Background: While alpha microdosimetry dates back a couple of decades, the effects of localized energy deposition of alpha particles are often still unclear since few comparative studies have been performed. Most modern alpha microdosimetry studies rely for large parts on simulations, which negatively impacts both the simplicity of the calculations and the reliability of the results. A novel microdosimetry method based on the Fluorescent Nuclear Track Detector, a versatile tool that can measure individual alpha particles at sub-micron resolution, yielding accurate energy, fluence and dose rate measurements, was introduced to address these issues. Methods: Both the detectors and U87 glioblastoma cell cultures were irradiated using an external Am241 alpha source. The alpha particle tracks measured with a Fluorescent Nuclear Track Detector were used together with high resolution 3D cell geometries images to calculate the nucleus dose distribution in the U87 glioblastoma cells. The experimentally obtained microdosimetry parameters were thereafter applied to simulations of 3D U87 cells cultures (spheroids) with various spatial distributions of isotopes to evaluate the effect of the nucleus dose distribution on the expected cell survival. Results: The new experimental method showed good agreement with the analytically derived nucleus dose distributions. Small differences (<5%) in the relative effectiveness were found for isotopes in the cytoplasm and on the cell membrane versus external irradiation, while isotopes located in the nucleus or on the nuclear membrane showed a substantial increase in relative effectiveness (33 - 51%). Conclusions: The ease-of-use, good accuracy and use of experimentally derived characteristics of the radiation field make this method superior to conventional simulation-based microdosimetry studies. Considering the uncertainties found in alpha radionuclide carriers in-vivo and in-vitro, together with the large contributions from the relative biological effectiveness and the oxygen enhancement ratio, it is expected that only carriers penetrating or surrounding the cell nucleus will substantially benefit from microdosimetry.@en

Alpha emitters have great potential in targeted tumour therapy, especially in destroying micrometastases, due to their high linear energy transfer (LET). To prevent toxicity caused by recoiled daughter atoms in healthy tissue, alpha emitters like ²²⁵Ac can be encapsulated in polymeric nanocarriers (polymersomes), which are capable of retaining the daughter atoms to a large degree. In the translation to a (pre-)clinical setting, it is essential to evaluate their therapeutic potential. As multicellular tumour spheroids mimic a tumour microenvironment more closely than a two-dimensional cellular monolayer, this study has focussed on the interaction of the polymersomes with U87 human glioma spheroids. We have found that polymersomes distribute themselves throughout the spheroid after 4 days which, considering the long half-life of ²²⁵Ac (9.9 d) (Vaidyanathan and Zalutsky, 1996), allows for irradiation of the entire spheroid. A decrease in spheroidal growth has been observed upon the addition of only 0.1 kBq ²²⁵Ac, an effect which was more pronounced for the ²²⁵Ac in polymersomes than when only coupled to DTPA. At higher activities (5 kBq), the spheroids have been found to be destroyed completely after two days. We have thus demonstrated that ²²⁵Ac containing polymersomes effectively inhibit tumour spheroid growth, making them very promising candidates for future in vivo testing.

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To answer the need for better tools for alpha radiation radiobiology and microdosimetry research, a novel irradiation setup based on a honeycomb collimator, in combination with Fluorescent Nuclear Track Detectors (FNTD) for alpha radiation dosimetry and spectroscopy, was introduced. FNTDs are a novel type of small, crystalline detector that can visualize individual alpha particles and simultaneously measure their location, velocity direction and energy with good accuracy. The performance of FNTDs for alpha radiation dosimetry was evaluated for the first time and the results were compared to extrapolation chamber measurements and simulations. The surface dose rate to water of the irradiation setup for two different honeycomb collimators, measured using FNTDs, agreed with the extrapolation chamber measurements within 6%. The simulations underestimated the surface dose rate to water for the first collimator and overestimated the dose for the second collimator, indicating the sensitivity to manufacturing errors in the collimators of this irradiation setup. The dose homogeneity in the setup was measured using radiochromic film and showed variations of less than 5%, making this setup, in combination with the rich information obtained regarding the spatial, angular and energy distributions of the alpha particles, obtained using the FNTDs, ideal for microdosimetry and radiobiology experiments. The accuracy and ease-of-use of FNTDs in addition to the surface or absorbed dose and fluence of the radiation field indicate that these detectors are prime candidates for research applications in the field of alpha radionuclide therapy.

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Structured illumination microscopy (SIM) for the imaging of alpha particle tracks in fluorescent nuclear track detectors (FNTD) was evaluated and compared to confocal laser scanning microscopy (CLSM). FNTDs were irradiated with an external alpha source and imaged using both methodologies. SIM imaging resulted in improved resolution, without increase in scan time. Alpha particle energy estimation based on the track length, direction and intensity produced results in good agreement with the expected alpha particle energy distribution. A pronounced difference was seen in the spatial scattering of alpha particles in the detectors, where SIM showed an almost 50% reduction compared to CLSM. The improved resolution of SIM allows for more detailed studies of the tracks induced by ionising particles. The combination of SIM and FNTDs for alpha radiation paves the way for affordable and fast alpha spectroscopy and dosimetry. Journal compilation

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Alpha radionuclide therapy has great potential for effective treatment of metastatic with reduced normal tissue complications. (Pre-clinical) research of alpha radiation of therapy does however suffer from a lack of proper tools for spectroscopy, (micro-) dosimetry and radiobiology. An attempt was made to develop and verify methods for the application of fluorescent nuclear track detectors (FNTD) for alpha radiation, to create an affordable and versatile 4 in 1 tool...@en

Introduction: The use of 225Ac for alpha radionuclide therapy is a relatively novel approach, where the dense energy deposition of alpha radiation is used to treat cancer more effectively. 225Ac has, compared to conventional radionuclides, a long half-life of 10 days and a long decay chain, yielding 4 alpha particles, 2 beta particles and several gamma rays. This long decay chain presents new challenges. Daughter radionuclides that separate from the radionuclide carrier during radioactive decay can end up freely circulating …@en

Fluorescent Nuclear Track Detector technology is a passive luminescent integrating detector technology having important advantages in measuring neutrons, heavy ions and even photons. FNTD is based on new aluminum oxide crystals doped with carbon and magnesium impurities (Al₂O₃:C,Mg) and confocal laser scanning fluorescent microscopy technique. The production and optical characteristics of Mg-doped aluminum oxide are discussed in details, as well as the progress made in the read-out instrumentation. Since the introduction of the technology, FNTDs have been successfully used for a wide range of applications in mixed neutron-gamma fields, medical dosimetry and radiobiological research and the results of these tests are discussed in detail.

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A robust and computationally efficient algorithm for automated tracking of high densities of particles travelling in (semi-) straight lines is presented. It extends the implementation of (Sbalzarini and Koumoutsakos 2005) and is intended for use in the analysis of single ion track detectors. By including information of existing tracks in the exclusion criteria and a recursive cost minimization function, the algorithm is robust to variations on the measured particle tracks. A trajectory relinking algorithm was included to resolve the crossing of tracks in high particle density images. Validation of the algorithm was performed using fluorescent nuclear track detectors (FNTD) irradiated with high- and low (heavy) ion fluences and showed less than 1% faulty trajectories in the latter.

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