A photo looking down into a nuclear reactor.

Credit: Stephanie DeMarco

From warhead to cancer-killer, the quest for more actinium-225

Actinium-225 is a radioactive isotope that kills cancer cells with a burst of alpha particles, but it was difficult to make enough of it — until now.
Stephanie DeMarco, PhD Headshot
| 18 min read

As a radioactive isotope, actinium-225 emits alpha particles that are great at killing cancer cells. The problem is that there’s not enough actinium-225 in the world to treat all of the patients who would benefit from it or even supply all of the clinical trials testing it. But now, researchers at a nuclear fuels company may have found a new way to make more actinium-225 than ever before.

Host: Stephanie DeMarco, PhD, Associate Editor, Team Lead

Guests:


Ian Horvath, Serva Energy

Ian Horvath, Serva Energy

Susan Moran, RayzeBio

Susan Moran, RayzeBio

Valery Radchenko, TRIUMF

Valery Radchenko, TRIUMF


More on this podcast:

DDN Dialogues is a new podcast from Drug Discovery News. Join us as we explore the stories behind the latest advances in drug discovery research.


Photos from Stephanie DeMarco's visit to the nuclear lab

A view of the nuclear reactor in the nuclear reactor laboratory at UC Irvine.
The nuclear reactor, located under the metal grate, emits Cherenkov radiation as it runs which appears as blue light.
Credit: Stephanie DeMarco
A stack of solid lead bricks sit on a wooden pallet on the floor of the nuclear reactor laboratory at UC Irvine.
Horvath, Sarah Finkeldei at UC Irvine, and their teams encase radioactive radium and actinium within solid lead bricks.
Credit: Stephanie DeMarco
The metal hatch that transports samples into the nuclear reactor.
After the researchers encapsulate their radium-226 target, they drop it down into the nuclear reactor via this hatch.
Credit: Stephanie DeMarco
A look into the center of a detector.
Researchers use detectors like this one to identify the different isotopes present in a sample.
Credit: Stephanie DeMarco
A pneumatic tube moves up against a wall with a “caution radiation area” sign nearby.
For samples that are particularly radioactive, scientists can use a pneumatic tube to transport them into the reactor.
Credit: Stephanie DeMarco
  A wooden panel with tags shows the arrangement of different components of the nuclear reactor.
A wood panel shows the arrangement of different components of the nuclear reactor.
Credit: Stephanie DeMarco


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Transcript

Stephanie DeMarco: Hi everyone! Welcome back to a new episode of DDN Dialogues! I’m your host, Stephanie DeMarco.

Today we’ve got something a little different from our previous episodes. Most of our stories focus on the biological side of drug discovery and development, but today we’re taking a brief detour into the realm of physics.

Imagine the periodic table of elements for a moment. There’s hydrogen and helium standing tall on either end. Off to the left sit the alkali and alkaline metals. Next to them is the big block of transition metals, and on their other side sit carbon, nitrogen, and oxygen before getting to the Nobel gases at the end. But, if you look below the main table, there are two more rows of elements that seem to just be floating underneath.

These are the Lanthanides and the Actinides. One of the things that makes these elements special is that many of them are naturally radioactive, or they can become radioactive depending on the number of neutrons they have in their nucleus. These are also known as different isotopes of the same element.

We typically think of radioactivity as dangerous because it can cause mutations in cells, which can lead to cancer. But when we use radiation against cancer cells, it’s very good at killing them.

One of these elements, in particular, has some very special properties when it comes to treating cancer. The element actinium, which gives the Actinides their name, is itself naturally radioactive. But under certain conditions, it forms the radioactive isotope actinium-225, which as a cancer treatment blows the rest out of the water.

Ian Horvath: Do you know much about actinium-225, like how it works?

DeMarco: That’s Ian Horvath, the CEO and founder of the nuclear fuels research and development company Serva Energy.

Horvath: We should start there because it's awesome. So, actinium-225 is what's called an alpha emitter, so that's a very unique kind of radiation that's extremely high energy. But the radiation has very low penetration, like it cannot make it through this sheet of paper on my notebook, so it can deposit a ton of energy in a very, very, very tiny range. If you attach it to an antibody that's only attaches onto enzymes found on cancer cells, then you deliver this giant alpha emitter directly to the tumor site, so it can have devastating effect on cancer, while at the same time, it doesn't really have much impact on the rest of the body.

DeMarco: Actinium-225 also has a half-life of only ten days, which is long enough to manufacture a drug using it and to deliver the actinium-based treatment to a patient. Ten days is also short enough that the actinium doesn’t stay in the body or the environment very long.

Horvath: It's a super effective drug. And as an example, so here's a guy, this is a famous picture, stage four, fully metastasized cancer, and then four treatments later… and you see results like this where the cancer is gone again and again.

DeMarco: So, if actinium-225 is basically the Goldilocks of radioisotopes, why aren’t we using it to cure cancer left and right?

Horvath: We aren't making enough.

DeMarco: In today’s story we’ll get into just what makes actiniun-225 such a good cancer killer as well as how scientists are figuring out ways to make more of it. To do all that, we’ll dive headfirst into the world of alpha and beta particles as well as neutrons, and we’ll even take a very special trip to an actual nuclear reactor.

Doctors have used radiation to treat cancer since the discovery of X-rays. The physicist Wilhelm Conrad Röntgen discovered these new rays in November of 1895, and just a few months later, doctors had already begun using X-rays to treat patients with throat, cervical, and breast cancer.

Around the same time, the French physicist Henri Becquerel discovered that uranium salts spontaneously emit another new kind of radiation. Working in Paris, Marie Curie and her husband Pierre investigated this new phenomenon and gave it the name “radioactivity.”

Since those early days, scientists have optimized different kinds of radiation therapy for cancer. Today, doctors can treat cancer by exposing parts of a person’s body to an external beam of radiation, or they can deliver the radioactive treatment internally. Doctors can either place a solid vessel containing a radioactive substance near the tumor site, or they can inject the radiation therapy as a liquid that moves throughout a person’s bloodstream.

More recently, researchers have developed targeted radiotherapies that can bring a radioactive isotope directly to a person’s tumor. By encapsulating a radioactive isotope using a chelator and attaching that to an antibody or small molecule that targets a marker on the tumor surface, researchers can direct the destructive radiation directly to the cancer. Susan Moran, the Chief Medical Officer of the radiotherapy company RayzeBio, compared this treatment strategy to antibody drug conjugates.

Susan Moran: Those are an antibody that take a chemotherapy payload, so similar to that, we have a binder that's taking a radiation payload. The difference is that it's likely to be far less toxic with this radiation payload versus the chemotherapy payload and all the different side effects that you can get from that sort of a payload. It's just delivering this little radioisotope bomb to the tumor cell.

DeMarco: The targeted radiotherapies that doctors use in the clinic right now are beta emitters. This means that when these radioactive isotopes decay, they release beta particles, which are high energy electrons, if they’re negatively charged, or positrons, if they have a positive charge. The most common beta emitter in approved radiotherapies is the isotope lutetium-177.

Beta particles can travel a few millimeters to bombard cancer cells around them, but most human cells are only 20 to 30 micrometers long, meaning that beta particles can easily overshoot the cancer cells and potentially harm healthy cells nearby. 

As an alpha emitter, actinium-225 releases alpha particles, which are high energy helium nuclei — just two protons and two neutrons bound tightly together. Alpha particles cause more damage to tumor DNA than beta particles, and because they are much heavier than beta particles, they don’t travel as far in the body. So, targeted radiotherapies using actinium-225 are likely to have fewer off-target effects than those made with lutetium-177.

For these reasons, Moran and her team at RayzeBio decided to design a new targeted radiotherapy using actinium-225.

Moran: RYZ101 is our first therapy in the clinic. It's currently in Phase 3. So it's actinium dotatate. It shares the same binder and chelator as the other approved lutetium based therapy. We've just swapped out the beta emitting lutetium-177 for the alpha emitting actinium-225. 

DeMarco: The “tate” part of the dotatate molecule is what brings the actinium-225 directly to the tumor. This “tate” molecule binds to stomatostatin receptors, which are expressed on the surface of more than 90 percent of gastroenteropancreatic neuroendocrine tumors, which are also called GEP-NETs.

For people who have GEP-NETs, the first round of treatment is typically a drug called a somatostatin analogue. These molecules bind to somatostatin receptors on the tumors and inhibit their growth. But sometimes these drugs stop working or never work for some patients.

Moran: Then they can be treated with the lutetium-based radiopharmaceutical, and then if they have progression, following the lutetium-based therapy, there’s actually not any other approved agent. There’s nothing in the guidelines for those patients. So, we’re happy to be, you know, filling this really high unmet need now with this trial with actinium dotatate, treating these patients that have had progression following prior lutetium-based therapy.

DeMarco: In addition to providing a new way to treat these patients, actinium-225 radiotherapy is actually also much easier for doctors to administer than lutetium-177-based therapies. Because beta particles can act over a long range, patients receiving treatment with beta emitters often emit radiation themselves for a few days.

Moran: When we dosed our first patient, actually, the treating physician called me on my cell phone, and he was so excited. He said, “We have the Geiger counter out, and my staff is waving it around, and we're not picking up any radiation!” And he's like, “This is great. Can you put actinium on everything?” He said, "My staff has no exposure while they're administering it."

And the other thing was, his patient had had a lutetium-based therapy. And now with the actinium-based therapy, because the exposure is so little to others, she could have her husband sit in the room with her while she got her infusion. She was really excited for that, as well as she could leave and go straight away to visit her grandchildren and hold her new grandbaby, whereas when you receive lutetium-based therapy, there are some personal restrictions for about five days where, you know, you shouldn't ride public transportation; you shouldn't sleep in the same bed as your partner; you shouldn't be exposed to vulnerable populations. So, I'm not sure that I'd fully appreciated you know, all of the benefits of actinium until we dosed that first patient, and I got that excited phone call.

DeMarco: Since that first patient, Moran and her team have continued enrolling patients from around the world to test their actinium-225-based treatment.

Moran: Enrollment is going very well because there is this pent-up demand and unmet need. We anticipate that we'll have enrollment complete in early 2025, and then it's an event driven trial. The primary endpoint is progression free survival. We project that it will be approximately a year after we complete enrollment when we'll have an interim analysis, and we'll have data that hopefully would support a regulatory filing, assuming that it's positive.

DeMarco: While the RayzeBio team have enough actinium-225 to run their clinical trials, that’s not the case for most radiopharmaceutical companies or research teams. 

Horvath: There's 20 million or so patients diagnosed each year with cancer, 10 million deaths each year. In order to service that large of a population if you want to use an actinium-based treatment, you're talking about 10s of 1000s of Curies. And Curies, you can think of as mass. It's how active it is, but if you think of it as mass, it's a little bit easier. So after 30 years of trying, the global supply is at 1.7. So, we're a little ways off from that 10,000 Curie marker that's really gonna be needed to fight cancer aggressively.

DeMarco: To make actinium-225, or any radionuclide for that matter, researchers need a starting material — often called a target. Luckily for researchers, the nuclear program in the 1940s produced a lot of radioactive waste that makes perfect targets for actinium-225 production. 

Moran: Most actinium comes from decay of thorium, which comes from decay of uranium from old nuclear warheads, which I think it's pretty amazing from a reduce, reuse, recycle, taking some things for a warhead and then turning it into a therapy to treat cancer, I think is pretty amazing.

DeMarco: During the Cold War, the US government studied the radioactive isotope uranium-233 for its potential use as a nuclear weapon and as a source of nuclear energy. While it was never used as a weapon, the two tons of uranium-233 produced by the government will eventually decay. And when it does, it will turn into thorium-229, which then decays into radium-225, and finally into actinium-225.

The problem is that while thorium-229 is radioactive, it has an 8,000-year half life. This means that it decays into actinium-225 very, very slowly.

Valery Radchenko: Your thorium always keep decaying to actinium, and then every couple of months, you can just remove the actinium. And then thorium start accumulating actinium again, and you can use this actinium in the patient.

DeMarco: That’s Valery Radchenko, who is a research scientist at TRI-University Meson Facility or TRIUMF, Canada’s particle accelerator center. He told me that the other downside of using thorium-229 as a starting material is that, now that the Cold War is over, no one is making more uranium-233 or thorium-229.

Radchenko: It's not as available anymore as it was available when two countries try to build the stocks. So, it's only a small supply versus the demand, but this is the most developed source of actinium because this is going on for decades, right?.

DeMarco: While waiting for thorium-229 to decay into actinium-225 certainly works, researchers at the Department of Energy in the US, TRIUMF in Canda, and many other groups around the world have taken advantage of particle accelerators and nuclear reactors to make actinium-225 faster. Using these technologies also means that they can use other starting materials besides thorium-229.

One of these other methods is called thorium spallation. In this approach, scientists use a particle accelerator to shoot a high energy beam of protons at a thorium target.

Radchenko: In our case, we're using the thorium-232, so this is the quasi-stable isotope of thorium. So, you can have grams of thorium, place it in the beam, and then if you have energy of protons high enough MeV, you would actually start spallate your thorium, so practically, you fragment your thorium in different fragments, which would then result in different radionuclides, and some of this radionuclides will be actinium-225.

This is a very efficient way to produce actinium because you can produce pretty much, you know, amount that would cover all requirements for many clinical trials, but one limitation is that we not only produce actinium-225, we produce different actinium isotopes as well. One of the isotopes is actinium-227, which has a 21, almost 22 years half life. And then the question is, if you use the actinium-225, is great, you get a therapeutic effect, but 227 actinium would be doing exactly the same what your 225 actinium. So, it would be accumulating in the tumor. It would be then distributing in the patient body, but then it will take a while to be removed.

DeMarco: Because actinium-227 would persist way too long in a person’s body, using only thorium spallation won’t work as a method to produce pure actinium-225 for radiotherapies. Luckily, the team at TRIUMF came up with a solution.

Radchenko: We extract different isotopes. We extract actinium directly too, but then we also extract the radium isotopes. We isolate the radium and then keep it for a couple of days, a week, that it accumulate actinium. And then we remove the actinium from radium a couple of times over this period of time, and then provide it to the researchers or clinicians who need the pure actinium-225.

DeMarco: With both pros and cons to starting with a thorium target, many researchers look to the highly radioactive radium-226 to produce actinium-225. In one method, researchers can use a medical cyclotron to bombard radium-226 with protons to produce actinium-225. Medical cyclotrons are often in hospital settings and are much more accessible than TRIUMF’s high energy cyclotron.

Radchenko: So, you practically add the proton to your radium. And if the energy is high enough to kick out two neutrons, you would convert your radium to the actinium.

DeMarco: Instead of using protons, another method of converting radium-226 to actinium-225 uses photons.

Radchenko: You start with electrons. You convert them to the photons, and then this photons would be added to the radium, and that would be 225 radium instead of 226 as a target material. And then your 225 would decay to actinium 225. But now it's the question, can you do it at the large scale? 

DeMarco: Each of these four different methods of making actinium-225 has advantages and disadvantages. But, even if scientists were to make actinium-225 by all four of these different methods, they would still not make enough for all of the clinical trials that want to use it.

Radchenko: Rather than seeing what's the best method, we're trying now to join forces in some way to just make the best we can and produce it by all possible routes, and hope that we can supply as many clinical trials as possible to move this radionuclide towards the clinical application.

DeMarco: In fact, a new possible route is on the horizon. To learn more, I drove down to the University of California, Irvine where I met up with Horvath and his colleague Sarah Finkeldei, who is a nuclear chemist at UC Irvine and who collaborates with Serva Energy.

DeMarco at UC Irvine: Okay, we made it! Alright, let’s see.

DeMarco: From the outside, the building they took me to certainly didn’t look like it had a nuclear reactor sitting in its basement. But, as they escorted me through a series of elevators and secure doors, there it was.

I placed a dosimeter around my neck to record any potential radiation exposure and walked through the negative pressure door into the reactor room. With the lights switched off, an otherworldly glow of blue light emanated from the floor. I stepped up onto a metal grate, and looked down into the blue, almost misty depths of the nuclear reactor.

Horvath: It's this very ethereal, like very beautiful, deep blue. The metal that the reactor's made of becomes like partially translucent. It's really kind of a magnificent thing to observe. There's a gentle hum, that's from the pumps that are running to keep the reactor cool. The water is perfectly crystal clear because it has to be demineralized. So when you first fire it up, before you turn on the pumps, it's like a sheet of glass that's up on top when you look down on this thing.

DeMarco: To create actinium-225, Horvath and his team start with radium-226. But unlike the methods that Radchenko described, the scientists at Serva Energy use the high energy neutrons produced in a nuclear reactor to turn radium into actinium. Their approach takes advantage of some unique features of nuclear reactors.

Horvath: We have technologies for nuclear reactors that allow us to alter what's called the radiation spectra. When things get out of line, these materials activate and then shut that down, and it makes reactors run smoother, safer, more repeatably; they have less fuel damage, that kind of stuff. But we can also use materials in the exact opposite fashion. We can create little tiny pockets inside the reactor where we can shift the spectra in a different way, and so by doing so, that means that we can now make isotopes in a nuclear reactor that no one's ever been able to make before.

DeMarco: Horvath and his team spent about three months finalizing their approach, and when they were ready, they contacted the Department of Energy to see if they could get access to some radium-226 to try making actinium-225.

Horvath: We went to them, we're like, “Hey, we have a need for some radium-226. We feel pretty confident we have a new technique for making actinium-225 that can work really well, like really ramp up the production numbers.” Then eventually, they got us in touch with an administrator. When we talked to him, he's like, “Alright, let me see if I understand this correctly. We've been working on this problem for 30 years with the best scientific minds in the world with the best equipment in the world, and you're saying you found something that we missed?” I'm like, “Yes, that's precisely what we're telling you.”

Well, he's like, “Alright, fine. I'll give you a meeting with our technical guys. We'll see what they had to say.” We met with them. Within a half an hour, they're like, “Oh, that should actually work.” They agreed to ship us the radium material. That was in September of 2022. We received it at the end of February of last year, which as I understand is light speed for the Department of Energy. But we were very happy to get the material. We ran our first experiment on April 4th, and it was just to test the apparatus. We weren't trying to make a lot of actinium. We actually got a good amount of actinium coming out. Since that time, we've been running a number of irradiations, making a lot of improvements, and it looks like we can make a lot of actinium using these new materials.

We expect to start producing actinium on the pilot scale sometime in the next few months, which is very exciting. That pilot scale will produce actinium that will actually be large enough to get us patient doses, which is awesome.

DeMarco: One of the advantages of this approach is that it produces pure actinium-225. There is no actinium-227 contaminating the sample. One disadvantage, though, is how pricey radium-226 is to use as a starting material.

Horvath: DOE has gobs of the stuff. It's really expensive, though. And this is the part which it's like, well, wait a minute, guys. Let me see if I got this straight. You have radium-226, where if no one takes it, taxpayer money is gonna have to be used to pay to dispose of this and basically bury it in a deep underground geological area for 10s of 1000s of years to let it decay away. Or we can take it. Stick it in a nuclear reactor. Turn it into actinium-225. Give it to patients who have cancer, in many cases cure their cancer. It decays down to bismuth-209, which is the same thing you find in Pepto Bismol, and the patient poops it out. And it's inert. It's gone forever. And you want to charge us for it? So, it's like, there's something in your math that's a little off here.

How much do you think it costs for one gram of radium-226 from DOE? And I'll give you a starting point. I think gold right now today, so it's February 22, 2024. It's probably like $60 a gram. That's gold. How much do you think radium is going for?

DeMarco: Hmm like $200 a gram? I don't know. That's my guess.

Horvath: That's one of the better guesses, uh: 3.22 million. 

DeMarco: For 1 gram?!

Horvath: A gram.

DeMarco: No!

Horvath: And if we take it, we’ll destroy it. Now, it takes a very long time to destroy radium inside of a nuclear reactor. This is not something that happens quickly. But there is a portion of it that goes away forever.

DeMarco: While radium-226 is expensive, Horvath told me that it’s worth it for the amount of actinium they hope to produce using their new technologies. The Serva Energy researchers can’t wait to get their actinium-225 into clinicians’ and researchers’ hands.

Horvath: Because we're using existing infrastructure, just with our new converter technologies, that allows us to have a lot better with scaling. If we scale up the size of our radium targets, then we scale fairly linearly for the amount of actinium that we produce. 

Finding homes for where the actinium goes is proving to be remarkably easy. I've got a list as long as my arm of people that are like, “I'll buy as much as you can produce.” And it's like, “Okay, we plan on making a lot guys, so careful what you wish for.” We're not going to make large scale quantities this year. We're gonna make mili-Curies. But to go from mili-Curies to Curies per week is going to be fairly trivial, so in 2025, we should have pretty substantial production coming out, which is very exciting.

DeMarco: The Serva Energy team is not alone in ramping up production of actinium-225. Many other groups around the world are as well, but Horvath is happy that others are joining them in the actinium-225 space.

Horvath: We're rooting for them too. The more actinium that can make it out to the market quicker, the better the outcomes are for the patients. Everybody gets to win on this.

Moran: We are planning to manufacture our own actinium. We do have a manufacturing facility in Indianapolis, and by the end of the year, we actually will be making our own actinium-225 in our RayzeBio facility.

DeMarco: For Radchenko and his colleagues at TRIUMF, they’re already looking beyond actinium-225 for even better radioisotopes to treat cancer.

Radchenko: Even with actinium, if we would able to produce all actinium in the world that we need for all the clinical trials, I believe there would be still other alpha emitters or other radionuclides which would be developed down the line, which would be also more efficient, more selective. So, one of the direction I'm currently working on is to develop kind of next generation, what's next. Everybody was excited 10 years ago about lutetium-177. Now, it's a standard in the clinic. Now, everybody excited about actinium. But let's say, next 10 years, what will be the next?

DeMarco: For now, with more actinium-225 production underway, the prospect of using it to treat different types of cancer has researchers really excited. 

Moran: It's been super rewarding and satisfying, just working with this new therapeutic modality that people are excited about, that has a lot of potential to treat the tumor, but then less side effects because it really is just this radioisotope, and then the whole thing is excreted. There's just so much interest from the field. It's been really fun and really exciting and really rewarding to hopefully bring efficacious therapy now with patients with cancer.

Horvath: Everybody knows somebody that's affected by cancer. And so, it's like you move forward as quickly as you possibly can because this affects real people. And it's not just the impact directly for the patient. It's the families. It's everyone. And to have something that has the potential for doing this much good on this kind of scale. This kind of speed. Whoo, this sounds amazing! You gotta give it everything you have, absolutely everything you have.

DeMarco: That’s it for this episode of DDN Dialogues. Thank you so much to Ian Horvath, Susan Moran, and Valery Radchenko for talking with me. And thank you to Sarah Finkledei and the rest of the nuclear reactor laboratory at UC Irvine for hosting me. Of course, thanks to all of you for listening, and until next time, I’m your host Stephanie DeMarco.

This episode of DDN Dialogues was reported, written, and produced by me with additional audio editing by Jessica Smart. To never miss an episode, subscribe to DDN Dialogues wherever you get your podcasts. And if you like the show, please rate us five stars and leave a review on your favorite podcasting platform. If you’d like to get in touch, you can send me an email at sdemarco@drugdiscoverynews.com.

And if you’d like to see some photos from my visit to the nuclear reactor lab, please go to our podcast episode page at drugdiscoverynews.com to check those out. I’ll leave the link in the show notes. It was, I have to say, a pretty rad experience!

Read more about the making of this podcast here.

About the Author

  • Stephanie DeMarco, PhD Headshot

    Stephanie joined Drug Discovery News as an Assistant Editor in 2021. She earned her PhD from the University of California Los Angeles in 2019 and has written for Discover Magazine, Quanta Magazine, and the Los Angeles Times. As an assistant editor at DDN, she writes about how microbes influence health to how art can change the brain. When not writing, Stephanie enjoys tap dancing and perfecting her pasta carbonara recipe.

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