Using Dendrimers to Design Multivalent Therapeutic Agents
Principal Investigator: Mary J Cloninger
Affiliation: Montana State University
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
- Binding of mannose-functionalized dendrimers with pea (Pisum sativum) lectinKristian 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...
- Cyanovirin-N binding to Manalpha1-2Man functionalized dendrimersShane 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...
- Mannose/glucose-functionalized dendrimers to investigate the predictable tunability of multivalent interactionsMark 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...
- Binding of monomeric and dimeric Concanavalin A to mannose-functionalized dendrimersShane 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...
- Indium triflate catalyzed peracetylation of carbohydratesNicholas 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...
- Measurement of monovalent and polyvalent carbohydrate-lectin binding by back-scattering interferometryAmanda 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....