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Influence of Albumin Binders on Tumor Uptake of 225Ac-mcp-PSMA-Radioconjugates

Mamat, C.; Reissig, F.; Zarschler, K.; Novy, Z.; Petrik, M.; Bendova, K.; Kurfurstova, D.; Bouchal, J.; Pietzsch, H.-J.; Kopka, K.


The prostate-specific membrane antigen (PSMA) is expressed in approx. 80% of prostate cancer at considerably higher levels in tumor cells compared to healthy tissues. Its upregulation occurs in all stages of the disease. Therefore, PSMA has emerged as an attractive target for molecular imaging and especially targeted radionuclide therapy (endoradiotherapy) of metastatic castration-resistant prostate cancer (mCRPC).
Due to its favorable nuclear physical properties, actinium-225 belongs to the clinically applied alpha emitters for therapeutic applications. More than ten clinical trials are displayed for actinium-225-DOTA-based conjugates. A trial using [225Ac]Ac-PSMA-617 as the IMP in men with PSMA-positive prostate cancer is projected to start. Actinium-225 can be chelated with the standard DOTA chelator, but requires rather harsh labeling conditions such as high temperatures (80–95°C) or microwave assistance. Alternatively, with the complexing agent macropa mild labeling conditions, low reaction temperature and high in vivo stability can be realized owing to its perfect characteristics for Ac3+ chelation.
Moreover, to further improve the tumor uptake for future targeted alpha therapy, albumin binding units based on 4-iodophenylbutyrate were introduced to increase the tumor uptake. Two 225Ac-radioconjugates with albumin binders were prepared, either containing one or two PSMA-binding units (based on PSMA-617), the second one to raise the binding affinity to the PSMA receptor. The synthetic approach consisted of the functionalization of one or two picolinic side arms with a clickable reactive site for the connection of the vector molecules. The azide-functionalized PSMA derivative, which also contains the albumin binder, was prepared using standard peptide coupling conditions. Cell culture-based studies regarding radioligand affinity and clonogenicity were performed using PSMA-positive LNCaP cells and the biodistribution of the radioconjugates was evaluated using LNCaP tumor-bearing mice.
Radiolabeling of both PSMA ligands with [225Ac]Ac3+ was performed at up to 5 MBq/nmol with >99% radiochemical purity. Cell binding and survival studies revealed a higher cell binding affinity and an improved cell killing efficiency for the radioconjugate with two PSMA-binding entities compared to the derivative with only one targeting motif. A considerable binding of both radioligands to mouse, rat and human serum proteins was confirmed. Biodistribution studies revealed enhanced blood circulation times of both albumin-binding PSMA ligands compared to their counterparts without the albumin binders. A substantially higher accumulation in LNCaP tumors up to 50 %ID/g (one PSMA-binding moiety) and 120 %ID/g (two PSMA-binding moieties) after 120 h p.i., respectively, was also observed. Additionally, a considerable DNA damage and a massive decrease in cell proliferation was observed by immunohistochemical examination of LNCaP tumors, whereas necrosis in the kidneys of the animals was not observed.

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