Anchoring Cationic Amphiphiles for Nucleotide Delivery Significance of DNA Release from Cationic Liposomes for Transfection(Medicinal Chemistry)
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概要
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We have designed and synthesized lithocholic acid-based cationic amphiphile molecules as components of cationic liposomes for gene transfection (lipofection). To study the relationship between the molecular structures of those amphiphilic molecules, particularly the extended hydrophobic appendant (anchor) at the 3-hydroxyl group, and transfection efficiency, we synthesized several lithocholic and isolithocholic acid derivatives, and examined their transfection efficiency. We also compared the physico-chemical properties of cationic liposomes prepared from these derivatives. We found that isolithocholic acid derivatives exhibit higher transfection efficiency than the corresponding lithocholic acid derivatives. This result indicates that the orientation and extension of hydrophobic regions influence the gene transfection process. Isolithocholic acid derivatives showed a high ability to encapsulate DNA in a compact liposome-DNA complex and to protect it from enzymatic degradation. Isolithocholic acid derivatives also facilitated the release of DNA from the liposome-DNA complex, which is a crucial step for DNA entry into the nucleus. Our results show that the transfection efficiency is directly influenced by the ability of the liposome complex to release DNA, rather than by the DNA-encapsulating ability. Molecular modeling revealed that isolithocholic acid derivatives take relatively extended conformations, while the lithocholic acid derivatives take folded structures. Thus, the efficiency of release of DNA from cationic liposomes in the cytoplasm, which contributes to high transfection efficiency, appears to be dependent upon the molecular shape of the cationic amphiphiles.
- 2007-06-01
著者
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Hirashima Naohide
Graduate School of Pharmaceutical Sciences, Nagoya City University
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NAKANISHI Mamoru
Graduate School of Pharmaceutical Sciences, Nagoya City University
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Nakanishi Mamoru
Graduate School Of Pharmaceutical Sciences Nagoya City University
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MINATANI Kazuhiro
Graduate School of Pharmaceutical Sciences, Nagoya City University
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HATTORI Yoshifumi
Graduate School of Pharmaceutical Sciences, Nagoya City University
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OHWADA Tomohiko
Graduate School of Pharmaceutical Sciences, The University of Tokyo
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Ohwada Tomohiko
Graduate School Of Pharmaceutical Sciences The University Of Tokyo
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Hirashima Naohide
Graduate School Of Pharmaceutical Sciences Naeoya City University
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Hattori Yoshifumi
Graduate School Of Pharmaceutical Sciences Nagoya City University : Graduate School Of Pharmaceutica
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Minatani Kazuhiro
Graduate School Of Pharmaceutical Sciences Nagoya City University
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