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  • Title: Active Drug Targeting of a Folate-Based Cyclodextrin-Doxorubicin Conjugate and the Cytotoxic Effect on Drug-Resistant Mammary Tumor Cells In Vitro.
    Author: Mizusako H, Tagami T, Hattori K, Ozeki T.
    Journal: J Pharm Sci; 2015 Sep; 104(9):2934-40. PubMed ID: 25940848.
    Abstract:
    Active drug targeting is an effective therapeutic approach for the treatment of malignant cancers and novel types of drug carriers have been developed. In this study, we developed a cyclodextrin (CD)-based novel carrier-drug conjugate, called per-FOL-β-CD-ss-DOX, which has folic acid (FA) molecules at the end of primary hydroxyl groups of β-CD and a pH-cleavable spacer with an anticancer drug, doxorubicin (DOX), at the end of secondary hydroxyl groups. This per-FOL-β-CD-ss-DOX exhibited a significant cellular uptake as compared with the free DOX solution by EMT6/P cells, which activate the expression of folate receptor (FR). Cellular uptake of per-FOL-β-CD-ss-DOX was significantly inhibited in the presence of FA and was also inhibited at 4°C. The conjugate exhibited remarkable cytotoxic effects in EMT6/AR1 cells, which are resistant to DOX, whereas free DOX solution did not exhibit this effect. These results suggest that per-FOL-β-CD-ss-DOX can be taken up into cells via FR-related endocytosis and the cleaved DOX derived from it in endosomes could escape the efflux caused by P-glycoprotein, resulting in the cytotoxic effect. Therefore, the drug delivery by per-FOL-β-CD-ss-DOX may be a useful approach for drug delivery to FR-expressing cells such as drug-resistant malignant cancers.
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