Malignant transformation is often associated with alteration of cell surface carbohydrates. The expression or over-expression of certain carbohydrates, such as sialyl Lewis X (sLex), sialyl Lewis a (sLea), Lewis X (Lex) and Lewis Y (Ley), has been correlated with the development of certain cancers. These cell surface carbohydrates can be used for cell-specific identification and targeting of carcinoma cells. The long-term goal of this project is the development of small molecule artificial receptors which can recognize target carbohydrate structures with high selectivity and affinity. Such receptors could be used for the development of fluorescent tags for cell- specific identification, tissue-specific imaging (such as MRI), and targeted delivery of therapeutic agents. In this study, we will use sLex as the model carbohydrate and use colon cancer as the model biological system because the expression of sLex is often associated with progression and metastasis of colon cancer. The short-term objective of this application is to develop tissue-specific fluorescent tags (sensors) which can recognize sLex with high affinity and selectivity. For the construction of such fluorescent sensors, we plan to use an integrated approach combining template-directed synthesis, combinatorial chemistry, and computer molecular modeling aided design. The sLex-specific artificial receptors have the potential to be used for cell identification, detection and tagging for the purpose of localization, staging, tissue biopsy, and fluorescence-directed surgical removal of colon cancer cells. Such tissue-specific compounds could also serve as vehicles for targeted delivery of cancer chemotherapeutic agents. These small molecule sensors may also have the following advantages over antibody-based detection/delivery systems: (1) greater stability during storage and in vivo; (2) increased permeability through biological membranes and, therefore, enhanced target accessibility; (3) intrinsic sensitivity to binding with significant fluorescence intensity increases, making detection and visualization easier and more suitable for high throughout screening, and (4) lower propensity to elicit undesirable immune responses. Similar methods, once developed, could also be used for the construction of fluorescent tags for other cell surface carbohydrates implicated in human malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA088343-01
Application #
6200138
Study Section
Special Emphasis Panel (ZCA1-SRRB-C (M1))
Program Officer
Mohla, Suresh
Project Start
2000-07-01
Project End
2004-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$148,044
Indirect Cost
Name
North Carolina State University Raleigh
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Raleigh
State
NC
Country
United States
Zip Code
27695
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Craig, Sandra (2012) Synthesis and evaluation of aryl boronic acids as fluorescent artificial receptors for biological carbohydrates. Bioorg Chem 40:137-42
Jin, Shan; Cheng, Yunfeng; Reid, Suazette et al. (2010) Carbohydrate recognition by boronolectins, small molecules, and lectins. Med Res Rev 30:171-257
Zheng, Shi-Long; Lin, Na; Reid, Suazette et al. (2007) Effect of extended conjugation with a phenylethynyl group on the fluorescent properties of water-soluble arylboronic acids. Tetrahedron 63:5427-5436