A Novel Tracking System May Improve Our Understanding of Targeted Alpha Therapy

In targeted alpha therapy (TαT), radioactive isotopes emit high-energy alpha particles that can destroy cancer cells with extreme precision while largely sparing healthy tissues. Actinium-225 (Ac-225) is one of the most intensively studied radionuclides—a kind of “in vivo nanogenerator” that produces a cascade of short-lived but highly radioactive daughter nuclides within the body. The problem is that these atoms do not always remain at the intended target site. In fact, they may travel to other parts of the body, where they can cause unexpected toxic effects. 

Two of these radioactive daughter nuclides—francium-221 (Fr-221) and bismuth-213 (Bi-213)—are particularly noteworthy. While Bi-213 has already been used in clinical studies, Fr-221 has until now remained virtually invisible. Its extremely short half-life of just under five minutes and high chemical reactivity have made it nearly impossible to study in living systems. A research team has now achieved a breakthrough in this area. 

A novel Ac-225/Fr-221 radionuclide generator system has been tested by researchers from Bayer, the German Cancer Research Center (DKFZ), and the HUN-REN Centre for Energy Research. Their findings were published in the European Journal of Nuclear Medicine and Molecular Imaging. Using a specialised resin (LN2) and a mildly acidic, biocompatible eluent, the researchers successfully produced Fr-221 in a form suitable for direct injection into live mice. This technical advance enabled, for the first time, detailed in vivo tracking of Fr-221 and its daughter nuclide Bi-213 throughout the body. 

The results were striking. In tumour-bearing mice, Fr-221 rapidly accumulated in high amounts in the kidneys, salivary glands, and both the small and large intestines, while it was barely detectable in the bloodstream just five minutes after injection. In contrast, Bi-213 showed predominant uptake in the kidneys and liver, with a partially overlapping but clearly distinct biodistribution pattern. These findings support earlier hypotheses that daughter nuclides of Ac-225 actively redistribute within the body and may contribute to the side effects observed during alpha therapy. 

This phenomenon is rooted in the laws of nuclear physics: the nuclear recoil effect is a unique and challenging characteristic of alpha-emitting radionuclides. Free atoms released during this process are carried through the bloodstream to other organs—often ones that were not initially targeted. 

According to the researchers, understanding the redistribution of daughter nuclides within the body is essential for the development of safer and more effective therapeutic approaches. Mapping their biodistribution patterns supports dose estimation, improves pharmacokinetic modelling, and may also contribute to the design of novel strategies. 

This study provides a previously missing link in understanding the mechanism of action of alpha therapy. By examining the biodistribution of Fr-221—which was previously untraceable—a more complete picture is now emerging of what happens in the body during Ac-225–based treatment. While the current findings are based on animal studies, this work represents an important step toward precision-guided radiotherapy—where not only the “bullets,” but also the “shrapnel,” can be tracked and controlled.