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通过噬菌体展示技术鉴定鼻脑归巢肽

Identification of nose-to-brain homing peptide through phage display.

作者信息

Wan Xiao-Mei, Chen Yong-Ping, Xu Wen-Rui, Yang Wen-Jun, Wen Long-Ping

机构信息

Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science & Technology of China, Hefei, Anhui 230027, PR China.

出版信息

Peptides. 2009 Feb;30(2):343-50. doi: 10.1016/j.peptides.2008.09.026. Epub 2008 Oct 21.

Abstract

Brain delivery of drug molecules through the nasal passage represents a viable approach for bypassing the blood-brain barrier (BBB) but remains a major challenge due to lack of efficient homing carriers. To screen for potential peptides with the ability to transport into the brain via the nasal passage, we applied a C7C phage peptide display library (Ph.D.-C7C) intra-nasally to anesthetized rats and recovered phage from the brain tissue 45 min after phage administration. After three rounds of panning, 10 positive phage clones were selected and sequenced. Clone7, which exhibited highest translocation efficiency, was chosen for further studies. After nasal administration, Clone7 entered the brain within 30 min and exhibited translocation efficiency about 50-fold higher than a random phage. A 11-amino acid synthetic peptide derived from the displayed sequence of Clone7 (ACTTPHAWLCG) efficiently inhibited the nasal-brain translocation of Clone7. Both phage recovery results and fluorescent microscopy images revealed the presence of many more Clone7 phage in the brain than in the liver, kidney and other internal organs after the nasal administration, suggesting that Clone7 bypassed the BBB and entered brain directly. Furthermore, both Clone7 and the ACTTPHAWLCG peptide were found to be heavily distributed along the olfactory nerve after the nasal administration, further suggesting a direct passage route into the brain via the olfactory region. These results demonstrated the feasibility of using the in vivo phage display approach for selecting peptides with the nose-to-brain homing capability and may have implications for the development of novel targeting carriers useful for brain delivery.

摘要

通过鼻腔通道将药物分子递送至大脑是一种绕过血脑屏障(BBB)的可行方法,但由于缺乏高效的归巢载体,仍然是一项重大挑战。为了筛选具有通过鼻腔通道转运至大脑能力的潜在肽段,我们将C7C噬菌体肽展示文库(Ph.D.-C7C)经鼻内应用于麻醉大鼠,并在噬菌体给药后45分钟从脑组织中回收噬菌体。经过三轮淘选,选择了10个阳性噬菌体克隆并进行测序。选择转运效率最高的克隆7进行进一步研究。经鼻给药后,克隆7在30分钟内进入大脑,其转运效率比随机噬菌体高约50倍。从克隆7的展示序列衍生的一个11氨基酸合成肽(ACTTPHAWLCG)有效地抑制了克隆7的鼻脑转运。噬菌体回收结果和荧光显微镜图像均显示,经鼻给药后,大脑中的克隆7噬菌体比肝脏、肾脏和其他内脏器官中的多得多,这表明克隆7绕过了血脑屏障并直接进入大脑。此外,经鼻给药后发现克隆7和ACTTPHAWLCG肽均沿嗅神经大量分布,进一步表明存在通过嗅觉区域直接进入大脑的途径。这些结果证明了使用体内噬菌体展示方法筛选具有鼻脑归巢能力的肽段的可行性,可能对开发用于脑递送的新型靶向载体具有启示意义。

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