Maarten van der Doelen

General introduction and outline of the thesis

positron is emitted. When compared to alpha particles, beta particles have lower linear energy transfer (0.2 keV/µm) and considerable longer range (1,000-10,000 µm). Figure 1 illustrates the difference between alpha and beta particle radiation ranges. Due to the high linear energy radiation, alpha particles have the ability to cause numerous ionization events, leading to irreparable double-strand deoxyribonucleic acid (DNA) breaks within the cell nucleus and subsequent apoptosis. Together with the short path-length, this potentially enables alpha particles to deliver localized tumor cell killing. However, to minimize unwanted toxicity from alpha particles to normal healthy tissues, targeted delivery to the sites of cancer cells is desirable. Based on the method of delivery, targeted alpha-radionuclide therapy (TAT) is categorized as mechanism mediated TAT and molecule-guided TAT. (31) In mechanism-mediated TAT, the targeting of the alpha-emitting radionuclide relies solely upon the innate physicochemical nature of the element and no specific vehicles are necessary to deliver nuclear energy to the tumor cells. In molecule-guided TAT, alpha-emitting radionuclides are coupled with monoclonal antibodies, peptides, small molecules or nanoparticles, which target tumor-associated antigens that are aberrantly present on the cancer cells and thereby selectively deliver cytotoxic radiation, while minimizing toxicity to surrounding healthy tissues. (32, 33)

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In this thesis, two targeted alpha-particle emitting radionuclides were evaluated for therapy of mCRPC: actinium-225 and radium-223.

A

B

Figure 1. Schematic overview showing the difference between radiation ranges when a bone metastasis located at the border of bone matrix (yellow) and bone marrow (red) is irradiated by a alpha or a beta particle. A . Short radiation range by an alpha particle (2 to 10 cell diameters). B . Long radiation range by a beta particle (10 to 1000 cell diameters), which might lead to bone marrow toxicity. Figure adapted from slide deck Bayer Health Care, based on Henriksen G, et al. (Cancer Res. 2002;62:3120–3125) and Brechbiel MW. (Dalton Trans. 2007;43:4918–4928). (34, 35)

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