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

Oral administration remains the most accessible and patient-friendly route for drug delivery. Paclitaxel, a potent anticancer agent sourced from natural origins, presents a highly lipophilic profile, and demonstrates substantial antineoplastic efficacy across various malignancies. However, its clinical application is limited by intrinsic hurdles, including low solubility, systemic toxicity, and limited bioavailability. In this study, we engineered folate-modified zein nanoparticles for oral delivery purposes. Our hypothesis posited that utilizing PEGylated zein as a biocompatible, stable nanocarrier, combined with folate receptor targeting on intestinal epithelial cells, could improve cellular uptake and translocation of these nanoformulations. Conjugation of folic acid was verified using FT-IR and H1NMR analyses. Atomic force microscopy (AFM) unveiled that the nanoparticles were nearly spherical, with a diameter under 200 nm, and maintained stability under gastrointestinal pH conditions. Furthermore, uptake assessments in multicellular spheroid and intestinal organoid models indicated that folate-conjugated nanoparticles exhibited significantly enhanced accumulation and penetration compared to non-targeted zein nanocarriers. Dir, a near-infrared dye, facilitated the in vivo assessment of nanoparticle biodistribution via oral administration, with folate-modified zein nanoparticles showing extended gastrointestinal retention in rats for up to 24 hours. Pharmacokinetic analysis in vivo demonstrated that targeted nanoparticles increased paclitaxel plasma concentrations in rabbits to over seven times that of the unformulated drug. Collectively, these findings underscore the effectiveness of folate-modified zein nanoparticles in enhancing the oral bioavailability of drugs with poor solubility, underscoring their potential in advanced oral delivery applications.