Research

Silver-111-labelled theranostic radiopharmaceuticals for CCK2R-expressing tumours – THERA.SI

Code:

J7-70266

Range:

01. March 2026 - 28. February 2029

Range:

0.90 FTE

Leader:

Marko Anderluh

Field:

1.09 Pharmacy

Abstract:

With 19.3 million new cases identified and 10 million cancer deaths reported in 2020, these diseases call for continued development and improvement of patient treatments, especially for malignancies that lack diagnostic and treatment options, like cholecystokinin receptor (CCK2R)-positive cancers. A promising and arising tool that has proven to be particularly effective in these cases, is a targeted radionuclide therapy, which is currently more or less limited to the use of 177Lu‑labelled radiopharmaceuticals. 177Lu can be produced with sufficient quality and purity only from isotopically enriched 176Yb, whose production and supply are limited and unreliable as it is produced only in Russia. Together with the growing potential of personalized medicine, radiopharmaceuticals with different therapeutic properties, which would contribute towards the management tailored to specific patient needs, are widely explored. An alternative radionuclide of high interest is silver-111, which can be produced from palladium with natural isotopic abundance, making it potentially much more sustainable to produce. Therefore, the proposed project addresses the development of novel radiopharmaceuticals based on silver-111 for use in theranostics of CCK2R-expressing tumours. For these purposes, protocols for silver-111 production with a nuclear reactor and subsequent purification to reach carrier-free form with sufficient radionuclidic and chemical purity suitable for radiolabelling will be developed. Simultaneously, novel antagonistic ligands for CCK2R will be designed, synthesized, optimized and evaluated. Finally, the most promising binding ligands will be radiolabelled with silver-111, tested in in vitro preclinical studies to determine their cytotoxic potential, receptor binding, and internalization rates on cell lines and compared to the 177Lu-labelled counterparts.

The project will be executed with the collaboration of three partners with complementary expertise. Jožef Stefan Institute will develop production and purification protocols for radionuclides of interest. The University of Ljubljana, Faculty of Pharmacy will synthesize binding ligands suitable for radiolabelling, while the University Medical Centre Ljubljana will perform the radiolabelling experiments and in vitro preclinical evaluation.

The project will foster green transition by developing protocols and procedures to produce medical radionuclides in small research nuclear reactors in the vicinity of medical centres. Currently, medical radionuclides are produced in only a handful of large research nuclear reactors worldwide, which implies demanding logistics, often involving air transport to medical centres. In addition, such production seems to be unsustainable as at the end of 2022 we were faced with a global shortage of the most important medical radionuclides like molybdenum-99, iodine-131 and lutetium-177, which affected the treatment protocols of many cancer patients. With the development of medical radionuclide production on small reactors, demanding logistics will be omitted, which will enable both green transition and improve the sustainability of radionuclide production.