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Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals

Abstract

The solubility characteristics of 40–70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents—acyclic cucurbituril-type containers—which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container–drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery.

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Figure 1: Synthesis of acyclic CB[n] containers 1 and 2.
Figure 2: X-ray crystal structures of 1 and 2.
Figure 3: Phase solubility diagrams allow a determination of the enhancement in solubility for poorly soluble drugs in the presence of molecular containers 1, 2 or HP-β-CD.
Figure 4: In vitro cell viability, cell death and haemolysis assays performed with container 1.
Figure 5: MTD study performed for container 1.
Figure 6: Cell death induction assays performed on cancer cells treated with staurosporine (Stx), 1, paclitaxel solubilized with 1 (1–P) and paclitaxel (P) alone.

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Acknowledgements

The authors acknowledge the Maryland Department of Business and Economic Development (Nano-Bio Initiative), the Maryland Technology Development Corporation and the National Science Foundation (CHE-1110911) for funding.

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D.M., G.H., V.B. and L.I. designed the research. D.M., G.H., D.N., B.Z., J.B.W. and P.Y.Z. performed the research. D.M., G.H., D.N., B.Z., J.B.W., P.Y.Z., V.B. and L.I. analysed data. D.M., G.H., V.B. and L.I. wrote the paper.

Corresponding authors

Correspondence to Volker Briken or Lyle Isaacs.

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Crystallographic data for compound 1. (CIF 70 kb)

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Crystallographic data for compound 2. (CIF 72 kb)

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Ma, D., Hettiarachchi, G., Nguyen, D. et al. Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals. Nature Chem 4, 503–510 (2012). https://doi.org/10.1038/nchem.1326

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