Design and evaluation of folate-appended α-, β-, and γ-cyclodextrins having a caproic acid as a tumor selective antitumor drug carrier in vitro and in vivo.

Abstract

We reported that per-6-folic acid (FA)-appended β-cyclodextrin (β-CyD) possessing two caproic acids between FA and a β-CyD molecule as a spacer (Fol-c2-β-CyD) could be useful as a promising antitumor drug carrier. However, the effects of the cavity size and the spacer length on the carrier ability are not still known. In this study, we designed and evaluated the FA-appended three kinds of CyDs possessing a caproic acid as a spacer between FA and a CyD molecule (Fol-c1-CyDs) as a tumor targeting carrier for antitumor drugs. The stability constant of the Fol-c1-β-CyD/doxorubicin (DOX) complex was much higher than those of Fol-c1-α-CyD and Fol-c1-γ-CyD at pH 7.3. Antitumor activity of DOX was increased by the complexation with Fol-c1-β-CyD, but not with Fol-c1-α-CyD or Fol-c1-γ-CyD in KB cells, a folate receptor-α-positive cell line. Also, Fol-c1-β-CyD increased antitumor activities of paclitaxel and vinblastine, but not 5-fluorouracil. Furthermore, Fol-c1-β-CyD accelerated cellular uptake of DOX and inhibited its efflux from KB cells. The Fol-c1-β-CyD/DOX complex showed much higher antitumor activity than DOX alone after intratumoral and intravenous administrations to tumor-bearing mice with a negligible change of the blood chemistry values. These findings suggest that Fol-c1-β-CyD could be useful as a tumor-selective carrier for antitumor drugs.

• Authors: Ayaka Okamatsu, Keiichi Motoyama, Risako Onodera, Taishi Higashi, Takahiro Koshigoe, Yasutaka Shimada, Kenjiro Hattori, Tomoko Takeuchi, Hidetoshi Arima
• Journal: Biomacromolecules (Biomacromolecules) Vol. 14 Issue 12 Pg. 4420-8 (Dec 09 2013) ISSN: 1526-4602 [Electronic] United States
• PMID: 24175976 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Caproates
• Cyclodextrins
• Drug Carriers
• Folate Receptor 1
• Doxorubicin
• Folic Acid
• Fluorouracil

Topics

• Animals
• Antibiotics, Antineoplastic (chemistry, metabolism, pharmacology)
• Caproates (chemistry)
• Cell Line, Tumor
• Cyclodextrins (chemistry)
• Doxorubicin (chemistry, metabolism, pharmacology)
• Drug Carriers (chemistry, metabolism, pharmacology)
• Drug Screening Assays, Antitumor
• Drug Stability
• Fluorouracil (chemistry, metabolism, pharmacology)
• Folate Receptor 1 (metabolism)
• Folic Acid (chemistry)
• Humans
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Tumor Burden (drug effects)