Enhancing oral bioavailability and reducing gastrointestinal toxicity of Tilianin via folic acid-modified nanocrystal liposomes

Enterohepatic circulation can prolong the residence time of drugs and also increase the gastrointestinal toxicity . Tilianin (Til), a flavonoid with significant anti-inflammatory potential, has limited clinical use due to poor water solubility. Nanotechnology, such as nanocrystals, can enhance Til's solubility and oral bioavailability, but the enterohepatic circulation properties of Til also increase gastrointestinal toxicity. To address this, we developed folic acid (FA) decorated phospholipid vesicle loading with Til nanocrystals (FA-Lipo@Til NCs) to improve the bioavailability and reduce enterohepatic circulation effects. FA-Lipo@Til NCs had a mean particle size of 139.92 ± 1.02 nm, were electrically neutral, and exhibited an encapsulation efficiency of 87.32 ± 0.53 % with a drug loading of 48.61 ± 0.65 %. Transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR) confirmed successful encapsulation, enhancing the stability and integrity of Til nanocrystals. In vitro release studies showed more controlled and sustained release compared to crude Til and unmodified Til NCs. Intestinal absorption studies demonstrated significant enhancement of Til absorption, particularly in the ileum and Peyer's patches (PPs). Pharmacokinetic analysis revealed that the area under the plasma concentration-time curve (AUC 0-∞ ) was 9.43-fold and 3.63-fold higher than that of crude Til and Til NCs, respectively, indicating a significant improvement in systemic exposure. Importantly, FA-Lipo@Til NCs did not exhibit secondary absorption peaks in the plasma concentration-time profile, suggesting a reduction in enterohepatic recirculation. This alteration in pharmacokinetics may contribute to reduced gastrointestinal toxicity while maintaining prolonged systemic circulation . Biocompatibility assessments in mice confirmed that FA-Lipo@Til NCs exhibited no observable toxicity in hepatic and intestinal tissues. In conclusion, FA-Lipo@Til NCs offer a promising strategy to enhance drug absorption while avoiding gastrointestinal toxicity and side effects . FA-Lipo@Til NCs improve Til's solubility, stability, and oral bioavailability (9.43-fold), avoid enterohepatic circulation, reduce gastrointestinal toxicity, and provide controlled release via FA functionalization and phospholipid encapsulation.