Optimizing hexacholorplatinate for clinical deployment

优化六氯铂以进行临床部署

基本信息

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
项目类别：
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

项目摘要

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，以瞄准新型氰化物 HCP 的衍生物和其他有机金属铅化合物进入亚细胞区室以减轻毒性，并测试HCP-DMSO及其衍生物与其他药剂的组合。就像里面的其他组件一样我们提议的 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。具体来说，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 是高度作为斑马鱼、小鼠、兔子和猪的氰化物对策是有效的。重要的是可以送货通过肌内注射快速。然而，最佳配方和递送的条件尚未确定。在与科学核心合作，我们将优化 HCP-DMSO 的配方以获得最大浓度，稳定性和吸收率。我们还将确认最终配方对兔子和猪的功效并评估配制的化合物的毒性。这一目标将提供一种优化的 HCP 配方，并具有良好的理解对兔子和猪的特性和卓越功效符合正式的 BARDA 高级开发标准目标 2. 优化有机金属铅化合物的细胞分布。化学衍生物有已开发出将铂化合物靶向特定的亚细胞位置，目的是增加其化疗细胞毒性。最近的工作还证明了铂影响的复杂性药物以及定位和时机在其功效和毒性中的作用。与癌症治疗不同，细胞毒性不是有效氰化物对策的先决条件。事实上，将铂靶向远离铂位点毒性可以提高其安全性而不降低其清除氰化物的能力。同样，针对 HCP 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具有抗氰化物活性的有机金属衍生物。目标 3. 评估我们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 的新型代谢调节剂相结合。利用我们在联盟中建立的多模型管道的高效性质过去几年，以及通过这种合作努力形成的见解，我们将测试以下内容的组合多种不同的既定解毒剂，其剂量、输送机制和时间安排均不同六氯铂酸盐以优化全新的对策方案。