February 22, 2024

This potential cancer treatment requires modern alchemy

In a part of the Los Alamos National Laboratory (LANL) that some call the Mesa, a beam of protons shoots through a mile-long tunnel across the New Mexico landscape. The particles are moving so fast that if they were not confined within the structure, they could orbit the Earth 2.5 times per second.

Five different facilities in the laboratory “sip” this beam and pull out the protons they need for various experiments. One of these, called the Isotope Production Facility, slams the protons into a stationary target. The protons settle in the target’s atoms and convert them into new elements.

The Isotope Production Facility is currently involved in a positive (pun intended) effort for the medical industry: producing a substance called actinium 225, an isotope with 89 protons and 136 neutrons. Isotopes are different forms of the same element with the same number of protons but different numbers of neutrons; the most common actinium isotope is 227, with two neutrons more than 225. Isotopes are radioactive when their nuclei are unstable, with a nervous combination of protons and neutrons, and they get rid of excess energy by emitting alpha, beta or gamma radiation . Actinium 225’s specific radioactivity is potentially powerful in the fight against prostate cancer, and studies on its effectiveness against other malignancies are in the works. Although many radioactive isotopes exist, actinium 225’s emission is strong enough to damage cancer cells without causing as much damage to healthy cells. And this isotope disappears in just the right amount of time, does its job and then decays.

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For years, scientists have produced this type of actinium by waiting for thorium (element 90, with one extra proton than actinium) to decay. But that method is slow and does not yield much at a time. If actinium 225 cancer treatments, currently in clinical trials, are approved by the U.S. Food and Drug Administration, the old way of doing things likely won’t meet demand.

Anticipating the potential need for actinium production to leap to new energy levels, the Department of Energy established a program in 2015 to develop new larger-batch production methods, involving LANL, Oak Ridge National Laboratory (ORNL) in Tennessee and Brookhaven National Laboratory were united. in upstate New York in the effort. Since then, the labs have been working steadily on the project, hoping to be ready when the medical industry is ready.

As actinium 225 decays, it emits radiation in the form of alpha particles (two protons and two neutrons bonded together). Kirk Rector, program director at LANL and laboratory point of contact for the Department of Energy’s Isotope Program, calls these particles “wrecking balls.” The energy they create is strong enough to break DNA strands like a lightsaber slicing through two jump ropes involved in a game of double dutch.

But alpha particles are heavy (at least for particles), so they don’t travel very far – as far as a few cells lined from membrane to membrane – meaning doctors can target radiation therapy to the right spot and minimize damage to the surrounding area. can limit tissue. . In addition, actinium 225 has a half-life of just under 10 days, so when placed in the body it contains sufficient time to reach the right cells, but not so much time that it becomes concentrated there, causing too much radioactivity to be released for too long.

The Hot Cell at the Los Alamos Neutron Science Center (LANSCE) Isotope Production Facility is used to load and unload targets into a beam of protons for irradiation. Credit: Courtesy of Los Alamos National Laboratory

However, to help the actinium not do any damage (or as little damage as possible), it needs an extra ingredient: something that makes it look for cancer cells and not healthy cells. Recently, researchers have developed FDA-approved treatments that can nestle into a molecule on the surface of prostate cancer cells and deliver radiation to the problem area.

“If it recognizes a prostate cancer cell, it sticks to it,” says Rector. “And it only sticks to those cells.” Now similar treatments are being developed with actinium 225 along for the ride. Such targeted drugs can deliver the radioactivity of that isotope exactly where it belongs to cause damage — like a “heat-seeking missile,” says Mitch Ferren, former deputy director of operations at the National Isotope Development Center. It is a form of a type of treatment called “targeted alpha therapy.”

About a dozen clinical trials have involved or are currently involved in actinium 225, testing treatments not only for prostate cancer, but also for conditions such as leukemia, solid tumors and carcinomas. The initial development of a targeted alpha compound with actinium 225, in 2013, “not only provided a new treatment option for prostate cancer, but also demonstrated the potential of the technology for the treatment of cancer in general,” says Alfred Morgenstern of the European Commission . The Commission’s Joint Research Centre, one of the few places where actinium 225 is currently produced.

Studies so far appear promising – and that promise has a long historical basis. Researchers have known for more than 30 years that actinium 225 would likely be useful for treating cancer, beginning with the publication of an article entitled “The Feasibility of 255Ac as a source of α-particles in radioimmunotherapy” in Nuclear medicine communication in 1993. Decades of research followed, but it was only after the compound was synthesized for targeted treatment that practical developments really started. Seeing that, the DOE stepped in to increase supply to meet future needs. “Demand has increased significantly and it is extremely important that new production facilities are put into operation quickly to alleviate the supply shortage,” says Morgenstern.

Currently, labs in Germany, Russia, and Canada are making this isotope, but most of Earth’s actinium 225 trickles from a stockpile of thorium 229 in the form of old nuclear waste living at ORNL. As this thorium ages, it decays into an isotope of radium, which then decays naturally to actinium 225. Strangely enough, everyone calls this “milking the thorium cow.” But the cow’s milk flow is low and there is not enough milk for the trials, let alone for the future treatments.

That’s why the DOE has initiated what it calls the Tri-Lab Effort (because of the three-way team of LANL, ORNL, and Brookhaven) to build a more golden cow, which produces actinium 225 in new ways.

“They started looking at different alternative routes,” said Karen Sikes, director of the National Isotope Development Center. But one stood out: shooting protons at targets made of thorium 232. Those protons that smash and stay in place create the right kind of actinium through a process called spallation. The Tri-Lab Effort has been working on the specific infrastructure and techniques to do this, using existing particle accelerators to create the shooting proton beams. It worked: the first batches were processed in 2018. In 2022, Tri-Lab researchers could produce more than six times as much as in 2018, although that is still likely a fraction of what the medical industry could ultimately demand. At LANL, initial work has begun on a new facility dedicated to the production of isotopes such as actinium 225. “This would allow us to dramatically scale up the amount we can make,” Rector says.

“What we are doing now is modern alchemy,” he proclaims. It’s a bit grandiose, but he’s not wrong: the basic idea of ​​alchemy is taking an element that is plentiful and cheap and converting it into something else that is rarer and more valuable. Previously, that meant pseudoscientific attempts to convert lead into gold using something often called a philosopher’s stone, which was said to contain the powers of the universe within its rockiness.

Nowadays that sounds crazy. But, says the rector, “we actually think they were right. We can carry out those transformations. They just had the wrong magic stone.” The modern magic stone is a particle accelerator, which changes the identity of atoms using fast protons. “We harness the forces of the universe to transform one element into another,” says Rector.

However, the actinium 225 made using this Tri-Lab method has a potential drawback compared to the thorium cow-made version: it is mixed with actinium 227 (which has two more neutrons), which cannot be easily separated from the desired isotope. “The advantage of the spallation process is that the target material thorium 232 is abundantly available and theoretically production can be increased more easily,” says Morgenstern. “However, the process requires expensive, large accelerators. And the actinium 225 product is contaminated with long-lived actinium 227, which causes problems in processing and disposal.”

To understand if and how that impurity affects supply, several tests may be needed. But that, too, is already in motion: The FDA accepted a “drug master file” in 2020 detailing the facilities and manufacturing processes for accelerator-based actinium.

When researchers or pharmaceutical companies want actinium 225 for their drugs, their orders can go through the National Isotope Development Center, a commercial arm of the DOE.

Some customers, like actinium 225 shoppers, are in the medical industry, but other isotopes go into atomic clocks, spacecraft, computers and oil and gas instruments. Rather than competing with the private sector, the center only sells isotopes that commercial industry does not produce in sufficient quantities or that have a production problem that needs to fill a gap. “What has certainly been a major effort in recent years is reducing our dependence on foreign supplies, particularly Russia and Ukraine,” says Rector, “and ensuring that the isotopes that we need and that are critical for industries like semiconductor manufacturing, or quantum computing are things that we have available in the United States.” Rector ensures that the right amount of the right isotopes are ready when needed, something the alchemists of the past could not achieve.

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