Using Targeted Alpha-Particle Therapy To Treat Cancer

A promising approach to treating cancer - called targeted alpha-particle therapy or TAT - could better harness the curative power of radiation treatments and lessen 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 like antibodies. As alpha-emitting radioisotopes decay, they emit radiation in the form of highly energetic particles called alpha particles. Cell-targeting antibodies guide these alpha-emitting radioisotopes, like super-tiny guided missiles, to their final destination: cancer cells.

While interest in TAT has been steeply growing in the past years, clinicians do not have a good method for monitoring whether these drugs actually hit their target once they've entered 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 can't 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 in the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) and Los Alamos National Laboratory (LANL) has led to the development of new methods for the large-scale production, purification, and use of the radioisotope cerium-134, which could serve as a tunable PET imaging surrogate for several alpha-emitting therapeutic isotopes.

Their findings, reported in the journal 9Nature Chemistry, also have implications for the use of a single molecular system for both the diagnosis and targeted treatment of cancer in real time.

"Our study demonstrates the power of designing small molecules that will control the chemistry of metallic elements for different applications in nuclear medicine," said senior author Rebecca Abergel, a faculty scientist who leads the BioActinide Chemistry and Heavy Element Chemistry groups in the Chemical Sciences Division at Berkeley Lab, and Assistant Professor in nuclear engineering at UC Berkeley. "But what's even more exciting is that the newly demonstrated large-scale production of new alpha-compatible PET-imaging isotopes through the DOE Isotope Program may also serve as a roadmap for making targeted alpha-emitting therapies more widely available," she added.

Knocking out neutrons: Ringside with cerium-134

Ever since whole-body PET scanning was first developed in the 1970s, scientists all over the world - including chemists and nuclear physicists at Berkeley Lab, a driving force in the emergence and growth of nuclear medicine since the 1930s - have been working 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 abundant, rare earth element - could be useful for PET. But proving that theory in practice has been a challenge, because very few research institutions have ready access to multidisciplinary teams with expertise in radiochemistry, nuclear physics, nuclear data, and medicine - the hallmarks of nuclear medicine.

Berkeley Lab, on the other hand, with its rich legacy in nuclear medicine, nuclear physics, and particle physics, has the resources, capabilities, and infrastructure to work with radioisotopes and chemicals in biological systems, and to collaborate with big scientific teams and laboratories, Abergel said.

"And what makes this such a beautiful project is that it is truly a collaboration between people from very different fields. It takes a lot of moving parts," she added, citing early inspiration for revisiting the idea of making cerium-134 from an informal brainstorming session with co-author Jonathan Engle, a nuclear physicist visiting from LANL at the time (now an assistant professor at the University of Wisconsin, Madison); and Jim O'Neil, a radiochemist in Berkeley Lab's Molecular Biophysics and Integrated Bioimaging Division who passed away just before Abergel and her team received funding to perform the work. (In recognition of O'Neil's contributions to those formative discussions, Abergel and co-authors dedicated the paper 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 credits an initial study performed 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 largest cerium-134 production possible. This effort was conducted alongside a nuclear data study at the Los Alamos Neutron Science Center (LANSCE) Isotope Production Facility (IPF) to expand the available energy range that could be investigated and to explore relevant production conditions.

At the IPF, a team led by co-author Etienne Vermeulen, a staff scientist at LANL, began the arduous process of making cerium-134 from lanthanum by irradiating a sample of naturally occurring lanthanum with a 100 mega-electron-volt (MeV) proton beam. The IPF is stewarded by the DOE Isotope Program that produces isotopes in short supply for a suite of applications, including medical applications.

Bombarding lanthanum with this proton beam generated 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 principal investigator for the LANL portion of the project.

The irradiated lanthanum targets are remotely handled inside protective "hot cells," behind two feet of leaded glass. The radioisotopes are then processed and purified at the Los Alamos Radiochemistry Facility.

Reference: Bailey TA, Mocko V, Shield KM, et al. Developing the ¹³⁴Ce and ¹³⁴La pair as companion positron emission tomography diagnostic isotopes for ²²⁵Ac and ²²⁷Th radiotherapeutics. Nat. Chem. 2020. doi:10.1038/s41557-020-00598-7

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