Enhancing Oral Performance of Paclitaxel Lipid‐Mimic Prodrug via Modulating Type of Fatty Acids

Owing to the serious clinical side effects of intravenous Taxol, an oral chemotherapeutic strategy is expected to be promising for paclitaxel (PTX) delivery. However, its poor solubility and permeability, high first‐pass metabolism, and gastrointestinal toxicity need to be overcome. A triglyceride (TG)‐like prodrug strategy facilitates oral drug delivery by bypassing liver metabolism. However, the effect of fatty acids (FAs) in sn‐1,3 on the oral absorption of prodrugs remains unclear. Herein, a series of TG‐mimetic prodrugs of PTX is explored with different carbon chain lengths and degrees of unsaturation of FAs at the sn‐1,3 position in an attempt to enhance oral antitumor effect and to guide the design of TG‐like prodrugs. Interestingly, the different FA lengths exhibit great influence on in vitro intestinal digestion behavior, lymph transport efficiency, and up to fourfold differences in plasma pharmacokinetics. The prodrug with long‐chain FAs shows a more effective antitumor effect, whereas the degree of unsaturation has a negligible impact. The findings illustrate how FAs structures affect the oral delivery efficiency of TG‐like PTX prodrugs and thus provide a theoretical basis for their rational design. Paclitaxel (PTX) lipid‐mimic prodrugs are designed to improve oral bioavailability of PTX by imitating absorption pathway of dietary lipids. On basis of stable digestive intermediates and reduction release sensitivity, the prodrug with long‐chain fatty acids shows an enhanced lymph transport efficiency, better pharmacokinetics behavior, and more effective antitumor effect than the medium‐chain one.