CHARACTERIZATION OF NEW PHOTOSENSITIZING DYES

（改编自申请人摘要）光动力疗法或 肿瘤疾病目前涉及使用衍生自 血卟啉，称为血卟啉衍生物（HPD）。 程度 全身HPD给药后的肿瘤定位是足够的 允许通过荧光成像鉴定肿瘤基因座，和 以催化选择性肿瘤根除，如果足够的光通量， 提供了 光动力疗法（PDT）的主要局限性是（1） 皮肤的持续光敏化，（2）要求 在630 nm下照射，这是电流难以达到的波长 技术，（3）630 nm光穿透组织的深度有限。 这 研究旨在探索新的光敏染料， 波长大于650 nm时的吸光度。 理想的敏化剂是 至少与HPD一样活跃，在体内的半衰期更有限。 循环，无暗毒性。 波长大于 750 nm将允许使用二极管激光器用于染料活化。 而 合理的考虑将支配药物设计，申请人将允许 未知因素可能在结构中起作用的可能性- 活动关系。 一个初始的屏幕将规则的染料与主机 毒性、PDT效率低或肿瘤定位不足。 工作将 然后直接描绘肌动蛋白的模式和染料的决定因素， 定位和分布。 新染料的相对有效性 成为已知的;申请人可以识别属性，预测为 上级肿瘤定位和光敏化行为。 实验 技术将涉及染料疏水性，运输， 对血浆蛋白和脂蛋白的亲和力，染料结合特性 位点和染料介导的光损伤的性质。有效性 将对维修系统进行评估。 其他生物学研究将 确定小鼠中染料分布的模式和药代动力学， 沿着潜在的协同抗肿瘤毒性， 同时高热 对这些现象的探索将有助于 设计用于PDT的新染料。

(Adapted from the applicant's abstract) The photodynamic therapy or neoplastic disease currently involves the use of a product derived from hematoporphyrin and termed hematoporphyrin derivative (HPD). The degree of tumor localization following systemic HPD administration is sufficient to permit identification of neoplastic loci by fluorescence imaging, and to catalyze selective tumor eradication if a sufficient light flux is provided. The major limitations of photodynamic therapy (PDT) are (1) a persistent photosensitization of the skin, (2) the requirement for irradiation at 630 nm, a wavelength difficult to achieve by current technology, (3) limited depth of tissue penetration by 630 nm light. This study is designed to explore new photosensitizing dyes with substantial absorbance at wavelengths greater than 650 nm. A ideal sensitizer will be at least as active as HPD, with a more limited half-life in the circulation, and no dark toxicity. Absorbance at wavelengths greater than 750 nm would permit the use of diode lasers, for dye activation. While rational considerations will govern drug design, the applicant will allow for the possibility that unknown factors may play a role in structure- activity relationships. An initial screen will rule by dyes with host toxicity, low PDT efficiency or inadequate tumor localization. Work will then be directed toward delineating modes of actin and determinants of dye localization and distribution. As the relative effectiveness of new dyes becomes known; the applicant can identify properties that predict for superior tumor-localizing and photosensitizing behavior. Experimental techniques will involve characterization of dye hydrophobicity, transport, affinity for plasma protein and lipoproteins, properties of dye-binding sites, and the nature of dye-mediated photo-damage. Effectiveness of repair systems will be evaluated. Additional biologic studies will determine patterns and pharmacokinetics of dye distribution in the mouse, along with the potential for synergistic antitumor toxicity from concurrent hyperthermia. Exploration of these phenomena should facilitate the design of new dyes for PDT.