Transepithelial transport of PAMAM dendrimers across isolated rat jejunal mucosae in ussing chambers.
Transepithelial transport of PAMAM dendrimers across isolated rat jejunal mucosae in ussing chambers.
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DOI：
10.1021/bm5004465
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发表时间：
2014-08-11
影响因子：
6.2
通讯作者：
Brayden, David J.
中科院分区：
文献类型：
--
作者：
Hubbard, Dallin;Ghandehari, Hamidreza;Brayden, David J.
口服递送对于渗透性差的亲水性大分子仍然是一个挑战。聚酰胺-胺（PAMAM）树枝状大分子具有良好的口服给药性能。使用安装在Ussing室中的分离的大鼠空肠粘膜评估了羧基封端的G3.5和胺封端的G4 PAMAM树枝状聚合物的跨上皮转运。将ImM FITC标记的树枝状聚合物添加到粘膜的顶侧。与单独的FITC相比，当与G3.5 PAMAM树枝状聚合物缀合时，FITC从顶侧到基底侧的表观渗透系数（Papp）显著增加。当粘膜暴露于两种树枝状聚合物时，在跨上皮电阻变化、卡巴胆碱诱导的短路电流刺激和组织学变化方面观察到最小的毒性迹象。在1 mM树枝状聚合物存在下，[14 C]-甘露醇通量没有改变，表明在该模型中，在该浓度下细胞旁途径没有受到影响。这些结果提供了深入了解PAMAM树枝状聚合物跨上皮大鼠空肠运输的机制，以及重要的口服药物递送的毒理学考虑。
Oral delivery remains a challenge for poorly permeable hydrophilic macromolecules. Poly(amido amine) (PAMAM) dendrimers have shown potential for their possible oral delivery. Transepithelial transport of carboxyl-terminated G3.5 and amine-terminated G4 PAMAM dendrimers was assessed using isolated rat jejunal mucosae mounted in Ussing chambers. The 1 mM FITC-labeled dendrimers were added to the apical side of mucosae. Apparent permeability coefficients (Papp) from the apical to the basolateral side were significantly increased for FITC when conjugated to G3.5 PAMAM dendrimer compared to FITC alone. Minimal signs of toxicity were observed when mucosae were exposed to both dendrimers with respect to transepithelial electrical resistance changes, carbachol-induced short circuit current stimulation, and histological changes. [14C]-mannitol fluxes were not altered in the presence of 1 mM dendrimers, suggesting that the paracellular pathway was not affected at this concentration in this model. These results give insight into the mechanism of PAMAM dendrimer transepithelial rat jejunal transport, as well as toxicological considerations important for oral drug delivery.
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作者：
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通讯作者：
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