The ex vivo neurotoxic, 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 using ex vivo models. 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.

Molecular Encapsulation of Histamine H2-Receptor Antagonists by Cucurbit[7]Uril: An Experimental and Computational Study

“…The tissue specific toxicity including neuro-, myo-and cardiotoxicity of CB [7] has been examined with the use of ex vivo electrophysiological models. The study reported that 1 mM of CB [7] did not exhibit statistically measurable neurotoxicity, although myotoxic and cardiotoxic activities were observed in the presence of CB [7] concentrations of 0.3 mM [6]. Very recently, we have studied the developmental and organ-specific toxicity profiles of CB [7] with live zebrafish models and concluded that CB [7] is relatively safe and biocompatible at functional levels, which is consistent with previous in vitro, ex vivo and in vivo results [7].…”

“…On the one hand, CB [7]'s safety profile and biocompatibility has been well studied with several in vitro, in vivo and ex vivo models [5][6][7]. For instance, several in vitro studies on cell cultures have shown that CB [7] exhibits very low toxicity at up to 1 mM concentrations.…”

The state-of-play and future of platinum drugs

“…While not highly soluble in pure water, they become soluble upon forming host-guest complexes with drugs and in solutions with high salt concentrations, such as blood serum, and gastric and nasal fluids (Walker et al 2011). Cucurbit[n]urils are relatively non-toxic (Oun et al 2014) and to date have been formulated into oral tablets, topical creams and eye drop solutions , Chu et al 2014, Seif et al 2014. For drug delivery the homologues of six, seven and eight subunits are of most importance as these have a cavity that is ideally sized to store and release platins.…”

Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor

“…11 It has also been shown that the myotoxicity and cardiotoxicity of cisplatin was significantly reduced after this drug had been encapsulated by CB [7]. 20 CB [7] was also found to inhibit amyloid fibrillation, thus potentially finding therapeutic applications to prevent or treat amyloidosis. 21 Additionally, the olfactory responses of tilapia fish to odorants was suppressed by CB [7] encapsulation.…”