Using Dendrimers to Design Multivalent Therapeutic Agents

Summary

Principal Investigator: Mary J Cloninger
Affiliation: Montana State University
Country: USA
Abstract: [unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable] [unreadable]
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. pmc End-group distributions of multiple generations of spin-labeled PAMAM dendrimers
    Karl B Sebby
    Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United States
    J Phys Chem B 115:4613-20. 2011
  3. pmc Using In(III) as a promoter for glycosylation
    Amanda L Mattson
    Department of Chemistry and Biochemistry, 103 Chemistry and Biochemistry Building, Montana State University, Bozeman, MT 59717, USA
    Carbohydr Res 347:142-6. 2012
  4. pmc Clusters of ligands on dendrimer surfaces
    Kristian H Schlick
    Montana State University, 103 Chemistry and Biochemistry Building, Bozeman, MT 59717, USA
    Bioorg Med Chem Lett 21:5078-83. 2011
  5. pmc Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes
    Santiago F Gonzalez
    The Immune Disease Institute and Program in Cellular and Molecular Medicine, Children s Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
    Nat Immunol 11:427-34. 2010
  6. pmc Characterization of protein aggregation via intrinsic fluorescence lifetime
    Kristian H Schlick
    Department of Chemistry and Biochemistry, 103 Chemistry and Biochemistry Building, Montana State University, Bozeman, Montana 59717, USA
    J Am Chem Soc 131:16608-9. 2009
  7. 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
  8. 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
  9. 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
  10. 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

Detail Information

Publications12

  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. pmc End-group distributions of multiple generations of spin-labeled PAMAM dendrimers
    Karl B Sebby
    Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United States
    J Phys Chem B 115:4613-20. 2011
    ..We observe a shift in the end-group distribution from generation 3 (G(3)) to G(4) dendrimers that indicates a change in morphology from an open, extended structure to a more dense, compact arrangement...
  3. pmc Using In(III) as a promoter for glycosylation
    Amanda L Mattson
    Department of Chemistry and Biochemistry, 103 Chemistry and Biochemistry Building, Montana State University, Bozeman, MT 59717, USA
    Carbohydr Res 347:142-6. 2012
    ..Disaccharide formation was demonstrated. In most cases, the In(III) compounds were shown to promote glycosylation better than the widely used promoter BF(3)·OEt(2)...
  4. pmc Clusters of ligands on dendrimer surfaces
    Kristian H Schlick
    Montana State University, 103 Chemistry and Biochemistry Building, Bozeman, MT 59717, USA
    Bioorg Med Chem Lett 21:5078-83. 2011
    ....
  5. pmc Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes
    Santiago F Gonzalez
    The Immune Disease Institute and Program in Cellular and Molecular Medicine, Children s Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
    Nat Immunol 11:427-34. 2010
    ..Thus, our results have important implications for the generation of durable humoral immunity to viral pathogens through vaccination...
  6. pmc Characterization of protein aggregation via intrinsic fluorescence lifetime
    Kristian H Schlick
    Department of Chemistry and Biochemistry, 103 Chemistry and Biochemistry Building, Montana State University, Bozeman, Montana 59717, USA
    J Am Chem Soc 131:16608-9. 2009
    ..Although self-quenching of tryptophan resonances that was induced by clustering was monitored in this study, the reported method is not limited to such and is viable for numerous binding studies...
  7. 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
    ....
  8. 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...
  9. 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...
  10. 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...
  11. 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...