Full Length ArticleRational design of hybrid nanomicelles integrating mucosal penetration and P-glycoprotein inhibition for efficient oral delivery of paclitaxel

•A dual functional material with P-gp inhibition and mucosal penetration is obtained.•Hybrid CS-VES/TPGS-SH nanomicelles were fabricated.•The P-gp inhibition effect of TPGS-SH was comparable with verapamil.•Hybrid nanomicelles reduced the distribution of paclitaxel in mucus layer.

A dual functional TPGS-succinic acid-mercaptoethylamine (TPGS-SH) material was synthesized to improve the oral absorption of anticancer drugs, aiming to integrate the advantages of mucosal penetration with P-glycoprotein (P-gp) inhibition. Paclitaxel-loaded hybrid nanomicelles (CS-VES/TPGS-SH) with a uniform particle size (234.2-273.9 nm), high drug loading (11.50 ± 0.91%), and good encapsulation efficiency (86.18 ± 3.73%) were fabricated. The absorption rate and apparent permeability coefficient were significantly improved in the whole intestine, especially in the duodenum segment, with a 3.68- and 3.22-fold enhancement being detected after perfusion with CS-VES/TPGS-SH hybrid nanomicelles. Moreover, TPGS-SH showed a considerable P-gp inhibition effect with verapamil. CS-VES/TPGS-SH nanomicelles can effectively pass through the mucosal layer and increase the intracellular drug content in duodenum, jejunum, and colon segments as further reflected by the in situ mucosal penetration study. Maximum concentration (Cmax) and area under curve (AUC(0-t)) values of hybrid nanomicelles were improved by 3.39- and 3.58-fold, respectively, compared to those of paclitaxel solution in rats. Therefore, the designed bifunctional hybrid CS-VES/TPGS-SH nanomicelles could function as efficient drug carriers, facilitating the oral absorption of hydrophobic anticancer drugs.

Graphical abstractBifunctional CS-VES/TPGS-SH hybrid nanomicelles could effectively improve the oral absorption of paclitaxel by mucosal penetration and P-glycoprotein inhibition, but the CS-VES nanomicelles are blocked by mucin fibers.Download high-res image (194KB)Download full-size image