Holmium-166 is a promising radionuclide for therapeutic and imaging applications due to its advantageous decay characteristics. However, these applications require or would benefit from a higher specific activity of ¹⁶⁶Ho than that obtained via a ¹⁶⁵Ho(n,γ)¹⁶⁶Ho reaction by irradiating a pure ¹⁶⁵Ho target. The specific activity is limited, because only a minor fraction of the ¹⁶⁵Ho target nuclides is converted into ¹⁶⁶Ho during irradiation and these isotopes are inseparable using conventional chemical methods, since they are of the same element. The Szilard-Chalmers effect facilitates this separation by changing the chemical state of the produced radionuclide due to the recoil induced by neutron absorption. Nevertheless, currently applied target materials, mainly ligands, are unsuitable for commercial scale production with sufficient yield and specific activity, because of: radiolysis, isotopic interchange and recombination. It is proposed that these processes can be significantly reduced by exploiting zeolites, which are materials with interconnected cavities, to bind ¹⁶⁵Ho target nuclides in the closed cages prior to irradiation. The concept behind is, that upon recoil the ¹⁶⁶Ho nuclides relocate to the open cages, from which they are extracted after irradiation, while the ¹⁶⁵Ho target nuclides remain locked in the closed cages. This results in an increased specific activity. Therefore, the aim of this thesis is to examine the increase in the specific activity of ¹⁶⁶Ho produced via a (n,γ) reaction by applying the Szilard-Chalmers effect using zeolite A.

A procedure to achieve the optimal loading of holmium into the open cages (18.3 wt% Ho) and closed cages (93.3% of total holmium) of zeolite A was investigated, as well as the efficiency of its extraction from the open cages (between 39 and 55%). The obtained specific activity and yield were analysed upon irradiation of these zeolite A samples. Irradiating zeolite A with ¹⁶⁵Ho exclusively in the open cages resulted in only a slight increase of the specific activity (maximal 3.3 GBq/g), but a relatively good yield (maximal 53%). In contrast, irradiation of zeolite A with ¹⁶⁵Ho loaded in both the closed and the open cages, resulted in a considerably lower yield (maximal 14.4%), but a substantially increased specific activity (maximal 7.3 GBq/g), which is a factor 5.2 higher than without the Szilard-Chalmers effect. 
Nevertheless, further improvement should be considered as a higher specific activity is key to successful radionuclide therapy. This could potentially be achieved by increasing the extraction efficiency by exploring other types of zeolites, in search of more suitable functional characteristics.

Iron deficiency is considered the most significant nutritional deficiency worldwide, affecting billions of people. Iron deficiency leads to a higher prevalence of iron deficiency anaemia; a condition responsible for over 50,000 deaths annually. Since anaemia is considered a global health problem, various countermeasures have been implemented to battle this disease. One of these countermeasures is the supplementation of iron. Different iron compounds are employed for supplementation, including ferrous sulphate and ferrous fumarate. However, since only 15% of the supplemented iron is absorbed by the human body, the remaining 85% can cause various health-related issues. Due to heightened amounts of iron present in the duodenum, a disbalance in the human gut is induced, leading to e.g. excessive growth of Escherichia coli (E.coli).
This study investigates the influence of 3 and 30 µM iron supplementation of ferric chloride and ferric sulphate; radiolabelled with Fe-55. These results have been reported in the form of growth curves, and the remaining amount of Fe-55 in the growth medium has been used to estimate iron uptakeby E.coli. No significant differences were observed between 3 and 30 µM iron supplementation of both compounds, indicating that iron concentration may not be considered as the main limiting growth factor of E.coli. Therefore, further research is recommended where the medium is analysed for the presence of other nutrients. Additionally, adjustments in the growth environment are recommended, to determine which growth conditions influence E.coli the most.

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.

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.

The recently discovered negative health effects of Gd(III) complexes based magnetic resonance imaging (MRI) contrast agents have stirred interest into the development of alternatives based on Mn(II) complexes
due to its biocompatibility, and hence less health concerns. One important aspect of investigation on contrast agents in general, and Mn(II) complexes in particular, is an accurate determination of their concentrations in solution. Therefore, in this study a known approach of determining the concentration of paramagnetic species in solution, via the Bulk Magnetic Susceptibility (BMS) shift, is applied for Mn(II) and the feasibility of the method is evaluated. A proof of principle using Gd-DOTP concentrations in the range 0.7 – 6.6 mM Gd(III) to verify the applied BMS method was successfully performed. Subsequently, BMS measurements were performed with MnDOTA as well as free Mn(II) and the obtained concentrations were verified with ICP-OES. A good agreement between the two methods was found within the concentration range of 0.4 - 15.1 mM Mn(II) for both MnDOTA and free Mn(II). Although, BMS measurements showed slightly higher concentrations than those found by ICP-OES for both Mn-DOTA and free Mn(II). Additionally, the deviations between ICP-OES and BMS were greater for free Mn(II) compared to Mn-DOTA. Experiments for determining the accuracy of the BMS method showed a 2.5% upward systematic error. The random error decreased from 20% for 0.27 mM Mn(II) to almost 0% for 4.0 mM Mn(II) and higher concentrations. In conclusion, the BMS method proved to be accurate for determining Mn(II) concentrations and has
promising prospects for future research into Mn(II) complexes. However, deviations between ICP-OES and BMS measurements need further investigations. Key words: Bulk Magnetic Susceptibility shift, contrast agent, Mn(II) complexes.

Conventional early-stage breast cancer treatments such as surgery, chemotherapy and external radiotherapy despite their proven short-term efficacy tend to have adverse long-term physiological and psychological implications on the patients. This is primarily due to their inability to spare healthy tissue surrounding the tumor. Use of radioactive palladium (¹⁰³Pd) seeds for producing localized effect with brachytherapy is already in practice. However, they are known to result in uneven dose distribution with creation of "hot spots" in the vicinity of seed implants. Alternatively, conventional thermal ablation or hyperthermia treatments using mechanical or electromagnetic systems also have difficulties with localizing the thermal effect to the target region. Composite and biocompatible palladium- (Ultra-small) superparamagnetic iron oxide nanoparticles (PdO-USPION) on the other hand have the potential to diffuse throughout the tumor ensuring relatively more uniform dose distribution and improve the ease of clearance from the biological system without causing long-term side effects. Magnetic property of (Ultra small) superparamagnetic iron oxide nanoparticles can be exploited to induce and deliver heat energy to kill cancerous cells upon exposure to Alternating magnetic field (AMF) and generate contrast enhanced magnetic resonance images (MRI) by subjecting them to static magnetic fields. Heating and contrast enhancement ability depends on the physical, chemical and magnetic properties of nanoparticles which in turn rely on the synthesis method. In this research, spark ablation technology is employed to produce the nanoparticles from metallic electrodes. Although, for the purpose of the current research, inactive palladium is used to reduce complexity given that the synthesis of PdO-USPIONs with this synthesis method is employed for the first time through this research. Inter-metallic Pd-Fe are generated in the spark discharge system and captured in an aqueous media resulting in (oxidized intermetallic palladium ultra-small superparamagnetic iron oxide nanoaparticles) PdO-USPIONs. Since the synthesis method is relatively new, major component of the research deals with investigating the influence of system parameters on production of nanoparticles. Characterization results associated with USPIONs and PdO-USPIONs are thoroughly analyzed to optimize the setup to generate tunable PdO-USPIONs and to evaluate their performance as thermal and contrast agents. Use of citric acid as surfactant to lower agglomeration resulting in improved T₁ relaxation behavior is also studied.

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.