Pancreatic ductal adenocarcinoma remains a highly aggressive and untreatable cancer. There is a need to develop a new PDAC-associated antigen-targeting drug delivery system to tackle this disease. We validated choosing ZIP4 as a putative target in PDAC theranostics. We developed a nanosystem composed of a fluorescent polystyrene core coated with gold nanoparticles onto which a ZIP4-specific polyclonal antibody is attached. The polystyrene core's fluorescence properties allow the nanosystem tracking by intravital imaging. We also developed two ZIP4-expressing cell lines by stably transfecting HEK293 and RWP1 cells with a ZIP4-coding plasmid that simultaneously provides cells with puromycin resistance. We studied the cell internalisation of the as-synthesised nanoparticles and demonstrated that ZIP4-expressing HEK293 and ZIP4-expressing RWP1 cells tended to take up more ZIP4-targeting nanoparticles. Moreover, we observed that ZIP4-targeting nanoparticles accumulated more in ZIP4-expressing HEK293 and RWP1 tumours when injected intravenously in a subcutaneous xenograft and an orthotopic in vivo model, respectively. Furthermore, the administration of these nanoparticles did not induce any significant systemic toxicity as determined by histological analysis of all organs. Altogether, these results provide the first evidence of the feasibility of using a ZIP4-targeting nanosystem further to design efficient therapeutic and diagnostic tools for PDAC.

Pilar Rivera Gil (PRG) acknowledges the Ministry of Science, Innovation and Universities (MICINN-AEI): CNS2023 - 143700 - MICIU/AEI/10.13039/501100011033/Unión Europea NextGenerationEU/PRTR and PID2022-140423NB-I00 for financial support. Rubén Vicente acknowledges the MICINN-AEI (PID2022-136511OB-I00). PRG acknowledges the AGAUR (Agència de Gestió d’Ajuts Universitaris i de Recerca) (2021 SGR 00175 and 2021 PROD 00041) for financial support. This work was also supported by grants from the Spanish Ministry of Science and Innovation (MICINN)/Instituto de Salud Carlos III (ISCIII)-European Regional Development Fund (ERDF) (PI20/00625 and PI23/00591) to Pilar Navarro.

Peer reviewed