Hirvonen J, Kalia Y N, Guy R H
Department of Biopharmaceutical Sciences, University of California-San Francisco, CA 94143-0446, USA.
Nat Biotechnol. 1996 Dec;14(13):1710-3. doi: 10.1038/nbt1296-1710.
Transdermal administration by iontophoresis (enhanced transport via the skin using the driving force of an applied electric field) has been successfully demonstrated but no formal relationship between peptide sequence/structure and efficiency of delivery has been established. There are notable examples, such as the lipophilic leutinizing hormone releasing hormone (LHRH) analogs, Nafarelin and Leuprolide, that exhibit down-regulation of their own transport across the skin under the influence of an iontophoretic current. The hypothesis that this phenomenon is due to neutralization of the skin's net negative charge by these cationic peptides was examined with LHRH oligopeptides. The impact of these compounds on the electroosmotic flow of solvent into the skin, which is induced by iontophoresis and which contributes significantly to the electrotransport of large, positively charged ions, was examined and quantified. Close juxtaposition of cationic and lipophilic residues profoundly inhibited electroosmosis and, presumably, peptide flux. The results indicate that the lipophilicity of the oligopeptides facilitates van der Waals interactions with hydrophobic patches along the transport route, thereby permitting the positively charged oligopeptide to interact with carboxylate side chains that give the skin its net negative charge at neutral pH. The lipophilic, cationic oligopeptide, therefore, becomes anchored in the transport path, neutralizing the original charge of the membrane, and completely altering the permselective properties of the skin.
通过离子电渗疗法进行透皮给药（利用施加电场的驱动力增强药物经皮肤转运）已得到成功验证，但尚未确立肽序列/结构与给药效率之间的正式关系。有一些显著的例子，比如亲脂性促黄体生成素释放激素（LHRH）类似物那法瑞林和亮丙瑞林，在离子电渗电流的影响下，它们自身经皮肤的转运出现下调。利用LHRH寡肽对这一现象是由于这些阳离子肽中和了皮肤净负电荷这一假说进行了检验。研究并量化了这些化合物对因离子电渗疗法诱导的溶剂向皮肤内电渗流的影响，而这种电渗流对大的带正电荷离子的电转运有显著贡献。阳离子残基与亲脂性残基紧密并列会显著抑制电渗作用，大概也会抑制肽通量。结果表明，寡肽的亲脂性促进了其与沿转运路径的疏水区域的范德华相互作用，从而使带正电荷的寡肽能够与羧基侧链相互作用，而羧基侧链在中性pH条件下赋予皮肤净负电荷。因此，亲脂性阳离子寡肽会固定在转运路径中，中和膜的原有电荷，并完全改变皮肤的选择透过特性。
