{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:44:07Z","timestamp":1788882247983,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T00:00:00Z","timestamp":1724630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Major Scientific Instruments and Equipments Development Project","award":["81627805"],"award-info":[{"award-number":["81627805"]}]},{"name":"National Major Scientific Instruments and Equipments Development Project","award":["2016YFC0106500"],"award-info":[{"award-number":["2016YFC0106500"]}]},{"name":"National Major Scientific Instruments and Equipments Development Project","award":["U1401254"],"award-info":[{"award-number":["U1401254"]}]},{"name":"National Key Research and Development Program","award":["81627805"],"award-info":[{"award-number":["81627805"]}]},{"name":"National Key Research and Development Program","award":["2016YFC0106500"],"award-info":[{"award-number":["2016YFC0106500"]}]},{"name":"National Key Research and Development Program","award":["U1401254"],"award-info":[{"award-number":["U1401254"]}]},{"name":"National Natural Science Foundation of China-Guangdong Union Foundation","award":["81627805"],"award-info":[{"award-number":["81627805"]}]},{"name":"National Natural Science Foundation of China-Guangdong Union Foundation","award":["2016YFC0106500"],"award-info":[{"award-number":["2016YFC0106500"]}]},{"name":"National Natural Science Foundation of China-Guangdong Union Foundation","award":["U1401254"],"award-info":[{"award-number":["U1401254"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>Lenvatinib resistance (LenR) presents a significant challenge in hepatocellular carcinoma (HCC) treatment, leading to high cancer-related mortality rates globally. Unlike traditional chemotherapy resistance mechanisms, LenR in HCC is primarily driven by increased cancer cell stemness. Disulfiram, (DSF), functioning as a Cu ionophore, can coordinate with Cu2+ to overcome LenR in HCC by inhibiting cancer cell stemness and cuproptosis. However, DSF faces challenges due to its poor water solubility, while copper ions present issues related to systemic toxicity during widespread use. To address this, DSF and CuO nanoparticles (NPs) were co-encapsulated to form an oil-in-water Pickering emulsion (DSF@CuO), effectively elevating DSF and copper ion concentrations within the tumor microenvironment (TME). DSF@CuO was then combined with sodium alginate (SA) to form a DSF@CuO-SA solution, which gelatinizes in situ with Ca2+ in the TME to form a DSF@CuO Gel, enhancing Pickering emulsion stability and sustaining DSF and copper ion release. A DSF@CuO Gel exhibits enhanced stability and therapeutic efficacy compared to conventional administration methods. It effectively induces mitochondrial dysfunction and cuproptosis in LenR HCC cells by downregulating DLAT, LIAS, and CDKN2A, while upregulating FDX1. Furthermore, it suppresses cancer stemness pathways through activation of the JNK\/p38 MAPK pathway and inhibition of the NF-\u03baB and NOTCH signaling pathways. These findings suggest that DSF@CuO Gels are a promising therapeutic strategy for treating LenR HCC. In vivo and in vitro LenR HCC models demonstrated significant therapeutic efficacy. In conclusion, this novel approach underscores DSF@CuO Gel\u2019s potential to overcome LenR in HCC, offering a novel approach to address this clinical challenge.<\/jats:p>","DOI":"10.3390\/polym16172418","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T03:51:06Z","timestamp":1724730666000},"page":"2418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Injectable Hydrogel-Encapsulating Pickering Emulsion for Overcoming Lenvatinib-Resistant Hepatocellular Carcinoma via Cuproptosis Induction and Stemness Inhibition"],"prefix":"10.3390","volume":"16","author":[{"given":"Xin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanyu","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanjie","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1653-0711","authenticated-orcid":false,"given":"Chihua","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China"},{"name":"Institute of Digital Intelligent Minimally Invasive Surger, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China"},{"name":"Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou 510280, China"},{"name":"South China Institute of National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Guangzhou 510280, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1002\/hep.30409","article-title":"Letter to the Editor: Hepatic Resection Compared to Chemoembolization in Intermediate- to Advanced-Stage Hepatocellular Carcinoma: A Comment For Moving Forward","volume":"70","author":"Mo","year":"2019","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.1200\/JCO.20.00808","article-title":"Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma","volume":"38","author":"Finn","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial","volume":"391","author":"Kudo","year":"2018","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/s41586-021-03741-7","article-title":"EGFR activation limits the response of liver cancer to lenvatinib","volume":"595","author":"Jin","year":"2021","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2309215","DOI":"10.1002\/smll.202309215","article-title":"An Ellagic Acid Coordinated Copper-Based Nanoplatform for Efficiently Overcoming Cancer Chemoresistance by Cuproptosis and Synergistic Inhibition of Cancer Cell Stemness","volume":"20","author":"Lu","year":"2024","journal-title":"Small"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1136\/gutjnl-2018-317440","article-title":"Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance","volume":"68","author":"Xiang","year":"2019","journal-title":"Gut"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1053\/j.gastro.2023.01.041","article-title":"N6-Methyladenosine-Mediated Up-Regulation of FZD10 Regulates Liver Cancer Stem Cells\u2019 Properties and Lenvatinib Resistance Through WNT\/\u03b2-Catenin and Hippo Signaling Pathways","volume":"164","author":"Wang","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1097\/HEP.0000000000000237","article-title":"Mechanisms of drug resistance in HCC","volume":"79","author":"Ladd","year":"2024","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41575-021-00508-3","article-title":"Cancer stem cells in hepatocellular carcinoma\u2014From origin to clinical implications","volume":"19","author":"Lee","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"110771","DOI":"10.1016\/j.cellsig.2023.110771","article-title":"Disulfiram suppresses epithelial-mesenchymal transition (EMT), migration and invasion in cervical cancer through the HSP90A\/NDRG1 pathway","volume":"109","author":"Zheng","year":"2023","journal-title":"Cell Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/s41586-020-03046-1","article-title":"Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis","volume":"589","author":"Pastushenko","year":"2021","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/nature25016","article-title":"Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4","volume":"552","author":"Skrott","year":"2017","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lu, Y., Pan, Q., Gao, W., Pu, Y., Luo, K., He, B., and Gu, Z. (2022). Leveraging disulfiram to treat cancer: Mechanisms of action, delivery strategies, and treatment regimens. Biomaterials, 281.","DOI":"10.1016\/j.biomaterials.2021.121335"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.7150\/thno.81571","article-title":"Disulfiram with Cu2+ alleviates dextran sulfate sodium-induced ulcerative colitis in mice","volume":"13","author":"Zhou","year":"2023","journal-title":"Theranostics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated TCA cycle proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101018","DOI":"10.1016\/j.drup.2023.101018","article-title":"Cuproptosis: A novel therapeutic target for overcoming cancer drug resistance","volume":"72","author":"Wang","year":"2024","journal-title":"Drug Resist. Updates"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Oliveri, V. (2022). Selective Targeting of Cancer Cells by Copper Ionophores: An Overview. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.841814"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6250","DOI":"10.1158\/1078-0432.CCR-20-4789","article-title":"Recurrent Human Papillomavirus-Related Head and Neck Cancer Undergoes Metabolic Reprogramming and Is Driven by Oxidative Phosphorylation","volume":"27","author":"Vyas","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yang, G.G., Zhou, D.J., Pan, Z.Y., Yang, J., Zhang, D.Y., Cao, Q., Ji, L.N., and Mao, Z.W. (2019). Multifunctional low-temperature photothermal nanodrug with in vivo clearance, ROS-Scavenging and anti-inflammatory abilities. Biomaterials, 216.","DOI":"10.1016\/j.biomaterials.2019.119280"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.cbi.2005.10.044","article-title":"The role of a novel copper complex in overcoming doxorubicin resistance in Ehrlich ascites carcinoma cells in vivo","volume":"159","author":"Majumder","year":"2006","journal-title":"Chem.-Biol. Interact."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kucinska, M., Pospieszna, J., Tang, J., Lisiak, N., Toton, E., Rubis, B., and Murias, M. (2024). The combination therapy using tyrosine kinase receptors inhibitors and repurposed drugs to target patient-derived glioblastoma stem cells. Biomed. Pharmacother., 176.","DOI":"10.1016\/j.biopha.2024.116892"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/j.1600-0447.1992.tb03310.x","article-title":"A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites","volume":"369","author":"Johansson","year":"1992","journal-title":"Acta Psychiatr. Scand. Suppl."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kannappan, V., Ali, M., Small, B., Rajendran, G., Elzhenni, S., Taj, H., Wang, W., and Dou, Q.P. (2021). Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.741316"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Butcher, K., Kannappan, V., Kilari, R.S., Morris, M.R., McConville, C., Armesilla, A.L., and Wang, W. (2018). Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4617-x"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.mam.2005.07.015","article-title":"Copper, oxidative stress, and human health","volume":"26","author":"Keen","year":"2005","journal-title":"Mol. Asp. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1080\/10717544.2020.1825543","article-title":"Protamine and BSA-dextran complex emulsion improves oral bioavailability and anti-tumor efficacy of paclitaxel","volume":"27","author":"Xu","year":"2020","journal-title":"Drug Deliv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e20230014","DOI":"10.1002\/INMD.20230014","article-title":"Pickering emulsion: From controllable fabrication to biomedical application","volume":"1","author":"Pan","year":"2023","journal-title":"Interdiscip. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Jeong, J., Kim, S.H., Lee, S., Lee, D.K., Han, Y., Jeon, S., and Cho, W.S. (2018). Differential Contribution of Constituent Metal Ions to the Cytotoxic Effects of Fast-Dissolving Metal-Oxide Nanoparticles. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00015"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Al-Musawi, M.M.S., Al-Shmgani, H., and Al-Bairuty, G.A. (2022). Histopathological and Biochemical Comparative Study of Copper Oxide Nanoparticles and Copper Sulphate Toxicity in Male Albino Mice Reproductive System. Int. J. Biomater., 2022.","DOI":"10.1155\/2022\/4877637"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e20230008","DOI":"10.1002\/INMD.20230008","article-title":"Engineering multifunctional adhesive hydrogel patches for biomedical applications","volume":"1","author":"Chakraborty","year":"2023","journal-title":"Interdiscip. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"26795","DOI":"10.1021\/acsami.8b08649","article-title":"Aquivion-Carbon Composites with Tunable Amphiphilicity for Pickering Interfacial Catalysis","volume":"10","author":"Zhang","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2100599","DOI":"10.1002\/adma.202100599","article-title":"A Systematic Strategy of Combinational Blow for Overcoming Cascade Drug Resistance via NIR-Light-Triggered Hyperthermia","volume":"33","author":"Wang","year":"2021","journal-title":"Adv. Mater."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11492","DOI":"10.1021\/acsnano.3c01369","article-title":"Tumor-Generated Reactive Oxygen Species Storm for High-Performance Ferroptosis Therapy","volume":"17","author":"Huang","year":"2023","journal-title":"ACS Nano"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.chembiol.2018.02.010","article-title":"Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells","volume":"25","author":"Shimada","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/bjc.2011.126","article-title":"Disulfiram modulated ROS-MAPK and NF\u03baB pathways and targeted breast cancer cells with cancer stem cell-like properties","volume":"104","author":"Yip","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13046-024-02972-6","article-title":"MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis","volume":"43","author":"Wang","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3102","DOI":"10.1158\/0008-5472.CAN-21-2934","article-title":"Caspase-3-Induced Activation of SREBP2 Drives Drug Resistance via Promotion of Cholesterol Biosynthesis in Hepatocellular Carcinoma","volume":"82","author":"Mok","year":"2022","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13045-020-0845-z","article-title":"CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma","volume":"13","author":"Ma","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s12943-022-01647-0","article-title":"The m(6)A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway","volume":"21","author":"Zhang","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1038\/s41418-023-01166-5","article-title":"Collagen I-DDR1 signaling promotes hepatocellular carcinoma cell stemness via Hippo signaling repression","volume":"30","author":"Xiong","year":"2023","journal-title":"Cell Death Differ."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1002\/hep.31571","article-title":"DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma","volume":"73","author":"Nevi","year":"2021","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1186\/s13046-020-01690-z","article-title":"TM4SF1 promotes EMT and cancer stemness via the Wnt\/\u03b2-catenin\/SOX2 pathway in colorectal cancer","volume":"39","author":"Tang","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/hep.28509","article-title":"Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma","volume":"64","author":"Liu","year":"2016","journal-title":"Hepatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1111\/liv.15412","article-title":"ABI2-mediated MEOX2\/KLF4-NANOG axis promotes liver cancer stem cell and drives tumour recurrence","volume":"42","author":"Chen","year":"2022","journal-title":"Liver Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3177","DOI":"10.1038\/s41388-022-02329-3","article-title":"Role of p38 MAP kinase in cancer stem cells and metastasis","volume":"41","author":"Kudaravalli","year":"2022","journal-title":"Oncogene"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"215935","DOI":"10.1016\/j.canlet.2022.215935","article-title":"CD55 in cancer: Complementing functions in a non-canonical manner","volume":"551","author":"Bharti","year":"2022","journal-title":"Cancer Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e31164","DOI":"10.1002\/jcp.31164","article-title":"Up-regulation of TNF-alpha\/NFkB\/SIRT1 axis drives aggressiveness and cancer stem cells accumulation in chemoresistant oral squamous cell carcinoma","volume":"239","author":"Milan","year":"2024","journal-title":"J. Cell. Physiol."},{"key":"ref_49","first-page":"1","article-title":"Sorafenib resistance in hepatocarcinoma: Role of hypoxia-inducible factors","volume":"50","author":"Fondevila","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Gong, M., Yang, H., Zhang, S., Yang, Y., Zhang, D., Qi, Y., and Zou, L. (2015). Superparamagnetic core\/shell GoldMag nanoparticles: Size-, concentration- and time-dependent cellular nanotoxicity on human umbilical vein endothelial cells and the suitable conditions for magnetic resonance imaging. J. Nanobiotechnol., 13.","DOI":"10.1186\/s12951-015-0080-x"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2200801","DOI":"10.1002\/adfm.202200801","article-title":"An Injectable Hydrogel Reshaping Adenosinergic Axis for Cancer Therapy","volume":"32","author":"Zhao","year":"2022","journal-title":"Adv. Funct. Mater."}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/16\/17\/2418\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:43:07Z","timestamp":1760110987000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/16\/17\/2418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,26]]},"references-count":51,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["polym16172418"],"URL":"https:\/\/doi.org\/10.3390\/polym16172418","relation":{},"ISSN":["2073-4360"],"issn-type":[{"value":"2073-4360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,26]]}}}