Maarten van der Doelen

Chapter 1

Actinium-225 Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein showing significant overexpression in high-grade and advanced stage prostate cancer. (36) Expression is further upregulated in mCRPC state and following treatment with second generation androgen-signaling inhibitors (37, 38). By the use of PSMA-targeting vehicles, such as antibodies (e.g. monoclonal antibody J591) or small molecule ligands (e.g. PSMA-617), that are labeled with a radionuclide, targeted imaging and radioligand therapy (RLT) can be obtained. (39) Actinium-225 is an alpha-emitter with a physical half-life of 9.9 days and decays to stable bismuth-209 by net production of four alpha particles with energies of 5.8-8.4 MeV. Targeted delivery of actinium-225 to the prostate cancer cells may be accomplished via actinium-225 labeled PSMA-617 ( 225 Ac-PSMA). Since PSMA is known to be highly expressed on prostate cancer cells at the primary tumor and within lymph node, bone and visceral metastases, the alpha particles may be directed to PSMA expressing cells regardless of their location. First results of 225 Ac-PSMA RLT in small cohorts of mCRPC patients are promising, with high rates of biochemical and radiological responses. (40, 41) Radium-223 Radium-223 (Xofigo®) is a radioactive isotope of the alkaline earth metal radium and has a physical half-life of 11.4 days. During its decay to stable lead-207, four alpha particles are emitted, with an average energy of 5.8-7.6 MeV. In addition, small amounts of beta radiation (3.6%) and gamma radiation (1.1%) are emitted. Complete decay to stable lead-207 results in a combined energy of 28.2 MeV. (42) Radium-223 naturally acts as a bone-seeking radionuclide. Radium-223 behaves as a calcium mimetic and is actively incorporated into the bone matrix via binding to hydroxyapatite at osteoblastic bone sites, but it also passively binds in areas of high bone turnover. There it affects both cancer cells and the tumor microenvironment. (43) The short range of high-energy alpha-radiation from radium-223 therapy (40-80 µm, <10 cell diameters) induces targeted tumor cell killing at sites of osteoblastic bone activity, while minimizing damage to the surrounding tissue, such as bone marrow. (34) Since 2013, radium-223 is approved as an alpha-emitting radiopharmaceutical for mCRPC patients with symptomatic bone metastases and no visceral metastases. The registration of radium-223 is based on an OS benefit of 3.6 months when compared to placebo, demonstrated in the phase 3, randomized, double-blind, placebo-controlled

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