A DNA Microarray-based Analysis of the Host Response to a Nonviral Gene Carrier: A Strategy for Improving the Immune Response
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概要
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The purpose of this study was to investigate the host response to systemically administered lipid nanoparticles (NPs) encapsulating pDNA in the spleen using a DNA microarray. As a model for NPs, we used a Multifunctional envelope-type nano device (MEND). Microarray analysis revealed that 1581 of the differentially expressed genes could be identified by PEG-unmodified NP using a 3-fold change relative to the control. As the result of PEGylation, the NP treatment resulted in the reduction in the expression of most of the genes. However, the expression of type I interferon (IFN) was specifically increased by PEGylation. Based on the microarray and a pathway analysis, we hypothesize that PEGylation inhibited the endosomal escape of NP, and extended the interaction of TLR9 with CpG-DNA accompanied by the production of type I IFN. This hypothesis was tested by introducing a pH-sensitive fusogenic peptide, GALA, which enhances the endosomal escape of PEGylated NP. As expected, type I IFN was reduced and IL-6 remained at the baseline. These findings indicate that a carrier design based on microarray analysis and the manipulation of intracellular trafficking constitutes a rational strategy for reducing the host immune response to NPs.
著者
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原島 秀吉
北大院・薬学研究科
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梶本 和昭
北海道大学大学院薬学研究院
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馬場 嘉信
徳島大学薬学部薬品物理化学教室
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Akita Hidetaka
Lab. For Molecular Design Of Pharmaceutics Fac. Of Pharmaceutical Sciences Hokkaido Univ.
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Shim Chang
Faculty Of Pharmaceutical Sciences University Of Tokyo : (present Address) College Of Pharmacy Seoul
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SHIGENOBU Kohki
Faculty of Pharmaceutical Sciences, University of Tokyo
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Baba Yoshinobu
Dep. Of Applied Chemistry Graduate School Of Engineering Nagoya Univ.
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Baba Yoshinobu
Department Of Applied Chemistry Graduate School Of Engineering Mext Innovative Research Center For P
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Kaji Noritada
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University
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Kaji Noritada
Mext Innovative Res. Center For Preventive Medical Engineering Nagoya Univ.
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Harashima Hideyoshi
Department Of Pharmacokinetics And Pharmaceutics Graduate School Of Pharmaceutical Sciences The Univ
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Akita Hidetaka
Graduate School Of Pharmaceutical Sciences Hokkaido University
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馬場 嘉信
Crest
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馬場 嘉信
徳島大学薬学部
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Hayashi Yasuhiro
Department Of Surgical Oncology Graduate School Of Medicine Hokkaido University
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Kajimoto Kazuaki
Department Of Epidemiology Divisions Of Preventive Medicine
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Hatakeyama Hiroto
Fac. Of Pharmaceutical Sciences Hokkaido Univ.
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馬場 嘉信
名古屋大学大学院工学研究科
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Kajimoto Kazuaki
Fac. Of Pharmaceutical Sciences Hokkaido Univ.
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