Light-responsive ruthenium compounds for applications in disease

光响应钌化合物在疾病中的应用

• 批准号: 9322360
• 负责人: Edith C Glazer
• 金额: $ 28.55万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322360
• 关键词: Adverse effects; Animals; Benchmarking; Biological; Biological Assay; Biotin; Cancer cell line; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Charge; Chemicals; Chemistry; Chromatography; Cisplatin; Combined Modality Therapy; Complex; DNA; DNA Damage; Development; Dimensions; Disease; Dose-Limiting; Drug Kinetics; Drug Utilization; Electron Microscopy; Engineering; Exhibits; Family; Genetic Transcription; Goals; Image; Imaging Device; In Vitro; Knowledge; Label; Lead; Ligands; Light; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Maximum Tolerated Dose; Metals; Modality; Modeling; Modification; Molecular; Motivation; Mus; Neutropenia; Nucleic Acids; PUVA Photochemotherapy; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Photochemistry; Phototoxicity; Platinum; Process; Prodrugs; Property; Radiation; Reaction; Reducing Agents; Resistance; Resistance profile; Resolution; Ruthenium; Ruthenium Compounds; Sampling; Singlet Oxygen; Site; System; Therapeutic; Tissues; Toxic effect; United States; Variant; Xenograft Model; analog; base; biological systems; cancer cell; cancer therapy; cancer type; cell killing; cell type; cellular targeting; chemotherapeutic agent; chemotherapy; clinical application; crosslink; cytotoxic; cytotoxicity; design; gel electrophoresis; in vivo; innovation; melanoma; novel; oxidative damage; pre-clinical trial; public health relevance; screening; small molecule; systemic toxicity; targeted agent; therapy development; translation assay; tumor

DESCRIPTION (provided by applicant): This proposal seeks to develop a new class of light-responsive inorganic materials as chemotherapeutic agents. Cisplatin and its analogues remain the standard therapy for a variety of cancers, despite their nonspecific mechanism of action with nucleic acids, resulting in general cytotoxicity and debilitating side-effects. A promising approach that will provide several key advantages is to combine the reactivity of metal- based drugs with the selectivity of photodynamic therapy (PDT) to increase the targeting of malignant tissues and reducing side-effects. We have recently shown that structural distortion can be utilized to promote photochemical reactions to create reactive ruthenium species that are strongly electrophilic and highly photo-toxic in cell based assays. We hypothesize that distortion can be used to control light-activated cytotoxicity for the creation of selective and potent chemotherapeutics. We propose a new class of ruthenium-based compounds that have a readily modifiable modular design to facilitate rapidly incorporation of key molecular components to efficiently develop materials exhibiting selectivity and controlled reactivity. Coordination chemistry will be used to generate a structurally diverse family of three-dimensional chiral ruthenium compounds in a self-assembled manner. The structural variations in the materials will be correlated to cytotoxic efficacy using high-throughput cell survival assays, and the most promising compounds will be assessed for Pharmacokinetic (PK) properties, Maximum Tolerated Dose (MTD) and efficacy in mouse xenograft models of lung cancer and melanoma. Mechanism of action studies will be used to define the currently unknown process of cell killing. In order to accomplish this aim, a novel chemical labeling strategy is proposed to facilitate imaging of the subcellular and potentially sub-organellar localization of active compounds using Electron Microscopy. If successfully validated, this approach could be extended to additional imaging applications in tissues. Alternative approaches utilize biotin-labeled ruthenium materials for target pull-down, with cellular targets identified through a process of gel electrophoresis, chromatography, and mass spectrometry. In vitro and in cell transcription and translation assays will support these findings. Cisplatin, the benchmark inorganic chemotherapeutic, will be used for comparison in all mechanism of action studies. The goal is to determine if the proposed ruthenium materials utilize the same biological target(s) as cisplatin, or may be directed to different functional targets via structural modification. Upon completion of these studies, we will have expanded our knowledge of the fundamental photochemistry of ruthenium complexes, developed potent and selective cytotoxic chemical entities, identified their mechanism of action, and developed a new tool for the imaging of small molecules in biological systems. 1

描述(申请人提供)：本提案旨在开发一类新型的光响应性无机材料作为化疗药物。顺铂及其类似物仍然是各种癌症的标准治疗方法，尽管它们与核酸的作用机制不具特异性，导致普遍的细胞毒性和衰弱的副作用。将金属类药物的反应性与光动力疗法(PDT)的选择性相结合，以增加对恶性组织的靶向性，减少副作用，是一种很有前途的方法。我们最近已经证明，在基于细胞的分析中，结构扭曲可以被用来促进光化学反应，以生成具有强烈亲电性和高度光毒性的活性Ru物种。我们假设扭曲可以用来控制光激活的细胞毒性，从而产生选择性和有效的化疗药物。我们提出了一类新的基于Ru的化合物，它具有易于修改的模块化设计，以促进关键分子组分的快速结合，从而有效地开发出具有选择性和可控反应活性的材料。配位化学将被用来以自组装的方式生成结构多样化的三维手性Ru化合物家族。这些材料的结构变化将通过高通量细胞存活分析与细胞毒疗效相关，最有希望的化合物将被评估药代动力学(PK)特性、最大耐受量(MTD)和在小鼠肺癌和黑色素瘤异种移植模型中的疗效。作用机制研究将被用来定义目前未知的细胞杀伤过程。为了实现这一目标，提出了一种新的化学标记策略，以便于使用电子显微镜对活性化合物的亚细胞和潜在的亚细胞器定位进行成像。如果成功验证，这种方法可能会扩展到组织中的其他成像应用。替代方法利用生物素标记的Ru材料进行靶标下拉，通过凝胶电泳、层析和质谱分析过程识别细胞靶标。体外和在细胞内的转录和翻译分析将支持这些发现。作为基准的无机化疗药物顺铂将在所有作用机制研究中用于比较。目的是确定所建议的Ru材料是否使用与顺铂相同的生物靶点(S)，或者可能通过结构修改针对不同的功能靶点。在完成这些研究后，我们会 扩展了我们对Ru络合物基本光化学的认识，开发了有效的和选择性的细胞毒性化学实体，确定了它们的作用机制，并开发了一种新的生物体系中小分子成像的工具。1