Accelerating access to an elusive medical isotope
Supplies of Ac-225 — a potential cancer-fighting isotope — are so scarce doctors have to scavenge decades-old nuclear weapons to produce it.
By Andrew Robertson, University of British Columbia PhD Candidate in Physics and TRIUMF Science Ambassador
When you think of people working in health care, you think of doctors and nurses. Maybe you also think of a chemist working to develop new drugs. Physicists usually don’t come to mind.
I first studied physics because of an intense curiosity about how the universe works, sparked by books by Stephen Hawking and Carl Sagan. Big ideas like black holes, relativity and quantum mechanics were things I felt compelled to know more about. But it was a desire to directly help people that made me apply my love of of physics to health care.
The research I conduct as part of my PhD takes place at TRIUMF, one of UBC campus’s coolest hidden gems. TRIUMF, Canada’s particle accelerator centre, uses the largest cyclotron in the world to accelerate protons to 75 per cent of the speed of light and slam them into things. These collisions allow scientists to study everything from the smallest building blocks of matter to large astrophysical processes. But TRIUMF’s cyclotron can also assist us with cutting-edge medicine.
My work focuses on the production of actinium-225 (Ac-225), an isotope that emits alpha radiation and can be used in an emerging type of cancer treatment called targeted alpha therapy.
Targeted alpha therapy drugs combine a radioactive isotope with a biological molecule that, when injected into the body, selectively seeks out and binds to the surface of cancer cells. Think of it as a homing missile for cancerous cells. This radioactive drug emits alpha radiation, a type of radiation so destructive that it kills all the cells it passes through. Luckily however, alpha radiation only travels a distance less than the width of a hair. By combining actinium with a cancer-seeking compound, we can create a drug that delivers a radioactive payload directly to cancer cells. Once there, the high toxicity and short range of alpha radiation kill cancer cells with minimal harm to surrounding healthy tissue.
At least, that’s the idea behind targeted alpha therapy. Medicine, of course, isn’t quite that simple. It is crucial that controlled clinical trials are conducted before definitive claims can be made about the efficacy of any new treatment. And for targeted alpha therapy and Ac-225, we aren’t there yet. The drug isn’t approved. Nor has it completed a stage III clinical trial, the gold standard.
The main reason these drugs are so poorly studied is the limited availability of the Ac-225 isotope itself. Currently, there is only enough Ac-225 produced in the world — mostly derived from decades-old nuclear weapons material — to treat a few thousand patients a year.
This scarcity makes the isotope prohibitively expensive for academic researchers. It also makes conducting large-scale research and bringing any Ac-225 drug to market very challenging.
My research efforts fell victim to this scarcity. The first year of my PhD was spent on a series of planned experiments that failed because we never had enough Ac-225 to work with. So I decided to focus on producing Ac-225 at scale with a particle accelerator. I figured if we helped make Ac-225 more available, other researchers could use it to test if targeted alpha therapy could work.
About a year and a half into my PhD I saw an image that not only made my jaw drop, but also changed the way I think about my efforts to produce Ac-225. This image had two PET scans in it. The first showed a PET image of a patient in his 70s with stage 4 terminal prostate cancer that had spread through much of his body. After he failed to respond to conventional treatments, his doctors gave him an experimental drug containing Ac-225 bound to a peptide called PSMA-617. PSMA-617 attaches to the prostate-specific membrane antigen found on the surface of prostate cancer cells. The second PET scan in the image showed the same patient nine months after receiving Ac-225. All of his bone metastases had completely disappeared.
This was the first time I realized the true potential of what I was working on. No longer did targeted alpha therapy seem like something that might work someday, nor did TRIUMF-produced Ac-225 seem like something researchers and clinicians might want. Now those were near certainties.
As much as scientists don’t like to put too much stock into a single result, it was impossible to ignore that this was something that clearly benefited this patient immensely and had the potential to benefit others. Since then, our work has demonstrated that TRIUMF can produce Ac-225 in clinically relevant quantities.
The first step in producing Ac-225 is to accelerate a protons to 75 per cent the speed of light (224,844 km per second) and shoot them at a piece of thorium, a slightly radioactive but naturally occurring metal. The collision blasts the large thorium nucleus into a large variety of smaller nuclei that encompasses nearly every element on the periodic table lighter than thorium. Somewhere in the radioactive aftermath of these collisions is Ac-225.
The challenge is separating it from the thorium and all the other radioactive elements.
To purify the Ac-225, all our chemistry has to be done inside a hot cell, an enclosure that allows us to remotely work on radioactive materials without being exposed to any radiation. Inside the hot cell, we dissolve our thorium in acid, and one 16-hour chemical process later, we have a purified Ac-225 product that can be attached to cancer-targeting biomolecules.
Our research provides proof of concept that, when scaled up, TRIUMF has the potential to be one of the largest Ac-225 suppliers in the world. Other suppliers — some who have been using similar methods — are likely to play a part too. The wide-spread use of any Ac-225 pharmaceutical could only be reliably enabled by a robust supply chain that doesn’t depend on a single supplier.
I feel incredibly fortunate that my PhD at UBC has allowed me to be part of such interesting and inspiring research with so much potential.