Development of Agents for Optimization of Photodynamic Therapy and Tumor Imaging

开发用于优化光动力治疗和肿瘤成像的试剂

• 批准号: 7611628
• 负责人: Ravindra K. Pandey
• 金额: $ 30.39万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611628
• 关键词: ABCG2 gene; Accounting; Address; Algorithms; Barrett Esophagus; Binding; Blood Vessels; Carbohydrates; Cells; Characteristics; Clinical Trials; Cutaneous; Detection; Development; Diffusion; Dose; Dysplasia; Employee Strikes; Equation; Ethers; Exhibits; Fluorescence; Funding; Galactose; Galectin 3; Generations; Goals; HPPH; Hand; Head and Neck Cancer; Head and neck structure; Image; Indium; Laboratories; Lactose; Lead; Light; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of larynx; Malignant neoplasm of lung; Metals; Minnesota; Modeling; Modification; Molecular Target; Multicenter Trials; Nuclear; Optics; Outcome; Penetration; Pennsylvania; Performance; Peripheral; Phase; Photochemotherapy; Photons; Photosensitization; Photosensitizing Agents; Phototherapy; Phototoxicity; Pleural; Porfimer Sodium; Positioning Attribute; Positron-Emission Tomography; Property; Proteins; Quantitative Structure-Activity Relationship; Research Personnel; Resolution; Series; Singlet Oxygen; Skin; System; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Triplet Multiple Birth; Tumor Stem Cells; Universities; absorption; analog; attenuation; base; cost effective; cyanine dye; fluorescence imaging; fluorophore; human ABCG2 protein; improved; in vivo; neoplastic cell; novel; optical imaging; programs; pyropheophorbide a; quantum; reconstruction; single molecule; tomography; tumor

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.

在当前和之前的PO 1资助期间，项目1取得了某些重要发现： 在SAR和QSAR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）、红嘌呤酰亚胺（700 nm）和细菌红嘌呤酰亚胺（800 nm）系列，其中一种PS（HPPH）是 目前在II期人体临床试验中，（ii）在碳水化合物-PS中，我们发现，与 HPPH（定位于线粒体），相应的半乳糖缀合物（溶酶体定位）显示 在某些肿瘤中具有最小皮肤光毒性的改进的光动力活性（iii）在Pyro系列中， 与HPPH相比，相应的铟类似物（In-HPPH）也定位于线粒体中 显示出8倍的功效增加，和（iv）在焦系列中，1-124标记的PS显示出 对肿瘤和肿瘤转移进行成像，这肯定需要进一步研究。在另一项研究中，我们 显示亲肿瘤光敏剂（例如HPPH）可以用作递送非肿瘤特异性的药物的媒介物。 将荧光团转移到靶位点用于荧光成像。特别地，花青染料与HPPH的缀合 导致有效的光学成像和PDT试剂。然而，一个显着的差异， 观察成像和PDT剂量（治疗剂量比所需剂量高~ 10倍 成像剂量）。因此，高效In-HPPH或其他金属类似物的缀合 基于与花青染料的SAR研究选择的PS可以产生优化的化合物， 荧光断层扫描和光疗。为了选择具有最佳成像和治疗效果的化合物， I期人体临床试验的潜力，该项目的目标如下： 目的1：合成半乳糖缀合的长波长吸收光敏剂（在 SAR研究的基础），并研究半乳糖部分对PDT功效的影响; 目的2：合成金属化长波长光敏剂并研究其作用 （选自目标1，具有或不具有碳水化合物部分）优化其光敏化能力; 目的3：合成1241-金属配合物（选自目的2）及相应的菁染料 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缀合物， PDT。