期刊
DRUG DELIVERY
卷 30, 期 1, 页码 -出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/10717544.2023.2173333
关键词
Apolipoprotein E mimetic peptide; blood-brain barrier; brain-targeting; liposomes; tissue clearing
This study screened and compared the functionality of eight BBB-penetrating peptides, and found that ApoEdp exhibited the best brain-targeting and BBB permeability. ApoEdp-SG-lipid was newly synthesized and ApoEdp-modified PEGylated liposomes were prepared. The results demonstrated that ApoEdp-modified PEGylated liposomes had the ability to cross the BBB and target the brain.
Liposomes are versatile carriers that can encapsulate various drugs; however, for delivery to the brain, they must be modified with a targeting ligand or other modifications to provide blood-brain barrier (BBB) permeability, while avoiding rapid clearance by reticuloendothelial systems through polyethylene glycol (PEG) modification. BBB-penetrating peptides act as brain-targeting ligands. In this study, to achieve efficient brain delivery of liposomes, we screened the functionality of eight BBB-penetrating peptides reported previously, based on high-throughput quantitative evaluation methods with in vitro BBB permeability evaluation system using Transwell, in situ brain perfusion system, and others. For apolipoprotein E mimetic tandem dimer peptide (ApoEdp), which showed the best brain-targeting and BBB permeability in the comparative evaluation of eight peptides, its lipid conjugate with serine-glycine (SG)(5) spacer (ApoEdp-SG-lipid) was newly synthesized and ApoEdp-modified PEGylated liposomes were prepared. ApoEdp-modified PEGylated liposomes were effectively associated with human brain capillary endothelial cells via the ApoEdp sequence and permeated the membrane in an in vitro BBB model. Moreover, ApoEdp-modified PEGylated liposomes accumulated in the brain 3.9-fold higher than PEGylated liposomes in mice. In addition, the ability of ApoEdp-modified PEGylated liposomes to localize beyond the BBB into the brain parenchyma in mice was demonstrated via three-dimensional imaging with tissue clearing. These results suggest that ApoEdp-SG-lipid modification is an effective approach for endowing PEGylated liposomes with the brain-targeting ability and BBB permeability.
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