A novel approach using functional peptides for efficient intestinal absorption of insulin
A novel approach using functional peptides for efficient intestinal absorption of insulin
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DOI：
10.1016/j.jconrel.2006.12.022
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发表时间：
2007-04-02
影响因子：
10.8
通讯作者：
Takayama, Kozo
中科院分区：
文献类型：
--
作者：
Morishita, Mariko;Kamei, Noriyasu;Takayama, Kozo
本研究的目的是评估寡精氨酸，一种细胞穿透肽（CPP），是否可以促进胰岛素在大鼠肠道的吸收。由精氨酸的6个（R-6）、8个（R-s）和10个（R-10）残基组成的肽用作CPP。单独给予胰岛素溶液后未观察到胰岛素吸收;然而，D-型R-6（D-R-6）和L-型R-6（L-R-6）联合给药后，胰岛素吸收以剂量依赖性方式显著增加。D-R-6对胰岛素吸收的作用比L-R-6更明显。在由6个、8个或10个精氨酸残基组成的寡聚精氨酸中，D-R-8对胰岛素肠吸收的促进作用最强。与此相反，肠道吸收的其他模型亲水性大分子，干扰素-β和异硫氰酸荧光素标记的葡聚糖4400，不受影响的共同管理与寡聚精氨酸。有效剂量的L-R6预处理未引起乳酸脱氢酶漏出和组织学损伤，提示寡精氨酸对肠粘膜无不良影响。我们的数据表明，共同管理的寡聚精氨酸增加肠道胰岛素的吸收显着，而不会造成可检测到的损害细胞的完整性，胰岛素和寡聚精氨酸之间的共价结合是不必要的这种效果。我们的结论是，寡聚体很可能成为克服胰岛素通过上皮细胞膜的低渗透性的有力工具，这是口服胰岛素输送的主要障碍。(c)2007 Elsevier B.V保留所有权利。
The aim of this study was to evaluate whether oligoarginine, a cell-penetrating peptide (CPP), can improve intestinal absorption of insulin in rats. Peptides composed of six (R-6) eight (R-s) and 10 (R-10) residues of arginine were used as the CPP. No insulin absorption was observed following administration of insulin solution alone; however, insulin absorption increased dramatically after coadministration of the D-form of R-6 (D-R-6) and the L-form of R-6 (L-R-6) in a dose-dependent manner. The effects on insulin absorption were more pronounced for D-R-6 than for L-R-6-Among oligoarginines composed of six, eight, or 10 arginine residues, D-R-8 showed the strongest enhancing effects on insulin intestinal absorption. In contrast, intestinal absorption of other model hydrophilic macromolecules, interferon-beta and fluorescein isothiocyanate-labeled dextran 4400, was not affected by coadministration with oligoarginine. Pretreatment by the effective dose of L-R6 did not induce lactate dehydrogenase' leakage or histological damage, suggesting that oligoarginine has no untoward effect on the intestinal mucosa. Our data demonstrate that coadministration of oligoarginine increases intestinal insulin absorption markedly without causing detectable damage in cellular integrity and that the covalent binding between insulin and oligoarginine is not necessary for this effect. We conclude that oligoarginines are likely to become powerful tools for overcoming the low permeability of insulin through the epithelial cell membrane, the major barrier to oral insulin delivery. (c) 2007 Elsevier B.V All rights reserved.