CHARACTERIZATION OF NEW PHOTOSENSITIZING DYES

(改编自申请人的摘要)光动力疗法或 目前，肿瘤性疾病涉及使用一种源自 血卟啉和称为血卟啉衍生物(Hpd)。学位 全身注射HPD后肿瘤定位就足够了 允许通过荧光成像识别肿瘤基因座，以及 如果足够的光通量是为了催化选择性的肿瘤根除 如果是这样的话。光动力疗法(Pdt)的主要局限性是：(1) 皮肤的持久光敏化，(2)对 630 nm的辐射，这是一个电流很难实现的波长 技术，(3)630 nm光限制组织穿透深度。这 这项研究旨在探索新的光敏染料与大量 波长大于650 nm的吸光度。理想的敏化剂将是 至少和HPD一样活跃，半衰期更有限 循环，无暗毒性。波长大于 750纳米将允许使用二极管激光来激活染料。而当 理性的考虑将主导药物设计，申请人将允许 未知因素可能在结构中发挥作用的可能性- 活动关系。初始屏幕将根据主机的染料而定 毒性、PDT效率低或肿瘤定位不足。工作将会 然后针对描述肌动蛋白的模式和染料的决定因素 本地化和分布化。作为新染料的相对有效性 变得为人所知；申请人可以识别预测 优越的肿瘤定位和光敏行为。实验 技术将涉及染料疏水性的表征，运输， 血浆蛋白和脂蛋白的亲和力、染料结合特性 地点，以及染料介导的光损害的性质。的有效性 将对维修系统进行评估。更多的生物学研究将 确定染料在小鼠体内的分布模式和药代动力学， 以及潜在的协同抗肿瘤毒性 并发高热。对这些现象的探索应该有助于 光动力转换用新型染料的设计。

(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.