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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062444-09
Application #
7738943
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2000-12-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
9
Fiscal Year
2010
Total Cost
$292,662
Indirect Cost
Name
Montana State University - Bozeman
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717
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:
Cousin, Jonathan M; Cloninger, Mary J (2015) Glycodendrimers: tools to explore multivalent galectin-1 interactions. Beilstein J Org Chem 11:739-47
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
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
Gonzalez, Santiago F; Lukacs-Kornek, Veronika; Kuligowski, Michael P et al. (2010) Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes. Nat Immunol 11:427-34

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