title: A novel small Odorranalectin-bearing cubosomes: preparation, brain delivery and pharmacodynamic study on amyloid-β₂₅₋₃₅-treated rats following intranasal administration.
abstract: Because of the immunogenicity and toxicity in vivo of large molecules such as lectins, the application of these molecules is remarkably restricted in drug delivery systems. In this study, to improve the brain drug delivery and reduce the immunogenicity of traditional lectin modified delivery system, Odorranalectin (OL, 1700 Da), a novel non-immunogenic small peptide, was selected to establish an OL-modified cubosomes (Cubs) system. The streptavidin (SA)-conjugated Cubs were prepared by incorporating maleimide-PEG-oleate and taking advantage of its thiol group binding reactivity to conjugate with 2-iminothiolane thiolated SA; mono-biotinylated OL was then coupled with the SA-modified Cubs. The OL-decorated Cubs (OL-Cubs) devised via a non-covalent SA-biotin "bridge" made it easy to conjugate OL and determine the number of ligands on the surface of the Cubs using sensitive chemiluminescent detection. Retention of the bio-recognitive activity of OL after covalent coupling was verified by hemagglutination testing. Nose-to-brain delivery characteristic of OL-Cubs was investigated by in vivo fluorescent biodistribution using coumarin-6 as a marker. The relative uptake of coumarin carried by OL-Cubs was 1.66- to 3.46-fold in brain tissues compared to that incorporated in the Cubs. Besides, Gly14-Humanin (S14G-HN) as a model peptide drug was loaded into cubosomes and evaluated for its pharmacodynamics on Alzheimer's disease (AD) rats following intranasal administration by Morris water maze test and acetylcholinesterase activity determination. The results suggested that OL functionalization enhanced the therapeutic effects of S14G-HN-loaded cubosomes on AD. Thus, OL-Cubs might offer a novel effective and noninvasive system for brain drug delivery, especially for peptides and proteins.
authors: School of Pharmacy, Fudan University, Shanghai, China.
authors: Hongbing
authors: H
authors: Wu
authors: Jianxu
authors: J
authors: Li
authors: Qizhi
authors: Q
authors: Zhang
authors: Xiluan
authors: X
authors: Yan
authors: Liangran
authors: L
authors: Guo
authors: Xiaoling
authors: X
authors: Gao
authors: Mingfeng
authors: M
authors: Qiu
authors: Xinguo
authors: X
authors: Jiang
authors: Ren
authors: R
authors: Lai
authors: Hongzhuan
authors: H
authors: Chen
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003374:Coumarins / Q000008:administration & dosage / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005998:Glycine / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D037102:Lectins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018782:Maze Learning / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D019809:Streptavidin / Q000737:chemistry; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D016229:Amyloid beta-Peptides; D003374:Coumarins; D004337:Drug Carriers; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D010446:Peptide Fragments; D013844:Thiazoles; C074636:amyloid beta-protein (25-35); C517282:coumarin 6; C427211:humanin; C530911:odorranalectin, Odorrana grahami; D019809:Streptavidin; D005998:Glycine