Radioactive metals for medicine get a boost from recently discovered protein

UNIVERSITY PARK, Pa. — A protein can be used to recover and purify radioactive metals such as actinium that could be beneficial for next-generation drugs used in cancer therapies and medical imaging, according to new research from Penn State and Lawrence Livermore National Laboratory (LLNL).

Radioactive metals are used in a variety of medical imaging and therapeutic applications. Actinium is a promising candidate for next-generation cancer therapies, and actinium-based therapies have treatment efficacy hundreds of times higher than current drugs. However, the chemistry of this metal is not well understood, and there are several limitations in the supply chain that have kept actinium-based drugs from reaching the market. 

“In this study, our team took advantage of a protein my lab previously discovered called lanmodulin and showed that it can be used to improve and simplify the recovery and purification of actinium,” said Joseph Cotruvo Jr., assistant professor of chemistry at Penn State and an author of the paper. The research team presents their results in a paper appearing Oct. 20 in the journal Science Advances.

Radioactive metals used in medical applications must be purified to extremely high levels through lengthy processes and, to minimize toxicity in the patient, they must form complexes with molecules called chelators that are tailored to bind the radioactive metal ions. The vast majority of these chelators are synthetic molecules that are arrived at through trial and error. In addition to these challenges, the actinium supply chain faces several difficulties. Actinium is extremely rare and must be produced in nuclear reactors or other large instruments, and knowledge of the element’s chemistry, which is necessary to develop optimal chelators, is limited.

“These challenges exist even for medical isotopes in relatively widespread use, such as radioactive yttrium, but they are even more taxing in the case of actinium,” said Gauthier Deblonde, a scientist at LLNL and lead author of the paper.

Because actinium is so rare, research efforts to understand and harness actinium chemistry have thus far focused on reusing or adapting similar known synthetic molecules used in the nuclear chemistry field, but results have been limited. The new research took a drastically different approach, leveraging the natural protein lanmodulin, which is exceptionally good at binding to valuable metals called rare Earth elements. This new strategy not only improves and simplifies the purification processes for actinium but can also be used to recover and detect other radioactive elements, even at extremely low levels.

The team showed how lanmodulin can be used to bind to, recover, and purify actinium (at least 99.5% purity obtained in a single step), as well as another medically relevant radioisotope, yttrium-90, which is used in cancer therapies and diagnostics. The unprecedented efficiency and simplicity of the protein-based approach also allows preparation of actinium at much lower cost and makes probing its chemistry more convenient. The process is likely extendable to many other radioactive isotopes used in radiation therapy and imaging.

“Our new technique represents a paradigm shift not just in the development of actinium chemistry and actinium-based pharmaceuticals, but also in nuclear medicine more generally,” said Cotruvo.

This study marks the first time actinium has been characterized bound to a protein — important knowledge if it may eventually be used inside humans. The researchers found that lanmodulin is so efficient compared to classic molecules that it specifically binds to actinium even in the presence of large quantities of impurities, like radium and strontium, or elements that are common in the body like calcium, zinc and copper. The study also demonstrates that the protein is more effective at binding actinium than binding rare earth elements, the metals it binds to in nature.

“Lanmodulin’s tight and specific binding allowed us to easily access minute quantities of radioactive metals, where traditional technologies based on synthetic chelators fail,” Deblonde said. “What we accomplished here was simply unfathomable a few years ago. The unique combination of skills in radiochemistry, metal separation, and biochemistry at LLNL and Penn State made this possible.”

The research not only offers insights into the fundamental chemistry of actinium but also suggests that the actinium-lanmodulin complex could be the basis for new actinium pharmaceuticals, as lanmodulin in some ways outperforms the synthetic chelators currently used with radioactive metals in the clinic and clinical trials.

“We believe that our results unify the fields of metal separations and biochemistry and have strong potential to revolutionize several critical steps in medicinal chemistry – from purifying isotopes to delivering therapeutic doses to patients,” Cotruvo said.

In addition to Cotruvo and Deblonde, the research team includes Joseph Mattocks, a graduate student at Penn State, and Ziye Dong, Paul Wooddy and Mavrik Zavarin at LLNL. The work is funded by LLNL’s Laboratory Directed Research and Development program and the Department of Energy Office of Science.