1. Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer
- Author
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Ke, Weilun, Shao, Kun, Huang, Rongqin, Han, Liang, Liu, Yang, Li, Jianfeng, Kuang, Yuyang, Ye, Liya, Lou, Jinning, and Jiang, Chen
- Subjects
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GENE therapy , *TARGETED drug delivery , *DENDRIMERS in medicine , *LIGANDS (Biochemistry) , *BRAIN , *NANOPARTICLES , *POLYETHYLENE glycol , *LOW density lipoproteins - Abstract
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. [Copyright &y& Elsevier]
- Published
- 2009
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