Near-IR Photorelease Chemistry: Discovery and Applications

近红外光释放化学：发现和应用

基本信息

批准号：
10262370
负责人：
Martin Schnermann
金额：
$ 90.04万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10262370
关键词：
Amines Antibody-drug conjugates Area Biological Chemistry Collaborations Drug Delivery Systems Drug Targeting Duocarmycin Fluorescence Gene Expression Profile Generations Goals Hydrolysis Lasers Light Mass Spectrum Analysis Methods Molecular Target Natural Products Penetration Pharmaceutical Preparations Phenols Process Reaction Reactive Oxygen Species Reporting Solid Neoplasm Source Techniques Therapeutic Agents Therapeutic Intervention Tissues Toxic effect anti-cancer base cyanine in vivo in vivo Model irradiation scaffold small molecule

Amines Antibody-drug conjugates Area Biological Chemistry Collaborations Drug Delivery Systems Drug Targeting Duocarmycin Fluorescence Gene Expression Profile Generations Goals Hydrolysis Lasers Light Mass Spectrum Analysis Methods Molecular Target Natural Products Penetration Pharmaceutical Preparations Phenols Process Reaction Reactive Oxygen Species Reporting Solid Neoplasm Source Techniques Therapeutic Agents Therapeutic Intervention Tissues Toxic effect anti-cancer base cyanine in vivo in vivo Model irradiation scaffold small molecule

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项目摘要

We have developed an uncaging reaction sequence initiated by near-IR light using readily synthesized C4'-dialkylamine-substituted heptamethine cyanines. We have shown that a variety of phenol- and amine- containing small molecules are quickly uncaged upon irradiation with low energy light. Detailed mechanistic studies involving mass spectrometry, NMR, and absorbance techniques have shown that release occurs through regioselective C-C cleavage and then hydrolysis of the C4'-amine. We are currently broadening the scope of the release process and examining aspects of the mechanism in detail using computational (collaboration with Dr. Joseph Ivanic) and experimental techniques. In this effort, we have developed an approach that enables the control release of amine payload through an approach that involves cyanine photooxidation followed by beta-elimination. Existing methods that use light for therapeutic interventions typically rely on the local generation of reactive oxygen species (ROS). The local delivery of potent therapeutic agents elicit alternative mechanistic paradigms, while achieving otherwise unattainable potency. We are applying our light-cleavable chemistry for targeted drug delivery. This approach merges the unique potency of small molecule drugs with the high spatial control afforded by light release and molecular targeting. The use of tissue penetrant, cytocompatible near-IR light is critical because existing uncaging chemistries using UV or blue light would not be suitable for this application. In this area, we reported the first example of near-IR light cleavable antibody drug conjugate strategy. We have developed conjugates that release the potent anticancer natural product, duocarmycin. These conjugates can be tracked in vivo using fluorescence and uncaged attainable flux from an external CW laser source. These compounds have shown highly promising antitumor activity in in vivo models. We are currently pursuing additional strategies to enable to the delivery of these molecules to various solid tumors.

我们已经开发了一个近红外光引发的分离反应序列，并使用易于合成的C4'Dialkylamine溶于二取代的己氨酸氰氨酸。我们已经表明，在低能量光线下照射时，各种含有苯酚和胺 - 含有小分子很快就会液化。涉及质谱，NMR和吸光度技术的详细机械研究表明，释放是通过区域选择性的C-C裂解进行的，然后进行C4'-胺的水解。目前，我们正在扩大发布过程的范围，并使用计算（与Joseph Ivanic博士的协作）和实验技术详细研究该机制的各个方面。在这项工作中，我们开发了一种方法，可以通过一种涉及氰氨基光氧化的方法来控制胺有效载荷，然后进行β淘汰。使用光进行治疗干预措施的现有方法通常取决于当地的活性氧（ROS）。有效的治疗剂的局部输送引起了替代机械范式，同时实现了无法实现的效力。我们正在将可裂解的化学应用于靶向药物递送。这种方法将小分子药物的独特效力与光释放和分子靶向提供的高空间控制。使用组织渗透剂，细胞相容的近红外光非常关键，因为现有的使用UV或蓝光的化学效果不适合此应用。在这一领域，我们报道了近红外光裂解抗体药物共轭策略的第一个例子。我们开发了释放有效的抗癌天然产品Duocarmycin的结合物。这些结合物可以使用荧光和外部CW激光源可实现的通量在体内进行跟踪。这些化合物在体内模型中显示出高度有希望的抗肿瘤活性。我们目前正在采取其他策略，以使这些分子递送到各种实体瘤。