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Splenic Gene Delivery System Using Self-assembling Nano-complex with Phosphatidylserine Analog

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Title: Splenic Gene Delivery System Using Self-assembling Nano-complex with Phosphatidylserine Analog
Authors: Kurosaki, Tomoaki / Nakasone, Chihiro / Kodama, Yukinobu / Egashira, Kanoko / Harasawa, Hitomi / Muro, Takahiro / Nakagawa, Hiroo / Kitahara, Takashi / Higuchi, Norihide / Nakamura, Tadahiro / Sasaki, Hitoshi
Issue Date: 1-Jan-2015
Publisher: 日本薬学会 / Pharmaceutical Society of Japan
Citation: Biological and Pharmaceutical Bulletin, 38(1), pp.23-29; 2015
Abstract: The recognition of phosphatidylserine on the erythrocyte membrane mediates erythrophagocytosis by resident spleen macrophages. The application of phosphatidylserine to a gene vector may be a novel approach for splenic drug delivery. Therefore, we chose 1,2-dioleoyl-sn-glycero-3-phospho-L-serin (DOPS) as an analogue of phosphatidylserine for splenic gene delivery of plasmid DNA (pDNA). In the present study, we successfully prepared a stable pDNA ternary complex using DOPS and polyethyleneimine (PEI) and evaluated its efficacy and safety. The pDNA/PEI complex had a positive charge and showed high transgene efficacy, although it caused cytotoxicity and agglutination. The addition of DOPS changed the ζ-potential of the pDNA/PEI complex to negative. It is known that anionic complexes are not taken up well by cells. Surprisingly, however, the pDNA/PEI/DOPS complex showed relatively high transgene efficacy in vitro. Fluorescence microscope observation revealed that the pDNA/PEI/DOPS complex internalized the cells while maintaining the complex formation. The injection of the pDNA/PEI complex killed most mice within 24 h at high doses, although all mice in the pDNA/PEI/DOPS complex group survived. The ternary complex with DOPS showed markedly better safety compared with the pDNA/PEI complex. The pDNA/PEI/DOPS complex showed high gene expression selectively in the spleen after intravenous injection into mice. Thus the ternary complex with DOPS can be used to deliver pDNA to the spleen, in which immune cells are abundant. It appears to have an excellent safety level, although further study to determine the mechanism of action is necessary.
Keywords: 1,2-dioleoyl-sn-glycero-3-phospo-L-serin / Gene delivery / Plasmid DNA / Spleen / Ternary complex
URI: http://hdl.handle.net/10069/35065
ISSN: 09186158
DOI: 10.1248/bpb.b14-00478
Rights: © 2015 The Pharmaceutical Society of Japan
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/35065

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