Article | Published:

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

Nature Chemistry volume 4, pages 503510 (2012) | Download Citation

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.

  • Compound C54H64N16Na4O24S4

    Tetrasodium 3-{[14,15,50,51-tetramethyl- 26,30,34,38,49,52,53,54- octaoxo-19,22,45-tris(3-sulfonatopropoxy)-1,3,6,8,11,13,16,25,27, 29,31,33,35,37,39,48-hexadecaazapentadecacyclo[37.10.2.13,6.18,11 .113,16.04,35.05,33.09,31.010,29.014,27.015,25.018,23.037,50.041,46.048,51 ]tetrapentaconta-18(23),19,21,41(46),42,44-hexaen-42-yl]oxy}propane-1-sulfonate

  • Compound C62H68N16Na4O24S4

    Tetrasodium 3-{[14,15,44,45-tetramethyl-30,34,38,42,46,60,61,62 -octaoxo-19,50,57-tris(3-sulfonatopropoxy)-1,3,6,8,11,13,16,29, 31,33,35,37,39,41,43,47-hexadecaazaheptadecacyclo[41.2.14.13,6.18,11.113,16 .04,39.05,37.09,35.010,33.014,31.015,29.018,27.020,25.041,45.044,47.0 49,58.051,56]dohexaconta-18,20,22,24,26,49,51,53,55,57-decaen-26-yl]oxy}propane-1-sulfonate

  • Compound C10H12N8O4

    Tetrahydro-5H,10H-2,3,4a,5a,7,8,9a,10a-octaazacycloocta[1,2,3-cd:5,6,7-c'd']dipentalene-1,4,6,9(2H,3H,7H,8H)-tetrone

  • Compound C10H14N4O4

    cis-Dimethyl-dihydro-8b,8c-1H,3H,4H,5H,7H,8H-2,6-dioxa-3a,4a,7a,8a-tetraazacyclopenta[def]fluorene-4,8-dione

  • Compound C30H36N16O10

    Octahydro-1H,3H,4H,5H,6H,7H,8H,9H,10H,11H,13H,14H,15H,16H,17H,18H,19H,20H-2,12-dioxa-3a,4a,5a,6a,7a,8a,9a,10a,13a,14a,15a,16a,17a,18a,19a,20a-hexadecaazabisbenzo[3',4']pentaleno[1',6':5,6,7]cycloocta [1,2,3-gh:1',2',3'-g'h']cycloocta[1,2,3-cd:5,6,7-c'd']dipentalene-4,6,8,10,14,16,18,20-octone

  • Compound C6H6O2

    Hydroquinone

  • Compound C10H8O2

    1,4-Naphthalenediol

  • Compound C12H16Na2O8S2

    Hydroquinone bis(gamma-sodiosulfopropyl) ether

  • Compound C16H18Na2O8S2

    1,4-Napthalenedioxy bis(gamma-sodiosulfopropyl)ether

  • Compound C3H6O3S

    1,3-Propanesultone

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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.

Author information

Author notes

    • Da Ma
    •  & Gaya Hettiarachchi

    These authors contributed equally to this work

Affiliations

  1. Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, USA

    • Da Ma
    • , Ben Zhang
    • , James B. Wittenberg
    • , Peter Y. Zavalij
    •  & Lyle Isaacs
  2. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA

    • Gaya Hettiarachchi
    • , Duc Nguyen
    •  & Volker Briken

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Contributions

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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DOI

https://doi.org/10.1038/nchem.1326

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