Mitoxantrone and Mitoxantrone-Loaded Iron Oxide Nanoparticles Induce Cell Death in Human Pancreatic Ductal Adenocarcinoma Cell Spheroids

Pancreatic ductal adenocarcinoma is a hard-to-treat, deadly malignancy. Traditional treatments, such as surgery, radiation and chemotherapy, unfortunately are still not able to significantly improve long-term survival. Three-dimensional (3D) cell cultures might be a platform to study new drug types in a highly reproducible, resource-saving model within a relevant pathophysiological cellular microenvironment. We used a 3D culture of human pancreatic ductal adenocarcinoma cell lines to investigate a potential new treatment approach using superparamagnetic iron oxide nanoparticles (SPIONs) as a drug delivery system for mitoxantrone (MTO), a chemotherapeutic agent. We established a PaCa DD183 cell line and generated PANC-1(SMAD4 (-/-)) cells by using the CRISPR-Cas9 system, differing in a prognostically relevant mutation in the TGF-beta pathway. Afterwards, we formed spheroids using PaCa DD183, PANC-1 and PANC-1(SMAD4 (-/-)) cells, and analyzed the uptake and cytotoxic effect of free MTO and MTO-loaded SPIONs by microscopy and flow cytometry. MTO and SPION-MTO-induced cell death in all tumor spheroids in a dose-dependent manner. Interestingly, spheroids with a SMAD4 mutation showed an increased uptake of MTO and SPION-MTO, while at the same time being more resistant to the cytotoxic effects of the chemotherapeutic agents. MTO-loaded SPIONs, with their ability for magnetic drug targeting, could be a future approach for treating pancreatic ductal adenocarcinomas.

Automated summary

Pancreatic ductal adenocarcinoma is a difficult-to-treat cancer with poor long-term survival rates. In this study, a 3D cell culture model of human pancreatic ductal adenocarcinoma was used to investigate the potential use of superparamagnetic iron oxide nanoparticles (SPIONs) as a drug delivery system for the chemotherapeutic agent mitoxantrone (MTO). The results showed that MTO-loaded SPIONs induced cell death in tumor spheroids, with increased uptake in spheroids with a SMAD4 mutation. This suggests that MTO-loaded SPIONs could be a promising approach for treating pancreatic ductal adenocarcinomas.