Synthesis, characterization, toxicity and morphology assessments of newly prepared microemulsion systems for delivery of valproic acid

Valproic acid (VPA), an anti-epileptic drug used to treat seizures, epilepsy, and psychological disorders, has shown promising antitumor potential; however, the side effects are a serious concern. This effort reports the nano-formulation and characterization of oil-in-water F127/lignin microemulsions to enhance the bioavailability of valproic acid (VPA). Microemulsions showed a high encapsulation efficiency and prolonged release. F127/VPA and lignin/VPA microemulsions were tested for their cytotoxic activity via MTT colorimetric assay and LDH leakage assay in cancerous (MCF7 and Hela) and normal (HUVEC) cell lines. High encapsulation efficiency and sustained release were observed for F127/VPA microemulsions. Cell proliferation assays showed that VPA microemulsions induced evident morphological alterations and were more effective than the free drug in inhibiting the growth of cancer cells. In contrast, normal cells seem to be less affected by these formulations. Moreover, F127/VPA microemulsions significantly increased caspase-3 activity in Hela cells (P < 0.05). In vivo administration of free VPA at the dose of 20 mg/kg significantly increased serum biochemical parameters and liver lipid peroxidation in rats compared to the control rats. In addition, the 20 mg/kg of free VPA significantly increased liver lipid peroxidation. The group treated with the 20 mg/kg dose of F127/VPA microemulsions showed increased toxicity compared to the group treated with lignin/VPA microemulsions and free VPA. Molecular simulations revealed that the formation of seven and six-member rings via HB interactions between VPA and F127 influence the stability of the corresponding microemulsion systems and may help to a better action of F127/VPA in comparison to free VPA. Together, our experimental and theoretical findings highlight the opportunity to exploit surfactant microemulsion systems for efficient VPA delivery to target progressive cancer cells and prevent undesirable toxicity leading to tissue injuries. © 2021 Elsevier B.V.