Pisal Dipak S, Yellepeddi Venkata K, Kumar Ajay, Palakurthi Srinath
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, South Dakota 57007, USA.
Drug Deliv. 2008 Nov;15(8):515-22. doi: 10.1080/10717540802321826.
The aim of our study was to prepare arginine-and ornithine-conjugated Polyamidoamine (PAMAM) dendrimers and study their permeability across IPEC-J2 cell monolayers, a new intestinal cell line model for drug absorption studies. Arginine and ornithine were conjugated to the amine terminals of the PAMAM(G4) dendrimers by Fmoc synthesis. The apical-to-basolateral (AB) and basolateral-to-apical (BA) apparent permeability coefficients (P(app)) for the PAMAM dendrimers increased by conjugating the dendrimers with both of these polyamines. The enhancement in permeability was dependent on the dendrimer concentration and duration of incubation. Correlation between monolayer permeability and the decrease in transepithelial electrical resistance (TEER) with the PAMAM dendrimers and the polyamine-conjugated dendrimers suggests that paracellular transport is one of the mechanisms of transport across the epithelial cells. Cytotoxicity of these surface-modified dendrimers was evaluated in IPEC-J2 cells by MTT (methylthiazoletetrazolium) assay. Arginine-conjugated dendrimers were insignificantly more toxic than PAMAM dendrimer as well as ornithine-conjugated dendrimers. Though investigations on the possible involvement of other transport mechanisms are in progress, results of the present study suggest the potential of dendrimer-polyamine conjugates as the carriers for antigen/drug delivery through the oral mucosa.
我们研究的目的是制备精氨酸和鸟氨酸共轭的聚酰胺-胺（PAMAM）树枝状大分子，并研究它们对IPEC-J2细胞单层的通透性，IPEC-J2细胞单层是一种用于药物吸收研究的新型肠道细胞系模型。通过Fmoc合成法将精氨酸和鸟氨酸与PAMAM（G4）树枝状大分子的胺端进行共轭。将树枝状大分子与这两种多胺共轭后，PAMAM树枝状大分子的顶侧到基底侧（AB）和基底侧到顶侧（BA）的表观渗透系数（P(app)）增加。通透性的增强取决于树枝状大分子的浓度和孵育时间。PAMAM树枝状大分子和多胺共轭树枝状大分子的单层通透性与跨上皮电阻（TEER）降低之间的相关性表明，细胞旁转运是跨上皮细胞转运的机制之一。通过MTT（噻唑蓝）法在IPEC-J2细胞中评估这些表面修饰树枝状大分子的细胞毒性。精氨酸共轭树枝状大分子的毒性比PAMAM树枝状大分子以及鸟氨酸共轭树枝状大分子略高，但差异不显著。尽管对其他转运机制可能参与情况的研究正在进行中，但本研究结果表明树枝状大分子-多胺共轭物作为通过口腔黏膜递送抗原/药物载体的潜力。
