title: 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.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Okamatsu
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.forename: Risako
authors.initials: R
authors.lastname: Onodera
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Koshigoe
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Shimada
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Hattori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002208:Caproates / Q000737:chemistry*; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000737:chemistry*; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005472:Fluorouracil / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D058975:Folate Receptor 1 / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D002208:Caproates; D003505:Cyclodextrins; D004337:Drug Carriers; D058975:Folate Receptor 1; D004317:Doxorubicin; D005492:Folic Acid; D005472:Fluorouracil