SYNTHESES AND CELLULAR STUDIES OF NEW PHOTOSENSITIZERS FOR MEDICAL APPLICATIONS

新型医疗应用光敏剂的合成和细胞研究

• 批准号: 7582084
• 负责人: Kevin M Smith
• 金额: $ 29.92万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582084
• 关键词: Adverse effects; Age related macular degeneration; Alkenes; Amino Acids; Apoptosis; Apoptotic; Area; Arterial Fatty Streak; Atherosclerosis; Autophagocytosis; Behavior; Biochemical; Biological; Biological feedback; Blood; Blood Transfusion; Bone Marrow; Bone Marrow Purging; Cardiovascular Diseases; Cardiovascular system; Cattle; Cause of Death; Cell Death; Cells; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Complex; Detection; Development; Diagnosis; Disease; Dose; Drug Design; Equilibrium; Event; Exposure to; FDA approved; Generations; Goals; Housing; Human; Intention; Investigation; Isomerism; Kinetics; Knowledge; Length; Light; Macular degeneration; Malignant Neoplasms; Medical; Medicine; Metals; Methods; Mitochondria; Modality; Modification; Mono-S; Myristica fragrans; Necrosis; Organelles; Organic Synthesis; Oxygen; Patients; Peptides; Pharmaceutical Preparations; Photochemotherapy; Photosensitivity; Photosensitization; Photosensitizing Agents; Phototoxicity; Polyethylene Glycols; Porfimer Sodium; Porphyrins; Prion Diseases; Production; Property; Protein Family; Public Health; Reaction; Relative (related person); Reporting; Research; Residual state; Route; Scrapie; Series; Sheep; Singlet Oxygen; Site; Skin; Specificity; Structure; Structure-Activity Relationship; Taporfin Sodium; Tetrapyrroles; Time; Tissues; Toxic effect; Transfusion; Treatment Efficacy; Tumor Tissue; Variant; Verteporfin; Viral; Virus; Work; absorption; amphiphilicity; base; cancer therapy; cellular targeting; chlorin; chlorin e6; chromophore; cytotoxic; cytotoxicity; design; improved; in vivo; monoaspartyl chlorin e6; neoplastic cell; phthalocyanine; porphycene; programs; public health relevance; success; tumor; uptake

DESCRIPTION (provided by applicant): This proposal focuses on the design, synthesis, development and optimization of promising tetrapyrrole photodynamic therapy (PDT) photosensitizers for use in diagnosis and treatment of cancer and age-related macular degeneration, for use against atherosclerotic lesions, in virus eradication from blood, bone marrow purging, and for inhibition of transmissible spongiform encephalopathies [bovine (BSE), sheep (scrapie) and human forms (Creutzfeld-Jacob disease)]. PDT is a binary therapy involving light-activation of a photosensitizer that has been targeted to specific cells. This results in the generation of singlet oxygen and other cytotoxic species that cause disease cell destruction while sparing healthy tissues. There are only two FDA-approved tetrapyrrole photosensitizers - Photofrin and Visudyne; both of these drugs are mixtures of compounds with limited selectivity for tumor tissue. It is proposed to develop new efficient organic synthesis methods to three types of tetrapyrrole photosensitizer: amino acid, peptide, and polyethylene glycol (PEG) conjugates of (1) chlorin e6, (2) isoporphyrins, and (3) benzoporphyrins and porphycenes. For the most part, the aim is to prepare cell- and specific organelle-targeted photosensitizers for the PDT treatment of diseased cells and plaque. The tetrapyrrole photosensitizers that are synthesized will be directed to specific organelles (preferably the mitochondria) by conjugation with one or more amino acid, short peptide, or PEG of defined length. Sufficient examples within any series of synthetic sensitizers will permit the investigation of mechanisms of cellular uptake, intracellular localization and cytotoxicity. Modes of cell death for the most promising sensitizers will also be determined. This research will result in structure/activity relationships that are crucial in the design and development of better and more effective PDT photosensitizers for use in cancer, cardiovascular, blood transfusion, bone marrow purging, and spongiform encephalopathy areas of medicine. Extensive preliminary studies have been completed and show viability of all aspects of the proposed research. The new drugs will also be investigated in house for cellular uptake, intracellular localization and dark/light toxicity, and with a consultant for modes of cell death (promoting apoptosis over necrosis); rapid modifications of approach will be possible based on feedback from the biological work. It will be possible to balance biochemical and physicochemical characteristics of drugs with their PDT efficacy, and to use mechanistic knowledge to develop more effective PDT sensitizers. It is intended to understand the mechanisms of cellular targeting, uptake and subcellular localization of new tetrapyrrole sensitizers and to develop new highly effective drugs for medical use. PUBLIC HEALTH RELEVANCE: The proposed program is of major relevance to public health because cancer remains the second most common cause of death in the USA, and macular degeneration, atherosclerosis, viral blood and bone marrow contaminants, and spongiform encephalopathies are major world problems. Photodynamic therapy (PDT) is a treatment modality already approved by the FDA that continues to gain clinical acceptance. The full potential can be realized only when new drugs with higher cellular selectivity and specificity are discovered, their mechanisms of biological action investigated, and their efficacy evaluated relative to existing modalities.

DESCRIPTION (provided by applicant): This proposal focuses on the design, synthesis, development and optimization of promising tetrapyrrole photodynamic therapy (PDT) photosensitizers for use in diagnosis and treatment of cancer and age-related macular degeneration, for use against atherosclerotic lesions, in virus eradication from blood, bone marrow purging, and for inhibition of transmissible spongiform encephalopathies [牛（BSE），绵羊（草皮）和人类形式（Creutzfeld-Jacob病）]。 PDT是一种二元疗法，涉及针对特定细胞的光敏剂的光激活。这会导致产生单线氧和其他细胞毒性物种，这些物种在保留健康组织的同时会导致疾病破坏。只有两个FDA批准的四吡咯的光敏剂-Photofrin和visudyne；这两种药物都是化合物的混合物，对肿瘤组织的选择性有限。提议将新的有效有机合成方法开发到三种类型的四吡咯的光敏剂：氨基酸，肽和聚乙烯乙二醇（PEG）（1）氯蛋白E6，（2）异戊丁蛋白和（3）苯甲酰磷脂和（3）苯甲酰磷脂和卟啉和卟啉的（PEG）偶联物。在大多数情况下，目的是准备细胞和特定的细胞器细胞靶向光敏剂，以治疗患病细胞和斑块的PDT治疗。合成的四吡咯的光敏剂将通过与一个或多个氨基酸，较短的肽或定义长度的钉子连接到特定细胞器（最好是线粒体）。任何系列合成敏化剂中的足够例子都可以研究细胞摄取，细胞内定位和细胞毒性的机制。还将确定最有前途的敏化剂的细胞死亡模式。这项研究将导致结构/活动关系对于在癌症，心血管，输血，骨髓清洗和海绵状脑病区域的设计和开发中至关重要，这对于更有效，更有效的PDT光敏剂。广泛的初步研究已经完成，并显示了拟议研究的各个方面的生存能力。新药还将在内部进行细胞摄取，细胞内定位和黑暗/轻毒性的研究，并使用顾问的细胞死亡模式（促进了坏死的细胞凋亡）；基于生物学工作的反馈，可以快速修改方法。可以平衡药物的生化和理化特征与其PDT疗效，并使用机械知识来开发更有效的PDT敏化剂。它旨在了解新四吡咯敏化剂的细胞靶向，摄取和亚细胞定位的机制，并开发新的高效药物供医疗用途。 公共卫生相关性：拟议的计划与公共卫生具有主要相关性，因为癌症仍然是美国第二常见的死亡原因，黄斑变性，动脉粥样硬化，病毒血液和骨髓污染物以及海绵状脑病是主要世界问题。光动力疗法（PDT）是FDA已经批准的治疗方式，继续获得临床接受。只有在发现具有较高细胞选择性和特异性的新药物，研究其生物作用机制以及相对于现有方式评估的疗效时，才能实现全部潜力。