title: Lactoferrin-modified PEG-co-PCL nanoparticles for enhanced brain delivery of NAP peptide following intranasal administration.
abstract: Development of effective non-invasive drug delivery systems is of great importance to the treatment of Alzheimer's diseases and has made great progress in recent years. In this work, lactoferrin (Lf), a natural iron binding protein, whose receptor is highly expressed in both respiratory epithelial cells and neurons is here utilized to facilitate the nose-to-brain drug delivery of neuroprotection peptides. The Lf-conjugated PEG-PCL nanoparticle (Lf-NP) was constructed via a maleimide-thiol reaction with the Lf conjugation confirmed by CBQCA Protein Quantitation and XPS analysis. Other important parameters such as particle size distribution, zeta potential and in vitro release of fluorescent probes were also characterized. Compared with unmodified nanoparticles (NP), Lf-NP exhibited a significantly enhanced cellular accumulation in 16HBE14o-cells through both caveolae-/clathrin-mediated endocytosis and direct translocation. Following intranasal administration, Lf-NP facilitated the brain distribution of the coumarin-6 incorporated with the AUC0-8h in rat cerebrum (with hippocampus removed), cerebellum, olfactory tract, olfactory bulb and hippocampus 1.36, 1.53, 1.70, 1.57 and 1.23 times higher than that of coumarin-6 carried by NP, respectively. Using a neuroprotective peptide - NAPVSIPQ (NAP) as the model drug, the neuroprotective and memory improvement effect of Lf-NP was observed even at lower dose than that of NP in a Morris water maze experiment, which was also confirmed by the evaluation of acetylcholinesterase, choline acetyltransferase activity and neuronal degeneration in the mice hippocampus. In conclusion, Lf-NP may serve as a promising nose-to-brain drug delivery carrier especially for peptides and proteins.
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors: Zhongyang
authors: Z
authors: Liu
authors: Mengyin
authors: M
authors: Jiang
authors: Ting
authors: T
authors: Kang
authors: Deyu
authors: D
authors: Miao
authors: Guangzhi
authors: G
authors: Gu
authors: Qingxiang
authors: Q
authors: Song
authors: Lei
authors: L
authors: Yao
authors: Quanyin
authors: Q
authors: Hu
authors: Yifan
authors: Y
authors: Tu
authors: Zhiqing
authors: Z
authors: Pang
authors: Hongzhuan
authors: H
authors: Chen
authors: Xinguo
authors: X
authors: Jiang
authors: Xiaoling
authors: X
authors: Gao
authors: Jun
authors: J
authors: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002232:Carbocyanines / Q000378:metabolism; D002460:Cell Line; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003374:Coumarins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D007051:Ibotenic Acid / Q000494:pharmacology; D007781:Lactoferrin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D003374:Coumarins; D018696:Neuroprotective Agents; D010455:Peptides; D011091:Polyesters; D013844:Thiazoles; C517282:coumarin 6; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); D007051:Ibotenic Acid; D011092:Polyethylene Glycols; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D007781:Lactoferrin