@article{oai:nagasaki-u.repo.nii.ac.jp:00019374,
 author = {Kakinoki, Atsufumi and Kaneo, Yoshiharu and Ikeda, Yuka and Tanaka, Tetsuro and Fujita, Kahee},
 issue = {1},
 journal = {Biological and Pharmaceutical Bulletin},
 month = {Jan},
 note = {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 g -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., Biological and Pharmaceutical Bulletin, 31(1), pp.103-110; 2008},
 pages = {103--110},
 title = {Synthesis of poly(vinyl alcohol)-doxorubicin conjugates containing cis-aconityl acid-cleavable bond and its isomer dependent doxorubicin release},
 volume = {31},
 year = {2008}
}