2005 Fiscal Year Final Research Report Summary
Development of topical gene delivery system for clinical application
| Project/Area Number |
15590133
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Nagasaki University Hospital of Medicine and Dentistry |
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Principal Investigator |
SASAKI Hitoshi Nagasaki University, Hospital of Medicine and Dentistry, Professor, 医学部・歯学部附属病院, 教授 (00170689)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Junzo Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (30115901)
NAKASHIMA Mikiro Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (00260737)
NISHIDA Koyo Nagasaki University, Graduate School of Biomedical Sciences, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (20237704)
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| Project Period (FY) |
2003 – 2005
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| Keywords | Topical application / Gene delivery / Drug delivery system / Liposomes / Polymer / Ophthalmology / Pharmacokinetics / Clinical application |
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| Research Abstract |
Gene therapy is a useful treatment for curing inborn and acquired diseases. The eye has a number of advantages as a target organ for gene delivery. The use of non-viral vectors attracts great interests for in vivo gene delivery because they lack some of the risks inherent in viral vector systems
We have investigated the transfection activity of plasmid DNA (pDNA)/cationic liposome complexes to the eye in rabbits. Among the transfection experiments with various lipids, pDNA complexed with DOTMA/Chol liposomes showed the highest transfection activity after intravitreal injection. The complexes at a charge raio of +2.0 produced maximal gene expression in the eye. In conlusion, optimizing the lipid composition of cationic liposomes and the charge ratio of pDNA/cationic liposome complexes should enhance the transfection efficiency to the eye.
We have examined the effect of blood components on gene delivery with polyethyleneimine (PEI) in a human endothelial cell line. The transfection activity with pDNA/PEI complex was markedly decreased in the presence of fetal bovine serum, bovine serum albumin, human blood, human plasma, cholesterol and fatty acids, although it was not affected by lecithin and bile salts. Ternary complexes using polyanion could decrease the influence of blood components on gene expression. On the other hand, the transfection activity with pDNA/PEI complex was increased 2-3 times by the presence of glucose. We also found that the gene expression of pDNA/PEI complex and pDNA/liposomes complex was influenced by the disease such as hepatitis.
We have developed the ocular pharmacokinetic/pharmacodynamic (PK/PD) model of model drug, bunazosin, on the basis of the concentration-time profiles and hypotensive profiles of bunazosin. The PK/PD models can predict the concentrations of bunazosin in the ocular tissues and its hypotensive effect after instillation and ocular injection. This PK/PD model must be useful for designing the gene delivery system.
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