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-carbohydrateinteractions 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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Fabian, Miles
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Montana State University - Bozeman
Schools of Arts and Sciences
United States
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Cousin, Jonathan M; Cloninger, Mary J (2016) The Role of Galectin-1 in Cancer Progression, and Synthetic Multivalent Systems for the Study of Galectin-1. Int J Mol Sci 17:
VanKoten, Harrison W; Dlakic, Wendy M; Engel, Robert et al. (2016) Synthesis and Biological Activity of Highly Cationic Dendrimer Antibiotics. Mol Pharm 13:3827-3834
Wolfenden, Mark; Cousin, Jonathan; Nangia-Makker, Pratima et al. (2015) Glycodendrimers and Modified ELISAs: Tools to Elucidate Multivalent Interactions of Galectins 1 and 3. Molecules 20:7059-96
Cousin, Jonathan M; Cloninger, Mary J (2015) Glycodendrimers: tools to explore multivalent galectin-1 interactions. Beilstein J Org Chem 11:739-47
Michel, Anna K; Nangia-Makker, Pratima; Raz, Avraham et al. (2014) Lactose-functionalized dendrimers arbitrate the interaction of galectin-3/MUC1 mediated cancer cellular aggregation. Chembiochem 15:2106-12
Goodman, Candace K; Wolfenden, Mark L; Nangia-Makker, Pratima et al. (2014) Multivalent scaffolds induce galectin-3 aggregation into nanoparticles. Beilstein J Org Chem 10:1570-7
Mattson, Amanda L; Michel, Anna K; Cloninger, Mary J (2012) Using In(III) as a promoter for glycosylation. Carbohydr Res 347:142-6
Sebby, Karl B; Walter, Eric D; Usselman, Robert J et al. (2011) End-group distributions of multiple generations of spin-labeled PAMAM dendrimers. J Phys Chem B 115:4613-20
Schlick, Kristian H; Morgan, Joel R; Weiel, Julianna J et al. (2011) Clusters of ligands on dendrimer surfaces. Bioorg Med Chem Lett 21:5078-83
Schlick, Kristian H; Cloninger, Mary J (2010) Inhibition binding studies of glycodendrimer-lectin interactions using surface plasmon resonance. Tetrahedron 66:5305-5310

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