Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
Adv Healthc Mater. 2023 Jul;12(19):e2203118. doi: 10.1002/adhm.202203118. Epub 2023 Mar 31.
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.
由于静脉注射紫杉醇（Taxol）会产生严重的临床副作用，因此人们期望口服化疗策略在紫杉醇（PTX）给药方面具有广阔的应用前景。然而，其较差的水溶性和渗透性、较高的首过代谢和胃肠道毒性仍需要克服。甘油三酯（TG）样前药策略通过绕过肝脏代谢来促进口服药物递送。然而，sn-1,3 位脂肪酸（FAs）在影响前药口服吸收方面的作用尚不清楚。在此，我们探索了一系列具有不同碳链长度和 sn-1,3 位不饱和程度的 TG 模拟 PTX 前药，以期增强口服抗肿瘤效果，并为 TG 类似物前药的设计提供指导。有趣的是，不同的 FA 长度对体外肠道消化行为、淋巴转运效率以及血浆药代动力学有四倍的差异有很大影响。长链 FA 的前药显示出更有效的抗肿瘤效果，而不饱和程度的影响可以忽略不计。这些发现说明了 FA 结构如何影响 TG 类似物 PTX 前药的口服递送效率，从而为其合理设计提供了理论依据。
