDNA) from ICC cells. Consequently, M1 polarization of cancer-associated macrophages enhanced the immune response against ICC. In the mouse model, the intravenous administration of cLipG/CuET transformed the ICC from “cold” into “hot”. Conclusions With a high biosafety, cLipG/CuET exerted a synergistic effect on the immune checkpoint inhibitor αCTLA-4 against ICC, and their combination provided a new therapeutic strategy. Graphical abstract
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2026
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IF 6
Xiaoxia Guo,Qingao Meng,Wengqiang Liu,Haoyi Rui,Xinxuan Ruan,Tong Guan,Anyang Dai,Yue Liu,Jiangtao Su,Chenfan Duan
First repurposing of CuET for topical psoriasis therapy. • Ternary PVP/PEG/CA nanofiber patch tailored for xerotic psoriatic skin. • Comparable efficacy to calcipotriol in IMQ-induced psoriasis model. • Resets Th17/Treg homeostasis via multi-target immunomodulation. • Excellent biosafety with high clinical translatability. The management of psoriasis remains challenging due to the limitations of current therapies. This study explores the repurposing of copper diethyldithiocarbamate (CuET)—a metabolite of the anti-alcoholism drug disulfiram—as a novel topical agent for psoriasis. To this end, we developed an advanced delivery platform by fabricating a CuET-loaded nanofiber patch via electrospinning of a polyvinylpyrrolidone/polyethylene glycol/citric acid (PVP/PEG/CA) blend. This rationally designed matrix provided optimal mechanical strength, moisture-activated adhesion, and precise local drug delivery performance, thereby addressing the application challenges associated with xerotic psoriatic skin. In an imiquimod-induced psoriasis mouse model, the nanofiber patch exhibited efficacy comparable to the that of clinical standard clobetasol propionate ointment, significantly alleviating clinical scores and epidermal hyperplasia. Mechanistically, the patch mediated a multimodal therapeutic action: it potently suppressed pathological angiogenesis (reducing CD31 + vessel density by 73.97%) and macrophage infiltration. Crucially, it normalized the dysregulated immune microenvironment by concurrently inhibiting key pro-inflammatory cytokines (IL-17A, IL-22, and IL-1β) and restoring the anti-inflammatory cytokine IL-10 to physiological levels, indicating a reset of the Th17/Treg balance. Comprehensive safety evaluation revealed no systemic toxicity. This work not only validates psoriasis as a new therapeutic indication for CuET but also presents a pioneering combined strategy of drug repurposing and material engineering, offering a safe and effective topical therapy that targets the core immune-vascular pathology of the disease. Download: Download high-res image (154KB) Download: Download full-size image
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高影响因子
iScience
·
2026
·Vol. 29
·期 4
·115438
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IF 4.5
Jie Zhang,Chengying Lei,Guangzhe Zheng,Bingxue Nie,Yiju Wei,Yanqin Lu,Shuping Zhang
The FDA-approved disulfiram (DSF) is metabolized to diethyldithiocarbamate-copper (CuET) in vivo , exhibiting excellent anti-tumor activity in various types of tumors. Although cuproptosis and ferroptosis are both reported to be involved in the tumor-killing effects of CuET, the specific crosstalk mechanism remains poorly understood. Herein, we found that CuET increased the concentration of copper ions significantly in non-small cell lung cancer (NSCLC) cells, thereby triggering the process of cuproptosis. Simultaneously, we observed an increase in lipid peroxidation (LPO) and ferroptosis. Mechanistically, CuET interacts directly with polyunsaturated phospholipids to generate free radicals, leading to LPO and ferroptosis, with limited dependence on iron accumulation. Additionally, lipid composition changes induced by CuET might also contribute to ferroptosis. In vivo anti-tumor experiments verified copper-mediated cell death. We uncovered that CuET induced ferroptosis through a copper-triggered, non-canonical, and radical-dependent pathway. Therefore, our data elucidate a therapeutic approach for NSCLC by co-targeting cuproptosis and ferroptosis. Biochemistry; Cell biology; Cancer
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International Journal of Nanomedicine
·
2026
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IF 8.7
Xiaoling Guo,Lina Zhou,Anya Buerliesi,Jiahui Ye,Yinhua Lv,Wenqian Wei,Jinlan Jiao,Weihong Ge,Yun Zhu,Weijie Zhang
Background: Paclitaxel is a cornerstone of breast cancer treatment, but its efficacy is often limited by low response rates and drug resistance. To address this, we developed MEVs@CuET, a novel therapeutic approach combining cuproptosis-inducing copper(II) complex (CuET) with macrophage-derived extracellular vesicles (MEVs), aiming to enhance paclitaxel’s antitumor effects.Methods: The tumor-targeting capability of MEVs@CuET was evaluated through cellular uptake and in vivo distribution studies. In vitro synergy was assessed using the ZIP model, while transcriptome sequencing analyzed gene expression changes. In vivo antitumor activity and immune modulation were examined in breast cancer models, with tumor growth inhibition, apoptosis, and Th17 lymphocyte levels measured.Results: MEVs@CuET demonstrated efficient tumor targeting and synergistic antiproliferative effects with paclitaxel in vitro (synergy score: 29.37). Transcriptomic analysis revealed significant alterations in immune-related pathways, particularly upregulation of the IL-17 signaling pathway. In vivo, the combination therapy markedly inhibited tumor growth, increased apoptosis, and elevated Th17 cell levels, aligning with the transcriptomic findings.Conclusion: MEVs@CuET significantly enhances paclitaxel’s efficacy by inducing cuproptosis and modulating antitumor immunity, offering a promising strategy to overcome resistance in breast cancer treatment.
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Advanced Healthcare Materials
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2023
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IF 10
Hongwen Liu,Lei Xu,Yiyang Zhang,Yiqiong Xie,Lishan Wang,Yue Zhou,Zhangding Wang,Yani Pan,Wenying Li,Lu Xu,Xinyun Xu,Ting Wang,Kui Meng,Jian He,Yudong Qiu,Guifang Xu,Weihong Ge,Yun Zhu,Lei Wang
Chemotherapy-induced adaptive resistance is a significant factor that contributes to low therapeutic efficacy in tumor cells. The unfolded protein response (UPR) is a key mechanism in the development of drug resistance and serves as a critical reactive system for endoplasmic reticulum stress. Cu(II) can reduce the abundance of 60S ribosomal subunits and inhibit rRNA processing, leading to a decrease in the translation efficiency of the GRP78/BiP mRNA, which serves as a primary sensor for UPR activation. In this study, CuET-Lipid@Cela, composed of CuET and tripterine (Cela), demonstrates a significant synergistic antitumor effect on cholangiocarcinoma (CCA) cells. RNA-Seq is used to investigate the underlying mechanism, which suggests that the transmembrane protein 2 (TMX2) gene may be crucial in Cu(II) regulation of UPR by inhibiting the activation of GRP78/BiP and PERK/eIF2 α . The synergistic antitumor efficacy of CuET-Lipid@Cela via inhibition of TMX2 is also confirmed in a myrAKT/YapS127A plasmid-induced primary CCA mouse model, providing new insights into the reversal of acquired chemotherapy-induced resistance in CCA.
研究领域:
肿瘤学
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分子生物学
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药理学
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高影响因子
CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Ying Peng,Peng Liu,Jinsong Ding,Wenhu Zhou
Disulfiram (DSF), an FDA-approved drug for alcoholism, has demonstrated promising anti-tumor effects combined with Cu 2+ . This combination is achieved through the metabolism of DSF into dithiocarbamate (DTC), which chelates with Cu 2+ to form the active form of DTC-copper complexes (CuET). Interestingly, our investigation revealed that Ca 2+ can serve as another amplifier to enhance the efficacy of DSF by inducing calcium overload in tumor cells. Building upon this finding, we developed biomineralized nanoparticles (CuCaP@DTC) capable of controlled release of DTC, Cu 2+ , and Ca 2+ in response to the acidic tumor microenvironment. These nanoparticles exhibited stability in the bloodstream for prolonged circulation, enabling their passive accumulation in tumors while efficiently releasing Ca 2+ and Cu 2+ /DTC to facilitate CuET generation within tumor cells. The combined effect of in-situ CuET generation and calcium overload resulted in amplified anti-tumor effects. This research underscores the potential of synergistically combining DSF, copper, and calcium as a promising approach for improving treatment outcomes. Furthermore, it emphasizes the importance of rational design in delivery carrier systems based on a comprehensive understanding of the therapeutic mechanisms to enhance the drug efficacy.
研究领域:
纳米技术
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癌症研究
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药学
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材料科学
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生物医学工程
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Xiaonan Qiu,Jiaying Liu,Li Song,Huijun Yu,Yunchao Wu,Qinxin Wang,Mengke Lu,Xuan Gu,Baoding Chen,Miaomiao Zhang,Fengyi Du
Bioorthogonal chemistry-based cancer therapy greatly reduces the side effects of chemotherapy drugs; however, complicated and expensive procedures limit its clinical application. Disulfiram (DSF), an FDA-approved anti-alcoholic drug, can combine with copper to form a DSF‑copper complex with remarkable tumor-killing effects. Inspired by the bioorthogonal chemistry, we fabricated an in situ crosslinked self-adaptive hyaluronic acid hydrogels (Cu-A/P@PH HGs) via a dynamic boronic ester bond-based reaction between Cu/5-aminolevulinic acid (5-ALA) self-assembled nanoparticles containing PVA (Cu-A/P NPs) and phenylboronic-grafted hyaluronic acid (PH). The prepared Cu-A/P@PH HGs exhibited favorable self-healing performance and ROS-responsive degradation. Upon in situ injection, the Cu-A/P NPs endowed the Cu-A/P@PH HGs with the ability to convert non-toxic DSF into cytotoxic diethyldithiocarbamate (CuET) at the desired tumor site. In addition, under the induction of glutathione (GSH), Cu-A/P NPs gradually released 5-ALA, which was specifically converted into protoporphyrin IX (PpIX) (a photosensitizer) in tumor cells, resulting in irreversible ROS-mediated oxidative damage under 660 nm laser exposure. Our study offers a promising bioorthogonal chemistry-inspired strategy for in situ photodynamic therapy and DSF chemotherapy to treat breast cancer.
研究领域:
癌症治疗
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纳米医学
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光动力治疗
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生物材料
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药物递送
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Nano Today
·
2022
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IF 18.962
Hao Zhang,Tingting Wang,Hanghang Liu,Yaobao Han,Qing Zheng,Qi Xu,Bolin Bao,Wei Xing,Zhen Li
Despite advances in early diagnosis and treatment of hepatocellular carcinoma (HCC), HCC shows a very high mortality and development of innovative drugs and treatment methods are highly desirable. Herein, we report an innovative therapy of HCC through the formation and amplification of vicious cycle between mitochondrial oxidative stress and ER stress by joint use of biodegradable ultrasmall Cu 2- x Se nanoparticles (CS NPs) and alcohol-abuse drug disulfiram (DSF). The CS NPs can alleviate the tumor hypoxia and generate reactive oxygen species (ROS) through their Fenton-like reaction with endogenous H 2 O 2 in tumor. Their released copper ions can react with DSF to in situ form active drug CuET to significantly suppress the growth of HCC and exhibit excellent anti-tumor effect. We reveal the novel anti-tumor mechanism of the formed CuET complex, which can immobilize nuclear protein localization protein 4 (NPL4) to inhibit the proteasome system to induce endoplasmic reticulum (ER) stress and increase the burden of Ca 2+ ions in mitochondria , leading to mitochondrial oxidative stress and the burst of ROS. The mitochondrial oxidative stress produces less ATP to induce the occurrence of autophagy, and the generated ROS further strengthens the ER stress. The formation of such vicious cycle between mitochondrial oxidative stress and ER stress significantly enhances the severe apoptosis of tumor cells and notable decrease in tumor size, which has been demonstrated in both subcutaneous and orthotopic HCC models. Our work provides insights into repurposing of metabolic nanoparticles and old drugs for new applications, demonstrates the great potential of this strategy in anti-tumor therapy.
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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分子生物学
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高影响因子
MOLECULAR PHARMACEUTICS
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2020
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IF 4.321
Ying Peng,Peng Liu,Yingcai Meng,Shuo Hu,Jinsong Ding,Wenhu Zhou
Disulfiram (DSF), an old alcohol-aversion drug, has been repurposed for cancer therapy, and mechanistic studies reveal that it needs to be metabolized to diethyldithiocarbamate (DTC) and subsequently coordinates with copper(II) to form the DTC–copper complex (CuET) for anticancer activation. Here, we utilized this mechanism to construct a CuET self-delivery nanosystem based on the metal coordination polymer for highly robust and selective cancer therapy. In our design, the nanoparticles were facilely prepared under mild conditions by virtue of the strong coordination between Cu2+ and DTC, yielding 100% CuET loading capacity and allowing for further hyaluronic acid (HA) modification (CuET@HA NPs). The CuET@HA NPs could selectively deliver into cancer cells and release the active component of CuET in response to both endo/lysosome acidic pH and intracellular abundant GSH, which induces strong cytotoxicity toward cancer cells over normal cells taking advantage of the p97 pathway interference mechanism. Upon intravenous injection, the self-assembled system could passively accumulate into a tumor and elicit potent tumor growth inhibition at a dose of 1 mg/kg without any noticeable side effects. Given the cost-effective and easily scaled-up preparation, our designed nanosystem provides a promising strategy to pave the way for clinical translation of DSF-based cancer chemotherapy.
研究领域:
纳米技术
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药学
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癌症研究
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材料科学
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生物医学工程
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高影响因子
ACS Nano
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2024
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IF 15.8
Hao Zhang,Li Yang,Mengxiao Han,Yaobao Han,Zhilin Jiang,Qing Zheng,Jun Dong,Tingting Wang,Zhen Li
The currently available immune checkpoint therapy shows a disappointing therapeutic efficacy for glioblastoma multiforme (GBM), and it is of great importance to discover better immune checkpoints and develop innovative targeting strategies. The discovered metabolic immune checkpoint ecto-5-nucleotidase (CD73) in a tumor contributes to its immune evasion due to the dysregulation of extracellular adenosine (ADO), which significantly inhibits the function of antitumor T cells and increases the activity of immunosuppressive cells. Herein, we drastically inhibit the expression of CD73 to reduce the production of ADO by using versatile Au@Cu2–xSe nanoparticles (ACS NPs). ACS NPs can decrease the expression of CD73 by alleviating the tumor hypoxia through their Fenton-like reaction to weaken the ADO-driven immunosuppression for enhancing antitumor T cell infiltration and activity of GBM. The copper ions (Cu2+) released from ACS NPs can chelate with disulfide, leading to the formation of cytotoxic bis(N,N-diethyldithiocarbamate)-copper complex (CuET), which can be combined with radiotherapy to recruit more antitumor T cells to infiltrate into the tumor site. Based on the inhibition of CD73 to promote the infiltration and activity of antitumor T cells, a cascade of enhancing GBM immunotherapy effects can be achieved. The significant increase in CD8+ T and CD4+ T cells within the tumor and the memory T cells in the spleen effectively reduces tumor size by 92%, which demonstrates the excellent efficacy of immunotherapy achieved by a combination of metabolic immune checkpoint CD73 inhibition with chemoradiotherapy. This work demonstrates that modulation of CD73-mediated tumor immunosuppression is an important strategy of improving the outcome of GBM immunotherapy.
研究领域:
肿瘤学
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免疫治疗
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纳米技术
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癌症研究
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高影响因子
Acta Biomaterialia
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2024
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IF 9.4
Jinpeng Yao,Yu Chen,Liang Zhang,Yuancun Cheng,Zheng Chen,Yanhui Zhang,Xiaoyi Zheng,Yanwei Lv,Shige Wang,Zhaoshen Li,Jiulong Zhao
The clinical treatment of inflammatory bowel disease (IBD) is challenging. We developed copper sulfate (CuS)/disulfiram (DSF)/methacrylic acid-ethyl acrylate copolymer (EL)/polyvinylpyrrolidone (PVP) nanoplatform (CuS/DSF/EL/PVP) and evaluated its efficiency for treating IBD. After oral administration, the pH-sensitive EL protected the CuS/DSF/EL/PVP against degradation by acidic gastric juices. Once the colon was reached, EL was dissolved, releasing DSF and Cu 2+ . Further, the main in vivo metabolite of DSF can bind to Cu 2+ and form copper (II) N, N-diethyldithiocarbamate (CuET), which significantly alleviated acute colitis in mice. Notably, CuS/DSF/EL/PVP outperformed CuS/EL/PVP and DSF/EL/PVP nanoplatforms in reducing colonic pathology and improving the secretion of inflammation-related cytokines (such as IL-4 and IL-10) in the colonic mucosa. RNA-seq analysis revealed that the nanoplatform reduced colonic inflammation and promoted intestinal mucosal repair by upregulating C-type lectin receptor (CLR)-related genes and signaling pathways. Furthermore, CuS/DSF/EL/PVP showed potential for improving colitis Th1/Th17 cells through innate immunity stimulation, down-regulation of inflammatory cytokines, and upregulation of anti-inflammatory cytokines. Additionally, the intervention with CuS/DSF/EL/PVP led to increased intestinal flora diversity, decreased Escherichia–Shigella abundance, and elevated levels of short-chain fatty acid (SCFA)-producing bacteria Prevotella, Lactobacillus , and Bifidobacterium , indicating their potential to modulate the dysregulated intestinal flora and suppress inflammation. Statement of Significance Our study introduces the CuS/DSF/EL/PVP nanoplatform as a therapeutic strategy for treating inflammatory bowel disease (IBD). This approach demonstrates significant efficacy in targeting the colon and alleviating acute colitis in mice. It uniquely modulates gut immunity and microbiota, exhibiting a notable impact on inflammation-related cytokines and promoting intestinal mucosal repair. The nanoplatform's ability to regulate gut flora diversity, combined with its cost-effective and scalable production, positions it as a potentially transformative treatment for IBD, offering new avenues for personalized medical interventions.
研究领域:
药学
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纳米技术
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胃肠病学
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免疫学
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微生物学
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高影响因子
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