# Optimizing hexacholorplatinate for clinical deployment

> **NIH NIH U54** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $616,193

## Abstract

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.

## Key facts

- **NIH application ID:** 10241500
- **Project number:** 5U54NS112107-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Calum A. MacRae
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $616,193
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241500

## Citation

> US National Institutes of Health, RePORTER application 10241500, Optimizing hexacholorplatinate for clinical deployment (5U54NS112107-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241500. Licensed CC0.

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