Optimizing hexacholorplatinate for clinical deployment

优化六氯铂以进行临床部署

• 批准号: 10241500
• 负责人: Calum A. MacRae
• 金额: $ 61.62万
• 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/10241500
• 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; efficacy evaluation; 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作为一种可部署的氰化物对抗物，以针对新的 六氯酚和其他有机金属铅化合物的衍生物到亚细胞室以减轻毒性， 并对HCP-DMSO及其衍生物与其他试剂进行联合检测。与内部的其他组件一样 我们建议的U54中心，该项目将包括产品开发活动和有针对性的发现 活动，这两项活动都利用了中心的专业知识和核心。具体地说，我们提出了以下目标： 目的1.研制六氯铂-二甲基亚砜作为氰化物的对抗剂。HCP-DMSO具有很高的 在斑马鱼、小鼠、兔子和猪身上有效对抗氰化物。重要的是，它可以交付 通过IM注射快速。然而，最佳配方和给药的条件尚未确定。在……里面 与科学核心合作，我们将优化HCP-DMSO的配方，以实现最大浓度， 稳定性和摄取性。我们还将确认最终配方在兔子和猪身上的疗效，并评估 配方化合物的毒性。这一目标将提供优化的HCP配方， 符合BARDA高级发育正式标准的兔和猪的性能和卓越疗效 目的2.优化金属有机铅化合物的细胞配置。化学衍生品有 已经开发出将铂化合物靶向特定的亚细胞位置，目的是增加它们的 化疗细胞毒性。最近的研究也证明了铂影响的复杂性。 药物及其定位和时机在其有效性和毒性中的作用。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，将铂定位在远离铂的位置 毒性可能会提高其安全性，而不会降低其清除氰化物的能力。同样，以HCP为目标 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 针对质膜、线粒体、细胞质的hcp形式，或排除 它们来自细胞以及其他具有抗氰化物活性的有机金属衍生物。 目的3.评价本中心开发的综合疗法的疗效。我们将测试 有机金属氰化物清除剂与项目2和3中的新型代谢调节剂的组合。 利用我们在整个财团建立的多车型渠道的高效性质 在过去的几年中，以及通过这种协作努力形成的洞察力，我们将测试 多个不同的已建立解毒剂的离散剂量、递送机制和计时方案 六氯铂酸盐，以优化一种全新的对抗方案。