Computed Tomography (CT) imaging is an important step in treatment planning for proton therapy. The conversion from Hounsfield Unit (HU) to stopping power ratio (SPR) accounts for more than half of the 3.5% error that is considered in treatment planning. The aim of the study is to investigate the efficacy of photon-counting CT (PCCT) for predicting the SPR in proton therapy. Its performance will be compared to single-energy CT (SECT) and dual-energy CT (DECT).

Fresh tissue samples—steak, ground beef, and bone marrow—were secured in 3D-printed holders to minimize air inclusion and maintain tissue stability during measurements. These
samples were secured in a head and a body configuration of a phantom and CT scans were conducted using standard clinical protocols. SPR values were derived from the CT data
using automated DirectSPR software for the DECT and PCCT scans, and converted from HUs to SPR using a Hounsfield look up table (HLUT) for the SECT scans. Results were validated
against actual SPR measurements obtained via proton beam measurements.

Two measurement series have been performed. For the validation of the first measurement series, proton beam energies of 150 and 175 MeV both resulted in an SPR value of 1.00 for the
ground beef sample. For the steak sample, SPR values of 1.02 and 1.03 were found. The CT-based SPR predictions resulted in errors up to 1.5% for ground beef and 3.5% for steak. For
the validation of the second measurement series, SPR values for ground beef (0.89-0.92), steak (0.96-0.98), and bone marrow (0.87-0.91) were obtained. The percentage error between the CT-based SPR predictions and the validation measurements showed no substantial differences between the CT-modalities, except for SECT providing lower SPRs for the bone marrow samples than DECT and PCCT. The validation measurements of the second series resulted in lower SPR values than found in literature and the first
series, indicating possible methodological inconsistencies. Factors such as sample heterogeneities and measurement errors might have contributed to these inconsistencies, but do not account for these inconsistencies completely. These results highlight the need
for further research with standardized phantoms and animal tissue samples to evaluate PCCT’s true potential in combination with DirectSPR prediction.

From this study it cannot be concluded that PCCT demon-
strates an advantage over SECT and DECT as CT-modality for
the HU-SPR conversion in proton therapy treatment planning

Female breast cancer is the second most common cancer worldwide. A promising novel technique to treat early-stage breast cancer is the use of thermo-brachy therapy. This thesis analysed the effect of the cancer biomarker glutathione (GSH) on the magnetic hyperthermal effects of iron oxide nanoparticles. The synthesised nanoparticles with a diameter of 10±4 nm have been coated with cysteine and treated with hydrogen peroxide leading to their aggregation upon cross-linking. As the GSH concentration is higher around cancerous cells (10 μM instead of 3 μM), these nanoparticles would be more monodispersed as GSH could break the disulfide bonds between the cysteines. Since aggregated nanoparticles exhibit lower heating efficiencies, it was assumed that this method would allow for (partially) selective heating of the tumour. The addition of 10 μM GSH resulted in an 11% higher heating efficiency compared to 3 μM GSH when analysing the coated nanoparticles in an alternating magnetic field. However, a GSH concentration of 10 mM (intracellular GSH concentration in cancerous cells) gave a decrease in heating efficiency. Another methodology was proposed as well. Uncoated nanoparticles were encapsulated in a ZIF-8 framework. This framework is less stable in environments with a lower pH value and higher GSH concentration, which is the case in the tumour microenvironment. This methodology gave a 27% higher heating efficiency in a tumour-related GSH concentration and pH value. The differences with both the cysteine and ZIF-8-based methods are yet too small to limit thermal damage to healthy tissue. Modelling the diffusion and its influence on the temperature change, gave very local heating near the injection site due to slow diffusion. Therefore, while this thesis provided insights into the heating efficiencies in tumour-related conditions with both methodologies, addressing the current limitations can lead to significant advancements.

¹⁶¹Tb is considered a promising alternative to ¹⁷⁷Lu in the treatment of neuroendocrine tumors and prostate cancer. It is produced via neutron irradiation of ¹⁶⁰Gd targets and its subsequent separation from said targets. Current separation methods have limitations so a fast removal method of the Gd bulk is desired. Such a method is developed in this research using solvent extraction techniques. Three extractants were investigated, the one with the highest potential, DEHPA, was used to optimize the extraction. This yielded a Tb extraction efficiency of 98.6 ± 0.2 % and a Gd extraction efficiency of 85.7 ± 5.5 % followed by a Tb back-extraction efficiency of 98.2 ± 0.1 % and a Gd back-extraction efficiency of more than 98.2 ± 0.1 %. The Tb/Gd separation was increased by adding the reverse size selective chelator MACROPA to the aqueous phase to preferentially complex Gd in the aqueous phase. This yielded a Tb and Gd extraction efficiency of 95.0 ± 0.2 % and 53.1 ± 3.0 % respectively. The ratio between total EEs of Tb and Gd after three subsequent extractions was approximately 10 demonstrating the potential of using sequential extractions to remove a bulk of Gd from Tb. The procedure of doing consecutive extractions must however be further optimized as nearly 80% of Tb was not extracted. Finally, it was shown that the resulting solution after bulk Gd removal can still be further purified using an ion exchange column. In future research, it is highly advised to investigate the recycling of Gd and MACROPA from the aqueous phase after extraction to allow for further irradiation of the Gd and re-usability of the MACROPA.

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.

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.

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.

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.

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.

Calcium is an important mineral which the body uses to maintain strong bones and carry out many important bodily functions. According to the Dutch nutrition center people in the Netherlands consume 80-90% of their calcium through milk and other milk products. Often times people will further ’process’ milk for other food products. Examples of these include boiling milk to make hot chocolate or freezing it for ice-cream. These temperature changes can have great influence on the bio-availability of the Calcium. The goal of this thesis was to find the effect of temperature on the bio-availability of Calcium in milk. This was done through 2 experiments. Dialysing skim bovine milk at temperatures between 4-90°C and heating or cooling the bovine milk to temperatures between -18°C-95°C and then dialysing at room temperature. The dialysis separates the soluble and insoluble phase of milk allowing for the calculation of percentage soluble calcium which is a good indicator for bio-availability of calcium in milk. It was found that there is a linear relationship between the temperature of the milk and the percentage soluble Calcium, the higher the temperature of the milk the lower the amount of bio-available calcium in the milk. Furthermore when looking at the heated milk it was found that heating to 60°C and above all showed a similar drop in percentage soluble calcium indicating some permanent loss of bio-available calcium. This permanent loss is however lower than what can be observed to be lost in the milk whilst hot indicating that a portion of the calcium that becomes insoluble upon heating returns to the soluble phase once returned to its original temperature.

Radionuclides are important in the diagnosis and treatment of, amongst others, cancer. A promising therapy is targeted radionuclide therapy, where the radionuclide is brought to the tumor by a targeting specific
vector. Bringing the radionuclide directly to the tumor, should reduce the dose to the healthy tissue. For targeted radionuclide therapy, a radionuclide with a high specific activity is required. Some radionuclides,
with promising half-lives and decay energies, are currently not produced with the required specific activity. This problem occurs mainly for radionuclides that are produced via (n,γ) reactions in nuclear reactors. For radionuclides that are produced via this reaction, it is nearly impossible to do a chemical separation between the target material and the produced radionuclide, because these are of the same element. This is why new production routes have to be investigated. In this thesis a feasibility study has been done for a new production method, which should increase the specific activity of radionuclides that are produced via a (n,γ) reaction. For this production method, the target material is labeled with a chelator. Due to the Szilard-Chalmers effect the bond with the chelator will be broken, when the target material is activated by a neutron. This enables the separation of the produced radionuclide from the target complex and therefore, the extraction of the radionuclide. The production method will be loop-based, in order to enable continuous activation of the target material and extraction of the radionuclide. Furthermore, the loop-based design should minimize the effect of radiolysis and relabeling. The loop will be placed close to the reactor core. In this thesis, the elements holmium and lutetium have been used. It has been determined which chelator is most suitable to label with holmium and lutetium. Furthermore, the stability of this complex has been investigated for: higher temperatures, time and the effect of the γ-radiation. The effect of the γ-radiation was determined because this results in radiolysis. The extraction of the radionuclide has also been investigated. These parameters have been used in the calculation of the possible achievable specific activity of 166Ho and 177Lu, when using this loop-based production method. Labeling was possible with the chelator DOTA, which resulted in a stable complex, even for higher temperatures. Labeling happened fast, which also results in fast relabeling. The effect of radiolysis, due to the γ-radiation, was determined by fitting the experimental data. The fit gave negative values for short irradiation times, which is not possible. Therefore, two possible fits were made, which did not give negative results. The first fit was shifted over the y-axis and for the second fit the negative values were assigned to be zero....

Calcium is an important nutrient for both young and elderly people which can, among others, stimulate healthy bone growth and prevent osteoporosis. Therefore, nutrition with sufficient calcium is of great importance. The highest calcium nutrient density for all foods can be found in bovine milk, which contains on average 1.2 g Ca / L. To increase the amount of bioavailable calcium, milk can be fortified by the addition of different calcium salts. In this research the bioavailability and exchangeability of calcium in unfortified and fortified skimmed milk was studied by in vitro methods using equilibrium dialysis and ultracentrifugation to separate different fractions in milk. Radioactive 45Ca was used to follow the exchange behaviour of calcium between the three different fractions in milk: casein micelles, serum proteins, and soluble calcium. For unfortified milk it was found that 34.9 ± 2.2% of the calcium was present in the soluble phase, 9.1 ± 0.6% was bound to serum proteins, and 56 ± 1.6% was present in the casein micelles, which confirmed the results in literature. In addition, with the investigation of the exchange behaviour of 45Ca, it was confirmed that ~40% of calcium in casein micelles is hardly exchanged.To investigate the influence of calcium fortification on the calcium equilibrium in milk, six different calcium salts were selected to be synthesized: calcium chloride, calcium carbonate, calciumgluconate, tri-calcium di-citrate, calcium lactate, and tri-calcium phosphate. Of these, calcium chloride, calcium carbonate, calcium gluconate, and tri-calcium di-citrate were successfully synthesized. Further experiments were performed with calcium chloride and calcium carbonate, intrinsically labelled with 45Ca. From fractionation with ultracentrifugation, it was concluded that addition of calcium chloride led to an increase of calcium in the soluble phase, which might indicate an increase in bioavailability. Fortification of milk with 45Ca labelled calciumcarbonate did not lead to an exchange of 45Ca with the calcium present in milk, indicating that calcium carbonate is unlikely to make calcium in milk more bioavailable. In conclusion, a better understanding of the solubility and exchangeability of Ca in milk and the influence of milk fortification with calcium chloride and calcium carbonate is obtained by using 45Ca as a tracer.

Most modern cancer treatments are a combination of therapies. In approximately 50% of these combinations radiation therapy plays a prominent role. Although external radiation therapy is very effective,
it still damages healthy tissue. Therefore, ways to increase radiation dose deposition at the tumor are sought. The interaction of radiation with the photocatalytic nanoparticle titanium dioxide, TiOኼ NPs, is investigated in effort to improve the effectiveness of radiation therapy, minimizing collateral damage to healthy tissue.
TiOኼ NPs, upon the absorption of light, are capable of producing reactive oxygen species, which are the main contributor to DNA strand breakage and cell damage through oxidative reactions in radiation therapy. Singlet oxygen is the most potent of these reactive oxygen species. This research aims to
determine whether TiOኼ NPs are capable of producing singlet oxygen when interacting with ionizing radiation. Efforts are made in uncovering the mechanisms and dependencies behind the production of singlet oxygen using the fluorescent probe Singlet Oxygen Sensor Green, SOSG. The oxidative capabilities of the TiOኼ NPs in combination with ionizing radiation are looked into with the probe Mythelene blue, MB, which degrades under oxidative reactions.
The results for aerobic conditions show a significant rise in fluorescent intensity by the probe SOSG when irradiated in the presence TiOኼ NPs. The rise in fluorescence appears to be linked to the presence of singlet oxygen but this could not be confirmed. SOSG has also shown a rise in fluorescence in
anaerobic circumstances not suitable for singlet oxygen production. This signal response is attributed to the increased presence of hydrated electrons, in line with hypothesized sensitivity of SOSG towards hydrated electrons. The mechanisms behind the production of singlet oxygen could not be uncovered
however the production does favour low photon energies and does not depend on dose rate.
The results from the MB degradation experiments indicate no significant amount of degradation is caused by the photocatalytic activity of TiOኼ NPs concentrations used in this thesis. The degradation that does occur is due to radiolysis, which favours low photon energies due to the increased absorbance.
The production of singlet oxygen through the oxidation of superoxide radicals, facilitated by the interaction of ionizing photon irradiation with TiOኼ NPs, is expected but could not be verified. Future research may verify the origin of the rise in fluorescencent SOSG to be hydrated electrons or singlet oxygen.

The Organ on Chip (OoC) market is fast-growing and has the promise to drastically reduce the cost of developing drugs and the need for animal testing. However, the growth could be obstructed by the difficulties of scaling up production of developed prototypes. Most OoC prototypes are not suited for mass production because of the material used, namely polydimethylsiloxane (PDMS). In this thesis a roadmap for the OoC prototyping process is proposed, which can be carried out in small labs without expensive equipment, and which can be directly scaled up to mass production. In the proposed roadmap the polymer cyclic olefin copolymer (COC) is used instead of PDMS. Expensive etching processes typically used to fabricate a mold are replaced by stereolithography printing and soft lithography. The final parts of the chip are soft embossed and for assembly thermal fusion bonding is suggested. These steps require relatively simple equipment, namely a stereolithography printer, a spin coater, a fume hood, and basic lab ware. Next to that, a press for embossing and bonding is required. Such a press is designed, fabricated, calibrated, and tested in this thesis. The press enables embossing and bonding experiments with high repeatability on a simple desktop and can be fabricated in roughly 2 - 3 days in a workshop with standard materials costing no more than € 250,-. Temperature of the compression platens can be controlled within 0.25oC precise up to 180oC. Compression forces up to 3.5 kN can be applied and an accuracy of ±32 N and ±80 N for forces up to respectively 1.3 kN and 2.0 kN can be reached. The performance of the press is tested by carrying out embossing experiments, which yielded replication accuracies comparable with literature for channels of 170 µm deep and 1 mm wide. Next to that, a protocol is produced for spin coating COC films with controllable thickness between 7.5 and 14 µm on top of a COC substrate.

Because diagnostics have improved tremendously, nowadays breast cancer is more frequently detected at an early stage. Long-term prognosis is excellent and therefore the new treatment should focus on minimizing long-term side effects and treatment burden. This research proposes cancer treatment using nanoparticles (NPs) for a combination of heat therapy and brachytherapy. For the NP design, superparamagnetic iron-oxide nanoparticles (SPIONs) will be used. Because of their biocompatibility and good magnetic properties, they are suitable candidates for heating using an alternating magnetic field. To make the NPs applicable for brachytherapy, the NPs are doped with holmium (Ho), a lanthanide with high magnetic moment and radioisotope Ho-166. Furthermore, SPIONs and Ho change the relaxivity of water
protons and therefore they can be used as contrast agents for magnetic resonance imaging. This makes it possible to image the NPs during the treatment and enables thermal planning and dose-rate calculations delivered to the cancer tissue to be performed. The incorporation of Ho inside the iron-oxide structure is expected to change the magnetic properties of the NPs. The success of using Ho as contrast agent and for brachytherapy purposes have been proven in several researches. However, the influence of Ho on the heating performance of these SPIONs is unknown. This research will characterize the magnetic properties of undoped and Ho-doped SPIONs and compare them, in order to examine the heating possibilities of Ho-doped NPs. For the synthesis of the NPs a spark discharge generator was used. Spark ablation is a synthesis
method able to yield narrow size distribution of different metallic particles and alloys. However, since spark ablation is relatively new, the synthetic methodology itself had to be developed. Therefore, this research was divided into two parts: 1) the synthesis of NPs using spark ablation and 2) the characterization of Ho-doped iron NPs and the comparison with undoped SPIONs. Since the first part focused on the spark ablation synthesis, the influence of the generator settings on the primary particle size was investigated using DLS and TEM. The VS-Particle generator was able to produce 4 nm Fe-Fe and Ho-Fe NPs, a size that is smaller than expected. The generator settings did not influence the primary particle size and therefore, the settings of the generator were chosen to maximize the yield. The initial set-up had low yield and therefore, the influence of micro-bubbler, electrode configuration and bubbling column were examined and changed to improve the yield. A bronze sintered filter with pore size 0.4-20 ��, solid iron electrodes and 60 mL bubbling column volume appeared to be the most optimal. During the second part of this research, 4 nm Ho-doped iron oxide NPs and un-doped iron oxides were produced. They were characterized using TEM, DLS, XRD, ICP, SEM-EDX, Mössbauer spectroscopy, SQUID and NMR. As a result of low concentrations obtained, no good qualification of the produced particles could be obtained. All particles showed superparamagnetic behavior and influenced the relaxivity times of water protons. To what extend the relaxivity was changed upon doping remains unfortunately unclear, because the composition of the NPs is unknown. It can be concluded that the used set-up was not able to produce reproducible NPs and therefore no reliable characterization could be done on the Ho doped particles. Future research should focus on a more controllable synthesis method to be able to examine the possibilities of Ho for heating purposes.