Cyclodextrins (CDs) are widely used both in pharmaceutical applications to improve drug bioavailability and in cell biology as cholesterol-depleting and -delivering agents. Recently, it was shown that β-CD covalently coupled to fluorescent dextran polymers accumulates in cholesterol-enriched lysosomal storage organelles of human fibroblasts (Rosenbaum et al., 2010). By employing a methyl-βCD tagged with fluorescein (FMβCD), we have characterized the cellular trafficking of the CD in mammalian cell lines and its distribution into the endocytic compartments within the first minutes following addition to cells. FMβCD enters mammalian cells via endocytosis. The colocalization of FMβCD with transferrin-containing endosomes and the inhibition of FMβCD internalization by chlorpromazine or by an antisense RNA against clathrin heavy chain indicate that FMβCD is taken up via receptor-mediated, clathrin-dependent endocytosis. These results not only highlight the possibility of using CDs to target drugs intracellularly, but also warn about potential unwanted effects on cell physiology other than cholesterol extraction/loading at high concentrations, high temperatures and prolonged incubation times.
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