Development of Imperatorin Nanostructured Lipid Carriers with Grape Seed Oil for Boosting Oral Absorption and...

Imperatorin (IPT) is a naturally occurring coumarin with recognized antioxidant and anti-aging properties; unfortunately, its poor water solubility and low oral bioavailability severely limit its practical use. To get around these issues, we formulated IPT-loaded NLCs using grape seed oil and glyceryl monostearate-both food-grade excipients-with the goal of enhancing oral absorption. Optimized IPT@NLCs were prepared by high-pressure homogenization, featuring uniform spherical morphology, an average particle size of 186.63 ± 1.65 nm, a PDI of 0.188 ± 0.008, an encapsulation efficiency of 99.54 ± 0.10%, and a drug loading capacity of 9.08 ± 0.23%. IPT@NLCs remained stable in SGF, while their cumulative in vitro release over 48 h reached 90.56 ± 3.12% in SIF. We established a Caco-2/HT29-MTX-E12 co-culture monolayer to examine mucus penetration, cellular uptake, and transcellular transport routes. In parallel, oxidative stress experiments using 3T3-L1 cells, along with in vivo pharmacokinetic and gastrointestinal safety evaluations, were conducted to provide complementary evidence. Our results indicate that NLC encapsulation significantly improves both the dissolution and intestinal uptake of IPT, primarily by shifting the absorption mechanism from passive diffusion to energy-dependent active transport. In addition, IPT@NLCs effectively reduce intracellular oxidative damage through modulation of endogenous antioxidant enzyme activities. Animal studies further reveal an approximately 9-fold increase in relative oral bioavailability, with no notable irritation to gastrointestinal tissues. Overall, GSO-based NLCs offer safe and efficient oral delivery, enhancing IPT bioavailability and antioxidant activity, providing a strategy for developing natural-product-based formulations.