Nanoparticle-mediated delivery of oligonucleotides to the blood-brain barrier: in vitro and in situ brain perfusion studies on the uptake mechanisms
- Authors
- Ko, Young Tag
- Issue Date
- Nov-2013
- Publisher
- INFORMA HEALTHCARE
- Keywords
- Blood-brain barrier; brain targeting; nanoparticles; oligodeoxynucleotides
- Citation
- JOURNAL OF DRUG TARGETING, v.21, no.9, pp.866 - 873
- Journal Title
- JOURNAL OF DRUG TARGETING
- Volume
- 21
- Number
- 9
- Start Page
- 866
- End Page
- 873
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/14138
- DOI
- 10.3109/1061186X.2013.829077
- ISSN
- 1061-186X
- Abstract
- Except for the few exceptions where topical administration is feasible, progress towards broad clinical application of nucleic acid therapeutics requires development of effective systemic delivery strategies. The central nervous system represents a particularly difficult organ for systemic delivery due to the blood-brain barrier. We previously reported a nanoparticulate delivery system for targeted brain delivery of oligonucleotides upon systemic administration, i.e. liposome-encapsulated polyethylenimine/oligonucleotides polyplexes. In this study, cellular uptake and intracellular trafficking of the nanoparticles were further investigated using in situ brain perfusion technique followed by colocalization and fluorescence resonance energy transfer techniques. The brain endothelial uptake and possibly parenchymal accumulation were readily visualized upon administration via internal carotid artery perfusion. The nanoparticles were colocalized with early-endosome antigen, which confirms the brain endothelial uptake through transferrin receptor-mediated endocytosis. Fluorescence resonance energy transfer analysis also suggested the nanoparticles entered the brain endothelial cells while maintaining their integrity. Together, the enhanced brain uptake, as claimed previously, of the antibody-targeted nanoparticles was clearly confirmed with more convincing evidences. In addition, the experimental techniques described here should be applicable to the studies involving nanoparticle-mediated brain delivery of nucleic acid therapeutics.
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