Enhanced Tumor Targeting with 225Ac-FL-020: A Promising PSMA-Directed Radionuclide Drug Conjugate

In the ongoing battle against metastatic castration-resistant prostate cancer (mCRPC), a condition that remains incurable, researchers have been focusing on the role of Prostate specific membrane antigen (PSMA), a marker that is closely linked with the severity and spread of prostate cancer. Lutetium-177 (177Lu)-PSMA-617, a medication approved in 2022, has shown limited effectiveness, particularly in patients with low PSMA expression levels. This has prompted the search for more effective therapies.

Actinium-225 (225Ac), an alpha particle emitter, is being explored for its superior cancer cell-killing potential and its shorter tissue penetration range, which is advantageous for targeted radiotherapy. Utilizing the Clear-X™ technology platform, a new PSMA-targeted radioligand candidate, 225Ac-FL-020, has been developed. This compound has shown promising preclinical characteristics.

In vitro testing revealed that the non-labeled vector FL-020 has a strong binding affinity to PSMA. The in vivo biodistribution of FL-020 was examined using Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) imaging and biodistribution studies with Indium-111 (111In)-FL-020 in mice bearing PSMA-expressing LNCaP tumors. The compound demonstrated high selectivity with minimal off-target effects across a wide range of targets.

The in vivo distribution of 111In-FL-020 was notably favorable, with sustained tumor uptake and rapid clearance from the body. Moreover, when tested in the LNCaP xenograft model, 225Ac-FL-020 outperformed 225Ac-PSMA-617 in terms of anti-tumor activity at equivalent dosages, while also showing a positive safety profile based on body weight and hematological assessments.

A deeper investigation into the mechanism of action of 225Ac-FL-020 in treated LNCaP tumors confirmed the presence of DNA double-strand breaks and tumor cell apoptosis, which are characteristic of alpha emitters' impact. The collective findings indicate that 225Ac-FL-020 is a potent and selective radioligand therapy candidate with enhanced anti-tumor effects and a favorable safety profile, suggesting its potential for further clinical advancement.