Improved oral bioavailability of paclitaxel through folate-engineered zein nanoparticles: Evaluation in intestinal organoid and in vivo models

Abstract

Oral administration remains the most accessible route for drug delivery. Paclitaxel is a natural lipophilic agent with significant antineoplastic efficacy against various malignancies. However, its clinical application is limited by low solubility, systemic toxicity, and poor bioavailability. In this study, we engineered modified zein nanoparticles for oral delivery by using PEGylated zein as a biocompatible nanocarrier, combined with folate receptor targeting on intestinal epithelial cells. The conjugation of folic acid was confirmed via FT-IR and ¹HNMR analyses. Atomic force microscopy (AFM) revealed that the nanoparticles were spherical, had a diameter under 200 nm, and maintained stability under gastrointestinal pH conditions. Furthermore, uptake assessments in multicellular spheroids and intestinal organoid models showed greater accumulation and penetration of conjugated zein nanocarriers compared to non-targeted particles. The in vivo assessment of nanoparticle biodistribution via oral administration showed extended retention of folate-modified zein nanoparticles in the rat gastrointestinal tract for up to 24 h. Pharmacokinetic analysis in vivo demonstrated that targeted nanoparticles increased paclitaxel plasma concentrations in rabbits to over seven times that of the unformulated drug. These findings highlight the novelty of folate-modified zein nanoparticles platform in improving the oral bioavailability of poorly soluble drugs, demonstrating their promise for advanced drug delivery.

Keywords: Folic acid; Intestinal organoids; Paclitaxel; Targeted oral delivery; Zein.