Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
Pharm Res. 2017 Jun;34(6):1320-1329. doi: 10.1007/s11095-017-2149-8. Epub 2017 Apr 3.
A major obstacle preventing oral administration of macromolecular therapeutics is poor absorption across the intestinal epithelium into the bloodstream. One strategy to improve transport across this barrier is the use of chemical permeation enhancers. Several molecular families with permeation enhancing potential have been identified previously, including piperazines. In particular, 1-phenylpiperazine has been shown to enhance transepithelial transport with minimal cytotoxicity compared to similarly effective molecules. To better understand how the chemistry of 1-phenylpiperazine affects its utility as an intestinal permeation enhancer, this study examined a small library of 13 derivatives of 1-phenylpiperazine.
The efficacy and cytotoxicity of 13 phenylpiperazine compounds were assessed in a Caco-2 model of the intestinal epithelium. Efficacy was measured using the paracellular diffusion marker calcein as well as by immunostaining and confocal imaging of Caco-2 monolayers.
Of the 13 derivatives, two enhanced the permeability of the fluorescent marker calcein over 100-fold. It was found that hydroxyl or primary amine substitutions on the phenyl ring significantly increased toxicity, while aliphatic substitutions resulted in efficacy and toxicity profiles comparable to 1-phenylpiperazine.
Several potent derivatives, including 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, displayed lower toxicity than 1-phenylpiperazine, suggesting promise in future applications.
阻止大分子治疗药物经口服进入血液循环的主要障碍是肠道上皮细胞的吸收不良。提高这种屏障通透性的一种策略是使用化学渗透增强剂。先前已经确定了几个具有渗透增强潜力的分子家族，包括哌嗪。特别是，与同样有效的分子相比，1-苯基哌嗪已被证明可在最小细胞毒性的情况下增强跨上皮转运。为了更好地了解 1-苯基哌嗪的化学性质如何影响其作为肠道渗透增强剂的用途，本研究研究了 1-苯基哌嗪的 13 种衍生物的一个小文库。
在肠上皮细胞的 Caco-2 模型中评估了 13 种苯哌嗪化合物的功效和细胞毒性。功效通过使用细胞旁扩散标记物 calcein 以及通过 Caco-2 单层的免疫染色和共焦成像来测量。
在 13 种衍生物中，有两种使荧光标记物 calcein 的通透性增强了 100 多倍。发现苯环上的羟基或伯胺取代会显著增加毒性，而脂肪族取代则会导致与 1-苯基哌嗪相当的功效和毒性特征。
几种有效的衍生物，包括 1-甲基-4-苯基哌嗪和 1-(4-甲基苯基)哌嗪，显示出比 1-苯基哌嗪更低的毒性，这表明在未来的应用中具有很大的潜力。
