A superior radionuclide for cancer treatment
Radioactive isotopes offer excellent treatments for cancers that have spread. The ILL is working with other institutions to produce and test a potentially new clinical radioisotope, terbium-161, that promises to be more effective in killing cancer cells than similar radioisotopes currently in clinical use.
Isotopes that emit short-range radiation in the form of electrons or alpha particles offer an ideal therapeutic tool, because they can deposit their energy in targeted cancer cells, breaking up their DNA and thus killing them. One beta-emitter, lutetium-177, is now successfully employed to treat various cancers.
An advantage of these radioisotopes is that they can reach cancers that have spread around the body. To seek out the cells, the isotope must first be attached to a biological ‘carrier’ molecule that preferentially binds to receptors found on the surfaces of cancer cells.
Theragnostics – a new approach
Today, there is growing interest in using one or more isotopes of the same element whose radiation characteristics enable diagnosis and therapy to be combined – theragnostics – to steer a more personalized and efficient treatment. One set of isotopes that shows promise are the four terbium ‘sisters’ (terbium-149, -152, -155 and -161). Terbium-161 is of particular interest because it emits both low-energy electrons suitable for radiotherapy and gamma-rays suitable for imaging. It has similar chemical properties to lutetium-177 but is potentially superior because it emits about twice as much short-range electrons for therapy.
We have been studying the potential clinical application of the terbium quartet for a decade, but – as for any new medical product – the research path from pre-clinical studies using tumour cells, through small-animal investigations, to clinical application is long and laborious. A required pre-condition is that the isotope must be very pure and its production highly reproducible. Our team has now demonstrated these requirements for terbium-161. It is made by irradiating a gadolinium-160 target with neutrons to generate gadolinium-161 (a neutron is captured); this is then decaying into terbium-161 (the neutron converts into a proton and an electron is emitted as beta radiation). The process was carried out using the ILL’s reactor but was repeated in other research reactors. The terbium isotope must then be chemically separated from the gadolinium. This was achieved with high purity in a process established at the Paul Scherrer Institut (PSI) in Villigen, Switzerland.
While the elements of the Periodic Table are defined by the number of protons in their nuclei, each element exists in several forms called isotopes that have differing numbers of neutrons. Some isotopes are unstable, emitting radiation as subatomic particles – helium nuclei (alpha radiation) electrons and positrons (beta radiation) – and also gamma-rays (high-energy electromagnetic radiation).
Many such radioisotopes have important applications including in hospitals to diagnose and treat a range of cancers. A gamma-ray-emitting isotope can provide an image of selected tissues after injection, using a special gamma-ray camera.
A gamma-ray image, 19 hours after terbium-161-DOTATOC was injected, showing its uptake in cancer cells in the liver (Li) (yellow arrows), as well as those spread to the spine and pelvis (red arrows). The excess radiopharmaceutical was eliminated via the kidneys (Ki) and bladder.
Credits: R. P. Baum et al., J. Nucl. Med., 2021, 61, 1391.
This work has opened up the path towards the first use of terbium-161 in humans. A peptide known to target neuroendocrine tumours, DOTATOC, was bound to terbium-161 to create a radiopharmaceutical whose distribution in the body could be followed over time (see the images above). It allowed us to collect the data needed to calculate the correct dose of the radiopharmaceutical. The data confirmed the expected tissue distribution, and showed that it was well tolerated with no adverse effects.
We have now been working on extending the terbium-based therapy to several tumour types, as well as comparing its effectiveness with that using lutetium-177. We used a different carrier molecule, PSMA-617, which targets prostate cancer cells. The data showed that terbium-161 clearly outperformed lutetium-177, both in cell cultures and in the body.
To find out where exactly in a cancer cell the electron radiation is most effective, the terbium and lutetium isotopes were bound to three different peptides that target neuroendocrine tumour cells. The DOTATOC carrier accumulates mainly in the cytoplasm, DOTATOC-NLS in the cell’s nucleus, and DOTA-LM3 in the cell membrane. Terbium-161 outperformed lutetium-177 in all cases. In terms of killing tumour cells at the lowest possible levels of radioactivity, DOTA-LM3 worked the best.
We will now obtain similar data for other tumour cell-types and carrier molecules. A clinical trial studying terbium-161-DOTA-LM3 will start this year. The ILL and PSI will play a key role in supplying terbium-161 for further preclinical and clinical research.
Article from:
J. Nucl. Med., (2021); doi: 10.2967/jnumed.120.258376.
Eur. J. Nucl. Med. Mol. Imaging, (2021); doi: 10.1007/s00259-021-05564-0.
References:
[1] C. Müller et al., ILL Annual Report, 2012, 80.
[2] N. Gracheva et al., EJNMMI Radiopharm. Chem., 2019, 4, 12.
[3] R. P. Baum et al., J. Nucl. Med., 2021, 61, 1391.
[4] C. Müller et al., Eur. J. Nucl. Med. Mol. Imaging, 2019, 46, 1919
[5] F. Borgna et al. Eur. J. Nucl. Med. Mol. Imaging. 2021, 49, 1113.
[6] J. P. Pouget et al. Radiat. Res., 2008, 170, 192.
ILL Instrument: the V4 high flux position for neutron irradiation.
Contact: Cristina Müller (Paul Scherrer Institute)
ILL contact: Ulli Köster