Objective(s): Recently, medicinal plants have grabbed much attention in the prevention and treatment of cancer due to their ability to increase the efficiency of chemotherapy agents. Luteolin is a flavonoid widely studied for its antitumor effects. However, luteolin has low bioavailability and poor efficacy due to its hydrophobicity. This study aimed to prepare luteolin nanoemulsion (NE) and evaluate its physicochemical and anti-tumor properties in combination with doxorubicin (DOX) in vitro. Materials and Methods: NE containing luteolin was prepared by the prob-sonicate method. The physicochemical properties of nanoparticles, including particle size, zeta potential, morphology, encapsulation efficiency, viscosity, pH, drug release profile, and thermal stability were investigated. Finally, the toxicity of free luteolin and luteolin NEs at different concentrations, with and without DOX, was assessed against normal L929 fibroblast and C26 colon cancer cells in vitro. Results: Luteolin NE was found to mimic a non-newtonian fluid with pH: 5.5 and an average particle size of 38.72 nm. The encapsulation efficiency was obtained at 79.61%. No significant changes were observed in particle size, PDI, and zeta potential after three months of storage at 4 °C. Seventy-two-hour drug release from these nanoparticles was about 25% in a neutral environment and 85% in an acidic environment. The combination of DOX and luteolin NE showed synergistic antitumor effects, while neither free luteolin nor luteolin NE showed significant toxicity against normal cells up to the 50 μg/ml concentration. Conclusion: The simultaneous administration of DOX and luteolin NE synergistically increased the cytotoxicity of DOX against the C26 cell line. Therefore, the novel formulation developed can be considered a suitable alternative to increase the anti-tumor efficiency of DOX.

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