A Peptide-Based Nanocarrier for an Enhanced Delivery and Targeting of Flurbiprofen into the Brain for the Treatment of Alzheimer's Disease: An In Vitro Study

被引:12
作者
Al-azzawi, Shafq [1 ,2 ]
Masheta, Dhafir [1 ,2 ]
Guildford, Anna [1 ,3 ]
Phillips, Gary [1 ,3 ]
Santin, Matteo [1 ]
机构
[1] Univ Brighton, Sch Pharm & Bimol Sci, Ctr Regenerat Med & Devices, Brighton BN2 4GJ, E Sussex, England
[2] Univ Babylon, Coll Pharm, Minist Higher Educ & Sci Res, Hilla 51002, Iraq
[3] Tissue Click Ltd, Brighton BN2 6SJ, E Sussex, England
关键词
Alzheimer's disease; neurodegenerative diseases; blood-brain barrier; ApoE-peptide; drug delivery system; flurbiprofen; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CAPILLARY ENDOTHELIAL-CELLS; APOE-DERIVED PEPTIDES; APOLIPOPROTEIN-E; GAMMA-SECRETASE; CELLULAR UPTAKE; BARRIER MODEL; RECEPTOR; DENDRIMER; TRANSCYTOSIS;
D O I
10.3390/nano10081590
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Alzheimer's disease (AD) is an age-related disease caused by abnormal accumulation of amyloid-beta in the brain leading to progressive tissue degeneration. Flurbiprofen (FP), a drug used to mitigate the disease progression, has low efficacy due to its limited permeability across the blood-brain barrier (BBB). In a previous work, FP was coupled at the uppermost branching of an epsilon-lysine-based branched carrier, its root presenting a phenylalanine moiety able to increase the hydrophobicity of the complex and enhance the transport across the BBB by adsorptive-mediated transcytosis (AMT). The present study explores a different molecular design of the FP-peptide delivery system, whereby its root presents an ApoE-mimicking peptide, a targeting ligand that could enhance transport across the BBB by receptor-mediated transcytosis (RMT). The functionalised complex was synthesised using a solid-phase peptide synthesis and characterised by mass spectrometry and FTIR. Cytotoxicity and permeability of this complex across an in vitro BBB model were analysed. Moreover, its activity and degradation to release the drug were investigated. The results revealed successful synthesis and grafting of FP molecules at the uppermost molecular branches of the lysine terminal without observed cytotoxicity. When covalently linked to the nanocarrier, FP was still active on target cells, albeit with a reduced activity, and was released as a free drug upon hydrolysis in a lysosome-mimicking medium. Noticeably, this work shows the high efficiency of RMT-driven FP delivery over delivery systems relying on AMT.
引用
收藏
页码:1 / 18
页数:18
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