Toxicity of cucurbit[7]uril and cucurbit[8]uril: an exploratory in vitro and in vivo study

Abstract

Cucurbit[n]urils (CB[n]) are potential stabilizing, solubilizing, activating, and delivering agents for drugs. The toxicity of the macrocyclic host molecules cucurbit[7]uril (CB[7]), the most water-soluble homologue, as well as cucurbit[8]uril (CB[8]) has been evaluated. In vitro studies on cell cultures revealed an IC(50) value of 0.53 +/- 0.02 mM for CB[7], corresponding to around 620 mg of CB[7] per kg of cell material. Live-cell imaging studies performed on cells treated with subtoxic amounts of CB[7] showed no detrimental effects on the cellular integrity as assessed by mitochondrial activity. For CB[8], no significant cytotoxicity was observed within its solubility range. The bioadaptability of the compounds was further examined through in vivo studies on mice, where intravenous administration of CB[7] showed a maximum tolerated dosage of 250 mg kg(-1), while oral administration of a CB[7]/CB[8] mixture showed a tolerance of up to 600 mg kg(-1). The combined results indicate a sufficiently low toxicity to encourage further exploration of CB[n] as additives for medicinal and pharmaceutical use.

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

“…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 effects observed for an intravenous single dose i.v. injection with a mouse model demonstrated that CB [7] has a very low acute toxicity at a dose of 250 mg/kg, based on a body weight change of less than 10% within 5 days of the injections [5]. The tissue specific toxicity including neuro-, myo-and cardiotoxicity of CB [7] has been examined with the use of ex vivo electrophysiological models.…”

pH-controlled release of auxin plant hormones from cucurbit[7]uril macrocycle

“…In addition to the hydrophobic interactions within the cavity, the polar carbonyl groups at the portals are capable of stabilizing host-guest complexes by forming hydrogen bonds and ion-dipole and dipole-dipole interactions with appropriate guests [4,5,10]. Research on the host-guest chemistry of CB[n] has attracted great attention on account of the potential application of these materials in the fields of biomedicine [11,12], photochemistry [13], materials science, and nanotechnology [4,5]. In particular, its higher water solubility (approximately 20 mM) [4,14] and intermediate cavity volume (210 Å 3 ) [15] make CB [7] (Figure 1) an attractive host for complexation of guest molecules used in biology and medicine [5,6,16].…”

The World of Cucurbiturils — From Peculiarity to Commodity

“…Moreover, it has become possible to contrast the inclusion properties and binding strengths of this new class of synthetic host molecules with established macrocyclic receptors, such as cyclodextrins and water-soluble calixarenes. In fact, cucurbiturils are competitive in several respects, such as their low toxicity, [13,14] and far superior in many others, particularly their high chemical stability, large complexation-induced pK a shifts, as well as their tight, selective binding (see articles in this special issue).…”

“…Moreover, it has become possible to contrast the inclusion properties and binding strengths of this new class of synthetic host molecules with established macrocyclic receptors, such as cyclodextrins and water-soluble calixarenes. In fact, cucurbiturils are competitive in several respects, such as their low toxicity, [13,14] and far superior in many others, particularly their high chemical stability, large complexation-induced pK a shifts, as well as their tight, selective binding (see articles in this special issue).Initial investigations on cucurbit[6]uril focused on its binding preferences and the determination of the binding constants of its host-guest complexes. [15][16][17] These studies have continued to attract attention also for the larger homologues, driven, among other things, by the exceptional kinetics and thermodynamics of binding.…”