Cocktail of lipophilic and hydrophilic chemotherapeutics in high-load core@shell nanocarriers to treat pancreatic tumours

Abstract

ITC/Toc@Gd₂(FLP)₃ core@shell nanocarriers with a chemotherapeutic cocktail of lipophilic irinotecan (ITC) as the particle core and hydrophilic fludarabine phosphate (FLP) in the particle shell are realized. They are prepared via a microemulsion approach with ITC dissolved in tocopherol (Toc) as droplet phase and stabilized by water-insoluble Gd₂(FLP)₃. The synthesis can be followed by zeta-potential analysis. X-ray powder diffraction, infrared spectroscopy, elemental analysis, thermogravimetry, and photometry show a drug load of 49 μg per mL ITC and 317 μg per mL FLP at a nanocarrier concentration of 1.5 mg mL⁻¹. Size and structure are evidenced by electron microscopy, resulting in a total diameter of 45 ± 16 nm, an inner core of 40 ± 17 nm, and a shell of 3–8 nm. In vitro studies with different cancer cell lines (i.e., human melanoma/SK-Mel-28, cervical cancer/HeLa, mouse pancreatic cancer/Panc02 and KPC as well as human pancreatic cancer/Capan-1 cells) prove efficient nanocarrier uptake and promising cytostatic efficacy. Specifically for KPC cells, ITC/Toc@Gd₂(FLP)₃ nanocarriers show an increased efficacy, with half maximal inhibitory concentration (IC₅₀: 4.2 μM) > 10 times lower than the free drugs (IC₅₀: ITC: 47.7 μM, FLP: 143 μM). This points to the synergistic effect of the ITC/FLP drug cocktail in the nanocarriers and may result in a promising strategy to treat pancreatic ductal adenocarcinoma (PDAC).