Development of Novel In-111/Ac-225-Labeled Agent Targeting PSMA for Highly Efficient Cancer Radiotheranostics

Prostate-specific membrane antigen (PSMA) is a promisingtargetfor metastatic castration-resistant prostate cancer. We previouslyreported the effectiveness of PSMA-DA1 as a PSMA-targeting radiotheranosticagent containing an albumin binder moiety. To further enhance tumoruptake, we newly designed PSMA-NAT-DA1 (PNT-DA1) by the introductionof a lipophilic linker into PSMA-DA1. The PSMA affinity of [In-111]In-PNT-DA1 was increased (K (d) = 8.20nM) compared with that of [In-111]In-PSMA-DA1 (K (d) = 89.4 nM). [In-111]In-PNT-DA1 showed markedlyhigh tumor accumulation (131.6% injected dose/g at 48 h post-injection),and [In-111]In-PNT-DA1 enabled the visualization of thetumor clearly at 24 h post-injection with SPECT/CT imaging. The administrationof [Ac-225]Ac-PNT-DA1 (2.5 kBq) led to shrinkage of thetumor without marked toxicity, and the antitumor effects of [Ac-225]Ac-PNT-DA1 were superior to those of [Ac-225]Ac-PSMA-DA1and [Ac-225]Ac-PSMA-617, which is the current gold standardfor PSMA-targeting Ac-225-endoradiotherapy. These resultssuggest that the combination of [In-111]In-PNT-DA1 and [Ac-225]Ac-PNT-DA1 comprises a promising method of PSMA-targetingradiotheranostics.

Automated summary

PSMA is a promising target for radiotherapy in metastatic castration-resistant prostate cancer. PNT-DA1 is a newly designed agent that enhances tumor uptake, and [Ac-225]Ac-PNT-DA1 has superior antitumor effects compared to current gold standard therapies. The combination of [In-111]In-PNT-DA1 and [Ac-225]Ac-PNT-DA1 holds promise for PSMA-targeted radiotheranostics.