Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers

Abstract

BackgroundMany 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 (Ka<104 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 (Ka>104 M−1) and therefore show great promise as a drug delivery system.MethodologyIn this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils (CB[5] and CB[7]) 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[7] 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[7] as when given in the unbound form. This result suggests that CB[7]-bound drug molecules can be released from the container to find their intracellular target.ConclusionOur 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.

Sugammadex: A neuromuscular blockade agent encapsulator

“…A medication of interest is calabadion 2, a nanocontainer capable of reversing steroidal and benzylisoquinoline NMBAs, the latter of which sugammadex cannot encapsulate. 14,50 This medication is an acyclic cucurbit[n]uril molecule suitable for binding to the hydrophobic steroidal NMBA due to its barrel-shaped cavity formed by a central glycoluril tetramer with four sulfonate groups which promote cation binding and water solubility. 51 After testing in rats, it was found that calabadion 2 was able to rapidly reverse vecuronium, rocuronium, and cisatracurium, even with profound neuromuscular blockade in a dose-dependent manner.…”

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].…”

Preparation and Properties of Temperature and pH Sensitive Chitosan Supramolecular Gel Based on Host-guest Interaction of Cucurbit[8]uril

“…羰基端口结构, 能与不同类型的客体形成主-客体包合 物, 这种主客体的超分子作用易受到温度、 pH 值及介质 等因素变化的影响, 并可通过改变环境条件的方法来调 节超分子结构和对材料功能进行调控 [7,8] ; 葫芦脲具有 高度的结构对称性、热稳定性和低毒性, 是一种具有广 阔 应 用 前 景 的 新 型 功 能 材 料 化 合 物 [9,10] . (6)上质子吸收峰, δ 1.878 为残留的 N-乙酰基上 的甲基质子吸收峰 [16] .…”