J. Am. Chem. Soc. 135, 7090–7093 (2013)

Selective transport of molecules across cell membranes is a key step in drug delivery, live-cell imaging and other theranostic applications. Many drug and probe compounds are unable to simply burrow their way through the cell membrane, and typically a receptor is required to recognize appropriate species and mediate endocytosis to enable them to enter the cell. Moreover, the complex soup of molecules that make up the cellular environment can compete for the binding sites of artificial receptors and thwart efforts to develop a generalized transmembrane shuttling solution. These problems often limit successful synthetic transporters to single receptor–target systems.

Now a team of researchers from California State University, Long Beach and the University of California, Riverside, led by Richard Hooley have developed a carboxylate-decorated, non-cytotoxic cavitand molecule that can embed itself into cell walls and act as an anchor to facilitate the transport of guest molecules across lipid membranes. In contrast to other shape-based receptors, which tend to offer a wide target scope but poor selectivity, this cavitand specifically recognizes choline-like salts. Once binding of a choline-tagged molecule occurs at the cell surface, the cavitand–target pair is endocytosed into the cell. Successful transport across cell membranes was demonstrated using a choline-modified fluorescein dye. In a control experiment using unmodified fluorescein there was virtually no internalized fluorescence, demonstrating that a choline-like group is essential for cavitand-mediated recognition and, in turn, transport into the cell.

Credit: © ACS 2013

Transmembrane transport also occurred — albeit at a slower rate — when an excess of choline was added to the system, demonstrating that transport is not completely inhibited by competitive binding. This finding suggests that, in principle, such cavitand-based receptors could be used to mediate transport even in cell types where choline and its derivatives are present in high concentrations. The ability to selectively induce endocytosis with a range of target choline-tagged compounds could lead to a generalized cell membrane transport and delivery system for further use in drug-delivery systems.