Nasal absorption enhancement strategies for therapeutic peptides: an in vitro study using cultured human nasal epithelium
Nasal absorption enhancement strategies for therapeutic peptides: an in vitro study using cultured human nasal epithelium
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DOI：
10.1016/s0378-5173(02)00039-x
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发表时间：
2002-04-26
影响因子：
5.8
通讯作者：
Verbeke, N
中科院分区：
文献类型：
--
作者：
Agu, RU;Dang, HV;Verbeke, N
这项研究探讨了培养的人鼻上皮作为模型来研究治疗性肽的鼻吸收增强策略的潜在用途。存在贝他汀和嘌呤霉素时亮氨酸脑啡肽 (Leu-Enk) 的转运。分别研究了这些蛋白酶抑制剂与能够抑制蛋白酶或保护肽免遭蛋白酶降解的吸收增强剂（甘胆酸盐、二甲基-β-环糊精（DMbetaCD））的各种组合。上皮膜扰动，蛋白质渗漏。贝他汀/嘌呤霉素吸收和氨肽酶活性反弹被用作毒理学终点。嘌呤霉素与甘胆酸盐或DMbetaCD的组合导致Leu-Enk的吸收增强(9-14%)比吸收促进剂与贝他汀组合时(1-3%)或抑制剂单独使用时(2-4%)更高。蛋白酶抑制剂与吸收增强剂的组合产生更高的吸收增强，导致上皮阻力显着降低并增加荧光素钠转运。尽管只有嘌呤霉素渗透人鼻上皮，但这两种蛋白酶抑制剂均诱导氨肽酶活性显着反弹（25-61%），这可能与蛋白质渗漏（21-46%）有关。这项研究强调了（i）培养的人鼻上皮作为研究治疗性肽的鼻吸收增强的模型的潜在用途：（ii）需要使用体内鼻模型进行进一步研究，以确定用蛋白酶抑制剂和吸收增强剂的各种组合观察到的膜扰动和细胞毒性是否确实引起安全问题。 (C) 2002 年，Elsevier Science B.V. 出版
This study examined the potential usefulness of cultured human nasal epithelium as a model to investigate nasal absorption enhancement strategies for therapeutic peptides. The transport of leucine enkephalin (Leu-Enk) in the presence of bestatin and puromycin. respectively and various combinations of these protease inhibitors with absorption enhancers capable of inhibiting proteases or protecting peptides against protease degradation (glycocholate, dimethyl-beta-cycloclextrin (DMbetaCD)) was studied. Epithelial membrane perturbation, protein leakage. bestatin/puromycin absorption and rebound aminopeptidase activity were used as toxicological end-points. The combination Of puromycin with glycocholate or DMbetaCD resulted in a higher absorption enhancement of Leu-Enk (9-14%) than when the absorption enhancers were combined with bestatin (1-3%) or when the inhibitors were used alone (2-4%). The higher absorption enhancement resulting from the combination of protease inhibitors with absorption enhancers caused a significant reduction of epithelial resistance and increased sodium fluorescein transport. Although only puromycin permeated the human nasal epithelium, both protease inhibitors induced a significant rebound aminopeptidase activity (25-61%), which can be associated with protein leakage (21-46%). This study highlighted (i) the potential usefulness of cultured human nasal epithelium as a model to study nasal absorption enhancement of therapeutic peptides: (ii) further studies using in vivo nasal models are required to ascertain whether the membrane perturbation and cytotoxicity observed with various combinations of the protease inhibitors and absorption enhancers really raise safety concerns. (C) 2002 Published by Elsevier Science B.V.