Using Dendrimers to Design Multivalent Therapeutic Agents

Summary

Principal Investigator: Mary J Cloninger
Affiliation: Montana State University
Country: USA
Abstract: We propose to study the roles of protein-carbohydrate and carbohydrate-carbohydrate interactions in cancer metastasis. We'll use dendrimers with clusters of carbohydrates, as well as heterogeneously-functionalized dendrimers synthesized using techniques developed in the last funding cycle, to study binding and adhesion processes associated with cancer metastasis. Specifically, the syntheses of N-acetyl galactosamine, lactose, and GM3-functionalized dendrimers are described. Binding assays to determine the affinity of the gal-NAc and lactose-functionalized dendrimers for galectin-3 and to determine the affinity of GM3-functionalized dendrimers for carbohydrate arrays are proposed. Carbohydrate-functionalized dendrimers that exhibit high affinity binding to their receptors will be further evaluated using cancer cell aggregation studies. Many reports suggest that cell surface carbohydrates serve a critical function in malignant transformation and metastasis, and so the development of artificial carbohydrate arrays such as those described in this proposal that can aptly mimic and interfere with cancer cell aggregation processes is critical. From the research proposed here, our goal is to advance fundamental knowledge regarding the role of protein-carbohydrate and carbohydrate-carbohydrate interactions in the metastatic spread of cancer. Concurrently, new therapeutic agents to arrest cancer cell aggregation may emerge. Advancing the fundamental knowledge of the associations that mediate metastatic processes and developing multivalent, nanoscale therapeutic agents to arrest cancer metastasis clearly have enormous implications for public health.
Funding Period: 2000-12-01 - 2010-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Binding of mannose-functionalized dendrimers with pea (Pisum sativum) lectin
    Kristian H Schlick
    Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, USA
    Mol Pharm 2:295-301. 2005
  2. ncbi Cyanovirin-N binding to Manalpha1-2Man functionalized dendrimers
    Shane L Mangold
    Department of Chemistry and Biochemistry and Center for Bioinspired Nanomaterials, 108 Gaines Hall, Montana State University, Bozeman, MT 59717, USA
    Org Biomol Chem 3:2354-8. 2005
  3. ncbi Mannose/glucose-functionalized dendrimers to investigate the predictable tunability of multivalent interactions
    Mark L Wolfenden
    Department of Chemistry and Biochemistry and Center for Bioinspired Nanomaterials, Montana State University, 108 Gaines Hall, Bozeman, Montana 59717, USA
    J Am Chem Soc 127:12168-9. 2005
  4. ncbi Binding of monomeric and dimeric Concanavalin A to mannose-functionalized dendrimers
    Shane L Mangold
    Department of Chemistry and Biochemistry, 108 Gaines Hall, Montana State University, Bozeman, 59717, USA
    Org Biomol Chem 4:2458-65. 2006
  5. pmc Indium triflate catalyzed peracetylation of carbohydrates
    Nicholas P Bizier
    Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
    Carbohydr Res 343:1814-8. 2008
  6. pmc Measurement of monovalent and polyvalent carbohydrate-lectin binding by back-scattering interferometry
    Amanda Kussrow
    Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, 4226 Stevenson Center, Nashville, Tennessee 37235, USA
    Anal Chem 81:4889-97. 2009

Detail Information

Publications6

  1. ncbi Binding of mannose-functionalized dendrimers with pea (Pisum sativum) lectin
    Kristian H Schlick
    Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, USA
    Mol Pharm 2:295-301. 2005
    ..Isothermal titration calorimetry (ITC) experiments are also described...
  2. ncbi Cyanovirin-N binding to Manalpha1-2Man functionalized dendrimers
    Shane L Mangold
    Department of Chemistry and Biochemistry and Center for Bioinspired Nanomaterials, 108 Gaines Hall, Montana State University, Bozeman, MT 59717, USA
    Org Biomol Chem 3:2354-8. 2005
    ..Precipitation assays to assess the binding of the dimannose-functionalized dendrimers to Cyanovirin-N, a HIV-inactivating protein that blocks virus-to-cell fusion through high mannose mediated interactions, are presented...
  3. ncbi Mannose/glucose-functionalized dendrimers to investigate the predictable tunability of multivalent interactions
    Mark L Wolfenden
    Department of Chemistry and Biochemistry and Center for Bioinspired Nanomaterials, Montana State University, 108 Gaines Hall, Bozeman, Montana 59717, USA
    J Am Chem Soc 127:12168-9. 2005
    ..The mannose/glucose-functionalized dendrimer results reported here suggest that the affinity of multivalent associations can be attenuated in predictable, reliable ways based on monovalent affinities of the ligands...
  4. ncbi Binding of monomeric and dimeric Concanavalin A to mannose-functionalized dendrimers
    Shane L Mangold
    Department of Chemistry and Biochemistry, 108 Gaines Hall, Montana State University, Bozeman, 59717, USA
    Org Biomol Chem 4:2458-65. 2006
    ..The results described here should allow for a more quantitative evaluation of the enhancements that are often observed in protein-carbohydrate interactions for glycosylated frameworks binding to Con A...
  5. pmc Indium triflate catalyzed peracetylation of carbohydrates
    Nicholas P Bizier
    Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
    Carbohydr Res 343:1814-8. 2008
    ..In(OTf)(3) has low toxicity and is mild and water tolerant, and the reactions are high yielding and efficient. Details regarding the scope and mechanism of the reaction are briefly discussed...
  6. pmc Measurement of monovalent and polyvalent carbohydrate-lectin binding by back-scattering interferometry
    Amanda Kussrow
    Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, 4226 Stevenson Center, Nashville, Tennessee 37235, USA
    Anal Chem 81:4889-97. 2009
    ....