Efficient Intestinal Digestion and On Site Tumor-Bioactivation are the Two Important Determinants for Chylomicron-Mediated Lymph-Targeting Triglyceride-Mimetic Docetaxel Oral Prodrugs.

The oral absorption of chemotherapeutical drugs is restricted by poor solubility and permeability, high first-pass metabolism, and gastrointestinal toxicity. Intestinal lymphatic transport of lipophilic prodrugs is a promising strategy to improve the oral delivery efficiency of anticancer drugs via entrapment into a lipid formulation and to avoid first-pass metabolism. However, several basic principles have still not been clarified, such as intestinal digestibility and stability and on-site tumor bioactivation. Herein, triglyceride-mimetic prodrugs of docetaxel (DTX) are designed by conjugating them to the sn-2 position of triglyceride (TG) through different linkage bonds. The role of intestinal digestion in oral absorption of TG-like prodrugs is then investigated by introducing significant steric-hindrance α-substituents into the prodrugs. It is surprisingly found that poor intestinal digestion leads to an unsatisfactory bioavailability but efficient intestinal digestion of TG-like prodrugs with a less steric-hindrance linkage (DTX-S-S-TG) facilitating oral absorption. Moreover, it is found that the TG-like reduction-sensitive prodrug (DTX-S-S-TG) has good stability during intestinal transport and blood circulation, and on-demand release of docetaxel at the tumor site, leading to a significantly improved antitumor efficiency with negligible gastrointestinal toxicity. In summary, the chylomicron-mediated lymph-targeting triglyceride-mimetic oral prodrug approach provides a good foundation for the development of oral chemotherapeutical formulations.