Abstract 4347: Toxicology and drug delivery by novel Cucurbit[n]uril-type molecular containers.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background. Many drug delivery systems are based on the ability of certain macrocyclic compounds - such as cyclodextrins - to act as molecular containers for pharmaceutical agents in water. 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 > 10ˆ4 Mˆ-1) and therefore show great promise as a drug delivery system (Isaacs, 2009). Initial in vitro toxicity analysis demonstrated good biocompatibility of five different CB[n]-type compounds. We hypothesized that these nanocontainers can be used to increase solubility of hydrophobic small chemical compound drugs. Methodology. In this study we investigated the toxicology and bioactivity of one novel cucurbit[n]urils CB[n]-type container (named Motor1). The container induced no toxicity at concentrations of up to 10 mM in human cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the Motor1 container was tolerated in mice without any toxicity after intravenous dosing of up to 1.5g/kg bodyweight. Interestingly, Motor1 was able to bind the cancer drug paclitaxel and increase its solubility in water by a factor of 2000. Finally, bioactivity assays showed that the increase in solubility by paclitaxel via Motor1 led to a more efficient killing of the cervical cancer cell line HeLa. Conclusion. Our study reveals very low toxicity of a novel member of the cucurbit[n]uril family of nanocontainers. It demonstrates the increase in solubility of four commercially available drugs by the containers by factors ranging from 400-2700fold. Importantly, the increase in solubility of paclitaxel led to increased killing of cancer cells in vitro. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system. Citation Format: Gaya Hettiarachchi, Da Ma, Duc Nguyen, Lyle Isaacs, Volker Briken. Toxicology and drug delivery by novel Cucurbit[n]uril-type molecular containers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4347. doi:10.1158/1538-7445.AM2013-4347