Light-responsive ruthenium compounds for applications in disease

光响应钌化合物在疾病中的应用

基本信息

批准号：
8761360
负责人：
Edith C Glazer
金额：
$ 27.13万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
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/8761360
关键词：
Adverse effects Animals Benchmarking Biological Biological Assay Biotin Cancer cell line Cell Death Cell Survival Cells Cessation of life Charge Chemicals Chemistry Chromatography Cisplatin Combined Modality Therapy Complex DNA DNA Damage Development Disease Dose-Limiting Drug Kinetics Electron Microscopy Engineering Exhibits Family Genetic Transcription Goals Health Image Imaging Device In Vitro Knowledge Label Lead Ligands Light Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Maps Mass Spectrum Analysis Maximum Tolerated Dose Metals Modality Modeling Modification Molecular Motivation Mus Neutropenia Nucleic Acids Pathway interactions Patients Pattern Pharmaceutical Preparations Photochemistry Photochemotherapy Platinum Process Prodrugs Property Radiation Reaction 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 injury cell killing cell type cellular targeting chemotherapeutic agent chemotherapy clinical application crosslink cytotoxic cytotoxicity design gel electrophoresis in vivo innovation killings lung melanoma novel oxidative damage preclinical study screening small molecule translation assay tumor

项目摘要

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（由申请人提供）：该提案旨在开发一种新的光反应无机材料作为化学治疗剂。顺铂及其类似物仍然是多种癌症的标准疗法，尽管它们具有非特异性的作用机理，从而导致一般的细胞毒性和使人衰弱的副作用。一种有前途的方法将提供多种关键优势，是将基于金属药物的反应性与光动力疗法（PDT）的选择性相结合，以增加恶性组织的靶向和降低副作用。我们最近表明，可以利用结构变形来促进光化学反应，以创建反电的反应性钌物种，这些物种在基于细胞的测定中具有强烈的亲电且高度毒性。我们假设失真可用于控制光激活的细胞毒性，以创建选择性和有效的化学治疗药。我们提出了一类新的基于氟苯基的化合物，具有易于修改的模块化设计，以促进迅速掺入关键分子成分，以有效地开发出具有选择性和控制反应性的材料。协调化学将用于以自组装方式产生三维性手性ruthenium化合物的结构多样性家族。材料中的结构变化将与使用高通量细胞存活测定法相关，并将评估最有希望的化合物的药代动力学特性（PK）特性，最大耐受剂量（MTD）和效应在小鼠肺癌和黑梅拉马瘤小鼠的小鼠中的功效。作用研究机理将用于定义当前未知的细胞杀戮过程。为了实现这一目标，提出了一种新型的化学标记策略，以促进使用电子显微镜对活性化合物的亚细胞和潜在的亚轨道定位进行成像。如果成功验证，则可以将这种方法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弦丁材料进行靶下拉，并通过凝胶电泳，色谱和质谱法鉴定细胞靶标。体外和细胞转录和翻译分析将支持这些发现。 Cisplatin，基准无机化疗，将用于所有作用研究机理中的比较。目的是确定所提出的唯一材料是利用与顺铂相同的生物学靶标，还是通过结构修饰将其针对不同的功能靶标。完成这些研究后，我们将已经扩展了我们对钌络合物的基本光化学的了解，开发了有效和选择性的细胞毒性化学实体，确定了其作用机理，并开发了一种新工具，用于对生物系统中小分子进行成像。 1