Preclinical Development of Magnetic Nanoparticles for Hyperthermia Treatment of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a very challenging disease with a very poor prognosis. It is characterized by a dense desmoplastic stroma that hampers drug penetration and limits the effectiveness of conventional chemotherapy (CT). As an alternative, the combination of CT with hyperthermia (HT) has been proposed as an innovative treatment modality for PDAC. In previous works, we reported on the development of iron oxide magnetic nanoparticles (MNPs) that, when exposed to time-varying magnetic fields, exhibit strong HT responses that inhibited the growth of pancreatic cancers. We report here on advances toward the clinical use of these MNPs as an intratumorally administered sterile magnetic fluid (the "NoCanTher ThermoTherapy" or "NTT" Agent) alongside intravenous standard-of-care drugs (gemcitabine and nab-paclitaxel) for the treatment of PDAC. In vitro cell viability assays show that the combination of low doses of CT and HT is highly synergistic, particularly in the BxPC-3 cell line. In vivo, biodistribution assays showed that the NTT Agent MNPs remained mainly within the tumor, concentrated around areas with a high stromal component. Moreover, the combined CT/HT treatment shows clear advantages over CT alone in terms of drug penetration and reduction of the tumor volume, suggesting a potential direct effect of HT in the disruption of the interstitial stroma to facilitate the access of the drugs to malignant cells. These studies have led to the approval and commencement of a clinical investigational study at the Vall d'Hebron University Hospital (Barcelona, Spain) of the NTT Agent alongside CT in patients with locally advanced PDAC.