Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release
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- Kakinoki Atsufumi
- Laboratory of Biopharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University
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- Kaneo Yoshiharu
- Laboratory of Biopharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University
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- Ikeda Yuka
- Laboratory of Biopharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University
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- Tanaka Tetsuro
- Laboratory of Biopharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University
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- Fujita Kahee
- Department of Molecular Medicinal Sciences, Graduate School of Biomedical Sciences, Nagasaki University
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Abstract
Aconityl-doxorubicin (ADOX) was synthesized by the modified method of Shen and Ryser. Two isomers of cis-ADOX (cis-configuration) and trans-ADOX (trans-configuration) were generated in the reaction of DOX and cis-aconitic anhydride. These products were separated completely by using HPLC and analyzed by TOF-MS spectroscopy and 1H- and 13C-NMR experiments. The yields of cis-ADOX and trans-ADOX were 36.3 and 44.8%, respectively. The free γ-carboxylic group of ADOX molecule was coupled to poly(vinyl alcohol) (PVA) via ethylenediamine spacer, resulting the macromolecular conjugates of PVA–cis-ADOX and PVA–trans-ADOX, respectively. The DOX content of the conjugates estimated by the hydrolysis method detected the aglycone of DOX which can be estimated as the PVA-bound DOX selectively was 4.4 w/w% which was similar to 4.6 w/w% by the ordinary UV method. Both PVA–cis-ADOX and PVA–trans-ADOX were very stable at neutral pH, but the release of DOX was increased markedly under acidic conditions. Half-life of the release of DOX from PVA–cis-ADOX at pH 5.0 was 3 h which was 4.7-fold shorter than that from PVA–trans-ADOX (14 h). The cytotoxicities of PVA–cis-ADOX and PVA–trans-ADOX were evaluated by using J774.1 cells employing a [3H]uridine incorporation assay as a measure of RNA synthesis. A significant difference in antitumor activity between PVA–cis-ADOX and PVA–trans-ADOX was observed where the former was much active than the later. It was suggested that the conjugate enters the cells and reaches the lysosomal/endosomal compartment, and that the aconityl spacer releases DOX from the conjugate in the acidic compartment of lysosomes/endosomes due to the participation of a free carboxylic group.
Journal
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- Biological and Pharmaceutical Bulletin
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Biological and Pharmaceutical Bulletin 31 (1), 103-110, 2008
The Pharmaceutical Society of Japan
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Keywords
Details 詳細情報について
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- CRID
- 1390001204625245184
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- NII Article ID
- 110006569983
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- NII Book ID
- AA10885497
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- ISSN
- 13475215
- 09186158
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- HANDLE
- 10069/18705
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- NDL BIB ID
- 9312501
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- Text Lang
- en
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- Data Source
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- JaLC
- IRDB
- NDL
- Crossref
- CiNii Articles
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- Abstract License Flag
- Disallowed