title: Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer.
abstract: Angiopep targeting to the low-density lipoprotein receptor-related protein-1 (LRP1) was identified to exhibit high transcytosis capacity and parenchymal accumulation. In this study, it was exploited as a ligand for effective brain-targeting gene delivery. Polyamidoamine dendrimers (PAMAM) were modified with angiopep through bifunctional PEG, then complexed with DNA, yielding PAMAM-PEG-Angiopep/DNA nanoparticles (NPs). The angiopep-modified NPs were observed to be internalized by brain capillary endothelial cells (BCECs) through a clathrin- and caveolae-mediated energy-depending endocytosis, also partly through marcopinocytosis. Also, the cellular uptake of the angiopep-modified NPs were competed by angiopep-2, receptor-associated protein (RAP) and lactoferrin, indicating that LRP1-mediated endocytosis may be the main mechanism of cellular internalization of angiopep-modified NPs. And the angiopep-modified NPs showed higher efficiency in crossing blood-brain barrier (BBB) than unmodified NPs in an in vitro BBB model, and accumulated in brain more in vivo. The angiopep-modified NPs also showed higher efficiency in gene expressing in brain than the unmodified NPs. In conclusion, PAMAM-PEG-Angiopep showed great potential to be applied in designing brain-targeting drug delivery system.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Weilun
authors.initials: W
authors.lastname: Ke
authors.forename: Kun
authors.initials: K
authors.lastname: Shao
authors.forename: Rongqin
authors.initials: R
authors.lastname: Huang
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Kuang
authors.forename: Liya
authors.initials: L
authors.lastname: Ye
authors.forename: Jinning
authors.initials: J
authors.lastname: Lou
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D018014:Gene Transfer Techniques / Q000295:instrumentation*; D006801:Humans; D008297:Male; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D011973:Receptors, LDL / Q000378:metabolism
chemical_list: C531860:Angiopep-2; D001672:Biocompatible Materials; D050091:Dendrimers; C104700:PAMAM Starburst; D010455:Peptides; D011073:Polyamines; D011973:Receptors, LDL; D011092:Polyethylene Glycols