期刊
BIOMATERIALS
卷 30, 期 36, 页码 6976-6985出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2009.08.049
关键词
Brain targeting; Gene delivery; LRP; Angiopep; Non-viral vector; Polyamidoamine
资金
- National Basic Research Program of China (973 Program) [2007CB935802]
- Shanghai Nanotechnology Project [0852nm04500]
- National Natural Science Foundation of China [30973652]
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. (C) 2009 Elsevier Ltd. All rights reserved.
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