Development of radioactive lanthanide-based nanoparticles for radiopharmaceutical applications

Nanoparticles (NPs) possess unique physical and chemical properties due to their high surface area and nanoscale size (typically 1-100 nm). Over the last decade, the development of nanoparticles for medical applications has become increasingly popular as they have shown the ability to overcome the limitations of conventional chemotherapy. One of the main advantages of NPs is that they can be chemically tailored in such a way to specifically target cancer cells and tissues and can be used in a variety of imaging modalities: fluorescent imaging (FI), magnetic imaging resonance (MRI). When coated with a matrix to target cancer cells, these NPs can be used to visualize cancer lesions using FI and/or MRI. 161Tb has gathered increasing interest in recent years due to its favorable properties for targeted radionuclide therapy (TRNT). 161Tb decays (t1/2 = 6.9 d) by the emission of low-energy β- particles (Eβ−average = 154 keV). These β- particles have a maximal tissue range of 0.29 mm and a linear energy transfer (LET) of around 0.32 keV/μm, which is suitable for the treatment of metastasized malignancies. In addition to this, the decay process of 161Tb releases Auger/conversion electrons (energy ≤ 50 keV). These Auger/conversion electrons release much higher local dose density due to their shorter range in tissue (0.5 – 30 µm), thereby contributing to the therapeutic anti-tumor effects of 161Tb (Muller et al. 2014) without causing additional renal side effects. Up to now, only a few studies have evaluated the therapeutic potential of 161Tb, which makes it an innovative radionuclide. These preliminary therapy studies revealed that the therapeutic effect of 161Tb-labelled compounds was superior to the effect of their 177Lu-, 67Cu- or 47Sc -labeled counterparts when applied at the same dose. 161Tb is typically bound to vector molecules (peptides, nanobodies, proteins, …) through coordination of the 161Tb atom to a chelating ligand such as DOTA. A potential issue with using such a 161Tb-construct is that these metal complexes can suffer from instability under physiological conditions. Therefore, chelator bound 161Tb has to risk to be released from the chelator which would result in off target accumulation of the free 161Tb. Therefore, we try to circumvent this issue by consolidating the 161Tb into a NP. By incorporating a therapeutic radionuclide such as 161Tb inside nanoparticles could drastically increase the application potential of 161Tb.