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.

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.

Radionuclides are often used in the field of nuclear medicine. For some deceases the use of radionuclides is the best possible care, or even the only means of diagnosis or treatment. For these medical applications high specific activity (high activity per unit of mass) is required. Commonly, medical radionuclides are man-made. They can either be produced by neutron activation, charged particle or photon activation or by means of radionuclide generator. Furthermore, hospitals prefer an ‘on demand’ supply. A radionuclide generator is ideal. Radionuclide generators can also be used to produce high specific activity. Conventional radionuclide generators work with the principle that the mother and daughter radionuclide have different electrostatic interactions with the column material. This allows for easy elution of the daughter radionuclide. However, when working with chemical identical mother-daughter radionuclide pairs (e.g. ^177mLu / ¹⁷⁷Lu) another separation principle is required. Utilising ‘hot atom’ chemical principles such a mother-daughter pairs can be separated. ‘Hot atom’ principles describe the chemical effects that occur due to nuclear interactions or due to decay. An example of these effects is bond rupture. The effective range of those principles is rather limited, requiring thin layers. A possible technique to apply these thin layers is atomic layer deposition (ALD). ALD is commonly used in the semi-conductor industry, but can due to its versatility also be used in the field of catalysis or pharmaceutical. The advantage of using ALD is that this gas phase deposition technique allows for thin conformal coating of complex structured materials. Furthermore, the amount of material that can be deposited can easily be adapted to need because ALD is a self-limiting process. In this thesis the usefulness of ALD in combination with radionuclide production is explored. Because of the versatility of ALD it can also be used to create target materials for charged particle activation and enrichment experiments (Chapter 2). This versatility is illustrated by three case studies, namely this production of targets for ⁶⁴Cu production, the production of ¹⁷⁷Lu by means of a radionuclide generator and the production of ⁹⁹Mo using three different routes. Also described is how ALD can be used to alter the surface chemistry of high surface area materials to increase their adsorption capacity for Mo (Chapter 3). The obtained particles with an alumina coating are then tested for their adsorption capacity and compared to acid activated alumina, the current used material in ⁹⁹Mo/^99mTc-radionuclide generators. The adsorption capacity of the obtained particles is twice that of acid activated alumina and has a 99mTc elution efficiency of 55%. Furthermore, the coating of nano-particles for the development of with Lu coated particles (Chapter 4) for the preparation of a radionuclide generator is described. ALD allows for a deposition of up to 15w% Lu. Furthermore, the gamma dose received during neutron activation has an influence on the specific activity produced (Chapter 5). Using Cu(II)-phthalocyanine as a target it is shown that an increase in gamma dose during neutron activation results in an increase in Cu release and hence a decrease in specific activity obtained.

Purpose/Objective: The aim of the thesis project is to design and build a sample-holder that is suited for radiobiological experiments on cell and tissue level in Holland PTC. In order to create accurate dose plans for radiobiological experiments, dosimetry and range calculations need to be worked out. Finally the sample-holder is used for the first radiobiological experiment at Holland PTC. Materials and Methods: The sample-holder is constructed as a slab phantom that allows secure and easy positioning of a 6-well cultivating plate, fully made out of polystyrene. Water equivalent thickness (WET) measurements are used to calculate the density of the slabs, which can be used for dose calculations in treatment planning and Monte Carlo software. Radiochromic EBT3 film is used to perform dosimetry during experiments, the films are calibrated using an ionization chamber to be able to perform absolute dosimetry. A 70 MeV single pencil beam is delivered to the sample-holder with EBT3 films in between the slabs to compare a reconstructed Bragg peak from the relative doses of the films with dose calculations performed in RayStation and TOPAS MC. Cell survival experiments with U2OS cells are performed by irradiating with X-rays and protons. Circumstances where such that the influence of cells being on room temperature for several hours and cells being without medium inside the wells during irradiation could be studied. With protons, cells were irradiated both in the plateau region and in the Bragg peak. LETd calculations are performed in TOPAS MC in order to study the RBE-LET relation. Results: The slabs of the phantom are uniform and have a density of either 1.04 g/cm3 or 1.06 g/cm3 Using these density values the range of a 70 MeV can be calculated with a 0.5 mm accuracy using TOPAS MC and RayStation. The relative central axis dose profile calculated with TOPAS was accurate within 5% compared to the measured values with EBT3 film. This was 20\% for calculations with RayStation. Absolute dose measurements with EBT3 film inside a RW3 phantom agree within 1\% with the delivered dose according to the ionization chamber. In the polystyrene sample-holder this difference is 11%. For X-ray irradiation, incubated cells were able to form more colonies after irradiation compared to cells that had been on room temperature for four hours. Cells that were irradiated without medium in the well had a higher surviving fraction than cells that had medium in the well. For proton irradiation the results are limited since all cells that received more than 0.91 Gy had died, but from the available data it can be seen that irradiation in the Bragg peak results in more cell death compared to irradiation in the plateau region. In addition to this, cells that had medium in the wells during irradiation formed less colonies than cells that had no medium in the wells, which is consistent with the results after X-ray irradiation. Dose-averaged LET (LET_d) values are calculated at cell depth for proton irradiation in the plateau region and in the Bragg peak and are 1.30 keV/um and 3.78 keV/um respectively. Conclusion: The sample-holder is well defined for use in RayStation and TOPAS MC and range calculations of a 70 MeV pencil beam are accurate within 0.5 mm. Absolute dose values obtained with EBT3 film inside the sample-holder are higher than expected, additional measurements are recommended. Cell survival experiments show that there is a difference in irradiating cells that are in medium vs cells that are not in medium and that long exposure to room temperature increases cell death after irradiation. Radiobiological experiments should be performed with cells that can be prepared and stored on site. The obtained LETd values are comparable with values found in literature. Due to the limited amount of cell survival data after proton irradiation, not link between RBE and LET can be studied.

A radio-fluorogenic (RFG) gel is a polymer gel that can be applied as a 3D radiation dosimeter in radiotherapy. The gel becomes fluorescent in UV light after exposure to high-energy radiation and the intensity of the fluorescence is proportional to the local radiation dose. This radiation-induced fluorescence is permanent, which distinguishes it from transitory optical emission or scintillation effects. In the thesis we demonstrate that a quasi-rigid RFG gel, consisting of tertiary-butyl acrylate (TBA) with ca 100 ppm maleimido-pyrene (MPy), has the potential to produce spatially resolved images of dose deposition. The work focuses on the fundamental radiation chemistry and photophysics of the medium. In particular, we have investigated the dose and dose-rate dependences of polymer formation and fluorescence intensity using cobalt-60 gamma-ray sources. We have also used collimated beams of 200 kVp X-rays to produce complex radiation fields for test purposes and constructed a tomographic method for reconstructing full 3D images of the dose distribution with submillimetre spatial resolution. Our ultimate goal is to provide a method of quantitative, spatially-resolved dosimetry that can be applied to particle beams and other forms of high-energy radiation that produce the complex radiation fields applied in modern radiotherapy treatment of cancer.