Further Enhancement in Intestinal Absorption of Paclitaxel by Using Transferrin-Modified Paclitaxel Nanocrystals.

The intestinal epithelium is considered to be a major obstacle to the gastrointestinal administration for water-insoluble drugs. To enhance the intestinal absorption of paclitaxel by improving its solubility and overcoming the intestinal epithelium barrier, transferrin-modified paclitaxel nanocrystals were prepared based on the specific transferrin receptor expressed on the apical membrane of the intestinal epithelium and examined to exhibit a mean size of around 178 nm, a rod-like morphology, a sustained release property, and an enhanced in vitro antitumor effect. The in situ intestinal perfusion study proved that the intestinal absorption of transferrin-modified paclitaxel nanocrystals was remarkably enhanced compared with that of Taxol and unmodified paclitaxel nanocrystals, which was further evidenced by the result of pharmacokinetic study. Their transcytosis pathway and intracellular trafficking track were disclosed using Caco-2 cell monolayers. The transcytosis of transferrin-modified paclitaxel nanocrystals and unmodified paclitaxel nanocrystals was principally mediated by clathrin and lipid rafts. The colocalization of both paclitaxel nanocrystals with the organelles observed under confocal microscopy suggested that the late endosomes, lysosomes, ER, and Golgi apparatus played a part in the transcellular transport of both paclitaxel nanocrystals during their transcytosis. Therefore, the designed transferrin-modified drug nanocrystals might have a great potential in the enhancement of intestinal absorption of water-insoluble drugs.