Many drug delivery systems are based on the ability of certain macrocyclic compounds – such as cyclodextrins (CDs) – to act as molecular containers for pharmaceutical agents in water. Indeed β-CD and its derivatives have been widely used in the formulation of hydrophobic pharmaceuticals despite their poor abilities to act as a molecular container (e.g., weak binding (K a<10 4 M −1) and their challenges toward chemical functionalization. Cucurbit[n]urils (CB[n]) are a class of molecular containers that bind to a variety of cationic and neutral species with high affinity (K a>10 4 M −1) and therefore show great promise as a drug delivery system.
In this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils (CB  and CB ) and three CB[n]-type containers (Pentamer 1, methyl hexamer 2, and phenyl hexamer 3). All five containers demonstrated high cell tolerance at concentrations of up to 1 mM in cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the CB  molecular container was efficiently internalized by macrophages indicating their potential for the intracellular delivery of drugs. Bioactivity assays showed that the first-line tuberculosis drug, ethambutol, was as efficient in treating mycobacteria infected macrophages when loaded into CB  as when given in the unbound form. This result suggests that CB -bound drug molecules can be released from the container to find their intracellular target.
Our study reveals very low toxicity of five members of the cucurbit[n]uril family of nanocontainers. It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.