The cucurbit[n]uril (CB[n]) family of macrocycles has been shown to have potential in drug
delivery where they are able to provide physical and chemical stability to drugs, improve drug
solubility, control drug release and mask the taste of drugs. Cisplatin is a small molecule
platinum-based anticancer drug that has severe dose-limiting side-effects. Cisplatin forms a
host–guest complex with cucurbituril (cisplatin@CB) with the platinum atom and both
chlorido ligands located inside the macrocycle, with binding stabilised by four hydrogen bonds
(2.15–2.44 A ˚ ). Whilst CB has no effect on the in vitro cytotoxicity of cisplatin in the human
ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-lines A2780/cp70 and MCP1,
there is a significant effect on in vivo cytotoxicity using human tumour xenografts.
Cisplatin@CB is just as effective on A2780 tumours compared with free cisplatin, and in the
cisplatin-resistant A2780/cp70 tumours cisplatin@CB markedly slows tumour growth. The
ability of cisplatin@CB to overcome resistance in vivo appears to be a pharmacokinetic effect.
Whilst the peak plasma level and tissue distribution are the same for cisplatin@CB and free
cisplatin, the total concentration of circulating cisplatin@CB over a period of 24 hours is
significantly higher than for free cisplatin when administered at the equivalent dose. The results
provide the first example of overcoming drug resistance via a purely pharmacokinetic effect rather
than drug design or better tumour targeting, and demonstrate that in vitro assays are no longer as important in screening advanced systems of drug delivery.