PSMA-targeted radiotheranostics in modern nuclear medicine: then, now, and what of the future?

Abstract

In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the landscape dramatically altered. Currently, men face a one-in-nine lifetime risk of PCa, accentuated by improved diagnostic methods and an ageing population. With more than three million men in the United States alone grappling with this disease, the overall risk of succumbing to stands at one in 39. The intricate clinical and biological diversity of PCa poses serious challenges in terms of imaging, ongoing monitoring, and disease management. In the field of theranostics, diagnostic and therapeutic approaches that harmoniously merge targeted imaging with treatments are integrated. A pivotal player in this arena is radiotheranostics, employing radionuclides for both imaging and therapy, with prostate-specific membrane antigen (PSMA) at the forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved 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 PSMA-targeted radiotherapeutic agents, such as [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^®, Novartis). Concurrently, ligand-drug and immune therapies designed to target PSMA are being advanced through rigorous preclinical research and clinical trials. This review delves into the annals of PSMA-targeted radiotheranostics, exploring its historical evolution as a signature molecule in PCa management. We scrutinise its clinical ramifications, acknowledge its limitations, and peer into the avenues that need further exploration. In the crucible of scientific inquiry, we aim to illuminate the path toward a future where the enigma of PCa is deciphered and where its menace is met with precise and effective countermeasures. In the following sections, we discuss the intriguing terrain of PCa radiotheranostics through the lens of PSMA, with the fervent hope of advancing our understanding and enhancing clinical practice.

Keywords: Antibodies; Inhibitors; Metastatic castration-resistant prostate cancer; Metastatic hormone-sensitive prostate cancer; Nanoparticles; Nuclear medicine; PSMA-targeted theranostics; Prostate cancer; Prostate-specific membrane antigen; Radiotheranostics.

Figure 1

Development of castration-resistant prostate cancer (CRPC) from hormone-sensitive prostate cancer (HSPC). The progression of CRPC is shown as a function of time by plotting an arbitrary tumour volume (ordinate) (arbitrary units). 28% of HSPC patients are diagnosed with CRPC.

Figure 2

A visual representation of the different components and structures involved in the study of these transmembrane proteins and tumour biology. Illustration showing (A) the various expression sites of the GCPII transmembrane protein, (B) the composition of the transmembrane protein PSMA, and (C) the solid tumour neovasculature. Figure 2B: Reproduced with permission from Springer Nature publisher .

Figure 3

Key components of a conventional PSMA-targeting radiopharmaceutical drug candidate include radiolabelled PSMA-binding domains, linkers, and chelators.

Figure 4

PSMA Glycoprotein Scheme. PSMA-specific antibodies and their recognised binding locations either in the N-terminal region, which is intracellular, or in the extracellular region.

Figure 5

PCa diagnosis and treatment involve employing PSMA-specific ligand-targeting strategies. This entails the utilisation of various labelling candidates, including labelled antibodies. Notably, "siRNA" denotes short interfering RNA, and "scFv" represents a single-chain variable fragment.

Figure 6

Phosphorus-based GCPII inhibitors. In this class, a variety of phosphonate-, phosphinate-, and phosphoramidate-based PSMA-targeting compounds were developed. Phosphoramidate inhibitors represented the most promising pharmacophores so far. Reproduced with permission from Springer Nature publisher .

Figure 7

Urea-based GCPII inhibitors. This group of ligands delivered most of clinically relevant PSMA-targeting compounds. The figure also depicts exemplary FDA-approved radioligands [¹⁸F]DCFPyL (PYLARIFY^®, Lantheus Holdings), [¹⁸F]rhPSMA-7.3 (POSLUMA^®, Blue Earth Diagnostics) and [¹⁷⁷Lu]Lu-PSMA-617(Pluvicto^®, Novartis). Reproduced with permission from Springer Nature publisher .

Figure 8

Thiol-based and other GCPII inhibitors. These PSMA-targeting compounds were mainly developed as analogous to phosphorus-based GCPII inhibitors. However, this class of ligands demonstrated overall low stability due to high sensitivity to oxidation. Reproduced with permission from Springer Nature publisher .

Figure 9

Examples of typical macrocyclic and acyclic chelators. Includes a comprehensive array of ligands, with an example of the commonly used SSTR2-targeting [¹⁷⁷Lu]Lu-DOTA-TATE (Lutathera^®). Reproduced with permission from Elsevier publisher .

Figure 10

Radionuclide chelators: (A) Acyclic chelators, (B) macrocyclic chelators — based on D18C6, (C) macrocyclic chelators — based on cyclen, (D) macrocyclic chelators — based on TACN, and (E) hybrid chelators. Reproduced with permission from Elsevier publisher .

Figure 10

Radionuclide chelators: (A) Acyclic chelators, (B) macrocyclic chelators — based on D18C6, (C) macrocyclic chelators — based on cyclen, (D) macrocyclic chelators — based on TACN, and (E) hybrid chelators. Reproduced with permission from Elsevier publisher .

Figure 11

Illustration of the main challenges faced by clinical PSMA-TRNT and possible answers to them.

Figure 12

Unlocking the potential of nanoparticles for cancer therapy: A comprehensive overview of surface functionalisation techniques, responsive stimuli, and modes of action. The figure showcases the versatility of nanoparticles, highlighting the diverse materials, shapes, and sizes that can be employed. Additionally, the illustration highlights the various surface functionalization techniques and responsive stimuli mechanisms, presenting a comprehensive understanding of the potential applications of nanoparticles in cancer therapy.