University of Wolverhampton
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
dc:description.abstractPancreatic 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.
Degree
thesis:*- Name dc:type.qualificationname
- PhD
- Grantor dc:publisher.institution
- University of Wolverhampton
- Year dc:date.issued
- 2025
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Small, Benjamin
- Advisor dc:contributor.advisor
-
- Wang, Weiguang