Potential use of the complex of doxorubicin with folate-conjugated methyl-β-cyclodextrin for tumor-selective cancer chemotherapy.
In a recent study, we attempted to confer a tumor-selective cytotoxic activity to methyl-β-cyclodextrin (M-β-CyD), we synthesized folate-conjugated M-β-CyD (FA-M-β-CyD), and demonstrated the potential of FA-M-β-CyD as a novel anticancer agent at a high dose. In the present study, to expand the application of FA-M-β-CyD for cancer chemotherapy, we evaluated the potential of FA-M-β-CyD as a tumor-targeting anticancer drug carrier at a low dose. FA-M-β-CyD formed an inclusion complex with doxorubicin (DOX) with a high-stability constant (3.0 × 105M-1). Antitumor activity of DOX was increased by the complexation with FA-M-β-CyD, but not with folate-conjugated β-CyD (FA-β-CyD) or M-β-CyD in KB cells, a folate receptor-α (FR-α)-expressing cell line. Also, FA-M-β-CyD increased antitumor activity of paclitaxel, a class IV compound in the biopharmaceutical classification system (BCS), but not 5-fluorouracil, a class III compound in the BCS. Furthermore, FA-M-β-CyD enhanced cellular uptake of DOX through a complexation in KB cells (FR-α (+)), compared to FA-β-CyD and M-β-CyD. The DOX/FA-M-β-CyD complex showed markedly high antitumor activity, compared to DOX alone and DOX/M-β-CyD complex, after an intravenous administration to FR-α-expressing tumor cell-bearing mice. These findings suggest that FA-M-β-CyD could be useful as a tumor-selective carrier for anticancer drugs.
a Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto Japan.
Keiichi
K
Motoyama
a Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto Japan.
Risako
R
Onodera
a Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto Japan.
Ayaka
A
Okamatsu
a Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto Japan.
Taishi
T
Higashi
b Division of Hematopoiesis, Center for AIDS Research, Kumamoto University Kumamoto Japan.
Ryusho
R
Kariya
b Division of Hematopoiesis, Center for AIDS Research, Kumamoto University Kumamoto Japan.
Seiji
S
Okada
a Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto Japan.
Hidetoshi
H
Arima
Anticancer drug; cancer chemotherapy; drug delivery system; folic acid; methyl-β-cyclodextrin; tumor targeting