Radionuclides Landscape in Prostate Cancer Theranostics

Abstract

Prostate cancer, a malignancy of significant prevalence, affects approximately half a million men in Europe, with one in twelve males receiving a diagnosis before reaching the age of 75. Radiotheranostics represents a paradigm shift in prostate cancer treatment, leveraging radionuclides for diagnostic and therapeutic applications, with PSMA emerging as the primary molecular target. Regulatory bodies have approved various PSMA-targeted radiodiagnostic agents, such as [¹⁸F]DCFPyL (PYLARIFY^®, Lantheus Holdings), [¹⁸F]rhPSMA-7.3 (POSLUMA^®, Blue Earth Diagnostics), and [⁶⁸Ga]Ga-PSMA-11 (LOCAMETZ^®, Novartis/ILLUCCIX^®, Telix Pharmaceuticals), as well as therapeutic agents like [¹⁷⁷Lu]Lu-PSMA-617 (PLUVICTO^®, 15 Novartis). The approval of PLUVICTO^® in March 2022 for patients with metastatic castration-resistant prostate cancer who have undergone prior treatments, including androgen receptor pathway-targeting agents and taxane-based chemotherapy, represents a significant advancement. Other radionuclides like ¹⁶¹Tb, ¹⁴⁹Tb, ²²⁵Ac, ²²⁷Th, ²²³Ra, ²¹¹At, ²¹³ Bi, ²¹²Pb, ⁸⁹Zr, and ¹²⁵I are presented, emphasizing their clinical implementation or the stage of clinical trial they are in in the flow to biomedical implementation. Three clinically wise used radionuclides ¹⁷⁷Lu, ²²⁵Ac, ²²³Ra are shown along with their characteristics. This review aims to elucidate the molecular mechanisms underpinning PSMA, explore the clinical applications of PSMA-targeted radiotheranostics, and critically examine the diverse challenges these therapies encounter in the treatment of prostate cancer.

Keywords: prostate cancer; prostate-specific membrane antigen; radionuclides; radiotherapy; theranostic.

Figure 1

Enzymatic activity pathways of PSMA loop involved in prostate tumorigenesis. PSMA transforms poly-γ-glutamated folates secreted by dead tumor cells to folate and glutamate. Folate is then taken up by living tumor cells through the proton-coupled folate transporter (PCFT), folate receptor (FR), and reduced folate carrier (RFC). Glutamate is taken up by the glutamate receptor (GR). Within the cell, folate is polyglutamated in the polyamine and nucleotide synthesis cycles as well as the methylation reactions for cell proliferation. GR after taking up the glutamate can stimulate methylation reactions, polyamine synthesis, and cellular proliferation yet again. Created in Biorender. Monica Neagu (2025).

Figure 2

Therapy targets involving PSMA and intracellular networks triggered by PSMA. In PC, glutamate is a signaling molecule linking membrane glutamate receptor (GR) to the intracellular activation of the PI3K-AKT pathway. The androgen receptor axis interplays with the GR through the PI3K-AKT pathway; thus, it can be a regulatory loop that therapy approaches can trigger (depicted with a dashed line). Androgen receptor activation can induce the transcription of androgen-related genes that regulate metabolic activities, as well as PSMA transcription inhibition. [¹⁷⁷Lu]Lu-PSMA-617 (depicted as labeled substrate for PSMA) is developed for theranostic approaches. Created in Biorender. Monica Neagu (2025).