細胞内遺伝子・核酸の定量的・動的イメージングを基盤とした細胞内動態解析及びその制御に関する研究

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In the 21st century the category of biomedicine is now expanding from low-molecular drugs to recombinant proteins, antibodies, and nucleic acids (e.q., siRNA and plasmid DNA). In this era also, development of a novel nanotechnology to control intracellular trafficking is highly desired. For a promising gene therapy, an efficient nuclear delivery vector is a minimum requirement. Quantitative and mechanism-based information on differences in transfection efficiency between viral and non-viral vectors would be highly useful to improve the effectiveness of non-viral vectors. In this review, we will summarize our recent progress in quantitative comparison and underlying mechanisms of the intracellular trafficking between adenovirus vectors and plasmid DNA (pDNA) transfected by non-viral vectors. Our analysis has revealed that poor post-nuclear delivery events, as well as the nuclear delivery process itself are key processes to focus on. Especially, less effective transcription and translation are most likely due to poor nuclear decondensation and excess electrostatic interaction between mRNA and the gene carrier, respectively. Meanwhile, we have developed a multi-functional envelope-type nano device (MEND), in which the pDNA/polycation core is encapsulated in the lipid bilayers. Based on feedback information concerning the rate-limiting processes of gene carriers, we controlled the number of lipid envelopes to enhance the decoating of encapsulated pDNA from the envelope structure. As an expanded application of this concept, we have developed a tetra-lamellar MEND (T-MEND), which is designed to overcome the endosome and nuclear membranes by step-wise membrane fusion.

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秋田英万
北海道大学大学院薬学研究院

細胞内遺伝子・核酸の定量的・動的イメージングを基盤とした細胞内動態解析及びその制御に関する研究

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