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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References
Hauss, D. J. Oral lipid-based formulations. Adv. Drug Deliv. Rev. 59, 667–676 (2007).
Lipinski, C. A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 44, 235–249 (2000).
Porter, C. J. H., Trevaskis, N. L. & Charman, W. N. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nature Rev. Drug Discov. 6, 231–248 (2007).
Leuner, C. & Dressman, J. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 50, 47–60 (2000).
Muller, R. H. & Keck, C. M. Challenges and solutions for the delivery of biotech drugs—a review of drug nanocrystal technology and lipid nanoparticles. J. Biotechnol. 113, 151–170 (2004).
Blagden, N., de Matas, M., Gavan, P. T. & York, P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv. Drug Deliv. Rev. 59, 617–630 (2007).
Patri, A. K., Kukowska-Latallo, J. F. & Baker, J. R. Targeted drug delivery with dendrimers: comparison of the drug release kinetics of covalently conjugated drug and non-covalent drug inclusion complex. Adv. Drug Deliv. Rev. 57, 2203–2214 (2005).
Serajuddin, A. T. M. Salt formation to improve drug solubility. Adv. Drug Deliv. Rev. 59, 603–616 (2007).
Stella, V. J. & Nti-Addae, K. W. Prodrug strategies to overcome poor water solubility. Adv. Drug Deliv. Rev. 59, 677–694 (2007).
Szente, L. & Szejtli, J. Highly soluble cyclodextrin derivatives: chemistry, properties, and trends in development. Adv. Drug Deliv. Rev. 36, 17–28 (1999).
Rekharsky, M. V. & Inoue, Y. Complexation thermodynamics of cyclodextrins. Chem. Rev. 98, 1875–1917 (1998).
Rajewski, R. A. & Stella, V. J. Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery. J. Pharm. Sci. 85, 1142–1169 (1996).
Stella, V. J. & Rajewski, R. A. Cyclodextrins: their future in drug formulation and delivery. Pharm. Res. 14, 556–567 (1997).
Okimoto, K., Rajewski, R. A., Uekama, K., Jona, J. A. & Stella, V. J. The interaction of charged and uncharged drugs with neutral (HP-β-CD) and anionically charged (SBE7-β-CD) β-cyclodextrins. Pharm. Res. 13, 256–264 (1996).
Gutsche, C. D. Calixarenes: An Introduction 2nd edn (Royal Society of Chemistry, 2008).
Diederich, F. Cyclophanes for complexing neutral molecules. Angew. Chem. Int. Ed. Engl. 27, 362–386 (1988).
Caulder, D. L. & Raymond, K. N. Supermolecules by design. Acc. Chem. Res. 32, 975–982 (1999).
Northrop, B. H., Zheng, Y.-R., Chi, K.-W. & Stang, P. J. Self-organization in coordination-driven self-assembly. Acc. Chem. Res. 42, 1554–1563 (2009).
Yoshizawa, M., Klosterman, J. K. & Fujita, M. Functional molecular flasks: new properties and reactions within discrete, self-assembled hosts. Angew. Chem. Int. Ed. 48, 3418–3438 (2009).
Breiner, B., Clegg, J. K. & Nitschke, J. R. Reactivity modulation in container molecules. Chem. Sci. 2, 51–56 (2011).
Fiedler, D., Leung, D. H., Bergman, R. G. & Raymond, K. N. Selective molecular recognition, C–H bond activation, and catalysis in nanoscale reaction vessels. Acc. Chem. Res. 38, 349–358 (2005).
Liu, S., Gan, H., Hermann, A. T., Rick, S. W. & Gibb, B. C. Kinetic resolution of constitutional isomers controlled by selective protection inside a supramolecular nanocapsule. Nature Chem. 2, 847–852 (2010).
Rebek, J. Molecular behavior in small spaces. Acc. Chem. Res. 42, 1660–1668 (2009).
Balzani, V., Credi, A., Raymo, F. M. & Stoddart, J. F. Artificial molecular machines. Angew. Chem. Int. Ed. 39, 3348–3391 (2000).
Ambrogio, M. W., Thomas, C. R., Zhao, Y.-L., Zink, J. I. & Stoddart, J. F. Mechanized silica nanoparticles: a new frontier in theranostic nanomedicine. Acc. Chem. Res. 44, 903–913 (2011).
Kay, E. R., Leigh, D. A. & Zerbetto, F. Synthetic molecular motors and mechanical machines. Angew. Chem. Int. Ed. 46, 72–191 (2007).
Isaacs, L. Cucurbit[n]urils: from mechanism to structure and function. Chem. Commun. 619–629 (2009).
Ko, Y. H., Kim, E., Hwang, I. & Kim, K. Supramolecular assemblies built with host-stabilized charge-transfer interactions. Chem. Commun. 1305–1315 (2007).
Nau, W. M., Florea, M. & Assaf, K. I. Deep inside cucurbiturils: physical properties and volumes of their inner cavity determine the hydrophobic driving force for host–guest complexation. Isr. J. Chem. 51, 559–577 (2011).
Lee, J. W., Samal, S., Selvapalam, N., Kim, H.-J. & Kim, K. Cucurbituril homologues and derivatives: new opportunities in supramolecular chemistry. Acc. Chem. Res. 36, 621–630 (2003).
Hettiarachchi, G. et al. Toxicology and drug delivery by cucurbit[n]uril type molecular containers. PLoS ONE 5, e10514 (2010).
Uzunova, V. D., Cullinane, C., Brix, K., Nau, W. M. & Day, A. I. Toxicity of cucurbit[7]uril and cucurbit[8]uril: an exploratory in vitro and in vivo study. Org. Biomol. Chem. 8, 2037–2042 (2010).
Jeon, Y. J. et al. Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug. Org. Biomol. Chem. 3, 2122–2125 (2005).
Macartney, D. H. Encapsulation of drug molecules by cucurbiturils: effects on their chemical properties in aqueous solution. Isr. J. Chem. 51, 600–615 (2011).
Walker, S., Oun, R., McInnes, F. J. & Wheate, N. J. The potential of cucurbit[n]urils in drug delivery. Isr. J. Chem. 51, 616–624 (2011).
Dong, N. et al. Cucurbit[n]urils (n=7, 8) binding of camptothecin and the effects on solubility and reactivity of the anticancer drug. Supramol. Chem. 20, 659–665 (2008).
Koner, A. L., Ghosh, I., Saleh, N. & Nau, W. M. Supramolecular encapsulation of benzimidazole derived drugs by cucurbit[7]uril. Can. J. Chem. 89, 139–147 (2011).
Dong, N., Wang, X., Pan, J. & Tao, Z. Influence of cucurbit(n = 7,8)uril on the solubility and stability of chlorambucil. Acta Chim. Sinica 69, 1431–1437 (2011).
Miskolczy, Z., Megyesi, M., Tarkanyi, G., Mizsei, R. & Biczok, L. Inclusion complex formation of sanguinarine alkaloid with cucurbit[7]uril: inhibition of nucleophilic attack and photooxidation. Org. Biomol. Chem. 9, 1061–1070 (2011).
Zhao, Y. et al. Solubilisation and cytotoxicity of albendazole encapsulated in cucurbit[n]uril. Org. Biomol. Chem. 6, 4509–4515 (2008).
Zhao, Y., Pourgholami, M. H., Morris, D. L., Collins, J. G. & Day, A. I. Enhanced cytotoxicity of benzimidazole carbamate derivatives and solubilisation by encapsulation in cucurbit[n]uril. Org. Biomol. Chem. 8, 3328–3337 (2010).
Goldoni, L., Grugni, M., De Munari, S., Cassin, M. & Bernardini, R. Cucurbit[7]uril inclusion complexes of platinum(II)-based anticancer drugs: further insight. Chem. Lett. 39, 676–677 (2010).
Liu, S. et al. The cucurbit[n]uril family: prime components for self-sorting systems. J. Am. Chem. Soc. 127, 15959–15967 (2005).
Lucas, D. & Isaacs, L. Recognition properties of acyclic glycoluril oligomers. Org. Lett. 13, 4112–4115 (2011).
Ma, D., Zavalij, P. Y. & Isaacs, L. Acyclic cucurbit[n]uril congeners are high affinity hosts. J. Org. Chem. 75, 4786–4795 (2010).
Jansen, K., Wego, A., Buschmann, H.-J., Schollmeyer, E. & Dopp, D. Glycoluril derivatives as precursors in the preparation of substituted cucurbit[n]urils. Des. Monom. Polym. 6, 43–55 (2003).
Mock, W. L. & Shih, N.-Y. Dynamics of molecular recognition involving cucurbituril. J. Am. Chem. Soc. 111, 2697–2699 (1989).
Marquez, C. & Nau, W. M. Two mechanisms of slow host–guest complexation between cucurbit[6]uril and cyclohexylmethylamine: pH-responsive supramolecular kinetics. Angew. Chem. Int. Ed. 40, 3155–3160 (2001).
Marquez, C., Hudgins, R. R. & Nau, W. M. Mechanism of host–guest complexation by cucurbituril. J. Am. Chem. Soc. 126, 5808–5816 (2004).
Connors, K. A. Binding Constants (Wiley, 1987).
Stella, V. J., Rao, V. M., Zannou, E. A. & Zia, V. Mechanisms of drug release form cyclodextrin complexes. Adv. Drug Deliv. Rev. 36, 3–16 (1999).
Gelderblom, H., Verweij, J., Nooter, K. & Sparreboom, A. Cremophorel: the drawbacks and advantages of vehicle selection for drug formulation. Eur. J. Cancer 37, 1590–1598 (2001).
Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nature Rev. Drug Discov. 9, 615–627 (2010).
Scheinberg, D. A., Villa, C. H., Escorcia, F. E. & McDevitt, M. R. Conscripts of the infinite armada: systemic cancer therapy using nanomaterials. Nature Rev. Clin. Oncol. 7, 266–276 (2010).
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.
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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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DOI: https://doi.org/10.1038/nchem.1326
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