Abstract
Abstract 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 and therefore show great promise as a drug delivery system. We hypothesized that these nanocontainers can be used to increase solubility of hydrophobic small chemical compound drugs. In this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils CB[n]-type containers (named Motor1 and Motor2). Both containers induced no toxicity at concentrations of up to 1 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. Motor2 demonstrated an increase of water solubility of camptothecin by 500fold. Finally, bioactivity assays showed that the increase in solubility by paclitaxel via Motor1 led to a more efficient killing of the ovarian cancer cell line SKOV-3. In conclusion, our study reveals very low toxicity of two novel members of the cucurbit[n]uril family of nanocontainers. It demonstrates the increase in solubility of two important cancer drugs by the containers which 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: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4429. doi:10.1158/1538-7445.AM2011-4429
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