Optimizing hexacholorplatinate for clinical deployment

优化六氯铂以进行临床部署

• 批准号: 9981042
• 负责人: Calum A. MacRae
• 金额: $ 59.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981042
• 关键词: Advanced Development; Anions; Antidotes; Cell Nucleus; Cell membrane; Cells; Chemicals; Cisplatin; Clinical; Cobalt; Collaborations; Combined Modality Therapy; Cyanides; Cytoplasm; Development; Dimethyl Sulfoxide; Dose; Exhibits; Family suidae; Formulation; Goals; Human; Hydroxocobalamin; Intramuscular Injections; Lead; Ligands; Literature; Location; Malignant Neoplasms; Metabolic; Mitochondria; Modeling; Mus; Nature; Organometallic Compounds; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacology; Platinum; Platinum Compounds; Property; Regimen; Reporting; Role; Route; Safety; Scheme; Site; Structure-Activity Relationship; Sulfur; Testing; Therapeutic; Thiocyanates; Toxic effect; Work; Zebrafish; base; chemotherapy; cytotoxic; cytotoxicity; design; improved; in vivo; insight; mass casualty; meetings; novel; product development; protective effect; screening; subcellular targeting; therapy development; uptake

In this project, we propose to develop HCP-DMSO as a deployable cyanide countermeasure, to target novel derivatives of HCP and other organometallic lead compounds to subcellular compartments to mitigate toxicity, and to test HCP-DMSO and its derivatives in combination with other agents. Like the other components within our proposed U54 Center, this project will consist of product development activities and targeted discovery activities, both of which exploit the expertise and cores of the center. Specifically, we propose the following aims: Aim 1. To develop hexachloroplatinate-DMSO as a cyanide countermeasure. HCP-DMSO is highly efficacious as a cyanide countermeasure in zebrafish, mice, rabbits, and pigs. Importantly, it can be delivered rapidly by IM injection. However, conditions for optimal formulation and delivery have not been identified. In collaboration with the scientific cores, we will optimize the formulation of HCP-DMSO for maximal concentration, stability, and uptake. We will also confirm efficacy of the final formulation in rabbits and pigs and evaluate the toxicity of the formulated compound. This aim will deliver an optimized HCP formulation with well-understood properties and excellent efficacy in rabbits and pigs meeting formal BARDA criteria for advanced development Aim 2. To optimize the cellular disposition of organometallic lead compounds. Chemical derivatives have been developed that target platinum compounds to specific subcellular locations, with the goal of increasing their chemotherapeutic cytotoxicity. Recent work has also demonstrated the complexity of the effects of platinum agents and the role of localization and timing in their efficacy and toxicity. Unlike cancer therapeutics, cytotoxicity is not a prerequisite for an effective cyanide countermeasure. In fact, targeting platins away from sites of platin toxicity may improve its safety without reducing its ability to scavenge cyanide. Similarly, targeting HCP to mitochondria or other cyanide subcellular targets may enhance its protective effects. We will investigate several forms of HCP designed to target them to the plasma membrane, the mitochondria, the cytoplasm, or to exclude them from the cell as well as other organometallic derivatives with activity against cyanide. Aim 3. To evaluate the efficacy of combinational therapies developed in our center. We will test organometallic cyanide scavengers in combination with novel metabolic modulators from Projects 2 and 3. Exploiting the efficient nature of the multi-model pipeline we have established across our consortium over the last few years, and the insights developed through this collaborative endeavor, we will test combinations of multiple, different established antidotes in discrete doses, delivery mechanisms and timing schemes with hexachloroplatinate to optimize an entirely novel countermeasure regimen.

在这个项目中，我们建议将HCP-DMSO开发为可部署的氰化物对策，以针对新颖 HCP和其他有机金属铅化合物的衍生物对亚细胞隔室，以降低毒性， 并与其他药物结合测试HCP-DMSO及其衍生物。像其他组件一样 我们提出的U54中心，该项目将包括产品开发活动和针对性的发现 活动，两者都利用了中心的专业知识和核心。具体来说，我们提出以下目的： 目的1。开发六氯片酸-DMSO作为氰化物对策。 HCP-DMSO高度 在斑马鱼，小鼠，兔子和猪中有效地为氰化物对策。重要的是，它可以交付 迅速通过IM注射。但是，尚未确定最佳配方和交付的条件。在 与科学核心的合作，我们将优化HCP-DMSO的配方，以达到最大浓度， 稳定和吸收。我们还将确认最终配方在兔子和猪中的功效，并评估 配制化合物的毒性。这个目标将提供优化的HCP配方，并理解为 兔子和猪的属性和出色的功效，满足正式的Barda标准用于高级开发 目标2。优化有机金属铅化合物的细胞处置。化学衍生物具有 已经开发出靶向铂化合物到特定亚细胞位置的开发，目的是增加其 化学治疗性细胞毒性。最近的工作还证明了铂的影响的复杂性 代理以及定位和时间在其功效和毒性中的作用。与癌症治疗不同，细胞毒性 不是有效的氰化物对策的先决条件。实际上，将Platins瞄准远离Platin的地点 毒性可以提高其安全性，而不会降低其清除氰化物的能力。同样，将HCP定为 线粒体或其他氰化物亚细胞靶标可能会增强其保护作用。我们将调查几个 HCP的形式旨在将其靶向质膜，线粒体，细胞质或排除 它们来自细胞以及其他有机金属衍生物，具有针对氰化物的活性。 目标3。评估中心开发的组合疗法的功效。我们将测试 有机金属氰化物清除剂与项目2和3的新代谢调节剂结合使用。 利用我们在整个财团上建立的多模型管道的有效性质 最近几年，以及通过这项合作努力发展的见解，我们将测试 具有离散剂量，输送机制和定时方案的多种不同的解毒剂 六氯扁桃液以优化一种完全新颖的对策方案。