Recent years have seen a swift rise in the use of α-emitting radionuclides such as 225Ac and 223Ra as various radiopharmaceuticals to treat (micro)metastasized tumors. They have shown remarkable effectiveness in clinical practice owing to the highly cytotoxic α-particles that are emitted, which have a very short range in tissue, causing mainly double-stranded DNA breaks. However, it is essential that both chelation and targeting strategies are optimized for their successful translation to clinical application, as α-emitting radionuclides have distinctly different features compared to β−-emitters, including their much larger atomic radius. Furthermore, upon α-decay, any daughter nuclide irrevocably breaks free from the targeting molecule, known as the recoil effect, dictating the need for faster targeting to prevent healthy tissue toxicity. In this review we provide a brief overview of the current status of targeted α-therapy and highlight innovations in α-emitter-based chelator design, focusing on the role of click chemistry to allow for fast complexation to biomolecules at mild labeling conditions. Finally, an outlook is provided on different targeting strategies and the role that pre-targeting can play in targeted alpha therapy.

Porous materials, such as zeolites, have great potential for biomedical applications, thanks to their ability to accommodate positively charged metal-ions and their facile surface functionalization. Although the latter aspect is important to endow the nanoparticles with chemical/colloidal stability and desired biological properties, the possibility for simple ion-exchange enables easy switching between imaging modalities and/or combination with therapy, depending on the envisioned application. In this study, the nanozeolite Linde type L (LTL) with already confirmed magnetic resonance imaging properties, generated by the paramagnetic gadolinium (GdIII) in the inner cavities, was successfully radiolabeled with a positron emission tomography (PET)-tracer zirconium-89 (89Zr). Thereby, exploiting 89Zr-chloride resulted in a slightly higher radiolabeling in the inner cavities compared to the commonly used 89Zr-oxalate, which apparently remained on the surface of LTL. Intravenous injection of PEGylated 89Zr/GdIII-LTL in healthy mice allowed for PET-computed tomography evaluation, revealing initial lung uptake followed by gradual migration of LTL to the liver and spleen. Ex vivo biodistribution confirmed the in vivo stability and integrity of the proposed multimodal probe by demonstrating the original metal/Si ratio being preserved in the organs. These findings reveal beneficial biological behavior of the nanozeolite LTL and hence open the door for follow-up theranostic studies by exploiting the immense variety of metal-based radioisotopes.