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

Abstract

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-1SMAD4 (−/−) cells by using the CRISPR-Cas9 system, differing in a prognostically relevant mutation in the TGF-β pathway. Afterwards, we formed spheroids using PaCa DD183, PANC-1 and PANC-1SMAD4 (−/−) 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.

Synergistic Effect of Chemotherapy and Magnetomechanical Actuation of Fe-Cr-Nb-B Magnetic Particles on Cancer Cells

“…According to several studies, − magnetic nanoparticles are coated and functionalized with polymers, surfactants, or proteins for the enhancement of the drug loading efficiency of antitumoral substances. The polymer coatings also may bring several disadvantages, such as possible cytotoxicity, high molecular weight with an increase of nanoparticle size, and specific surface chemistry that leads to limited drug choices and more steps in particle synthesis.…”

CRISPR/Cas9 systems: Delivery technologies and biomedical applications

“…Superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as a groundbreaking agent for the diagnosis and treatment of cancer [111] . Magnetic drug targeting utilizing SPIONs enables the precise delivery of therapy under the control of an external magnetic field, offering the advantages of high effectiveness, efficiency, and minimal side effects [112] .…”