**6. Prostate-specific membrane antigen (PSMA)-targeting ligands**

After promising results with 131I-labeled prostate-specific membrane antigen (PSMA) ligands for prostate cancer therapy, it was introduced 177Lu-PSMA by the German Cancer Research Center in 2015 [45]. PSMA is known as folate hydrolase 1 (FOLH1) or glutamate carboxypeptidase II (GCP II) and is overexpressed on the membrane of prostate cancer cells [45–47]. It remains high even after multiple lines of therapy [45, 46]. Metastatic castration-resistant prostate cancer (mCRPC) patients who shown ineffective by chemotherapy, radioligand therapy targeting the PSMA is a promising therapy approach [41, 45, 46]. First data showed that 177Lu-PSMA is safe and effective in reducing tumor burden. It has been widely adopted in German and international sites, with likely more than a thousand therapy cycles performed [45].

PSMA targeting ligand using the beta emitter lutetium-177 [177Lu]Lu-PSMA-617 or [177Lu]Lu-PSMA-I&T) are currently being tested in phase III trials. It revealed encouraging data in several studies in mCRPC patients [46, 48, 49]. PSMAtargeting ligand using alpha emitters as actinium-225 may be advantageous compared to PSMA-targeting ligan with beta emitters. Clinical studies using 225Ac-labeled PSMA-ligands ([225Ac]Ac-PSMA-617 or [225Ac]Ac-PSMA-I&T) have reported remarkable therapeutic results lately. However, it shows more substantial radiobiological effect of alpha particles on the organs at risk [46]. Combining alpha emitters in adjusted doses with beta emitters called 'tandem therapy' may reduce these significant adverse effects compared to using alpha emitters alone [46]. Furthermore, a novel alpha therapy approach with a thorium-227-labeled PSMA antibody shows strongly in vitro potency in several PSMA-positive cell lines and in vivo efficacy in xenograft models of prostate cancer [47]. These treatment approaches need more studies for effectiveness and limited toxicity.
