期刊
JOURNAL OF CONTROLLED RELEASE
卷 143, 期 3, 页码 359-366出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2010.01.020
关键词
Gene delivery; Blood-brain barrier; Non-viral transfection; Biodegradable polyamines; Nuclear targeting; NLS peptide
资金
- National Institute of Neurodegenerative Diseases and Stroke [R01 NS050660]
With the goal of rational design of systemic gene delivery system and efficient transfection of capillary endothelial cells forming the blood-brain barrier (BBB), we synthesized several short polyamines with reducible disulfide backbones for pDNA packaging, internalization and consequent release from endosomal compartments. The synthetic cationic polymers prepared from short linear PEI (pLPEI), triethylenetetramine (pTETA), and spermine (pSPE), demonstrated very low toxicity, good condensation capacity, and high levels of pDNA protection, producing small particulate nanoformulations. Mild reduction of the disulfide backbone allowed complete release of pDNA from these polyplexes. In vitro transfection of murine brain capillary endothelial bEnd.3 cells with pSPE, pTETA, and pLPEI polyplexes was 2.3-4.9 times more effective compared with the non-degradable LPEI 22 kDa reagent (ExGen500) in the presence of serum. Their transfection ability was noticeably decreased following inhibition of the cellular reduced glutathione (GSH). After cellular uptake of biodegradable polyplexes, a disperse distribution of labeled pDNA in the cytoplasm of transfected cells was observed in contrast to ExGen500. Based on these polyamines, novel multifunctional polyplexes have been developed for efficient nuclear delivery of pDNA by co-application of NLS peptide and PEG-modified intercalating conjugates. Significant increase of nuclear accumulation was observed, and the transfection of bEnd.3 cells was additionally enhanced nearly 2-fold, demonstrating 8.5-, 6.3- and 3.7-fold better levels for pLPEI, pTETA, and pSPE, respectively, compared to ExGen500. Following brain-specific targeting, these safe and effective polyplexes may be converted into systemic nanocarriers for gene delivery and transfection of the BBB. (C) 2010 Elsevier B.V. All rights reserved.
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