HOPO 14-1: A Revolutionary Drug for Removing Radioactive Particles and Toxic Metals

2023-08-02 08:14:00

When Russian forces occupied the Zaporizhia nuclear power plant in Ukraine more than a year ago, each side accused the other of recklessness and sabotage that could damage the facility and cause a nuclear accident. Now, after three decades of research and development, scientists are testing a drug that could help remove radioactive particles from the bodies of exposed victims if such an incident were to occur.

The threat of radioactive contamination, whether due to war or an accident in a nuclear power plant, has always occupied an important place in the collective imagination. There Chernobyl disaster, in 1986, resulted in twenty-eight acute radiation deaths, 350,000 evacuations and thousands of cases of thyroid cancer. Before Chernobyl, the worst nuclear accident took place in the United States, at the Three Mile Island power plant in Pennsylvania, but did not cause a similar increase in the number of cancers.

Shortly after Three Mile Island, the U.S. government made a huge push to fund research to develop new medical countermeasures against nuclear threats, says Rebecca Abergel, an inorganic chemist at both the University of California at Berkeley and at the Lawrence-Berkeley National Laboratory. Today, she and her colleagues from SRI Internationala Californian research institute, began the clinical tests of a promising drug, HOPO 14-1, which acts on radioactive contaminants such as uranium and plutonium.

Phase I clinical trials will verify the safety of HOPO 14-1 in a small population of healthy human subjects.

We are all exposed to ionizing radiation, a general term for radiation capable of stripping electrons from atoms and molecules, because the entire universe is impregnated with it.

The disintegration of an unstable atom releases energy in the form of radiation. The latter can itself take various forms, each with its own characteristics. Gamma rays, for example, are electromagnetic waves that can penetrate deep into the body. They are often used in medical contexts such as imaging or cancer therapy. Alpha radiation, on the other hand, comes from positively charged energy particles that are ejected from the nucleus of an atom. Our skin can stop these, but when substances emitting alpha radiation, such as plutonium, manage to enter our body, they continuously irradiate the surrounding tissues, seep into us and destroy immune cells in the bone marrow, putting us at risk of infection, cancer and death.

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“Dirty bombs” or “radiological dispersal devices”, for example, disperse radioactive materials, such as cesium or theuranium, which can be inhaled or seep into penetrating wounds. As for nuclear accidents, they can contaminate water and air with radioactive iodine and cesium.

How we are exposed matters. We can avoid external sources of radiation, such as x-ray machines, or protect ourselves from them. Internal contamination, on the other hand, must be eliminated to end its harmful effects.

For decades, options were limited when it came to irradiation. Irradiation by actinides, radioactive heavy metals often used in atomic weapons and nuclear power plants, for example, could only be treated with a chemical called diethylene triamine pentaacetic acid (DTPA). Approved in the 1960s by the Food and Drug Administrationthe US Federal Food and Drug Control Agency, DTPA is a chelating agent, i.e. a molecule that seizes toxic metals and transports them to the kidneys, which evacuate them from the body through the urines.

The DTPA comes with serious caveats, however. First of all, it only works on three actinides: plutonium, americium and curium. Next, the compound must be administered quickly, within twenty-four hours of exposure, or it will greatly lose effectiveness as radioactive contaminants lodge in tissues and organs. Finally, it is a healthcare professional who must inject it intravenously, which makes it impractical to deploy in scenarios involving very many victims. What remains even more worrying, however, is the tendency of DTPA to take over essential minerals that our bodies need, such as calcium and zinc.

“Prolonged use of DTPA can significantly affect the body’s mineral balance,” says Julian Rees, co-founder of HOPO Therapeuticsa company studying the commercial uses of HOPO 14-1, and Rebecca Abergel’s former post-doctoral fellow at the Lawrence-Berkeley National Laboratory.

To develop a better chelating agent for these radioactive substances, scientists turned to nature, specifically bacteria and how they transport iron.

It is an essential nutrient for many organisms. This is why bacteria have developed very specific chelating agents to capture it. “During the invasion of a host-guest system, bacteria send molecules called siderophores, which capture iron, form very stable complexes with it and bring it back into the bacterial cell”, explains Rebecca Abergel who is also co-founder of HOPO Therapeutics.

Inspired by these host-guest complexes, Kenneth Raymond and Patricia Durbin, who advised Rebecca Abergel during her studies at the University of California, Berkeley campus, relied on the chemical similarities between iron and heavy metals and started designing chelators thirty years ago.

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HOPO 14-1, the drug currently in clinical trials, emerged as a top candidate, showing affinity with uranium, neptunium, plutonium, americium and curium. Some of these metals are large, so a chelator “must be able to envelop them completely,” says Rebecca Abergel. With four molecular “claws” and two binding sites per claw, the HOPO 14-1 can grab a target radioactive metal in eight places, attach it firmly, and deliver it to the intestine to be eliminated in the faeces .

Furthermore, the drug does not appear to capture calcium or other important physiological molecules, which makes it less toxic than DTPA. Even at a dose a hundred times higher than normal, human cells cultured in Petri dishes continue to function and appear normal.

Unlike the DPTA, it remains effective when administered up to forty-eight hours before or seven days after radiation exposure. It is important to extend this window because often, “after an industrial accident, it can take some time before we can reach the patients”, explains David Cassatt, radiobiologist within the Radiation and Nuclear Countermeasures Program from the US National Institute of Allergy and Infectious Diseases, Maryland.

Sascha Goonewardena, a cardiologist at the University of Michigan and physician-investigator of the Phase I clinical trial, is perhaps more enthusiastic about the fact that HOPO 14-1 comes in tablet form. “It’s a simpler and more convenient solution than others currently available,” she says. The tablets could, for example, be air-dropped into contaminated areas so that people can self-administer the drug without exposing first responders to unnecessary radiation.

Rebecca Abergel points out, however, that the HOPO 14-1 could not treat the victims of a nuclear explosion, such as that of Hiroshima, who would be subjected to external irradiation. It would still be useful for people far enough away from the initial explosion, but who would be within the radius of the radioactive fallout.

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“It’s very rewarding” to be in the clinical trial stage, says Polly Chang, a radiation biologist at SRI International who frequently collaborates with Rebecca Abergel. The groundwork to get to this point spans decades and relies on institutions ranging from university labs to nonprofit research institutes to government-funded agencies.

HOPO 14-1 is an essential element in the nuclear field, but it is only one strategy among others that the US National Institute of Allergy and Infectious Diseases funds, explains Andrea DiCarlo- Cohen, director of Radiation and Nuclear Countermeasures Program. “The goal of the program is to make the US government more medically prepared” in the event of a nuclear accident or attack.

Meanwhile, Julian Rees and Rebecca Abergel list other uses for HOPO 14-1, including as a chelating agent for non-radioactive, yet toxic metals, such as lead and cadmium. A third of children in the world being affected by lead poisoning, Julian Rees sees this problem as “a huge unmet need”.

The elimination of gadolinium, an ingredient in the contrast medium used in MRI scans, is another potential use for HOPO 14-1. Once thought to be harmless, it has been discovered that gadolinium can persist in the bones, brain and other organs, possibly causing pain, memory loss and other chronic disorders. Tests carried out on mice suggest that HOPO 14-1, given just before or just after an MRI, could prevent up to 96% of gadolinium from depositing in the organs.

According to Andrea DiCarlo-Cohen, it is these more day-to-day uses of the HOPO 14-1 that will allow the United States to have sufficient supplies when needed. If gadolinium removal becomes routine clinical practice, for example, hospitals will need to have HOPO 14-1 on hand, just in case.

For Ryan Marino, emergency physician and medical toxicologist at theUniversity Hospitals Cleveland Medical Centerthe arrival of the HOPO 14-1 on the market will not be long in coming.

“One of my concerns is that there aren’t always treatments available, or that these can be difficult to obtain,” laments Ryan Marino, who was not involved in the HOPO research. 14-1. “This molecule could therefore be a game-changer. »

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