The medical interest in targeted alpha therapy (TAT) has increased the demand for actinium-225 (225Ac), a promising isotope for cancer treatment. However, the production falls short. One potential route is the generation of 225Ac via proton irradiation of radium-226 (226Ra), introducing the challenge of separating these radionuclides. In this study, lanthanum and barium were used as chemical analogues for actinium and radium, respectively. This study investigates the production and characterisation of α-titanium phosphate (α-Ti(HPO4)2 · H2O, α-TiP) and its feasibility for the separation of lanthanum and barium using ion exchange.

Three synthesis methods were used with different titanium precursors: TiO2, Ti powder and TiOSO4. The resulting α-TiP samples were characterised using X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS), confirming phase purity but showing morphological differences.

The ion exchange behaviour of α-TiP was found to be closely linked to morphology and exchange site accessibility. Batch adsorption experiments demonstrated that α-TiP exhibits strong selectivity for trivalent lanthanum (La3+) over divalent barium (Ba2+) ions at acidic pH and relevant concentration ([La3+] = 2.5 μM and [Ba2+] = 1.0 mM).

The results support the potential of α-TiP as a viable material for lanthanum–barium separation. However, further studies are required to confirm radiation stability, reversibility of ion uptake and performance in column-based separation systems. Additionally, experiments should validate whether similar separation behaviour will be achieved for actinium and radium separation.

The radionuclide technetium-99m (99𝑚Tc) is utilized in 80-85% of in-vivo nuclear medicine diagnostics due to its ideal physical and chemical properties, including a short half-life, gamma emission suitable for imaging, and versatile chemistry. Its production relies on molybdenum-99 (99Mo), traditionally generated through uranium fission. However, the transition to low-enriched uranium (LEU) targets and growing demand for 99𝑚Tc have driven the search for alternative production methods and materials. This study investigates the potential of molybdenum silicide (MoSi2) materials as targets for neutron-activated 99Mo production and as generators for 99𝑚Tc extraction. Three synthesis methods were explored to produce nanoscale molybdenum silicides. A sol-gel carbothermic reduction method failed to produce MoSi2, yielding elemental molybdenum, molybdenum dioxide, and molybdenum carbide due to oxygen contamination. The sol-gel preoxidation method successfully coated commercial MoSi2 with an amorphous silica layer, enhancing the material’s stability. The magnesiothermic reduction method successfully produced an oxide mixture intermediate (SiO2/MoO3) with nanosphere structures, initially containing 0.57 wt% molybdenum. The molybdenum content was later increased to 23.96 wt%. However, synthesis of the Si/MoSi2 nanocomposites from this intermediate was not completed due to time constraints. The chemical stability, extraction and retention behavior of commercial and silica-coated MoSi2 were evaluated in MilliQ and methyl ethyl ketone (MEK). The silica coating reduced molybdenum leaching and exhibited selective 99𝑚Tc extraction. Retention studies highlighted the significant role of solvent interactions in governing radionuclide adsorption. In MEK, the silica-coated material exhibited lower 99𝑚Tc retention, likely due to reduced adsorption sites caused by solvent interactions with silanol groups, while 99Mo retention could not be evaluated due to insufficient extraction data. The results demonstrate the potential of silica-coated MoSi2 in 99Mo/99𝑚Tc generator applications. However, further work is needed to optimize synthesis, increase surface area and evaluate long-term performance under irradiation. This could pave the way for sustainable and efficient isotope production systems.

Radionuclide therapy is an important cancer treatment modality that makes use of the local irradiation from radionuclides at the tumor sites. Radiopharmaceuticals are normally composed of three components: radionuclide, carrier and tumor targeting agent. In terms of the radionuclide carriers, macrocyclic and acyclic chelators are commonly used to complex the radiometallic ions. Besides conventional chelators, inorganic nanoparticles have also been proposed as radionuclide carriers in previous research but have been mainly focused on the diagnostic applications. In this thesis, various types of inorganic nanoparticles were radiolabeled with therapeutic radionuclides including α, β- and Auger electron (AE) emitters. The behavior of some radionuclides on the host materials during internal conversion was studied. Moreover, the cell uptake and tumor killing efficiency of the AE emitters radiolabeled nanoparticles were assessed in vitro to evaluate their potential for cancer treatment.

The main objective of this research was to determine the feasibility of using the Timepix3 detector, a novel hybrid-pixel detector developed by CERN, as a tool for imaging ex-vivo slices of tumour tissue treated with 225Ac Targeted Alpha Therapy. Targeted Alpha Therapy using 225Ac-PSMA shows promise as a therapeutic method, as it allows direct targeting of the tumour and precise irradiation of cancer cells while sparing healthy tissue due to the short range of α-particles (typically 50-100μm). However, due to the recoil effect, the daughters of 225Ac can break loose from the targeting vector, potentially diffusing away from the tumour site and harming healthy tissue resulting in unwanted side effects. To investigate this, several experiments were conducted using the Timepix3 detector, capable of energy, spatial and time-resolved measurements. Before experiments could be conducted, a data processing tool was developed and an optimal bias voltage of 30V was determined. Subsequently, the Timepix was calibrated using a γ and α calibration, which yielded energy resolutions of 4.27±0.06% and 4.96±0.06% compared to 6.35±0.04% without calibration when measuring α-particles from 225Ac locally. The Timepix3 was then tested using different collimators for whole surface measurements. For a plastic collimator (L/D=2.5, ⌀=1mm) the energy resolution improved from 15.7±0.3% to 11.9% and 9.6±0.1%. For a lead-glass collimator (L/D=50, ⌀=24.8μm) the energy resolution improved to 13.5% and 12.6±0.4%, here the uncalibrated resolution could not be determined. Finally, the spatial resolution of the Timepix was determined using the plastic collimator, which was 310±10μm. Based on the findings, the Timepix3 detector is not suitable for the proposed application, an imaging tool to determine nuclide distribution in 225Ac-PSMA treated tissue samples, using this particular setup. However, using a different collimator with a more suitable L/D ratio should definitely be capable as this improves spatial and energy resolution further. Furthermore, the Timepix3 detector was used in a clinical test to directly measure and determine the nuclide contents of the radio-pharmaceutical 225Ac-PSMA separated by high-performance liquid chromatography. The results indicated an initially lower amount of 213Po in the sample which grew over time This indicates that the HPLC is capable of separating individual nuclides. This result also demonstrated the potential use of the Timepix3 detector for these types of applications. In experiments where the Timepix3 was placed inside a 70MeV and 120MeV proton beam to test its feasibility as a beam verification tool, the results were less successful due to the high intensity of the proton beam. However, it was concluded that it was still possible to measure scattered protons and secondary products. 

Photosensitizers play a key role in photodynamic therapy as a drug that is activated by light. In this thesis, the effect of ionizing radiation on the generation of singlet oxygen when using photosensitizers (Chlorin e6) and photocatalysts (titanium dioxide) was studied. By using radionuclides and photosensitizers (PS), cells can be killed with reactive oxygen species (ROS) which are produced by PS under influence of radiation that is emitted by radioactive decay. ROS are produced naturally in cells, but an excess of ROS can lead to damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis. The focus of this thesis is the production of singlet oxygen which is a type of ROS.
Indium-111, lutetium-177 and yttrium-90 which decay by different types of radiation have been used as radiation sources. In this research, the influence of these different radiation sources have been tested on Ce6 and TiO2 and their ability to produce singlet oxygen. Results show that Ce6 and TiO2 have increased production of singlet oxygen when exposed to ionizing radiation. Ce6 generates singlet oxygen when irradiated by both low energy gamma sources
and high energy beta-minus radiation, while TiO2 generates singlet oxygen when irradiated by high energy beta-minus radiation.

Cancer is often treated by radiation therapy. There are three types of radiation therapy: external beam therapy, brachytherapy and radionuclide therapy. A downside to radiation therapy is its damaging effect on healthy tissue. A different type of treatment is photodynamic therapy. In PDT photo-active substances are being used to generate reactive oxygen species under irradiation. These ROS are a group of radicals which can cause damage to the DNA and in some cases cause necrotic or apoptotic cell death. By combining radiotherapy and PDT, the effectiveness of the treatment can be enhanced. Among different ROS, singlet oxygen is the most effective in causing DNA damage. As the nanoparticle titaniumdioxide and the photo-active molecule chlorin e6 can generate ROS under ionizing radiation, it is very attractive to look further into how much singlet oxygen they can generate. This report will focus on the singlet oxygen generating abilities of the photo-active substances TiO2 and Ce6 under the irradiation of lutetium-177 and iodine-125. The relative amounts of generated singlet oxygen are measured using a probe called Singlet Oxygen Sensor Green and fluorescence spectroscopy. The experiments using 177Lu, did not show a lot of promise as a decrease in fluorescence intensity was seen in the radioactive samples. It is possible that 177Lu precipitates despite of its chelation with DTPA and the beta-minus particles might have destroyed the SOSG probe. When comparing the Ce6 samples with the TiO2 samples, the TiO2 samples show much higher intensities. A possible explanation for this result might be the fact that 177Lu destroys both the SOSG and Ce6, whereas TiO2 is not an organic molecules and it thus not destroyed by 177Lu. The intensities of the Ce6 samples was higher than the control group. This suggests there is some positive influence of Ce6 on the generation of singlet oxygen under irradiation of 177Lu. The experiments using 125I showed promise as the control samples and Ce6 samples showed an increased intensity in the presence of 125I. This suggest that under irradiation of 125I more singlet oxygen is generated than without. The TiO2 samples show inconclusive results and thus no trend can be seen between the exposed and non-exposed samples. This is possible due to some TiO2 particles being present in the eluate.

A radioisotope used in radionuclide therapy is Holmium-166 (Ho-166). The treatment effectiveness of Ho-166 could be improved by the use of a so called in vivo Dysprosium-166(Dy-166)/Ho-166 generator. The application of this generator is hindered by an effect called internal conversion (IC). This affect can arise after the decay of Dy-166 to Ho-166, which can cause separation of Ho-166 from its carrier.
Polymeric micelles might form a solution in the application of the Dy-166/Ho-166 generator in radionuclide therapy. The main goal of this thesis was to investigate and understand the loading mechanism of metallic species and polymeric micelles with a focus on the loading of Dy/Dy-166 and Ho-166.

It was found that it was not effective to load metallic species (Dy/Dy-166) as free ions or as solid precipitates. Loading metallic species as aqueous hydroxides showed to be crucial for achieving a good loading and high stability. The second goal was to study if polymeric micelles were able to retain Ho-166 inside their core under the effects of internal conversion. No additional losses of Ho-166 were found when Dy/Dy-166 and Ho-166 were loaded into the micelles. It was concluded that the PCL-PEO micelles prevented the loss of Ho-166 under internal conversion effects.

Background:
Cancer is one of the leading causes of death worldwide. Targeted radionuclide therapy has become a important treatment, this is when a carrier molecule is attached to a radionuclide to deliver cytotoxic radiation levels to diseased cells. β
− emitters are frequently used in RNT because they have a long penetration depth, such as the dysprosium-166/holmium-166 (166Dy/166Ho) in vivo generator. The 166Dy/166Ho in vivo generator shows great potential for large tumors because of the long half-life time of the mother nuclide 166Dy and the emission of high energy β− from the daughter nuclide 166Ho. Previous research shows the release of 72 % of the 166Ho when 166Ho is bound to conventional chelators due to internal conversion after the β− decay. The aim of this thesis is to synthesize an iron oxide nanoparticle as carrier for the 166Dy/166Ho in vivo generator. This iron oxide nanoparticles (SPIONs) should prevent internal conversion and thus the loss of the daughter nuclide 166Ho.
Results:
The dysprosium doped iron oxide nanoparticles were synthesized successfully with an average diameter of 6.1 ± 1.5 nm, measured with TEM. The DLS and TEM results showed that the SPIONs were aggregating. The labeling efficiency represents how much Dy is retained in the Dy doped SPIONs, for the non-radioactive Dy this was measured with the ICP/OES. The labelling efficiency was 3.21 ± 0.8 %. The 166Dy doped iron oxide nanoparticles were also synthesized successfully with a radiolabelling efficiency of 3.12 ± 2.2 %, measured with a 2480 Wizard 2 Gamma counter. The retention of 166Dy + 166Ho was 79.2 ± 1.8 % after 96 h.
Conclusion:
The retention of 166Dy + 166Ho in iron oxide nanoparticles was 79.2±1.8 % after 96 hours. This is much higher than the retention of 28% by conventional chelators. This means that the iron oxide nanoparticls is a safer carrier for the 166Dy/166Ho in vivo generator than the conventional chelator.

In the human body calcium is the most abundant mineral and is involved in a lot of vital processes. Calcium deficiency occurs when there is not enough calcium present in the bloodstream. In the Netherlands one in three women will face this problem in their lifetime. A major factor contributing to this problem is that the intake of calcium on average is below the recommended amount which is around 950 mg/day for adults in the Netherlands. Calcium deficiency when left unattended can lead to osteoporosis. Therefore it is important to consume enough calcium rich products or take calcium supplements. Milk is a good source of calcium and is considered a staple food. This makes bovine milk a good candidate for calcium fortification. Milk can be fortified by using calcium salts to increase the bioavailability the calcium present. In this thesis in vitro methods were used to study the effects of calcium salt fortification on the phase distribution of calcium in bovine skimmed milk under different pH conditions and by using the radioactive isotope 45Ca to track the exchange between the phase casein micelles, serum proteins and the soluble phase when fortifying the milk. For unfortified milk it was found that 36.0±0.9% was present in the soluble phase, 3.7±2.9% was present in the serum proteins phase and 60.3±3.0% in the casein micelles. Acidifying the milk to simulate the gastric environment resulted in an increase of the soluble phase from 55.1±2.7% to 97.0±3.3% which corresponds to a decrease in pH from pH 6 to pH 2. For the fortification of the milk, five calcium salts were selected for synthesis. The salts were calcium carbonate, tricalcium di-citrate, calcium gluconate, calcium lactate and tri-calcium phosphate. The fortification was performed with all of the synthesized salts except calcium lactate and tri-calcium phosphate. The starting material for the syntheses, calcium chloride, was also used for fortification. It was found that for the fortification of CaCO3 under gastric conditions a bioavailability of 100% could be achieved. However the acidic environment also resulted in coagulation of the milk and therefore the bioavailability could not be accurately assessed. Calcium gluconate had the only increase in bioavailability under normal conditions. In conclusion a better understanding of fortification with calcium salts was achieved and the influence of pH on the bioavailability of calcium in milk and the effects on the salt fortification.

Polymeric micelles are increasingly used in chemotherapy. To get a greater understanding of the behaviour of these micelles is important. Nuclear imaging, such as SPECT and PET can provide relevant information about the behaviour of the micelles. However, to use these techniques, the micelles must be radiolabelled. In this thesis a chelator free method will be described to radiolabel micelles. The goal of this thesis is to radiolabel block copolymers with Zr-89. For this purpose series of experiments were carried out. In these experiments three different concentrations ZrCl4 are applied, C1 = 0.04mM, C2 = 0.07mM and C3 = 1mM. These experiments are conducted for two different types of polymer micelles, PCL-PEO 2800-2000 and PLA-PEO 10500-5000. With these polymers, micelles are prepared, which are used for the radiolabeling process. The fractions obtained by the SEC (size exclusion chromatography) were analysed and the data was processed. At the first concentration C1 = 0.04mM, PCL-PEO 2800-2000 had an efficiency of 37,65 ± 2,48 %. PLA-PEO 10500-5000 gave a radiolabeling efficiency of 28,27 ± 1,23 %. The second concentration, C2 = 0.07mM, showed a decrease in radiolabeling efficiency. For the PCL-PEO-2800-2000 polymeric micelles a radiolabeling efficiency of 23,30 ± 13,94 % was found and for the PLA-PEO 10500-5000 micelles an efficiency of 19,76 ± 1,70 was found. Lastly at the third concentration, C3 = 1mM, for PCL-PEO 2800-2000 the radiolabeling efficiency was found to be 0,88 ± 0,07 %. The PLA-PEO 10500-5000 micelles gave back 2,91 ± 1,68 % as radiolabeling efficiency. A stablity test was performed at C1 = 0.04mM. The PCL-PEO 2800-2000 polymeric micelles had a retention ratio of 37,57 ± 4,35 %. The PLA-PEO 10500-5000 performed better, 69,03 ± 1,27 % of the zirconium was still found to be in the micelles after being challenged by diethylenetriaminepentaacetic acid, or in short, DTPA. A stability test was also performed at C3 = 1mM, but results were found that are not usable. This experiment should be done again in future research.

Radiotherapy is a vital component in the treatment of malignancies, with approximately 50 to 70% of cancer patients receiving it at some point. This therapy consists of irradiating the affected body part with an external beam of ionising radiation. A limitation of this technique is its damaging effect on healthy cells surrounding the tumour. Semiconducting nanoparticles could offer a solution to this, as these compounds can generate reactive oxygen species (ROS). ROS are a group of free radicals that are known to be able to damage DNA and potentially cause necrotic or apoptotic cell death. Using these metal nanoparticles could increase the radiation damage to malignant cells during radiotherapy, without raising the risk of cell death for the surrounding tissue. Especially TiO2 nanoparticles have been increasingly studied due to their ability to produce singlet oxygen, one of the most reactive ROS, while also having low toxicity and cost. However, many aspects of the ROS-formation remain unclear, including certain ROS production pathways. This report will therefore focus on the ability of TiO2 to produce specific ROS in response to ionising radiation, which will primarily be compared to the ROS formation through the radiolysis of water. The focus lies on the detection of singlet oxygen and hydrogen peroxide (H2O2 ) after irradiation by either a Co-60 gamma or a low energy X-ray source over a range of 5 to 40 Gy. Their concentrations are detected by fluorescence spectroscopy for singlet oxygen, and by UV-VIS spectroscopy for hydrogen peroxide. The results were promising for the use of TiO2 in radiotherapy, with both MilliQ water and TiO2 being able to produce singlet oxygen in increasing amounts over the entire researched irradiation range for both radiation sources; Moreover, TiO2 could produce a significantly larger amount of this ROS than the MilliQ water samples did. The hydrogen peroxide detection experiments were first conducted with ZnO instead of TiO2 . During these, the trends observed for the H2O2 concentration were similar to the ones obtained during the singlet oxygen experiments. The main difference was that the ZnO samples produced approximately the same amount of H2O2 as the MilliQ water samples for X-ray irradiation, instead of higher values. Lastly, the hydrogen peroxide concentration in both TiO2 and ZnO samples was measured after irradiation by Co-60. ZnO exhibited an upward trend in which the H2O2 molarity increased as the applied dose got higher. The detected H2O2 levels in the TiO2 samples were, on the other hand, relatively stagnant. This observation is likely attributed to a relatively high extent of either the degradation, conversion, or adsorption of this ROS at the surface of TiO2

Nano-carriers have the potential to be an enormous game-changer in medicinal drug delivery systems. The polymeric nano-carriers used in this study are a product of the self-assembly of amphiphilic block copolymers, a complicated process which must be understood completely to finely tune the desired morphology for drug delivery. The goal of this thesis is to gain a better understanding of the self-assembly process of amphiphilic block copolymers. Specifically, it will focus on the ’opaque phase’ observed for poly(1,2-butadiene)-b-poly(ethylene oxide) (PBd-PEO) block copolymers, which seems to occur in the early stages of the self-assembly process. A nano-precipitation method has been developed at the TU Delft, which induces selfassembly and brings forward the opaque phase. The used block copolymer has a hydrophobic PBd block and a hydrophilic PEO block. This block copolymer dissolves well in acetone, but upon water (H2O) addition, it starts to self-assemble into spherical aggregates, useful for drug delivery. At small volumes of H2O, the opaque phase appears and disappears as more H2O is added. In this thesis, multiple samples have been prepared with the so-called Inverse Nanoprecipitation method and different experimental parameters among which the volume percentage of H2O present in the sample, have been varied. The samples have been studied using Visual Inspection, Dynamic Light Scattering and Spin Echo Small Angle Neutron Scattering. The experiments show that the time intervals between H2O addition do not affect the formation of aggregates, but rather the ‘when’ of adding the H2O. If this is added to the acetone before the block copolymer is dissolved, it affects the self-assembly process. A visual experiment showed that the opaque phase occurred 1.2±0.1 vol% H2O earlier than in previous research, which might be a result of the lower room temperature during this thesis. Another significant result might be that the addition of acetone-D6 or D2O affects the self-assembly process, which must be considered for future SESANS measurements. Lastly, during the opaque phase a strong temperature sensitivity is observed (which was already found in previous research at TU Delft, by E. Remmelts and further researched by R. Baaijens), high light scattering intensities are detected with DLS and for SESANS measurements the scattered neutron intensities were low. These observations all strongly point to a theory called ‘pre-micellization’, which gives a better understanding of the opaque phase.

Combining different treatment modalities has proven to improve patient outcome compared to applying single treatments. Consequently, mild hyperthermia (HT) and radiotherapy (RT) are combined to radiosensitize tumour cells by inhibiting DNA damage repair mechanisms. In this study, it was investigated if combining both treatment modalities shows an improved therapeutic effect on 3D tumour models made of FaDu cells. To this end, the spheroid size and cell viability were measured over time after treatment. It was also attempted to obtain further qualitative information of the effect on the spheroids using confocal microscopy. During experiments spheroids were formed of FaDu tumour cells, cells of a head-and-neck squamous cell carcinoma, using Matrigel®. These spheroids grew fast within the first 10 days of seeding up to a size of 550-600 𝜇m reliably. These spheroids were then exposed to both single HT and RT as well as combined HT and RT. Both single treatment modalities showed a decrease in cell growth and cell viability with increasing treatment dose. The thermal doses of 30 and 120 CEM43 and radiation doses of 2 and 6 Gy were chosen to be used in the combined treatment experiments. Combined treatment showed an improved effect on the cell growth and cell viability for most treatment groups, both for HT followed by RT and the other way around, with the determining factor seemingly being the thermal dose. The thermal dose of 120 CEM43 combined with 6 Gy of radiation dose showed the highest cell killing potential, with 9±2% of the cell viability remaining when using radiotherapy before hyperthermia and 18±3% when starting with HT before using RT. The most significant difference in effect due to the order in which RT and HT were administered was seen in the group treated with 2 Gy of radiation dose and 120 CEM43 of thermal dose. In this group RT preceding HT resulted in a cell viability of 13±2% on day 7 after treatment, whilst HT preceding RT resulted in a cell viability of 48±8%. Visual inspection of the spheroids showed an increased effect in the form of less growth, as well as flaking around the edges of the spheroids. Obtaining qualitative information on the effect that combined treatment had on spheroids using confocal microscopy was unsuccessful. Both using a live and dead cell staining kit, as well as PI staining proved ineffective in accurately visualizing the dead cells in spheroids.

Breast cancer is one of the most dangerous forms of cancer worldwide. Continuous research is therefore essential in order to find realistic treatment options. 3D tumor spheroids have been proven to imitate the structural and physiological TME of in vivo tumors relatively more accurate than the more widely used 2D cell cultures.
During this study, the aim was to find the optimal conditions for single spheroid formation, employing breast cancer cells and utilizing GrowDex. Different concentrations and cell densities were used, as
well as differing methods (GrowDex addition prior or (days) after cell cluster formation). The liquid overlay technique was used to grow the spheroids, which were observed for a maximum of 14-16 days. Finally, an ATP viability assay was performed to determine whether the spheroids contained a proliferation zone, which corresponds to active cells.
Single spheroids were obtained for all cell densities. The relatively high GrowDex concentrations responded well to a cell density of 2000 cells, while the relatively low GrowDex concentrations responded well to cell densities of 5000 and 10000 cells. Through the ATP viability assay the samples illustrated
the presence of a proliferation zone, and thus active cells.

Anaemia affects a third of women and almost 50% of infants and toddlers worldwide. Iron deficiency is the most common cause of anaemia, and the most common nutritional disorder in the world. To increase dietary iron intake, iron fortification of staple foods commonly consumed by the general public is an effective approach to prevent and control iron deficiency anaemia. It is important to maximise the iron bioavailability (absorption by the human body) in these fortified products, since iron overload is also known to cause Since the diet of infants and toddlers revolves around milk, milk is a good food carrier to address iron deficiency anaemia in children. The aim of this project is to assess the influence of five factors on the bioavailability of iron fortified skim milk: (1) iron concentration, (2) molecular form of the added iron, (3) storage time after fortification, (4) the addition of an iron enhancer and (5) the addition of an iron inhibitor.
Skim milk was fortified with FeC l2 and FeC l3 to 5 and 20 mmol Fe L−1
and stored for 24 hours or one week.
Part of the milk was further left untreated and to another part ascorbic acid (vitamin C) or tannic acid were added as respectively iron enhancer and iron inhibitor. The bioavailability of the iron in these milk samples was assessed on phase distribution and oxidation state, since it is believed that iron in the soluble phase of the milk and in the oxidation state Fe2+ is more bioavailable.
Analysis showed that the difference in iron concentration induced a pH decrease, which was greater for the higher concentrations of iron and the molecular form FeC l3. The pH difference caused the percentage of iron present in the casein fraction to increase, in the protein fraction to decrease and did not influence the iron in the soluble phase. It was also found that the 20 mmol L −1 FeC l2 showed more iron in the soluble phase and more Fe2+, whereas no statistical difference was observed for the 5 mmol L −1 , which might also be due
to the pH difference. The increase in storage time to one week was reflected by an increase in iron bound to the caseins. This shift was not reflected in a change of oxidation state. The addition of the iron enhancer (ascorbic acid) increased the iron present in the protein fraction and soluble phase, which was strengthened by the further decrease in pH. The chelation of iron by ascorbic acid did not necessarily reduce Fe3+ tot Fe2+; the Fe2+ decreased for the 20 mmol L −1 FeC l2, whereas it increased for the 20 mmol L −1 FeC l3. Lastly the
addition of the iron inhibitor resulted in a significant decrease of Fe2+. Most iron was bound to the casein or precipitated as iron-tannic acid complex.
Overall, this research confirmed that the bioavailability of milk is not easily evaluated, since the behaviour of iron in milk depends on many different factors that can not be studied isolated. Only by evaluating many possible combinations of concentration, molecular forms, additives and storage conditions, the bigger puzzle can be solved. This project attributed to a part of the solution and is therefore a valuable contribution in the development of bioavailable milk products, that will reduce iron deficiency anaemia in children.

Targeted Alpha Therapy (TAT) is an interesting technique in tumour treatments, especially in the treatment of local tumours or the treatments of solid tumours while minimizing unwanted radiation to surrounding tissue. The use of Ac-225 in TAT is especially interesting as in the decay of Ac-225 four alpha particles are emitted. The recoil effect will however disrupt the daughter nuclide from the targetting molecule, allowing the daughter nuclide to drift away from the tumour cells to healthy tissue. In order to study the redistribution of radionuclides due to the recoil effect imaging tools are required. An existing technique is the classic alpha camera, this technique is based on the scintillation of alpha particles. Emitted photons by the scintillating layer are registered by a charge coupled device. This technique allows for a spatial resolution of up to 35 μm but is limited by the uptake of other radiation forms (photon, beta). Another alpha imaging technique is called the Timepix, this is a hybrid pixelated semiconducting sensor that consists of an array of 55 μm square pixels. The semiconducting material (silicon) converts ionizing radiation into charge carriers that are collected at pixel sites. In this research the limitations of the Timepix chip with regard to spatial & energy resolution in alpha particle imaging are investigated. The spatial resolution was investigated by the use of fine edged alpha absorbing objects, a small pitched collimators to ensure a monochromatic beam of alpha particles, and an alpha emitting source (Am-241). The Timepix chip registered the incoming alpha particles. By binning the counted alpha particles in small inter- vals a step function was obtained, from which a Gaussian function was obtained. The Full Width at Halve Maximum (FWHM) is a measure of (spatial) resolution of the Gaussian function. Results showed a spatial resolution of 9.8 μm obtained by a collimator with pitch of 6 μm. The obtained spatial resolution shows that sub-pixel resolution in alpha particle imaging is possible. The energy resolution of the Timepix chip was investigated by the use of a collimator to ensure a monochro- matic beam of alpha particles, several Mylar foils to slow down the alpha particles and an alpha emitting source (Am-241). The use of the time over threshold mode (TOT) indicates the amount of time a signal is above threshold, which is a direct indication of the particles energy. Output of the chip is Gaussian shaped, from which the energy resolution was obtained. The obtained energy resolution of the Timepix chip was 0.8 MeV, which allows for identification of most daughter nuclides from the decay chain of Ac-225. This energy resolution does not allow for the identification of the disintegration of Fr-221 (6.64 MeV) and Ac-225 (5.94 MeV).

High dose-rate (HDR) brachytheraphy (BT) is radiation therapy (RT) which temporarily inserts a highly radioactive source into the planning target volume (PTV) with the use of an afterloader, applicator, transfer tubes, needles and planning software. The dose delivered to a point in the tumour depends on the type and activity of the source, the distance to the source and the time the source dwells at a predetermined dwell position. Current therapies have proven to be capable of tumour control. However, in contrast with other RTs there is no suitable integrated dose verification method available for HDR BT which does not disturb the clinical workflow. The focus of this research is on the dose verification for the most commonly used form of HDR BT. The one with the Ir-192 source. An optical in vivo dosimetry (OIVD) sensor assembly consists of a capsuled scintillator coupled into an optical fibre, which connects to a photodiode capable of processing the light signal generated in the scintillator. These systems are currently only available in experimental set-ups and not jet integrated with the afterloader, making them clinically unusable. Furthermore, the system needs to be coupled with an optical fibre of 100-300μm, give a linear output signal to remodel the delivered dose, be non-hygroscopic, be suitable at treatment temperatures, and have low production costs. By adding a OIVD sensor to the current clinical BT workflow, better treatment can be achieved. This sensor assembly needs to be made with a suitable scintillator and shape to have a high coupling efficiency in the OIVD sensor system to give reliable dose verification. Both a literature study and simulations are executed as part of my master thesis to provide a context for the project and to find the best-suited shape and scintillator, This report provides an overview of the current status of knowledge of OIVD from the available experiments and clinical studies derived from the published data, so knowledge for choosing the scintillator material, fibre diameter and the coupling geometry can be obtained. Special attention is given to identifying why scintillators excite light of a specific wavelength and how to achieve an efficient light coupling. The inorganic scintillator ZnSe : O has favourable scintillation characteristics and is has proven itself to be helpful in a OIVD sensor for Ir-192 BT with its high intensity, good energy resolution, slight afterglow and low production cost. The experimental part of this research is the verification of the OIVD sensor assembly with simulations executed within the COMSOL Multiphysics®ray-tracing package, which compares multiple similar OIVD sensor assembly heads. The OIVD model is inspired by the experimental set-up from E.Andersen and simulates for multiple configurations on a range of parameters (5). The simulations of the OIVD sensor assembly can conclude the following: 1. The most favourable scintillator is ZnSe :O, this scintillator has the highest light yield and low absorption. 2. With a fibre diameter of 200μ m, sufficient light yield reaches the detector to verify the dose delivery. 3. Couple the fibres off the centre from the central axis of the scintillator will negatively influence the coupling efficiency. The outcome of this research contributes to the design of a OIVD sensor assembly for HDR BT for with Ir-192 . These simulations lead to an optimal design that will fit the current afterloader system. Next to this, the OIVD sensor assembly head can be made with simple manufacturing steps so that it can be produced at a minimal cost. The combination of the COMSOL model with the scintillation properties from the literature shows that a sensor assembly of a ball coupled ZnsSe :O scintillation is has a higher light throughput than the prototype from E.Andersen (5), this shows that it is favourable to verify the dose delivery of Ir-192 HDR BT (5).

Cancer is still one of the most serious diseases for humanity. Internal radiation therapy with alpha particles is a promising method to battle cancer, but it is currently limited to easily accessible tumors. A more advanced and selective method for alpha radiation therapy that will have better outcomes, fewer side effects, and higher efficacy is needed. A promising alternative is a two-step approach in which super paramagnetic iron oxide nanoparticles (SPION’s) are first delivered to the cancer cells and then receive the radiotherapeutics in a targeted manner. One of the most important conditions for this strategy is retention of SPIONs at the cell membranes in order to ensure in vivo click-reaction between the azide-functionalized nanoparticles and cyclooctyne-conjugated radiotracer. The goal of this study is to observe the behavior of two types of SPION’s on the glioblastoma multiforme (GBM) cancer cell line U87 and to verify whether the nanoparticles are internalized by the cancer cells or stay on the outside of the membrane. This has been done by growing U87 spheroids, incubating them with the nanoparticles, performing a cryosection on these spheroids, photographing the slices of the cryosection with a fluorescence microscope and analyzing the iron-content of the slices with inductively coupled plasma optical emission spectrometry (ICP-OES). The second part of the study concerns the preliminary in vitro click-reaction of the nanoparticles by adding beta emitter 177Lu coupled to DOTA-cyclooctyne complex to spheroids that were incubated with the nanoparticles. The fluorescence microscope analysis concludes that the nanoparticles functionalized with polyethylene glycol (PEG) penetrate the U87 spheroids less than the nanoparticles without PEG. The azide click reaction between the nanoparticles and 177Lu-DOTA-cyclooctyne complex was observed and showed more cell damage to the spheroid incubated with nanoparticles then the spheroids that were only treated with 177LuDOTA-cyclooctyne.