Enabling oral novel Taxanes-based Chemotherapy with Lipophilic prodrug Self-nanoemulsifying drug delivery system.

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-10-20 DOI:10.1016/j.bioorg.2024.107902

Yifan Miao, Jinrui Liu, Hongying Xiao, Jia Deng, Wenqian Xu, Can Zhao, Qian Lu, Zhonggui He, Bingjun Sun, Chutong Tian, Jin Sun

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Abstract

Larotaxel (LTX) and SB-T-1214 (SBT), two new synthetic experimental toxoids, have shown broad-spectrum antitumor activity, especially against tumors that are resistant to other drugs. However, their poor solubility, membrane permeability, and first-pass effect limits their use in oral administration. We designed and synthesized two long-chain triglyceride-mimic prodrugs of LTX (LTXSSTG) and SBT (SBTSSTG), which are bridged by disulfide bonds and efficiently incorporated them into Self-nanoemulsifying drug delivery system (SNEDDS). These prodrugs can bypass hepatic metabolism by entering the blood through intestinal lymphatic transport, following a similar oral absorption pathway to dietary lipids. It was found that LTXSSTG and SBTSSTG significantly improved oral bioavailability (about 4.5-fold for LTX and 3.4-fold for SBT) compared to their solution forms. Moreover, with LTXSSTG and SBTSSTG incorporating reduction stimulus-responsive spacer were much more effective in suppressing tumor growth in vivo with eliminated adverse effects than solution form. To sum up, this strategy provides a new avenue to enhance oral delivery of new toxoids.

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利用亲脂性原药自纳米乳化给药系统实现新型紫杉醇类口服化疗。

拉罗他赛（LTX）和 SB-T-1214 （SBT）是两种新合成的实验性毒物，已显示出广谱的抗肿瘤活性，尤其是对其他药物产生抗药性的肿瘤。然而，它们的溶解性、膜渗透性和首过效应较差，限制了它们的口服应用。我们设计并合成了以二硫键为桥的 LTX（LTXSSTG）和 SBT（SBTSSTG）的两种长链甘油三酯模拟原药，并将它们有效地加入到自纳米乳化给药系统（SNEDDS）中。这些原药可以绕过肝脏代谢，通过肠道淋巴转运进入血液，其口服吸收途径与膳食脂类相似。研究发现，与溶液形式相比，LTXSSTG 和 SBTSSTG 能显著提高口服生物利用度（LTX 约为 4.5 倍，SBT 约为 3.4 倍）。此外，与溶液剂相比，LTXSSTG 和 SBTSSTG 加入了还原刺激响应垫片，能更有效地抑制肿瘤在体内的生长，同时消除不良反应。总之，这种策略为加强新毒物的口服给药提供了一条新途径。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.