Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system.
Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system.
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DOI：
10.1016/j.jconrel.2018.07.022
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发表时间：
2018-09-28
期刊：
影响因子：
--
通讯作者：
Gershkovich P
中科院分区：
文献类型：
--
作者：
Lee JB;Zgair A;Malec J;Kim TH;Kim MG;Ali J;Qin C;Feng W;Chiang M;Gao X;Voronin G;Garces AE;Lau CL;Chan TH;Hume A;McIntosh TM;Soukarieh F;Al-Hayali M;Cipolla E;Collins HM;Heery DM;Shin BS;Yoo SD;Kagan L;Stocks MJ;Bradshaw TD;Fischer PM;Gershkovich P
肠淋巴系统在淋巴瘤、癌症转移、自身免疫性疾病和人类免疫缺陷病毒（HIV）感染等多种疾病的病理生理学中起重要作用。因此，它是用于递送药物以治疗与淋巴系统相关的疾病的重要隔室。亲脂性前药方法在过去已被用于利用肠淋巴转运过程将药物递送至肠淋巴系统。以前采用的大多数方法都是基于非常庞大的前药部分，如模拟甘油三酯（TG）的那些。我们现在报告了一项研究，其中使用亲脂性前药方法，使用活化的酯前药将贝沙罗汀（BEX）和视黄酸（RA）有效地递送至肠淋巴系统。设计并合成了一系列BEX的羧酸酯前药，并且所有酯均显示出与乳糜微粒的改善的结合，这表明递送至肠淋巴系统的潜力改善。前药转化为BEX的转化率是BEX向肠粘膜转运的主要决定因素，制备活化酯前药以提高转化率。因此，与BEX本身给药时相比，BEX的4-（羟甲基）-1，3-二氧杂环戊烯-2-酮酯前药能够使肠系膜淋巴结（MLN）暴露于BEX的量增加17倍。活化酯前药方法也应用于另一种药物RA，其中通过应用类似的环状活化前药，MLN的暴露增加了2.4倍。BEX和RA之间的协同作用也证明了在体外细胞生长抑制试验使用淋巴瘤细胞系。总之，活化酯前药方法导致药物有效递送至肠淋巴系统，这可以使受大量病理状况影响的患者受益。
The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions.
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影响因子：
4.6
作者：
Gershkovich, P;Hoffman, A
通讯作者：
Hoffman, A
DOI：
10.1016/j.jchromb.2016.11.024
发表时间：
2017-01-01
影响因子：
3
作者：
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通讯作者：
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DOI：
10.1073/pnas.1318249111
发表时间：
2014-02-11
影响因子：
11.1
作者：
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通讯作者：
Schacker, Timothy W.
影响因子：
3.3
作者：
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通讯作者：
Hoffman, Amnon
影响因子：
2.7
作者：
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通讯作者：
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