Incomplete eradication of residual tumor cells and/or acquired drug resistance against conventional therapies dramatically affect morbidity and mortality of cancer patients. A potential solution could be targeted a-radionuclide therapy (TAT). TAT has the ability to specifically kill isolated cancer cells, and causes little damage to healthy cells, because TAT induces internal radiation using lethal short-range alpha particles. To be successful, the radionuclide that produces such a-particles has to be linked to a targeting molecule, to ensure that this therapeutic agent is only delivered to the tumor cells. In this study, we will exploit the unique combination of the a-particle emitter 213Bi and nanobodies. Nanobodies have been successfully used by the In Vivo Cellular and Molecular Imaging (ICMI) research group of the Vrije Universiteit Brussel (VUB) for both nuclear imaging (1)(2) and targeted therapy (3)(4)(5). Nanobodies could be particularly suited for TAT because of their exceptional binding potential to extracellular targets and fast clearance from healthy tissues. Recently a first clinical trial was completed at the UZ Brussel, evaluating a 68Ga-labeled anti-HER2 nanobody for the detection of HER2 positive tumor lesions in breast cancer patients (6). In the past, the same anti-HER2 nanobody, but radiolabeled with 177Lu has been successfully used as a therapeutic and preclinically validated in several mouse models (5).
213Bi is one of the alpha-emitting radionuclides that shows significant promise for TAT (7)(8)(9). Although it is a radionuclide with a relatively short half-life of 46 minutes, it can be made readily available to the hospital over a minimum of 10 days period when using an 225Ac/213Bi generator (10)(11). Presently, 225Ac (t1/2 = 10 d) is predominantly obtained from the decay of the long-lived 229Th (t1/2 = 7880 y) of which the worldwide availability is limited. However, SCK•CEN is in the possession of 229Th-sources originating from the historical Actinium Project (12). The smallest of these sources is very suited to perform research into the development of a mobile 225Ac/213Bi generator and further use of 213Bi in TAT.
The short half-life of 213Bi has the advantage that the lethal radiation is released rapidly after injection. This characteristic matches with the fast binding and clearance of nanobodies, making both ideal partners for TAT. The combination of 213Bi and nanobodies might become a promising treatment option to target residual and metastatic disease.
This research project will be conducted at the Radiochemistry expert group (RCA) of the Belgian Nuclear Research Centre (SCK•CEN) and the In Vivo Cellular and Molecular Imaging (ICMI) research group of the Vrije Universiteit Brussel (VUB). RCA will use its expertise to develop and validate the 225Ac/213Bi generator. In addition, there will be a focus on radiochemical procedures to develop stable 213Bi-labeled nanobodies. ICMI will contribute through its expertise in the preclinical evaluation of radiolabeled nanobodies. The facilities at ICMI will allow the in vitro and in vivo characterization of developed 213Bi-labeled nanobodies.