The overall goal of this project is to develop certain porphyrin-based photosensitizers with improved tumorselectivity. In order to achieve our objective, we propose to target the photosensitizers to certain cellular carbohydrate receptors that are over-expressed in a variety of malignant tissues. Among such targets, the expression of certain galectins is reported to correlate with tumor grade and malignant potential of several types of tumors including brain tumors and metastases to the brain. We have recently synthesized and evaluated certain carbohydrate conjugates, and our preliminary in vitro as well as in vivo results support the feasibility of this approach in improving selectivity of photodynamic therapy. Since galectins play important roles in numerous biological events it is important to consider the possible influence of these conjugates might have on these functions. Therefore, we propose to synthesize a series of carbohydrate conjugated photosensitizers with variable galectin-binding affinities and evaluate them for detailed biological studies in close collaboration with Projects II and III.
The specific aims of this project are: (1) To synthesize carbohydrate conjugates of purpurinimides (700 nm) and bacteriopurpurinimides (800 nm) for the purpose of further verifying and quantitating their galectin-binding ability in vitro and in vivo. (2) To optimize photosensitizer carbohydrate conjugate structures, generated in Aiml, in terms of their in vivo activity and selectivity. (3) To determine the ability of photosensitizer-carbohydrate conjugates to improve PDT selectivity in rodent tumor models.
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