Zonula occludens toxin increases the permeability of molecular weight markers and chemotherapeutic agents across the bovine brain microvessel endothelial cells
Zonula occludens toxin increases the permeability of molecular weight markers and chemotherapeutic agents across the bovine brain microvessel endothelial cells
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DOI：
10.1002/jps.10310
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发表时间：
2003-02-01
影响因子：
3.8
通讯作者：
Eddington, ND
中科院分区：
文献类型：
--
作者：
Karyekar, CS;Fasano, A;Eddington, ND
本研究的目的是检测闭锁带毒素(Zot)可逆地开放牛脑微血管内皮细胞(BBMECs)紧密连接的能力，以促进药物通过细胞旁途径传递。通过BBMEC单层转运检测分子量标志物和化疗药物([C-14]蔗糖、[C-14]菊粉、[H-3]普奈洛尔、[H-3]阿霉素和[C-14]紫杉醇)与Zot(0.0-4.0µg/mL)。测定单层TERE以评价Zot的疗效和可逆性。台盼蓝拒染法检测Zot对BBMEC细胞活性的影响。表观通透性(P-APP)、增强率(R)和转运增加百分比用方差分析进行统计学比较。对[C-14]蔗糖、[C-14]菊糖、[H-3]阿霉素和[C-14]紫杉醇的转运，当Zot浓度为4.0mg/mL时，P-APP的转运显著增加(p<；0.05)。用Zot治疗后，TEER显著降低，并在撤药后迅速恢复到基线水平。Zot(4µg/mL)孵育2小时后对BBMECs无毒。总之，Zot以一种可逆的、浓度依赖的方式增加了BBMEC的细胞旁转运。Zot对细胞旁转运的调节可能被用来增加强大的中枢神经系统活性药物的大脑通透性，包括抗癌药物。(C)2003年Wiley-Liss，Inc.和美国药学协会。
The purpose of this study was to examine the ability of Zonula occludens toxin (Zot) to reversibly open tight junctions in bovine brain microvessel endothelial cells (BBMECs) to enhance drug delivery via the paracellular pathway. Transport across BBMEC monolayers was examined for molecular weight markers and chemotherapeutic, agents ([C-14]sucrose, [C-14]inulin, [H-3]propranolol, [H-3]doxorubicin, and [C-14] paclitaxel) with Zot (0.0-4.0 mug/mL). TEER of monolayers was measured to assess effect and reversibility of Zot. Cell viability of BBMEC in the presence of Zot was assessed by trypan blue exclusion staining. Apparent permeability (P-app), enhancement ratio (R), and percent increase in transport determined were statistically compared by ANOVA. A significant increase (p < 0.05) in P-app was observed for the transport of [C-14] sucrose, [C-14]inulin, [H-3]doxorubicin, and [C-14]paclitaxel at a 4.0 mu g/mL concentration of Zot. A significant concentration-dependent decrease in TEER was observed on treatment with Zot with rapid reversal to baseline after removal. Zot (4 mu g/mL) was found to be nontoxic to the BBMECs after 2 hours incubation. In conclusion, Zot increased paracellular transport across the BBMEC in a reversible, concentration-dependent manner. Modulation of paracellular transport with Zot may be used to increase the brain permeability of potent central nervous system-active drugs, including anticancer agents. (C) 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association.