title: Theex vivoneurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles.
abstract: The cucurbituril family of drug delivery vehicles have been examined for their tissue specific toxicity usingex vivomodels. Cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]) and the linear cucurbituril-derivative Motor2 were examined for their neuro-, myo- and cardiotoxic activity and compared with β-cyclodextrin. The protective effect of drug encapsulation by CB[7] was also examined on the platinum-based anticancer drug cisplatin. The results show that none of the cucurbiturils have statistically measurable neurotoxicity as measured using mouse sciatic nerve compound action potential. Cucurbituril myotoxicity was measured by nerve-muscle force of contraction through chemical and electrical stimulation. Motor2 was found to display no myotoxicity, whereas both CB[6] and CB[7] showed myotoxic activity via a presynaptic effect. Finally, cardiotoxicity, which was measured by changes in the rate and force of right and left atria contraction, was observed for all three cucurbiturils. Free cisplatin displays neuro-, myo- and cardiotoxic activity, consistent with the side-effects seen in the clinic. Whilst CB[7] had no effect on the level of cisplatin's neurotoxic activity, drug encapsulation within the macrocycle had a marked reduction in both the drug's myo- and cardiotoxic activity. Overall the results are consistent with the relative lack of toxicity displayed by these macrocycles in whole animal acute systemic toxicity studies and indicate continued potential of cucurbiturils as drug delivery vehicles for the reduction of the side effects associated with platinum-based chemotherapy.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, United Kingdom.
authors.forename: Rabbab
authors.initials: R
authors.lastname: Oun
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, United Kingdom.
authors.forename: Rafael S
authors.initials: RS
authors.lastname: Floriano
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, United States of America.
authors.forename: Lyle
authors.initials: L
authors.lastname: Isaacs
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, United Kingdom.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Rowan
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW, 2006, Australia.
authors.forename: Nial J
authors.initials: NJ
authors.lastname: Wheate
keywords: cardiotoxicity; cisplatin; cucurbituril; cyclodextrin; myotoxicity; neurotoxicity