Project 1

本项目的总体目标是开发具有更高肿瘤选择性的卟啉类光敏剂。 为了实现我们的目标，我们建议将光敏剂靶向某些在各种恶性组织中过度表达的细胞碳水化合物受体。在这些靶标中，据报道某些半乳糖凝集素的表达与几种类型的肿瘤（包括脑肿瘤）的肿瘤分级和恶性潜能相关。 肿瘤和脑转移我们最近合成并评估了某些碳水化合物缀合物，我们的初步体外和体内结果支持这种方法在提高光动力治疗的选择性方面的可行性。由于半乳糖凝集素在许多生物学事件中发挥重要作用，因此考虑这些缀合物可能对这些功能产生的影响是重要的。因此，我们建议合成一系列的碳水化合物共轭光敏剂与可变半乳糖凝集素结合亲和力，并评估他们的详细的生物学研究与项目II和III密切合作。 本课题的具体目标是：（1）合成红嘌呤酰亚胺（700 nm）和细菌红嘌呤酰亚胺（800 nm）的糖缀合物，以进一步验证和定量它们在体内外与半乳糖凝集素的结合能力。 (2)优化Aiml中产生的光敏剂碳水化合物缀合物结构，考虑其体内活性和选择性。(3)确定光敏剂-碳水化合物缀合物改善啮齿动物肿瘤模型中PDT选择性的能力。

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.