{"id":{"repo_id":"wlv","oai_identifier":"oai:wlv.openrepository.com:2436/626016"},"canonical_url":"https://search.dev.ndltd.org/etd/wlv/oai:wlv.openrepository.com:2436/626016","repository":{"repo_id":"wlv","name":"University of Wolverhampton","base_url":"https://wlv.openrepository.com/server/oai/request"},"display":{"title":"In vitro investigation of the anticancer activity and molecular mechanisms of action of albumin nano-encapsulated copper/zinc diethyldithiocarbamate in human pancreatic cancer cells","abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a 5-year survival rate of 12%, and is projected to become the second leading cause of cancer-related mortality by 2030. Chemotherapy remains the main treatment option but offers limited benefits due to toxicity and chemoresistance, underscoring the need for novel, effective therapies. Disulfiram (DSF), an FDA-approved anti-alcoholism drug, has demonstrated potent anticancer activity when chelated with Cu²⁺ or Zn²⁺ ions to form copper diethyldithiocarbamate (Cu(DDC)₂) or zinc diethyldithiocarbamate (Zn(DDC)₂). However, the clinical anticancer application of DSF is hindered by a short plasma half-life (<4 minutes) and bioavailability challenges from separate Cu/Zn supplementation. To address these limitations, we developed albumin-based nanoparticles (Alb-CuDDC and Alb-ZnDDC) that encapsulate Cu(DDC)₂ or Zn(DDC)₂ to achieve stable, soluble, and long-circulating formulations. Alb-CuDDC and Alb-ZnDDC nanoparticles exhibited potent anticancer efficacy in PDAC patient-derived cultures from primary, circulating and metastatic sites, under normoxic, hypoxic and spheroid conditions. The albumin formulations showed effective cytotoxicity across a panel of PDAC cells and had similar IC₅₀ values to free drug (Alb-CuDDC: 193 ± 11 nM vs Free Cu(DDC)2: 210 ± 76 nM and Alb- ZnDDC: 7076 ± 612 vs Free Zn(DDC)2: 7122 ± 487 nM). Furthermore, Alb-CuDDC and Alb-ZnDDC synergistically enhanced the activity of gemcitabine and paclitaxel. To evaluate the potential for acquired resistance, long-term exposure studies were conducted in PANC1 and MDA-MB231 cells. Resistance emerged to Alb-ZnDDC but not to Alb-CuDDC or free DSF + Cu. The resistant cell lines (PANC1ZR6 and MDAMB231ZR7) represent a significant finding, being the first report of such resistance in the context of dithiocarbamate-based agents. Transcriptomic analysis led to the identification of a putative resistance mechanism which implicated cysteine protease inhibitor, CST1, as a mediator of Alb-ZnDDC resistance. This study highlights Alb-CuDDC and Alb-ZnDDC as promising nanotherapeutics for PDAC. However, the resistance profile of Alb-ZnDDC underscores the superior therapeutic potential of Alb-CuDDC. Moreover, the identification of CST1 provides insight into resistance mechanisms and highlights potential targets for overcoming similar resistance pathways.","abstract_html":"Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a 5-year survival rate of 12%, and is projected to become the second leading cause of cancer-related mortality by 2030. Chemotherapy remains the main treatment option but offers limited benefits due to toxicity and chemoresistance, underscoring the need for novel, effective therapies. Disulfiram (DSF), an FDA-approved anti-alcoholism drug, has demonstrated potent anticancer activity when chelated with Cu²⁺ or Zn²⁺ ions to form copper diethyldithiocarbamate (Cu(DDC)₂) or zinc diethyldithiocarbamate (Zn(DDC)₂). However, the clinical anticancer application of DSF is hindered by a short plasma half-life (&lt;4 minutes) and bioavailability challenges from separate Cu/Zn supplementation. To address these limitations, we developed albumin-based nanoparticles (Alb-CuDDC and Alb-ZnDDC) that encapsulate Cu(DDC)₂ or Zn(DDC)₂ to achieve stable, soluble, and long-circulating formulations. Alb-CuDDC and Alb-ZnDDC nanoparticles exhibited potent anticancer efficacy in PDAC patient-derived cultures from primary, circulating and metastatic sites, under normoxic, hypoxic and spheroid conditions. The albumin formulations showed effective cytotoxicity across a panel of PDAC cells and had similar IC₅₀ values to free drug (Alb-CuDDC: 193 ± 11 nM vs Free Cu(DDC)2: 210 ± 76 nM and Alb- ZnDDC: 7076 ± 612 vs Free Zn(DDC)2: 7122 ± 487 nM). Furthermore, Alb-CuDDC and Alb-ZnDDC synergistically enhanced the activity of gemcitabine and paclitaxel. To evaluate the potential for acquired resistance, long-term exposure studies were conducted in PANC1 and MDA-MB231 cells. Resistance emerged to Alb-ZnDDC but not to Alb-CuDDC or free DSF + Cu. The resistant cell lines (PANC1ZR6 and MDAMB231ZR7) represent a significant finding, being the first report of such resistance in the context of dithiocarbamate-based agents. Transcriptomic analysis led to the identification of a putative resistance mechanism which implicated cysteine protease inhibitor, CST1, as a mediator of Alb-ZnDDC resistance. This study highlights Alb-CuDDC and Alb-ZnDDC as promising nanotherapeutics for PDAC. However, the resistance profile of Alb-ZnDDC underscores the superior therapeutic potential of Alb-CuDDC. Moreover, the identification of CST1 provides insight into resistance mechanisms and highlights potential targets for overcoming similar resistance pathways.","abstract_has_math":false,"creators":["Small, Benjamin"],"institution":"University of Wolverhampton","degree_name":"PhD","degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Wang, Weiguang"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025","date_published":"2025","updated_at":"2026-07-24T06:09:17Z","subjects":["pancreatic ductal adenocarcinoma","disulfiram","zinc diethyldithiocarbamate","copper diethyldithiocarbamate","acquired resistance","lysosomal membrane permeabilization","cystatin","cancer stem cells","epithelial to mesenchymal transition"],"languages":[],"rights":[],"rights_urls":["https://wlv.openrepository.com/bitstreams/e9a6f65c-5d5e-45d1-b4e7-34032afd5ebc/download"],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Wang, Weiguang"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["European Regional Development Fund"]},{"key":"dc:creator","label":"Author","values":["Small, Benjamin"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Wolverhampton"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://wlv.openrepository.com/handle/2436/626016"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or dissertation"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["pancreatic ductal adenocarcinoma","disulfiram","zinc diethyldithiocarbamate","copper diethyldithiocarbamate","acquired resistance","lysosomal membrane permeabilization","cystatin","cancer stem cells","epithelial to mesenchymal transition"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["https://wlv.openrepository.com/bitstreams/e9a6f65c-5d5e-45d1-b4e7-34032afd5ebc/download"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://wlv.openrepository.com/bitstreams/d6372a34-21b7-4861-88ba-c0cc964ebc5b/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a 5-year survival rate of 12%, and is projected to become the second leading cause of cancer-related mortality by 2030. Chemotherapy remains the main treatment option but offers limited benefits due to toxicity and chemoresistance, underscoring the need for novel, effective therapies. Disulfiram (DSF), an FDA-approved anti-alcoholism drug, has demonstrated potent anticancer activity when chelated with Cu²⁺ or Zn²⁺ ions to form copper diethyldithiocarbamate (Cu(DDC)₂) or zinc diethyldithiocarbamate (Zn(DDC)₂). However, the clinical anticancer application of DSF is hindered by a short plasma half-life (<4 minutes) and bioavailability challenges from separate Cu/Zn supplementation. To address these limitations, we developed albumin-based nanoparticles (Alb-CuDDC and Alb-ZnDDC) that encapsulate Cu(DDC)₂ or Zn(DDC)₂ to achieve stable, soluble, and long-circulating formulations. Alb-CuDDC and Alb-ZnDDC nanoparticles exhibited potent anticancer efficacy in PDAC patient-derived cultures from primary, circulating and metastatic sites, under normoxic, hypoxic and spheroid conditions. The albumin formulations showed effective cytotoxicity across a panel of PDAC cells and had similar IC₅₀ values to free drug (Alb-CuDDC: 193 ± 11 nM vs Free Cu(DDC)2: 210 ± 76 nM and Alb- ZnDDC: 7076 ± 612 vs Free Zn(DDC)2: 7122 ± 487 nM). Furthermore, Alb-CuDDC and Alb-ZnDDC synergistically enhanced the activity of gemcitabine and paclitaxel. To evaluate the potential for acquired resistance, long-term exposure studies were conducted in PANC1 and MDA-MB231 cells. Resistance emerged to Alb-ZnDDC but not to Alb-CuDDC or free DSF + Cu. The resistant cell lines (PANC1ZR6 and MDAMB231ZR7) represent a significant finding, being the first report of such resistance in the context of dithiocarbamate-based agents. Transcriptomic analysis led to the identification of a putative resistance mechanism which implicated cysteine protease inhibitor, CST1, as a mediator of Alb-ZnDDC resistance. This study highlights Alb-CuDDC and Alb-ZnDDC as promising nanotherapeutics for PDAC. However, the resistance profile of Alb-ZnDDC underscores the superior therapeutic potential of Alb-CuDDC. Moreover, the identification of CST1 provides insight into resistance mechanisms and highlights potential targets for overcoming similar resistance pathways."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["8648e4f22ba348ebe65beb488bb8e572","79cc9c558089c2829a28510d0296eb06","49a995938c878f1c9245bb20ead47903"]},{"key":"dc:title","label":"Title","values":["In vitro investigation of the anticancer activity and molecular mechanisms of action of albumin nano-encapsulated copper/zinc diethyldithiocarbamate in human pancreatic cancer cells"]}]}],"canonical_facts":{"dc:contributor.advisor":["Wang, Weiguang"],"dc:contributor.sponsor":["European Regional Development Fund"],"dc:creator":["Small, Benjamin"],"dc:date.issued":["2025"],"dc:description.abstract":["Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a 5-year survival rate of 12%, and is projected to become the second leading cause of cancer-related mortality by 2030. Chemotherapy remains the main treatment option but offers limited benefits due to toxicity and chemoresistance, underscoring the need for novel, effective therapies. Disulfiram (DSF), an FDA-approved anti-alcoholism drug, has demonstrated potent anticancer activity when chelated with Cu²⁺ or Zn²⁺ ions to form copper diethyldithiocarbamate (Cu(DDC)₂) or zinc diethyldithiocarbamate (Zn(DDC)₂). However, the clinical anticancer application of DSF is hindered by a short plasma half-life (<4 minutes) and bioavailability challenges from separate Cu/Zn supplementation. To address these limitations, we developed albumin-based nanoparticles (Alb-CuDDC and Alb-ZnDDC) that encapsulate Cu(DDC)₂ or Zn(DDC)₂ to achieve stable, soluble, and long-circulating formulations. Alb-CuDDC and Alb-ZnDDC nanoparticles exhibited potent anticancer efficacy in PDAC patient-derived cultures from primary, circulating and metastatic sites, under normoxic, hypoxic and spheroid conditions. The albumin formulations showed effective cytotoxicity across a panel of PDAC cells and had similar IC₅₀ values to free drug (Alb-CuDDC: 193 ± 11 nM vs Free Cu(DDC)2: 210 ± 76 nM and Alb- ZnDDC: 7076 ± 612 vs Free Zn(DDC)2: 7122 ± 487 nM). Furthermore, Alb-CuDDC and Alb-ZnDDC synergistically enhanced the activity of gemcitabine and paclitaxel. To evaluate the potential for acquired resistance, long-term exposure studies were conducted in PANC1 and MDA-MB231 cells. Resistance emerged to Alb-ZnDDC but not to Alb-CuDDC or free DSF + Cu. The resistant cell lines (PANC1ZR6 and MDAMB231ZR7) represent a significant finding, being the first report of such resistance in the context of dithiocarbamate-based agents. Transcriptomic analysis led to the identification of a putative resistance mechanism which implicated cysteine protease inhibitor, CST1, as a mediator of Alb-ZnDDC resistance. This study highlights Alb-CuDDC and Alb-ZnDDC as promising nanotherapeutics for PDAC. 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Moreover, the identification of CST1 provides insight into resistance mechanisms and highlights potential targets for overcoming similar resistance pathways."],"dc:format.checksum.md5":["8648e4f22ba348ebe65beb488bb8e572","79cc9c558089c2829a28510d0296eb06","49a995938c878f1c9245bb20ead47903"],"dc:identifier.uri":["https://wlv.openrepository.com/bitstreams/d6372a34-21b7-4861-88ba-c0cc964ebc5b/download"],"dc:publisher.institution":["University of Wolverhampton"],"dc:relation.isreferencedby":["https://wlv.openrepository.com/handle/2436/626016"],"dc:rights":["https://wlv.openrepository.com/bitstreams/e9a6f65c-5d5e-45d1-b4e7-34032afd5ebc/download"],"dc:subject":["pancreatic ductal adenocarcinoma","disulfiram","zinc diethyldithiocarbamate","copper diethyldithiocarbamate","acquired resistance","lysosomal membrane permeabilization","cystatin","cancer stem cells","epithelial to mesenchymal transition"],"dc:title":["In vitro investigation of the anticancer activity and molecular mechanisms of action of albumin nano-encapsulated copper/zinc diethyldithiocarbamate in human pancreatic cancer cells"],"dc:type":["Thesis or dissertation"],"dc:type.qualificationname":["PhD"]},"updated_at":"2026-07-24T06:09:17Z"}