The 2019 SCINEMA Science International Film Festival short film The Rarest Drug on Earth follows the efforts of TRIUMF’s (Canada’s particle physics laboratory) efforts to produce a rare radioactive isotope, actinium-225, for use as a radiopharmaceutical that could revolutionise the way we treat cancer.

But how does it work and why is it so rare? We catch up on how the efforts for its clinical applications are going now, a couple of years after the film was made.

What is a radiopharmaceutical?

Radiopharmaceuticals are a group of drugs that use radiation to provide diagnostic information about how specific organs are functioning, and for the treatment of certain kinds of cancer and other diseases.

Diagram of a radiopharmaceutical showing it's components: the radioactive compound, linker, targeting molecule. And the protein target on a cancer cell.
Radiopharmaceuticals consist of a radioactive molecule, a targeting molecule, and a linker that joins the two. Credit: National Cancer Institute

They contain radioactive isotopes (also called radioisotopes), a type of atomic isotope that is unstable and spontaneously emits ionising radiation to release excess energy in the form of alpha, beta, and gamma rays.

This process is called radioactive decay and is measured with a time-period called a half-life. This is the time it takes for half of the atoms in any given sample to decay away and is unique to each radioisotope.

The radioisotope is attached to a molecule that allows it to accumulate in a specific organ or tumour tissue. When it decays it gives off radiation and it is the strength of that radiation, as well as the half-life of the radioisotope, that influences the kinds of applications for which it can be used.

For example: a radioisotope with a short half-life (in the realm of hours) and which emits weak radiation is ideal for imaging organs without delivering a significant radiation dose to the patient.

One with a longer half-life (measured in days) and higher energy decay can be used to treat cancer. This is what a new field of research – targeted alpha therapy (TAT) – is based on.

How does targeted alpha therapy work?

Alpha particles – which include two protons and two neutrons – are emitted from the nucleus of a decaying radioisotope. Slower and heavier compared to the other forms of radiation, they can’t penetrate very far through biological tissue. But that’s what makes them so useful.

Alpha-emitting isotopes are promising for cancer treatment because of this short path length – typically only the range of a few cell diameters – and its high energy transfer. The radiation is so powerful that it can tear apart DNA, killing cancerous cells.

Obviously, we don’t want that alpha radiation tearing apart any old cell’s DNA. By attaching the radioisotope onto a biological molecule – for instance an antibody that will specifically seek out and bind to receptors only found on cancerous cells – the radioisotope can be delivered directly and specifically to cancer cells.

Once there, the short path length of the radiation makes sure that it only kills the cancerous cells without also effecting close-by healthy tissue.

But you can’t just choose any alpha-radiation-emitting radioactive isotope and expect it to work; some leave behind poisonous bi-products, some can’t be attached to a drug molecule, or decay too quickly before they reach a cancerous cell.

This is where actinium-225 – the subject of The Rarest Drug on Earth – comes in.

Actinium-225 (Ac-225): the rarest drug

Discovered in 1947 simultaneously by two different research teams, Ac-225 undergoes alpha decay with a half-life of 10 days.

This is long enough for it to be incorporated into a radiopharmaceutical, have time to circulate in the body, and collect in target areas, but short enough that it doesn’t hang around in the body for months and decays to stable products without adverse consequences.

The first indications that Ac-225 had potential as a cancer treatment came in 1993, although it wasn’t until 2014 that it was shown to have remarkable clinical results in late-stage, metastatic castrate-resistant prostate cancer patients.

It’s been used in other clinical research since then, but there’s just one problem – it’s extremely rare, which has restricted the amount of research that can be done with it.

For decades most Ac-225 had come in tiny amounts scavenged from the decay of thorium-229, a byproduct of nuclear programs in the 1940s and 50s.

But as global demand grew, scientists figured out that they could also produce it with the use of particle accelerators called cyclotrons. These send extremely fast-moving protons at a sheet of thorium, blasting atoms apart, with one of the hundreds of different products being Ac-225.

The more Ac-225 that can be made, the more clinical research can be done with it.

The future of actinium-225 in radiopharmaceuticals

Since the 2019 film there have been a few more developments in the world of actinium-225, however, there’s still not a US Food and Drug Administration-approved treatment – yet.

However, the FDA has accepted the Drug Master File (DMF) for Ac-225 – important because this is required for any active pharmaceutical ingredient before any products that contain the ingredient can be approved.

TRIUMF, shown in the film, announced a research partnership with Fusion Pharmaceuticals in December 2020 to increase the availability of cyclotron-produced Ac-225 for clinical research. More recently they announced their nomination of a TAT candidate under a partnership with AstraZeneca, using Ac-225 attached to a cancer specific antibody, and intent to commence Phase 1 clinical trials.

Of course, there are other clinical trials currently underway. It’s crucial that more are conducted to show that TAT therapy using Ac-225 can be safe and effective in humans before it can be approved as a cancer treatment. So far, a phase III clinical trial – the gold standard for approving a drug intervention – has not yet been completed.

Another year of SCINEMA is drawing closer – keep your eye out for more announcements.

Film submissions for this year’s festival close 31 January.




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