Year of Award:
Molecular & Cellular Analysis Technologies
Other PI or Project Leader:
GEORGIA STATE UNIVERSITY
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. Recently, we have developed boronic acid-based small molecule lectin mimics (named boronolectins) that can recognize certain carbohydrates with selectivity. The same or similar methods can be used for the preparation of lectin mimics for a wide variety of carbohydrates. The long-term goal of this project is the development of conjugates of boronolectin-MRI contrast agents as biomarker-directed cancer imaging agents. Specifically, such conjugates can be used for the delivery of MRI contrast agents based on cell-surface carbohydrate biomarkers. In the R21 phase of this application, we plan to study the feasibility of this approach by (1) synthesizing boronolectin-MRI contrast agent conjugates using a boronolectin which is known selectively bind to sialyl Lewis X, (2) studying their ability to bind to cells with the target carbohydrate biomarkers, and (3) examining their ability to image implanted tumors in both an ex vivo and in vivo models. If the R21 phase is successful, in the R33 phase we plan to expand our biological evaluation to include tumors implanted at different positions, and to search for other lectin mimics that can bind specifically for other important carbohydrate-based cancer biomarkers. In addition, we also plan to examine the cytotoxicity of the boronolectin-MRI contrast agent conjugates. These small molecule-based recognition/delivery systems may have the following advantages over antibody-based systems: (1) greater stability during storage and in vivo; (2) lower propensity to elicit undesirable immune responses, (3) easier conjugation chemistry, and (4) more desirable pharmaceutical properties.