Potential use of folate-appended methyl-β-cyclodextrin as a novel antitumor agent

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  • Motoyama Keiichi
    Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
  • Higashi Taishi
    Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
  • Arima Hidetoshi
    Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University

Bibliographic Information

Other Title
  • 葉酸修飾メチル-β-シクロデキストリンを用いたがん治療
  • ヨウサン シュウショク メチル-v-シクロデキストリン オ モチイタ ガン チリョウ
  • Potential use of folate-appended methyl-^|^beta;-cyclodextrin as a novel antitumor agent

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Description

The conventional anticancer agents often have some unexpected limitations such as poor distribution, tissue damage, and lack of target specificity. In order to overcome these problems, the drug delivery technique to tumor cells has attracted considerable attention. Meanwhile, the widespread use of folic acid (FA) as a tumor-targeting ligand has been known, because folate receptor-α (FR-α) overexpresses in various kinds of epithelial tumor cells. On the other hand, methyl-β-cyclodextrin (M-β-CyD) is acknowledged to disrupt the structures of lipid rafts, through the extraction of cholesterol from the microdomains. Grosse et al. reported that intraperitoneal administration of M-β-CyD had antitumor activity in human tumor xenografted athymic nude mice. However, the antitumor activity of M-β-CyD has a lack of a tumor cell-selectivity. Therefore, in the present study, to make an attempt to confer a tumor cell-selectivity to M-β-CyD, we newly synthesized folate-appended M-β-CyD (FA-M-β-CyD), and evaluated the potentials as its novel antitumor agent. FA-M-β-CyD showed the potent antitumor activity in various FR-α-positive cells such as KB cells, Ihara cells and M213 cells, but not in FR-α-negative cells, A549 cells. In sharp contrast to M-β-CyD, FA-M-β-CyD did not change the DNA content, but significantly elevated the mitochondrial transmembrane potential in KB cells. Additionally, activation of caspase-3/7 in KB cells did not occur after treatment with FA-M-β-CyD, indicating that FA-M-β-CyD caused cell-death in a apoptosis-independent pathway. FA-M-β-CyD induced the formation of autophagic vacuoles in KB cells. In addition, the antitumor activity of FA-M-β-CyD, not M-β-CyD, was inhibited by the addition of chloroquine and bafilomycin A1, autophagy inhibitors, in KB cells. A single intravenous injection of FA-M-β-CyD drastically inhibited the tumor growth and significantly improved survival rate, in Colon-26 cells-allografted or M213 cells-xenografted mice. In conclusion, the present study demonstrated the potentials of FA-M-β-CyD as a novel tumor-selective anticancer agent, due to the FR-α-mediated cellular uptake. The present results will give useful information for design and development for novel antitumor drug carriers and antitumor drugs based on CyDs.

Journal

  • Drug Delivery System

    Drug Delivery System 28 (2), 99-108, 2013

    THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM

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