Department of Chemical Engineering, University of California, Santa Barbara 93106, USA.
J Control Release. 2013 Dec 10;172(2):541-9. doi: 10.1016/j.jconrel.2013.05.002. Epub 2013 May 14.
Delivery of therapeutic macromolecules is limited by the physiological limitations of the gastrointestinal tract including poor intestinal permeability, low pH and enzymatic activity. Several permeation enhancers have been proposed to enhance intestinal permeability of macromolecules; however their utility is often hindered by toxicity and limited potency. Here, we report on a novel permeation enhancer, Dimethyl palmitoyl ammonio propanesulfonate (PPS), with excellent enhancement potential and minimal toxicity. PPS was tested for dose- and time-dependent cytotoxicity, delivery of two model fluorescent molecules, sulforhodamine-B and FITC-insulin in vitro, and absorption enhancement of salmon calcitonin (sCT) in vivo. Caco-2 studies revealed that PPS is an effective enhancer of macromolecular transport while being minimally toxic. TEER measurements in Caco-2 monolayers confirmed the reversibility of the effect of PPS. Confocal microscopy studies revealed that molecules permeate via both paracellular and transcellular pathways in the presence of PPS. In vivo studies in rats showed that PPS enhanced relative bioavailability of sCT by 45-fold after intestinal administration. Histological studies showed that PPS does not induce damage to the intestine. PPS is an excellent permeation enhancer which provides new opportunities for developing efficacious oral/intestinal delivery systems for therapeutic macromolecules.
治疗性大分子的递送受到胃肠道生理限制的限制，包括肠道通透性差、pH 值低和酶活性低。已经提出了几种渗透增强剂来增强大分子的肠道通透性；然而，它们的实用性常常受到毒性和有限效力的阻碍。在这里，我们报告了一种新型渗透增强剂，二甲基棕榈酰氨丙磺酸酯（PPS），具有优异的增强潜力和最小的毒性。测试了 PPS 的剂量和时间依赖性细胞毒性、两种模型荧光分子（磺基罗丹明 B 和 FITC-胰岛素）的体外递送以及鲑鱼降钙素（sCT）的体内吸收增强作用。Caco-2 研究表明，PPS 是一种有效的大分子转运增强剂，同时具有最小的毒性。Caco-2 单层中的 TEER 测量证实了 PPS 作用的可逆性。共聚焦显微镜研究表明，在 PPS 的存在下，分子通过细胞旁和细胞内途径渗透。在大鼠体内研究中，PPS 经肠道给药后将 sCT 的相对生物利用度提高了 45 倍。组织学研究表明，PPS 不会对肠道造成损伤。PPS 是一种优秀的渗透增强剂，为开发治疗性大分子的有效口服/肠道递送系统提供了新的机会。
