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 (GI) 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, we explored a series of TG-mimetic prodrugs of PTX 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 exhibited great influence on in vitro intestinal digestion behavior, lymph transport efficiency, and up to 4-fold differences in plasma pharmacokinetics. The prodrug with long-chain FAs showed a more effective antitumor effect, whereas the degree of unsaturation had a negligible impact. Our findings illustrated how FAs structures affect the oral delivery efficiency of TG-like PTX prodrugs and thus provide a theoretical basis for their rational design. This article is protected by copyright. All rights reserved.