JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2025
·Vol. 44
·期 1
·1-25
·
IF 12.8
Wang Pengyu,Guo Weihua,Liu Shuyue,Li Shouyi,Li Jiaqi,Ding Bowen,Yin Fengyi,Yang Yang,Li Xingjiang,Cao Pei,Ma Chaozhe,Zhang Wanying,Song Yidan,Geng Yating,Liu Lantao,Hu Jing,Hao Jihui,Feng Yukuan
Background Copper accumulation triggers mitochondrial-driven cell death, known as cuproptosis, offering a promising mechanism for targeted cancer therapy. Recent studies have highlighted the critical role of intratumoral copper levels in regulating the expression of programmed cell death ligand-1 (PD-L1), suggesting that copper-induced cuproptosis not only enhances cancer cell death but may also amplify the effects of anti-PD-L1 antibodies (αPD-L1). However, in tumors where monotherapy with αPD-L1 shows limited efficacy, particularly in pancreatic ductal adenocarcinoma (PDAC), the role of copper-induced cuproptosis in enhancing αPD-L1 treatment efficacy and its underlying mechanisms remain unclear. Meanwhile, inadequate tumor drug accumulation and glycolysis significantly restrict the efficacy of cuproptosis. To address these challenges, we have synthesized a novel nanozyme, Pt@PCN-Cu, designed to stabilize intracellular copper accumulation and effectively induce cuproptosis. Additionally, we aim to determine whether this strong induction of cuproptosis can synergize with αPD-L1 to enhance cancer therapy, ultimately paving the way for novel strategies to improve PDAC treatment. Methods Pt@PCN-Cu was synthesized via a one-pot method, and its therapeutic potential was assessed in combination with αPD-L1 for the treatment of PDAC. Initially, the material’s properties were characterized, and its efficient cellular uptake was confirmed. Anti-tumor efficacy was evaluated by inducing cuproptosis in PDAC cell lines and xenograft models. RNA sequencing (RNA-seq) was utilized to identify key regulators involved in the modulation of PD-L1 expression by cuproptosis. Lastly, the therapeutic efficacy of Pt@PCN-Cu combined with αPD-L1 was evaluated in vivo, focusing on tumor growth inhibition and immune modulation within the tumor microenvironment (TME). Results Pt@PCN-Cu demonstrates excellent physicochemical properties and remarkable cascade catalytic activity, providing a solid foundation for further in vitro and in vivo studies. In vitro, Pt@PCN-Cu efficiently transports copper and induces cuproptosis primarily through mitochondrial dysfunction. Mechanistic studies show that Pt@PCN-Cu triggers the dissociation of hexokinase 2 (HK2) from mitochondria, leading to a reduction in HK2 activity. This decline in HK2 activity impairs glycolysis, a metabolic pathway essential for tumor energy metabolism, which in turn results in elevated PD-L1 levels. In vivo, Pt@PCN-Cu demonstrates excellent safety and accumulates at the tumor site in a subcutaneous PDAC mouse model, inducing cuproptosis. Moreover, the combination of Pt@PCN-Cu with αPD-L1 further enhanced its therapeutic efficacy and effectively reprogrammed the immunosuppressive TME. Conclusion This study presents strong evidence confirming the safety and therapeutic potential of Pt@PCN-Cu in PDAC treatment. Importantly, Pt@PCN-Cu not only induces cuproptosis but also significantly enhances antitumor efficacy in combination with αPD-L1 by regulating PD-L1 expression through HK2 modulation. These findings underscore a more effective and innovative approach for treating PDAC.
研究领域:
肿瘤学
·
分子生物学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR ONCOLOGY
·
2023
·
IF 6.6
Wei Wanhui,Lu Yuanyuan,Hu Qian,Yin Jinwen,Wang Youwei,Zhang Heng,Zhao Qiu,Liu Lan
Purpose The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets. Methods First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC–MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay. Results Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis. Conclusions In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Peng Song,Junqi Dong,Tingting Yu,Zexun Pan,Ziwen Chen,Ruixue Wang,Ming Wang,Liang Zhao,Xianbao Wang,Jinhua Li
The accurate diagnosis of pancreatic ductal adenocarcinoma (PDAC) suffers low specify, and low sensitivity of biomarker detection. In complex biological fluid environments, nonspecific adsorption is prevalent, posing challenges to the accurate detection of biomarkers at low concentrations. Herein, a highly sensitive and selective solution-gated graphene transistor (SGGT) is fabricated for the detection of miRNA-196a in exosomes to diagnose PDAC. The antifouling modification on the surface of the gate electrode is employed through using bovine serum albumin as a common sealing agent and poly adenine (polyA 8 ) to enhance surface hydrophilicity. The effect of background noise on the detection is effectively reduced. The limit of detection reached 1.82 × 10 −19 m without the need for labeling or amplification, and the detection time is within 25 min. The clinical experiments verify that receiver operating characteristic curve values of miRNA-196a detection in clinical diagnosis are higher than that of carbohydrate antigen 19-9 biomarker, and are as high as 0.98. The miRNA-196a detection can well distinguish PDAC from non-PDAC subjects. The SGGT sensor platform demonstrates significant potential for the accurate detection and diagnosis of PDAC within the milieu of complex biological samples.
研究领域:
医学诊断
·
生物传感器
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2025
·Vol. 21
·期 8
·3555
·
IF 10
Pengyi Liu,Minmin Shi,Yang Liu,Yihao Liu,Jiayu Lin,Shuyu Zhai,Yizhi Cao,Dongjie Chen,Yongsheng Jiang,Chenghong Peng,Lei Zhang,Chunyong Ding,Lingxi Jiang,Baiyong Shen
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited treatment options and poor response to immunotherapy. The immunosuppressive tumor microenvironment, characterized by a dense extracellular matrix, and immunosuppressive cells, plays a crucial role in this resistance. The cGAS-STING pathway, traditionally recognized for antiviral defense, has emerged as a potential target for cancer immunotherapy due to its ability to activate both innate and adaptive immune responses. Methods: A novel small-molecule STING agonist, D166, was synthesized by incorporating deuterium into the structure, leading to improved stability and activation of the STING pathway. The effects of D166 were evaluated using human pancreatic tumor organoids, mouse pancreatic tumor models, and various in vitro and in vivo assays, including flow cytometry, RNA sequencing, ELISA and western blotting. And an organoid-immune cells co-culture system was established for further investigate the effects on immune cells. Results: D166 demonstrated significant anti-tumor activity, effectively activating the cGAS-STING pathway in a time- and dose-dependent manner. D166 inhibited the progression of pancreatic tumor organoids and mouse pancreatic tumors, reshaping the tumor immune microenvironment. The drug enhanced T cell activation, promoted macrophage polarization toward the M1 phenotype, and increased the infiltration of immune cells. Additionally, D166 acted as a sensitizer for anti-PD-1 therapy, significantly improving therapeutic efficacy in combination treatments. Conclusion: D166 is a novel and stable STING agonist that inhibits pancreatic tumor progression by activating the cGAS-STING pathway and remodeling the tumor immune microenvironment. Its combination with anti-PD-1 antibodies offers a promising strategy for overcoming the immunosuppressive barriers in pancreatic cancer, providing new therapeutic insights and directions.
研究领域:
肿瘤学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Qixin Zhao,Shenglu Liu,Tao Bi,Ting Wang,Lei Chen,Juan Huang,Xuemei Yang,Xiyu Dai,Zengjin Liu,Qin Sun
Pancreatic malignancies rank among the most aggressive and fatal carcinomas in modern oncology, presenting significant therapeutic challenges due to their inherent chemoresistance. In the context of our experimental investigations, we have developed a mitochondria-targeted hydrogel formulation, termed SWMU690@PUE, which demonstrates the ability to modulate mitochondrial homeostasis effectively. The hydrogel construct was precisely designed via the spontaneous supramolecular assembly of puerarin (PUE) and SWMU690 components, facilitated under carefully controlled thermodynamic conditions. Comprehensive in vitro analyses of the SWMU690@PUE complex were conducted to rigorously evaluate its efficacy in regulating mitochondrial homeostasis. The experimental findings revealed that SWMU690@PUE exhibited pronounced selectivity for mitochondrial targeting, subsequently diminishing mitochondrial membrane potential—a pivotal parameter in cellular bioenergetics. Our study further demonstrated that SWMU690@PUE effectively mitigates the chemoresistance phenotype associated with mitochondrial dysfunction. This therapeutic potential was exemplified by its capacity to induce mitochondria-mediated apoptotic and ferroptotic cell death, critical oncocidal pathways, in pancreatic carcinoma cells across both in vitro and in vivo models. Additionally, SWMU690@PUE displayed significant antineoplastic activity, as evidenced by its robust inhibition of pancreatic cancer cell proliferation in both experimental frameworks. In conclusion, this study presents an innovative therapeutic approach specifically designed to overcome the persistent challenge of chemoresistance in the treatment of pancreatic neoplasms.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Jia Qi,Caiyun Fang,Chunhui Deng,Fangying Shi,Qunyan Yao
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer, typically diagnosed at advanced stages due to its asymptomatic onset and challenges in early detection. To address the critical need for the early diagnosis of PDAC, we developed a laser desorption/ionization mass spectrometry (LDI-MS) platform based on mesoporous silica-modified magnetic graphene (MG@mSiO2). MG@mSiO2 exhibited exceptional ultraviolet (UV) absorption, efficient ionization, and minimal background interference, enabling high-resolution profiling of serum metabolic fingerprints (SMFs). Based on the extracted SMFs, we constructed a Random Forest (RF) model to classify PDAC patients, high-risk (HR) individuals, and healthy controls (HC), achieving an accuracy of 97.5% in the independent test set. Additionally, a six-metabolite biomarker panel was identified, showing strong diagnostic potential with sensitivity and accuracy exceeding 89.1% for distinguishing HC from PDAC. When coupled with the serological marker carbohydrate antigen 19–9 (CA19–9), the integrated strategy delivered significantly improved diagnostic performance, achieving high accuracy ranging from 95.3% to 100% in distinguishing HR and PDAC patients from HC. Furthermore, metabolic pathway analysis revealed key pathways associated with PDAC progression, providing mechanistic insights into the disease. This work provides a powerful diagnostic tool for PDAC screening, establishing a foundation for early detection and precision medicine in clinical practice.
研究领域:
医学
·
生物化学
·
诊断学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2017
·
IF 8.402
Hui Li,Ping Wang,Yunxiang Deng,Meiying Zeng,Yan Tang,Wei-Hong Zhu,Yingsheng Cheng
Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating malignancies in patients, and there is an urgent need for an effective treatment method. Herein, we report a novel gold nanocluster-based platform for confocal laser endomicroscopy-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for PDAC, which consists of four components: the PTT-carrier gold nanocluster, an active targeting ligand U11 peptide, a Cathepsin E (CTSE)-sensitive PDT therapy prodrug, and a CTSE-sensitive imaging agent (cyanine dye Cy5.5). Due to the strong coupling among cross-linked gold nanoparticles (AuNPs), the surface plasmon resonance peak of nanoclusters shifts to the near-infrared (NIR) region, thus making the nanoclusters useful in the effective PTT therapy. In the system, the labeling of nanoclusters with U11 peptide can distinctly increase their affinity and accelerate their uptake by pancreatic cancer cells. Cell apoptosis staining demonstrates that, upon incorporation of the uPAR-targeted unit, the antitumor efficacy of CTSE-sensitive nanocluster AuS-U11 is significantly enhanced with respect to that of the non-targeted nanocluster AuS-PEG and the insensitive nanocluster AuC-PEG. In vivo and ex vivo optical imaging confirms the high accumulation of AuS-U11 in the in situ pancreatic tumor model. Therapeutic studies further show that the combination of active targeting for tumor tissue, enzyme-triggered drug release of 5-ALA and fluorescent dye Cy5.5 in nanoclusters AuS-U11 could achieve optimal therapeutic efficacy with endomicroscopy-guided photothermal/photodynamic therapy with minimal side effects. As a consequence, the delicate gold nanocluster concept provides a promising strategy to enhance the therapy efficiency in the most challenging PDAC treatment.
研究领域:
肿瘤学
·
纳米医学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2017
·Vol. 7
·期 5
·1700912
·
IF 5.11
Hui Li,Ping Wang,Wenyu Gong,Qi Wang,Jia Zhou,Wei-Hong Zhu,Yingsheng Cheng
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. Early detection of precancerous pancreatic intraepithelial neoplasia (PanIN) tissues is an urgent challenge to improve the PDAC prognosis. Here, a urokinase-type plasminogen activator receptor (uPAR)-targeted magnetic resonance (MR)/near-infrared fluorescence (NIRF) dual-modal nanoprobe dendron-grafted polylysine (DGL)-U11 for ultra-early detection of pancreatic precancerosis is reported. Because of its good biocompatibility and biodegradability, globular architecture, and well-defined reactive groups, the DGL is chosen as the platform to load with a pancreatic tumor-targeting peptide U11, a magnetic resonance contrast agent Gd 3+ -diethylene triamine pentaacetic acid, and a near-infrared fluorescent cyanine dye Cy5.5. The nanoprobe DGL-U11 has several preferable characteristics, such as active peptide targeting to activator receptor, good biocompatibility, dual-modal imaging diagnosis, and well controlled diameter in a range of 15–25 nm. Upon incorporation of the active U11 peptide target to the overexpressed activator receptor uPAR, the targeted nanoprobe DGL-U11 can increase to the earlier PanIN-II stage through in vivo NIRF imaging. Labeled with both MR and NIRF bioimaging reporters, the uPAR-targeted dual-modal nanoprobe is very effective in the targeted imaging of precancerous PanINs and PDAC lesions with high sensitivity and spatial resolution, providing a promising platform to the ultra-early detection of PDAC.
研究领域:
医学影像学
·
肿瘤学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2025
·
IF 4.9
Zhijie Liang,Jinzhuai Li,Hai Huang,Hongmian Jiang,Lifeng Luo,Shaorong Li,Huali Huang,Fangdi Hu
Pancreatic ductal adenocarcinoma (PDAC) poses significant therapeutic challenges due to its unique tumor microenvironment, which is characterized by collapsed blood vessels and elevated intratumoral pressure, severely hindering drug penetration and distribution. Consequently, we synthesized glucose-modified PEG-PLA (polyethylene-polylactice acid) nanoparticles as a drug delivery system for doxorubicin (DOX). We successfully enhanced the permeability and targeting capability of the nanoparticles in pancreatic cancer cells using glycosylation modification, significantly increasing drug accumulation within the tumor microenvironment. Our study demonstrated excellent cellular uptake of the nanoparticles in vitro and their improved penetration in 3D tumor spheroid models. Additionally, in vivo experiments revealed a notable increase in nanoparticle accumulation at the tumor site, along with favorable drug release characteristics. Hence, glucose-modified PEG-PLA nanoparticles hold substantial potential for clinical application in PDAC treatment, effectively enhancing the therapeutic efficacy of chemotherapeutic agents.
研究领域:
药剂学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Qian Wang,Hao Yan,Yushen Jin,Zihua Wang,Wenhui Huang,Jia Qiu,Feiyu Kang,Kun Wang,Xinming Zhao,Jie Tian
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human malignancies with poor patient outcomes often resulting from delayed diagnosis. Therefore, early diagnosis can lead to a better prognosis and improved outcomes. In this study, we have developed a novel conjugate complex of plectin/integrin-targeted bispecific molecular probe , termed Gd-Cy7-PTP/RGD, to be used for magnetic resonance/near-infrared imaging (MRI/NIRF) of pancreatic cancer in vivo . This bispecific molecular probe comprises four parts: Gd(III) for MRI, cyanine 7 (Cy7) for NIRF, the peptide PTP for binding to plectin-1 specifically overexpressed on the surface of PDAC cells, and the peptide RGD for targeting integrin widely expressed on pancreatic duct epithelial cells and angiogenesis . Remarkably, the combination of PTP and RGD greatly increased the targeting efficiency in vitro and in vivo compared to that of either single peptide. Moreover, such bispecific molecular probes target pancreatic neoplasms and angiogenesis simultaneously, producing a “multi-level” targeting effect confirmed by immunofluorescence testing in vitro and in vivo . Under the guidance of MRI/NIRF dual-modality imaging, NIRF-guided delineation of surgical margins during operations was successfully achieved in orthotopic pancreatic cancer. This study promotes further exploration of bispecific molecular probes for clinical application.
研究领域:
肿瘤学
·
医学影像学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT ISSUES IN MOLECULAR BIOLOGY
·
2025
·Vol. 47
·期 12
·991
·
IF 3
Lisha Li,Zhen Yu,Xuehua Lu,Pei Yang,Shuxia Zhang,Qinghua Lin,Junyong Han
Background: Adhesion G protein-coupled receptor G6 ( ADGRG6 ), also known as GPR126 , has been implicated in several malignancies. However, its expression pattern, clinical significance, and mechanistic role in pancreatic adenocarcinoma (PAAD) remain unclear. Methods: We combined multi-omics analyses, tissue microarray immunohistochemistry, and a series of functional experiments, including 2D and 3D spheroid cultures, zebrafish xenografts, and murine tumor models—to investigate the expression, clinical significance, and mechanism of ADGRG6 in PAAD. The association between ADGRG6 expression and immune infiltration was assessed using TIMER and GEPIA databases, followed by mechanistic validation through ADGRG6 modulation in PAAD cell lines. Results: ADGRG6 was significantly overexpressed in PAAD and correlated with larger tumor size, higher grade, advanced TNM stage, and poor overall survival. Multivariate logistic regression confirmed that high ADGRG6 expression was independently associated with higher pathological grade. Functionally, ADGRG6 silencing markedly inhibited PAAD cell proliferation, migration, and invasion in both 2D and 3D cultures, as well as in zebrafish and nude mouse xenograft models. Integrated transcriptomic and immune analyses revealed that ADGRG6 expression positively correlated with mast cells, macrophages (M1/M2), Th2/Th17 subsets, and interferon–responsive neutrophils. Mechanistically, ADGRG6 silencing reduced STAT6 phosphorylation and GATA3 expression, consistent with the suppression of the NF-κB→STAT6→GATA3 axis. Conclusions: ADGRG6 functions as an oncogenic driver in PAAD, promoting tumor progression and fostering an immunosuppressive microenvironment via NF-κB/STAT6 signaling. These findings not only broaden the mechanistic understanding of ADGRG6 function but also suggest it as a promising target for therapeutic intervention in PAAD.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2017
·
IF 7.504
Ting Jiang,Bo Zhang,Shun Shen,Yanyan Tuo,Zimiao Luo,Yu Hu,Zhiqing Pang,Xinguo Jiang
Due to the rich stroma content and poor blood perfusion, pancreatic ductal adenocarcinoma (PDA) is a tough cancer that can hardly be effectively treated by chemotherapeutic drugs. Tumor microenvironment modulation or advanced design of nanomedicine to achieve better therapeutic benefits for PDA treatment was widely advocated by many reviews. In the present study, a new photothermal therapy strategy of PDA was developed by combination of tumor microenvironment modulation and advanced design of biomimetic gold nanorods. On one hand, biomimetic gold nanorods were developed by coating gold nanorods (GNRs) with erythrocyte membrane (MGNRs). It was shown that MGNRs exhibited significantly higher colloidal stability in vitro, stronger photothermal therapeutic efficacy in vitro, and longer circulation in vivo than GNRs. On the other hand, tumor microenvironment modulation by cyclopamine treatment successfully disrupted the extracellular matrix of PDA and improved tumor blood perfusion. Moreover, cyclopamine treatment significantly increased the accumulation of MGNRs in tumors by 1.8-fold and therefore produced higher photothermal efficiency in vivo than the control group. Finally, cyclopamine treatment combined with photothermal MGNRs achieved the most significant shrinkage of Capan-2 tumor xenografts among all the treatment groups. Therefore, with the integrated advantages of tumor microenvironment regulation and long-circulation biomimetic MGNRs, effective photothermal therapy of PDA was achieved. In general, this new strategy of combining tumor microenvironment modulation and advanced design of biomimetic nanoparticles might have great potential in PDA therapy.
研究领域:
肿瘤学
·
纳米技术
·
生物医学工程
✓ 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）