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 various medical and therapeutic imaging applications. Actinium is a promising candidate for next-generation cancer therapies, and actinium-based therapies have therapeutic efficacy hundreds of times that of current drugs. However, the chemistry of this metal is not well understood, and there are several limitations in the supply chain that have prevented actinium-based drugs from reaching the market.
“In this study, our team took advantage of a protein that 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 article. The research team presents its results in an article published on October 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 which are designed to bind radioactive metal ions. The vast majority of these chelators are synthetic molecules obtained through trial and error. In addition to these challenges, the actinium supply chain faces several challenges. Actinium is extremely rare and must be produced in nuclear reactors or other large instruments, and knowledge of the chemistry of the element, which is necessary to develop optimal chelators, is limited.
“These challenges exist even for relatively widely used medical isotopes, such as radioactive yttrium, but they are even more painful in the case of actinium,” said Gauthier Deblonde, scientist at LLNL and lead author of the ‘article.
Because actinium is so rare, research efforts to understand and exploit the chemistry of actinium have so far focused on the reuse or adaptation of similar known synthetic molecules used in the field of nuclear chemistry. , but the results were limited. The new research has taken a radically different approach, taking advantage of the natural protein lanmodulin, which is exceptionally good at binding to precious metals called rare earth elements. This new strategy not only improves and simplifies the actinium purification processes, 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 achieved in one step), as well as another medically relevant radioisotope, l ‘yttrium-90, which is used in cancer therapy and diagnosis. . The unprecedented efficiency and simplicity of the protein-based approach also allows the preparation of actinium at a much lower cost and makes the research of its chemistry more convenient. The process is probably scalable to many other radioactive isotopes used in radiation therapy and imaging.
“Our new technique represents a paradigm shift not only in the development of actinium chemistry and actinium-based pharmaceuticals, but also in nuclear medicine more generally,” Cotruvo said.
This study marks the first time that actinium has been characterized as bound to a protein – important knowledge if it could possibly be used in humans. Researchers have found that lanmodulin is so effective compared to conventional molecules that it binds specifically to actinium even in the presence of large amounts of impurities, such as radium and strontium, or common elements in it. organism such as calcium, zinc and copper. The study also shows that the protein is more efficient at binding actinium than rare earth elements, the metals to which it binds in nature.
“The tight and specific binding of lanmodulin has given us easy access to minute amounts of radioactive metals, where traditional technologies based on synthetic chelators fail,” Deblonde said. âWhat we accomplished here was just unfathomable a few years ago. The unique combination of radiochemistry, metal separation, and biochemistry skills at LLNL and Penn State made this possible. “
The research not only offers insight into the basic chemistry of actinium, but also suggests that the actinium-lanmodulin complex may be the basis for new actinium-based pharmaceuticals, as lanmodulin in some ways outperforms currently synthetic chelators. used with radioactive metals in clinic and clinical trials. .
“We believe our results unify the fields of metal separation and biochemistry and have great potential to revolutionize several critical steps in medicinal chemistry – from isotope purification to the delivery of therapeutic doses to patients,” said said Cotruvo.
In addition to Cotruvo and Deblonde, the research team includes Joseph Mattocks, graduate student at Penn State, and Ziye Dong, Paul Wooddy, and Mavrik Zavarin at LLNL. The work is funded by the laboratory-led research and development program of LLNL and the Department of Energy Office of Science.