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: 8230221
• 负责人: Ravindra K. Pandey
• 金额: $ 30.94万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230221
• 关键词: ABCG2 gene; Accounting; Address; Algorithms; Barrett Esophagus; Binding; Blood Vessels; Carbohydrates; Cells; Characteristics; Clinical Trials; Cutaneous; Development; Diffusion; Dose; Dysplasia; Employee Strikes; Equation; Ethers; Exhibits; Fluorescence; Funding; Galactose; Galectin 3; Generations; Goals; Head and Neck Cancer; Human; Image; Indium; Investigation; Label; Laboratories; Lactose; Lead; Light; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of larynx; Malignant neoplasm of lung; Metals; Minnesota; Mitochondria; Modeling; Modification; Molecular Target; Multicenter Trials; Neoplasm Metastasis; Optics; Outcome; Penetration; Pennsylvania; 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; Site; Skin; System; Therapeutic; Three-Dimensional Image; Tissues; Toxic effect; Treatment Efficacy; Triplet Multiple Birth; Tumor Stem Cells; Universities; absorption; analog; attenuation; base; cyanine dye; fluorescence imaging; fluorophore; human ABCG2 protein; improved; in vivo; neoplastic cell; novel; optical imaging; programs; pyropheophorbide a; quantum; reconstruction; single photon emission computed tomography; 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 PO1 资助期间，项目 1 取得了一些重要发现：(i) 在SAR和QSAR研究的基础上，我们能够从焦脱镁叶绿酸-a中选择出高效的PS (660 nm)、红紫酰亚胺 (700 nm) 和细菌红紫酰亚胺 (800 nm) 系列，其中 PS (HPPH) 是 目前正在进行 II 期人体临床试验，(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）表现出 改善某些肿瘤的光动力活性，同时将皮肤光毒性降至最低 (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 显示功效增加了 8 倍，并且 (iv) 在pyro系列中，1-124标记的PS显示出潜在的 对肿瘤和肿瘤转移进行成像，这当然值得进一步研究。在一项单独的研究中，我们 研究表明，亲肿瘤光敏剂（例如 HPPH）可用作传递非肿瘤特异性的载体 荧光团到目标位点进行荧光成像。特别是花青染料与 HPPH 的缀合 产生了一种高效的光学成像和 PDT 试剂。然而，两者之间存在显着差异 观察成像和PDT剂量剂量（治疗剂量比所需剂量高-10倍） 成像剂量）。因此，高效 In-HPPH 或其他金属化类似物的缀合 根据花青染料 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。用于选择具有最佳成像和治疗效果的化合物 该项目具有进行一期人体临床试验的潜力，其目标如下： 目的 1：合成半乳糖共轭长波长吸收光敏剂（选自 SAR 研究的基础）并研究半乳糖部分对 PDT 疗效的影响； 目标2：合成某些金属化长波长光敏剂并研究其效果 （选自目标1，有或没有碳水化合物部分）优化其光敏能力； 目标3：合成金属化1241-光敏剂（选自目标2）和相应的花青 用于开发肿瘤成像（PET、荧光断层扫描）多功能试剂的染料缀合物 太平洋夏令时。