Breakthrough could lead to single molecular systems for both diagnosing and treating cancer in real time

Abergel Berkeley Lab

Katherine Shield (from left), Dahlia An, Tyler Bailey of Lawrence Berkeley National Laboratory on Tuesday, November 17, 2020 in Berkeley, California. Credit: Marilyn Sargent / Berkeley Lab

Scientists are recruiting new atomic heavyweights in a targeted fight against cancer.

A promising approach to cancer treatment – called targeted alpha particle therapy or TAT – could better harness the curative power of radiation treatments and reduce the severity of their more debilitating side effects.

TAT recruits drugs containing radioactive materials called alpha-emitting radioisotopes or radionuclides, combined with cell-targeting molecules such as antibodies. As alpha-emitting radioisotopes decay, they emit radiation in the form of high-energy particles called alpha particles. Cell-directed antibodies guide these alpha-emitting radioisotopes, like super-small guided missiles, to their final destination: cancer cells.

While interest in TAT has grown significantly in recent years, clinicians do not have a good method of monitoring whether these drugs hit their target once they enter a patient’s bloodstream. That’s because the gold standard for imaging in nuclear medicine – positron emission tomography, or PET – only detects positron-emitting radioisotopes and therefore cannot directly detect the alpha-emitting radioisotopes central to TAT.

Now a solution is in sight. A collaboration between researchers supported by the DOE Isotope Program at the Lawrence Berkeley National Laboratory (Berkeley Lab) of the U.S. Department of Energy and the Los Alamos National Laboratory (LANL) has led to the development of new methods for large-scale production, purification and use of the radioisotope cerium-134, which could serve as a tunable PET surrogate for imaging various alpha-emitting therapeutic isotopes.

Their findings, reported in the journal Nature Chemistry, also affect the use of a single molecular system for both diagnosis and targeted cancer treatment in real time.

“Our study demonstrates the power of designing small molecules that regulate the chemistry of metallic elements for various nuclear medicine applications,” said senior author Rebecca Abergel, a faculty scientist who leads the BioActinide Chemistry and Heavy Element Chemistry groups in the field. Chemical Sciences Division. at Berkeley Lab, and assistant professor of nuclear engineering at UC Berkeley. “But what’s even more exciting is that the recently demonstrated large-scale production of novel alpha-compatible PET imaging isotopes through the DOE Isotope Program can also serve as a roadmap to make targeted alpha-emitting therapies more widely available,” she added .

Switching off neutrons: Ringside with cerium-134

Ever since whole-body PET scanning was first developed in the 1970s, scientists around the world – including Berkeley Lab chemists and nuclear physicists, a driving force behind the rise and growth of nuclear medicine since the 1930s – have worked on ways to produce new radioisotopes for PET imaging and other medical applications.

In the 1990s, researchers proposed that cerium-134 – a radioisotope of cerium, an abundantly rare earth element – could be useful for PET. But proving that theory in practice has been challenging, because very few research institutions have direct access to multidisciplinary teams with expertise in radiochemistry, nuclear physics, nuclear data and medicine – the hallmarks of nuclear medicine.

In contrast, Berkeley Lab, with its rich heritage in nuclear medicine, nuclear physics and particle physics, has the resources, capabilities and infrastructure to work with radioisotopes and chemicals in biological systems, as well as to collaborate with large scientific teams and laboratories. , Abergel said.

“And what makes this such a great project is that it really is a collaboration between people from very different fields. It takes a lot of moving parts, ”she added, gaining early inspiration for revisiting the idea of ​​making cerium-134 based on an informal brainstorming session with co-author Jonathan Engle, a visiting nuclear physicist. at LANL at the time (now assistant professor at the University of Wisconsin, Madison); and Jim O’Neil, a radio chemist with Berkeley Lab’s Molecular Biophysics and Integrated Bioimaging Division, who died just before Abergel and her team received funding to carry out the work. (In recognition of O’Neil’s contributions to those formative discussions, Abergel and co-authors dedicated the article to O’Neil.)

To produce cerium-134, one must induce nuclear reactions by irradiating a naturally occurring stable element such as lanthanum, a neighbor of cerium in the periodic table. Abergel cites an initial study conducted at Berkeley Lab’s 88-inch Cyclotron and led by Lee Bernstein, head of Berkeley Lab’s Nuclear Data Group and a UC Berkeley associate professor of nuclear engineering, for insight into the best irradiation parameters for the greatest cerium-134 production possible . This effort was conducted in addition to a nuclear data study at Los Alamos Neutron Science Center’s Isotopic Production Facility (LANSCE) (IPF) to expand the available energy range that could be investigated and to investigate relevant production conditions.

At the IPF, a team led by co-author Etienne Vermeulen, a staff scientist at LANL, began the painstaking process of making cerium-134 from lanthanum by irradiating a sample of naturally occurring lanthanum with a 100 mega-electron-volt (MeV ) proton radius. The IPF is managed by the DOE Isotope Program which produces isotopes that are scarce for a range of applications including medical applications.

Bombarding lanthanum with this proton beam triggered a nuclear reaction that knocked out not just one, but ‘two, three, four, five, six neutrons’ and generated cerium-134 within the lanthanum target, said Stosh Kozimor, the LANL section’s lead investigator. of the project.

The irradiated lanthanum targets are wielded remotely in protective “hot cells”, behind 2 feet of stained glass. The radioisotopes are then processed and purified in the Los Alamos Radiochemistry Facility.

Manipulating metals with electrons

Purifying and separating cerium-134 from an irradiated lanthanum sample is much easier said than done. On the periodic table, cerium and lanthanum sit side by side in the heavy metal “f-block” – the lanthanides. And because cerium-134 has a very short half-life – or the amount of time it takes for half of the radioisotope to decay – of just 76 hours, such a procedure should be done quickly, Abergel said.

All lanthanides are large oxygen-loving atoms and are most stable in an oxidation state of +3, which means it can acquire three electrons to form a chemical bond.

And when lanthanides sit next to each other in a piece of rock, for example an oxygen-loving one atom likes to stick to the same molecular handle as the other oxygen-loving atom. “Separating adjacent lanthanides from each other is one of the most difficult separations in inorganic chemistry,” says Kozimor.

However, by removing one of cerium-134’s negatively charged electrons and thus changing the oxidation state from +3 to +4, you can easily separate cerium-134 from lanthanum and other impurities, which is how the team processed the irradiated lanthanum sample.

X-ray experiments conducted at the Stanford Synchrotron Radiation Laboratory of the SLAC National Accelerator Laboratory confirmed the final oxidation states of the material after processing.

The results of the separation and purification experiment – a high yield of over 80% – are astounding, Kozimor said, adding that the impressive result yields amounts of high-purity cerium-134 that several PET scans could deliver.

Demonstration of PET isotopes for alpha-emitting cancer therapies

Two promising targeted alpha-emitting therapies for prostate cancer and leukemia are the actinide isotopes actinium-225 and thorium-227. Actinium-225 has an oxidation state of + 3 and thorium-227 has an oxidation state of + 4 – these different chemistries cause them to adopt different biochemical behaviors and follow different pathways throughout the body.

To demonstrate companion PET isotopes for alpha-emitting therapies, the researchers matched the oxidation state of cerium-134 to either actinium-225’s +3 privileged state or thorium-227’s +4 state. Having the same oxidation state as alpha-emitting therapy would send cerium-134 to either actinium-225’s + 3 pathway, or thorium-227’s + 4 pathway to diseased cells before leaving the body, the scientists reasoned.

To this end, they encapsulated cerium-134 in metal-binding molecules called chelators. This was to prevent the radioactive metal from reacting randomly in the body, with the chelator maintaining the oxidation state of cerium-134 at +3 or +4.

PET scans of mouse models performed by Abergel and her team at Berkeley Lab showed that the chelators effectively maintained the tuned oxidation state of cerium-134. For example, cerium-134 radioisotopes attune to a stable oxidation state of +3 when bound to polyaminocarboxylate chelator DTPA and cleared through the kidney and urinary tract – the same route followed by the alpha-emitting therapy actinium-225.

In contrast, cerium-134 radioisotopes were tuned to a stable oxidation state of +4 when bound to HOPO, a hydroxypyridinonate chelator, and were eliminated from the body via the liver and fecal excretion, the scientists reported.

Encouraged by these early results, the researchers next plan to investigate methods for attaching cell-targeting antibodies to the chelated cerium-134, and to demonstrate the targeting of cancer cells in animal models for diagnostic and therapeutic medical applications.

If successful, their technique could revolutionize the way we treat cancer, Abergel said. Doctors could check in real time whether a patient is responding to alpha-emitting therapies such as actinium-225 or thorium-227, she said.

Their study could also help medical researchers develop personalized medicine, Kozimor added. “If you’re developing a new drug and you have a radionuclide that does PET imaging, you can use our technique to monitor how a patient responds to a new drug. To view your medicine in real time – that’s the new frontier. “

Reference: December 14, 2020, Nature Chemistry.
DOI: 10.1038 / s41557-020-00598-7

Co-authors with Abergel, Engle, Kozimor, and Vermeulen include lead author Tyler Bailey, Katherine Shield, Dahlia An, Stacey Gauny and Andrew Lakes of Berkeley Lab; and Veronika Mocko, Andrew Akin, Eva Birnbaum, Mark Brugh, Jason Cooley, Michael Fassbender, Meiring Nortier, Ellen O’Brien, Sara Thiemann and Frankie White from LANL.

The isotope production facility at LANL is operated by the DOE Isotope Program in the Office of Science.

The Stanford Synchrotron Radiation Lightsource (SSRL) is a DOE Office of Science User Facility at SLAC National Accelerator Laboratory (SLAC).

The research was supported by the DOE Office of Science.