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: 8197646
• 负责人: Kevin M Smith
• 金额: $ 29.59万
• 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/8197646
• 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; 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; drug development; 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.

描述（申请人提供）：该提案集中于设计、合成、开发和优化有前景的四吡咯光动力疗法（PDT）光敏剂，用于诊断和治疗癌症和年龄相关性黄斑变性，用于抗动脉粥样硬化病变，用于从血液中根除病毒，骨髓净化，以及用于抑制传染性海绵状脑病[牛（BSE），绵羊（羊瘙痒病）和人类形式（克雅氏病）]。PDT是一种二元疗法，涉及针对特定细胞的光敏剂的光激活。这导致单线态氧和其他细胞毒性物质的产生，这些物质导致疾病细胞破坏，同时保护健康组织。只有两种FDA批准的四吡咯光敏剂- Photofrin和Visudyne;这两种药物都是对肿瘤组织选择性有限的化合物的混合物。本文提出了三种四吡咯光敏剂：（1）二氢卟啉e6，（2）异卟啉，（3）苯并卟啉和卟啉的氨基酸、肽和聚乙二醇（PEG）共轭物的有机合成新方法。在大多数情况下，目的是制备细胞和特定细胞器靶向的光敏剂，用于病变细胞和斑块的PDT治疗。所合成的四吡咯光敏剂将通过与一个或多个氨基酸、短肽或限定长度的PEG缀合而导向特定的细胞器（优选线粒体）。任何系列的合成致敏剂中的足够实例将允许研究细胞摄取、细胞内定位和细胞毒性的机制。还将确定最有希望的致敏剂的细胞死亡模式。这项研究将导致结构/活性关系，这对于设计和开发更好，更有效的PDT光敏剂用于癌症，心血管，输血，骨髓净化和海绵状脑病医学领域至关重要。广泛的初步研究已经完成，并显示拟议研究的各个方面的可行性。还将在内部研究新药的细胞摄取，细胞内定位和暗/光毒性，并与顾问一起研究细胞死亡模式（促进细胞凋亡而不是坏死）;根据生物学工作的反馈，可以快速修改方法。这将有可能平衡药物的生化和物理化学特性与其PDT功效，并使用机制知识来开发更有效的PDT增敏剂。其目的是了解新的四吡咯敏化剂的细胞靶向、摄取和亚细胞定位的机制，并开发用于医疗用途的新的高效药物。 公共卫生相关性：拟议的计划与公共卫生有重大关系，因为癌症仍然是美国第二大最常见的死亡原因，黄斑变性、动脉粥样硬化、病毒性血液和骨髓污染物以及海绵状脑病是主要的世界性问题。光动力疗法（PDT）是一种已经被FDA批准的治疗方式，并继续获得临床认可。只有当发现具有更高细胞选择性和特异性的新药、研究其生物作用机制并评估其相对于现有模式的功效时，才能充分发挥其潜力。