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，我们建议开发HCP-DMSO作为可部署的氰化物对策，以针对新的 HCP和其它有机金属化合物的衍生物引导化合物进入亚细胞区室以减轻毒性， 并测试HCP-DMSO及其衍生物与其他试剂的组合。就像里面的其他组件一样 我们建议的U 54中心，该项目将包括产品开发活动和有针对性的发现 活动，两者都利用了该中心的专业知识和核心。具体而言，我们提出以下目标： 目标1.开发六氯铂酸盐-DMSO作为氰化物对策。HCP-DMSO是高度 在斑马鱼、小鼠、兔子和猪中作为氰化物对抗剂有效。重要的是，它可以交付 快速注射。然而，尚未确定最佳配方和交付的条件。在 与科学核心合作，我们将优化HCP-DMSO的处方，以获得最大浓度， 稳定性和吸收。我们还将确认最终制剂在兔和猪中的功效，并评估其在动物中的作用。 配制化合物的毒性。这一目标将提供一种优化的HCP配方， 在符合正式巴尔达高级开发标准的家兔和猪中的特性和优异功效 目标二。优化有机金属铅化合物的细胞配置。化学衍生物具有 已经开发了将铂化合物靶向特定亚细胞位置的方法，目的是增加它们的活性。 化疗的细胞毒性。最近的工作也证明了铂的影响的复杂性 药物以及定位和时机在其疗效和毒性中的作用。与癌症治疗不同，细胞毒性 并不是有效对抗氰化物的先决条件事实上，靶向铂远离铂的位点， 毒性可以提高其安全性而不降低其消除氰化物的能力。同样，将HCP靶向至 线粒体或其它氰化物亚细胞靶点可增强其保护作用。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 它们从电池以及其他有机金属衍生物的活性，对氰化物。 目标3。评价本中心开发的联合疗法的疗效。我们将测试 有机金属氰化物清除剂与项目2和3的新型代谢调节剂组合。 利用我们在整个联盟中建立的多型号管道的高效性， 过去几年，通过这种合作奋进发展的见解，我们将测试 以离散剂量、递送机制和定时方案的多种不同的已建立解毒剂， 六氯铂酸盐，以优化一个全新的对策方案。