Abstract:
Gemcitabine is the gold-standard treatment in pancreatic cancer. However, the poor pharmacokinetics of gemcitabine necessitates its frequent administration at high dose, contributing to its adverse effect. Considering the synergistic effects exhibited by gemcitabine and tocotrienols in pancreatic cancer, entrapping gemcitabine and tocotrienols in a nanocarrier as a combination therapy would be potential strategy to tackle the issue. Therefore, this study aims to identify a nanocarrier that can co-encapsulate both gemcitabine and tocotrienols in a system to have an effect on pancreatic cancer cells. Niosomes composed of Span 60, cholesterol and D-α-tocopheryl polyethylene glycol 1000 succinate at molar ratio 1:1:0.22 were produced by stirring and film hydration methods. The niosomes were characterised for morphology, size, polydispersity index, zeta potential, entrapment efficiency and stability. Gemcitabine and tocotrienols were loaded at different ratios (1:1 to 1:5) and the best ratio was dose-escalated (0.5 to 2.5 mg/mL). The optimum formulation was used for in vitro analysis. In align with the first goal of this study to prepare and characterise niosomes co-entrapping the dual drugs, this work compared the effect of two preparation techniques on niosomes’ physicochemical properties. Film hydration produced spherical, smaller, more uniform and more stable niosomes than stirring niosomes. Film hydration niosomes with drug ratio of 1:1 and concentration 1 mg/mL with maximum entrapment efficiencies of 20.07 ± 0.215% for gemcitabine and 34.52 ± 0.100% for tocotrienol-rich-fraction (TRF) was chosen as the optimum formulation. In line with second objective, the formulation was tested on pancreatic cancer cells in vitro. Enhancement of gemcitabine’s antiproliferative effect by TRF and significant 2.78-fold reduction in growth inhibitory concentration for 50% of cell population of gemcitabine when given in combination with TRF were observed in Panc 10.05 cells. Niosomes further significantly improved the efficacy of gemcitabine and TRF combination supported by the cell morphological changes and the enhanced cellular uptake of the drugs in Panc 10.05 cells. In conclusion, this is a proof-of-concept that the entrapment of the gemcitabine and TRF in niosomes can be promising strategy combination therapy in specific type of pancreatic cancer.
