Figure 1.

Lutetium-177-PSMA-617 mechanism of action. Prostate-Specific Membrane Antigen (PSMA) is a type II transmembrane glycoprotein. It is mainly expressed in prostate tissue but can also be expressed in the peripheral and central nervous system, small intestine, and salivary gland tissues. In aggressive forms of prostate cancer PSMA is significantly overexpressed, making it an important target for both imaging and treatment of prostate cancer. Compared to whole antibodies, small molecule inhibitors like PSMA-617 can bind to PSMA more rapidly and with higher affinity, making them ideal for radionuclide therapy. Lutetium-177 (177Lu) is a β-emitter complex with a PSMA-binding small molecule inhibitor (PSMA- 617) (1). 177Lu-PSMA-617 binds rapidly to PSMA (2) and is endocytosed into the cell (3), where it remains over the 6.7-day half-life of 177Lu. The β-decay of 177Lu (4) induces different types of DNA damage (6), including both single-strand breaks (SSBs) and double-strand breaks (DSBs). Furthermore, 177Lu has a maximal tissue penetration of about 2 mm, so it can reach even adjacent cells (5) that may express lower levels of PSMA. 177Lu also emits low energy γ-rays on decay, enabling image acquisition and dosimetric calculation using SPECT (7) or planar scintigraphy. This theranostic approach allows for direct visualization of tumour and normal tissues, while also providing the ability to estimate the delivered dose of radiotherapy.