Development of Agents for Optimization of Photodynamic Therapy and Tumor Imaging

在当前和之前的PO1资助期间，项目1取得了一些重要发现：(I)关于 在构效关系和定量构效关系研究的基础上，我们能够从焦脱镁叶绿酸-a中筛选出高效的PS (660 Nm)、紫质酰亚胺(700 Nm)和细菌紫质酰亚胺(800 Nm)系列，其中一种PS(HPPH)是 目前在第二阶段的人体临床试验中，(Ii)在碳水化合物-PS中，我们发现，与 HPPH(定位于线粒体)，相应的半乳糖结合物(溶酶体定位) 以最小的皮肤光毒性改善某些肿瘤的光动力活性(III)在吡咯系列中， 与HPPH相比，相应的铟类似物(In-HPPH)也定位于线粒体 显示出8倍的有效性和(Iv)在火系中，1-124标记的PS显示出 成像肿瘤和肿瘤转移，这当然值得进一步研究。在另一项研究中，我们 表明肿瘤亲和型光敏剂(如HPPH)可以作为载体来传递非肿瘤特异性 将荧光团发送到目标位置以进行荧光成像。具体地说，菁染料与HPPH的偶联 产生了一种高效的光学成像和PDT试剂。然而，两者之间的一个显著差异是 观察影像剂量和光动力治疗剂量(治疗剂量是所需剂量的-10倍 成像剂量)。因此，高能In-HPPh或其他金属类似物的共轭 根据与菁染料的SAR研究选择的PS可以生成优化的化合物 荧光断层扫描和光疗。选择具有最佳成像和治疗效果的化合物 关于第一阶段人体临床试验的潜力，该项目的目标如下： 目的1：合成半乳糖偶联长波吸收光敏剂 SAR研究的基础)，并调查半乳糖部分对PDT疗效的影响； 目的2：合成金属化长波长光敏剂并考察其作用效果 (选自目标1，具有或不具有碳水化合物部分)，以优化其光敏能力； 目的3：合成金属1241-光敏剂(选自目标2)和相应的花菁 用于开发用于肿瘤成像(PET、荧光断层扫描)的多功能试剂的染料结合物 光动力疗法。

During the current and prior PO1 funding, Project 1 has made certain important discoveries: (i) on the basis of SAR and QSAR studies, we were able to select the highly effective PS from pyropheophorbide-a (660 nm), purpurinimides (700 nm) and bacteriopurpurinimide (800 nm) series and one of the PS (HPPH) is currently in Phase II human clinical trials, (ii) among the carbohydrate-PS, we discovered that, compared to HPPH (localized in mitochondria), the corresponding galactose conjugate (lysosomal localization) exhibits improved photodynamic activity in certain tumors with minimal skin phototoxicity (iii) in the pyro-series, compared to HPPH, the corresponding Indium analog (In-HPPH), which also localizes in mitochondria showed 8-fold increase in efficacy and (iv) in the pyro- series, an 1-124 labeled PS showed the potential of imaging tumor and tumor metastases, which certainly warrants further investigation. In a separate study, we showed that tumor-avid photosensitizers (e.g. HPPH) can be used as a vehicle to deliver non tumor-specific fluorophores to target sites for fluorescence imaging. In particular, conjugation of a cyanine dye to HPPH resulted in an efficient optical imaging and PDT agent. However, a significant difference between the imaging and PDT dose dose was observed (the therapeutic dose was -10-fold higher than the required imaging dose). Therefore, the conjugation of the highly potent In-HPPH or the metallated analogs of other PS selected on the basis of SAR studies with the cyanine dye could generate optimized compounds for fluorescence tomography and phototherapy. For selecting a compound with optimal imaging and therapeutic potential for Phase I human clinical trials, the aims of the project are as follows: Aim 1: To synthesize galactose conjugated long-wavelength absorbing photosensitizers (selected on the basis of SAR studies) and investigate the impact of the galactose moiety in PDT efficacy; Aim 2: To synthesize and investigate the effect of certain metallated long wavelength photosensitizers (selected from Aim 1, with or without a carbohydrate moiety) in optimizing their photosensitizing ability; Aim 3: To synthesize metallated 1241-photosensitizers (selected from Aim 2) and the corresponding cyanine dye conjugates for developing multifunctional agents for tumor imaging (PET, fluorescence tomography) and PDT.