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Drug Delivery System Utilizing Transporters That Recognize Substrates of Relatively Large Molecular Sizes

利用可识别相对较大分子尺寸底物的转运蛋白的药物输送系统

基本信息

批准号：
07557142
负责人：
KAMO Naoki
金额：
$ 4.74万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

PEPT1 is a peptide-transporter that recognizes a wide variety of substances, then our investigation focused this transporter for construction of drug delivery system. Our strategy is that when we attach a drug to a substrate that is transported by a transporter whose substrate recognition is not strict, this drug may be taken up fast. As a model cell, we chosen Caco-2 cell that expresses PEPT1 as an only peptide transporter, and as a model combination of drugs and substrates, we chosen fluorescent dyes (fluorescein isocyanate and coumarin-3-carboxylic acid) and dipeptides (Val-Lys and Lys-Sar).Initial uptake rates of these 'drugs' were proportional to the concentrations of the drug. Since the drivingforce of the transport by PEPT1 is a proton-motive-force, addition of an uncoupler, CCCP should decrease or diminish the transport. In fact, the uptake of Lys-Sar was diminished completely. The uptake rate of model drugs (the peptides with fluorescent probes), on the contrary to our expectation, increased appreciably. These facts imply that an efflux transporter may express the cell and extrude these fluorescent drugs. When substances that are considered to be transported were added, the uptake of the fluorescent drugs increased markedly. Anti-cancer drugs are expelled by this efflux transporters, hence this fact suggests that the presence of these fluorescent drugs suppress the efflux of anti-cancer drugs, which increases the availability of anticancer drugs.In addition, we can estimate the factors that determine the substrate recognition of PEPTl, although fluorescent compounds synthesized in this study are not transported into cells.

PEPT 1是一种识别多种物质的肽转运蛋白，因此我们的研究集中在构建药物传递系统方面。我们的策略是，当我们将药物连接到由底物识别不严格的转运蛋白转运的底物上时，这种药物可能会被快速吸收。以表达PEPT 1的Caco-2细胞为模型细胞，以荧光染料（异氰酸荧光素和香豆素-3-羧酸）和二肽（Val-Lys和Lys-Sar）为模型底物，药物的初始摄取速率与药物浓度成正比。由于PEPT 1的运输驱动力是质子动力，因此加入解偶联剂CCCP会降低或减弱运输。事实上，Lys-Sar的摄取完全减少。与我们的预期相反，模型药物（具有荧光探针的肽）的摄取率明显增加。这些事实意味着外排转运蛋白可能表达细胞并挤出这些荧光药物。当被认为是运输的物质被添加时，荧光药物的摄取显著增加。抗癌药物通过这种外排转运体排出，因此这一事实表明，这些荧光药物的存在抑制了抗癌药物的外排，这增加了抗癌药物的可用性。此外，我们可以估计决定PEPT 1的底物识别的因素，尽管本研究中合成的荧光化合物不被转运到细胞中。