Folate-Appended β-Cyclodextrin as a Promising Tumor Targeting Carrier for Antitumor Drugsin Vitroandin Vivo

Abstract

A large number of antitumor drug delivery carriers based on passive targeting and/or active targeting have been developed. However, encapsulation of antitumor drugs into these drug carriers is often complicated, and antitumor activities of these targeting systems are not satisfactory. In the present study, we first prepared heptakis-6-folic acid (FA)-appended β-cyclodextrin (β-CyD) possessing two caproic acids between FA and a β-CyD molecule as a spacer (Fol-c(2)-β-CyD) and evaluated the potential as a novel tumor targeting carrier for antitumor drugs through a complexation. Fol-c(2)-β-CyD formed an inclusion complex with doxorubicin (DOX) at a 1:1 molar ratio with a markedly high stability constant (>10(6) M(-1)). Cellular uptake of DOX was increased by the addition of Fol-c(2)-β-CyD in KB cells, a folate receptor-α (FR-α)-positive cell line. Additionally, Fol-c(2)-β-CyD increased in vitro antitumor activities of antitumor drugs such as DOX, vinblastine (VBL), and paclitaxel (PTX) in KB cells, but not in A549 cells, a FR-α-negative cell line. The complex of DOX with Fol-c(2)-β-CyD markedly increased antitumor activity of DOX, not only after intratumoral administration but also after intravenous administration to mice subcutaneously inoculated Colon-26 cells, a FR-α-positive cell line. These findings suggest that Fol-c(2)-β-CyD could be useful as a promising antitumor drug carrier.

Anionic cyclodextrins as versatile hosts for pharmaceutical nanotechnology: Synthesis, drug delivery, enantioselectivity, contrast agents for MRI

“…Specifically, the per(6-folic acid) appended α-, β-and γ-CDs 19a-c having one caproic acid spacer between folic acid (FA) and the CD macrocycles (Scheme 9) (Okamatsu et al, 2013a) and the corresponding 19d derivative of β-CD with two caproic acid units as spacer (Scheme 9) (Okamatsu et al, 2013b) have been synthesized. The synthesis has initiated from per(6-amino-6-deoxy)-α-, β-and γ-CDs, which were condensed with Boc-caproic acid (Boc-6-aminohexanoic acid) using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), followed by deprotection, which resulted in the fully per-substituted-6-amino-caproic acid-CDs 18a-c (Scheme 9).…”

“…The single-isomer per(6-folic acid-appended)-CDs 19a-d via caproic acid linkers have been evaluated as carriers for antitumor drugs. Analogues of α-, β-and γ-CDs were linked with tumor targeting folic acid molecules (FA) via one caproic acid (19a-c, Scheme 9) (Okamatsu et al, 2013a) or for the β-CD analogue 19d via two caproic acid molecules (Okamatsu et al, 2013b). These ionisable derivatives (mixed anionic and cationic moieties) forming strong complexes with doxorubicin (DOX) under a specific pH value and weaker in another, in combination with the targeting properties of FA (Su et al, 2014) can develop into appropriate drug carriers.…”

Potential Use of Cyclodextrins as Drug Carriers and Active Pharmaceutical Ingredients

“…Thereby, there are few reports that achieved targeting of anticancer drug in vivo using FA-conjugated CyDs. More recently, Okamatsu et al 29,30) prepared folate-appended CyD possessing a caproic acid between FA and a CyD molecule as spacer (Fol-c 1 -CyD), and evaluated the inclusion complexation ability with doxorubicin (DOX) and the antitumor effects of the DOX complex in vitro and in vivo. In general, many studies report that administration in CyD solutions has no effect on drug pharmacokinetics due to low stability constant of the complexes.…”

Multifunctional drug nanocarriers formed by cRGD-conjugated βCD-PAMAM-PEG for targeted cancer therapy

“…PEGylation has been more widely studied because in addition to reduced cytotoxicity, PEGylation also sterically shields the nanocarriers from opsonization thereby increasing their circulation time in the bloodstream and consequently enhancing the in vivo tumor accumulation of the therapeutic agent via the EPR effect [19-27]. However, the extent of passive tumor-targeting alone via the EPR effect is often limited [28-29]. It has been demonstrated that PEGylated nanocarriers modified using active tumor targeting ligands specific to receptors overexpressed in cancer cells can further enhance the in vivo tumor accumulation of nanocarriers [30-36].…”