Unveiling the Cytotoxicity Potential of Nanoemulsion of Peltophorum pterocarpum Extract: A Natural Hemocompatible Injection Competing with Doxorubicin

<b>Background/Objectives</b>: According to the WHO, more than one million deaths of liver cancer patients will occur in 2030. Hepatocellular carcinoma (HCC) is the third leading cause of death among all cancer types. Doxorubicin is commonly used for the treatment of HCC, yet it possesses major side effects. The aim of this work was to formulate a nanoemulsion of <i>Peltophorum pterocarpum</i> extract containing bergenin intended for intravenous injection as a natural alternative to doxorubicin. <b>Methods</b>: The saturation solubility of the extract in different oils, surfactants, and co-surfactants was determined. Surfactant to co-surfactant mixtures (Smix) were used at six different weight ratios. A pseudoternary phase diagram was constructed, and the ratio with the highest area was chosen. Six formulations were prepared by changing the oil-to-Smix ratio. They were evaluated by percentage transmission, dilution test, self-emulsification, pH, viscosity, drug content, droplet size, PDI, zeta potential, TEM, in vitro drug release, stability, in vitro hemolysis percentage, and cytotoxicity (for the optimized formula). <b>Results</b>: F6 of oil-to-Smix ratio (1:6) was chosen for further investigations, as it possesses the lowest droplet size, the highest zeta potential, drug content, and in vitro drug release. The pH, viscosity, and self-emulsification time of F6 were also acceptable. F6 possesses shelf-life stability and is hemocompatible. It possesses high cytotoxicity against the HepG-2 cell line (IC₅₀ = 14.19 µg/mL). <b>Conclusions</b>: Although the nanoemulsion is less potent than doxorubicin in terms of IC₅₀, it offers a safer profile and natural origin, which may be used for the treatment of HCC.