Researchers at the Paul Scherrer Institute (PSI) are using its large-scale research facility SINQ (Swiss Spallation Neutron Source) to produce radionuclides for medical research. Especially promising is the radioactive metal terbium-161. Coupled to a molecular complex, it docks selectively to tumour cells in the body and can destroy them with its particle radiation. With it, PSI researchers have developed a drug that should fight cancer more efficiently than the active agents used to date. An initial medical trial with patients is planned one year from now.
"We view terbium-161 as the therapeutic radionuclide of the future", says Nick van der Meulen, head of the Radionuclide Development group at PSI. Currently, there are radioactive drugs - so-called radiopharmaceuticals - that consist of a molecule coupled to a radionuclide. They are injected into the bloodstream of cancer patients. The specially developed radiopharmaceutical reaches the tumour in the body and attaches selectively to the cancer cells. The radiation can then unleash its destructive effect precisely. With terbium-161, the researchers at PSI hope they have found a radionuclide that is particularly well suited for this form of therapy.
Only the stable terbium 159 occurs in nature. Other forms of terbium, so-called isotopes, are unstable and usually decay within a few hours or days. The radioactive isotope terbium-161, for example, has the same number of protons in the nucleus as the stable isotope, but two additional neutrons, and it must be produced artificially. This requires neutrons, as generated in a nuclear reactor or in SINQ at PSI. "At SINQ we add neutrons to the atomic nuclei of stable isotopes and thereby make them unstable", explains Roger Schibli, head of the Center for Radiopharmaceutical Sciences at PSI and a professor at ETH Zurich. The unstable isotope thus produced, in turn, converts a neutron into a proton and simultaneously releases an electron, a process known technically as beta decay. "This electron can be used for cancer therapy", Schibli says. Depending on how much energy this electron has, it can travel shorter or longer distances. When it releases its energy, it can damage the genetic material DNA of the cancer cell or form radicals that have further destructive effects on cancer cells.
To the middle of the neutron source through pneumatic tubes
"The production of terbium-161 is a highlight at SINQ", says van der Meulen. But it comes by way of a roundabout path. The starting material is another related element: gadolinium, like terbium, a rare earth element. A few milligrams are sealed in an ampoule made of quartz glass, which is welded into an aluminium transport capsule. This capsule is automatically shot from the outside into the centre of SINQ through a short system of tubes. The transport system works like a pneumatic letter chute. In the centre, the capsule is irradiated with neutrons. When gadolinium-160 captures a neutron, gadolinium-161 is formed, but within minutes a neutron decays into a proton and a beta particle. Now the atomic nucleus contains one more proton, and a new element has formed: the desired terbium-161, which decays with a half-life of seven days.
Once the ampoule has been irradiated in SINQ for two to three weeks, it is transported to the radiochemistry laboratory as radioactive cargo in a special container. Here, the researchers must separate the desired terbium-161 from the gadolinium target material – a complicated task that takes place in a lead-shielded, so-called "hot cell" behind a lead-glass window. With externally-controlled manipulators, a researcher positions the irradiated material and operates small valves and pumps. "We have developed the apparatus and procedure ourselves here at PSI", van der Meulen says.
Plucking the needle from the haystack
The most important utensil used in this procedure is a 20-centimetre-long separation column that contains an ion exchange resin. Onto this drips the liquid in which the starting material is dissolved. The resin acts as a kind of filter for the elements gadolinium and terbium that are dissolved in the liquid. The one element – gadolinium – lingers longer on the resin, while the other, terbium, continues to flow through. This is how the two substances are separated. After a further purification step, a colourless solution is obtained that contains terbium-161 in such a pure form that it can be used to radioactively label molecules. "With this procedure, we separate the needle from the haystack", Schibli says.
Among experts, there is great interest in such radiopharmaceuticals that can irradiate tumours directly in the body. In the past two years, for example, Novartis has bought two companies, each of which is developing a radioactive drug, for several billion Swiss francs. One is used for the treatment of so-called neuroendocrine tumours. These usually occur in the stomach, intenstine, or pancreas. The other is to fight prostate cancer. Both drugs contain the radionuclide lutetium-177, which is clinically approved and has been in use to treat patients for some time. Like terbium, lutetium is a rare earth element. The two metals are quite similar chemically, but different in terms of their radioactive decay. In addition to the beta particle, terbium-161 also emits another type of electrons, which are especially well suited for therapy targeted at individual cancer cells.
Short path – major destruction
The beta particles are ejected directly out of the atomic nucleus during radioactive decay, when a neutron disintegrates into a proton and an electron. Additional electrons can also be released from the atomic shell of the radionuclides, however. This effect was discovered in the 1920s by the physicists Pierre Auger and Lise Meitner. Today the particles are called Auger electrons. Beta particles have a high energy, while Auger electrons are significantly less energetic. What may seem disadvantageous at first glance proves to be an advantage in fighting tumours. The beta particles (high-energy electrons) can “fly” a few millimetres in water, thus, penetrating a few cell diameters and causing damage over a large distance. Auger electrons, on the other hand, fly only a few micrometres. The energy that they release penetrates just one cell and, thus, works only there, with a much more destructive effect.
"If we can get close to the DNA, an Auger electron destroys it much more efficiently than a beta particle", Schibli says. While the yield of Auger electrons is relatively low for lutetium-177, it is much higher for terbium-161. That's why the PSI researchers are convinced they're on the right track. "We were the first to produce and do research with larger quantities of terbium-161", says van der Meulen – a pioneering achievement that has received international recognition. In 2018 Cristina Müller, a group leader at the Centre for Radiopharmaceutical Sciences, received the Marie Curie Award for her preclinical research on the application of terbium-161 in prostate cancer therapy. Now the researchers want to show that their radionuclide also works better in patients than the lutetium-177 already in use today. Supported by a research grant from the Boston-based Neuroendocrine Tumor Research Foundation, they plan to carry out an initial medical trial in late 2020 as part of a clinical feasibility study, in collaboration with a medical centre in Bad Berka, Germany.
Text: Barbara Vonarburg