PHOTO THERAPY OF BLADDER CANCER WITH HEMATOPORPHYRINS

该项目的总体目标是推进 膀胱癌的光疗。我们已经取得了实质性进展 在过去的基础研究和临床前研究资助期 血卟啉治疗的临床研究进展 衍生物(HpD)作为光敏剂。第三阶段临床试验 对于HPD-光疗现在正在进行中。我们现在集中力量 浅谈通过寻找更多的方法来改进和扩大这一治疗 有效的光敏剂。 我们打算从高肿瘤的方向来研究这项研究- 对光敏元件的选择性。我们的目标是一群恶嗪 相关染料已经证明，从早期和从我们的 关于一些系统的初步工作，将在 定位于肿瘤。我们能够增强生物的光活性 恶嗪类药物购买修饰它们的结构；高达65%的绝对值 实现了单线态氧的产额。在这个项目中，我们 建议对这些化合物进行评估并进一步开发成 用于肿瘤光疗的有效和选择性增敏剂。 这项调查的一个重要部分是我们努力 生色团的分子结构与它们之间的关系 物理化学和光化学性质，并进一步与 它们在细胞内和细胞内的选择性定位和光活性 肿瘤。 本项目的具体目标是：(1)选择、综合 并表征了一系列系统地选择的恶嗪衍生物 使我们能够确定结构与功能之间的关系 与选择性肿瘤定位、光动力活性有关。 (2)评价这些恶嗪衍生物对肿瘤的选择性。 在动物肿瘤模型和培养细胞中的定位。(3)至 评估和优化恶嗪类药物的治疗效果 在体外介导光细胞毒性，光破坏单个， 浸润性、微观性和转移性肿瘤及其 暗毒性。(4)研究分子调控机制 发色团的选择性肿瘤定位和光活性研究 研究分子结构与光化学之间的关系 和光物理性质，以及肿瘤选择性和 生色团的光活性。 该项目可能会通过以下方式改善光疗 发现新的、有效的、具有肿瘤选择性的增敏剂。这 可能会扩大这种疗法的用途，以治疗危及生命的疾病 浸润性和转移性肿瘤。我们的研究可以提供一种 更好地理解决定肿瘤的分子因素- 选择性和光反应性。这将为以下方面提供指导 未来发展更好的感光材料和更好的 光疗的应用。最后，我们预计这个项目 将获得关于这些染料的充分信息，为提供依据 用于午餐临床前和临床研究。

The overall goal of this project is to advance the technique of phototherapy for bladder cancer. We have made substantial progress during the past funding period in basic studies and in preclinical and clinical development of this treatment using hematoporphyrin derivative (HPD) as the photosensitizer. Phase III clinical trials for HPD-phototherapy are now underway. We now focus our efforts on improving and expanding this treatment by searching for more effective photosensitizers. We intend to approach this search from the direction of high tumor- selectivity for the photosensiti. Our target is a group of oxazine related dyes that have demonstrated, from early and from our preliminary work on a number of systems, to be highly selective in localizing in tumors. We are able to enhance the photoactivity of the oxazines buy modifying their structures; up to 65% absolute singlet oxygen yield has been achieved. In this project, we propose to evaluate and further develop these compounds into effective and selective sensitizers for phototherapy of tumors. An important part of this investigation is in our efforts to correlate molecular structures of chromophores with their physicochemical and photochemical properties, and further with their selective localization and photoactivity in cells and in tumors. The specific aims of this project are: (1) To select, synthesize and characterize a systematic series of oxazine derivatives chosen to allow us to determine structure-function relationships pertaining to selective-tumor localization, photodynamic activity. (2) To evaluate these oxazine derivatives for their selective tumor localization in animal tumor models and in cultured cells. (3) To evaluate and optimize the effectiveness of the oxazines in mediating photo-cytotoxicity in vitro, photodestruction of single, infiltrating, microscopic and metastatic tumors, as well as their dark toxicity. (4) To investigate molecular mechanisms dictating selective-tumor localization and photoactivity of chromophores by examining relationships between molecular structure, photochemical and photophysical properties, and tumor-selectivity and photoavtivity of chromophores. This project will likely lead to improvement of phototherapy by discovering new, effective and tumor-selective sensitizers. This may expand the utility of this therapy to treat life-threatening infiltrating and metastatic tumors. Our study could provide a better understanding for molecular factors dictating tumor- selective and photoreactivity. This will provide guidances for future development of even better photosensiti and greater utilizations of phototherapy. Finally, we expect that this project will obtain adequate information on these dyes to provide the basis for lunching preclinical and clinical studies.