Nanoparticles for Electron Emission Cancer Tumor Treatment.

The goal of this thesis was to study silica and gold nanoparticles from synthesis to characterization to biomedical application. Nanoparticles (NPs) are typically defined as materials with at least one of its dimension in the range of 1 nm to 100 nm. In this way the NP will behave like a molecule and like bulk material. NPs have unique electronic, optical, magnetic and catalytic properties. Because of these unique properties, nanoparticles can open up new research lines and applications in a variety of sectors. The biomedical applications of nanoparticles include therapeutics, antimicrobial agents and fluorescent labels. In order to use these nanoparticles in biomedical applications, it is very critical to completely characterize the nanoparticles. Since minor changes in composition can change the effect of nanoparticles. The characterization tools used throughout this thesis, were dynamic light scattering, UV-vis spectroscopy, zeta-potential, transmission electron microscopy and small angle X-ray scattering. These tools were discussed in detail. Small angle X-ray scattering has been described in more depth, since it is not the most common technique. In view of this, an integrated system was developed where we can simultaneous do dynamic light scattering and small angle X-ray scattering. Simultaneous SAXS and DLS measurements were performed to monitor the silica NP synthesis with variable synthesis conditions. The nucleation phase was seperated from the growth phase, to improve the standard deviation of the nanoparticles and to influence the size of the nanoparticles. The size of the NPs changed, however no influence was found on the size dispersion.
We focussed on two biomedical applications of NPs.
The first one was coronary heart disease (CHD). CHD is one of the major causes of death worldwide. The disease process initiates when the inner wall of the arteries getting damaged from large quantities of lipids, as a consequence an inflammatory reaction starts. Today, this disease is mostly treated symptomatically by opening the arteries mechanically. In our research, we paved the way towards a system that can do photodynamic therapy (PDT). In PDT, one makes use of a photosensitizer which releases reactive oxygen species which will kill the cells causing the inflammation. The rapid clearance of the photosensitizers prevented their optimal use. We tried to solve this by loading the photosensitizers inside mesoporous silica nanoparticles (MSNPs). These MSNPs degrade over time. The influence of synthesis and experimental parameters on the morphology and biodegradability of MSNPs was investigated by means of an optimized molybdenum blue chemistry. Upon increasing synthesis temperature and increasing amount of TEA, the degradation duration extended while the degradation rate in the beginning decreased. The degradation kinetics were slowest for non-functionalized, followed by carboxylated and amino-functionalized MSNPs. In a second step two photosensitizers were loaded (one via chemisorption and one via physisorption) into the MSNPs. We estimated the amount of photosensitizer present in the MSNPs by refractive index matching and this showed that the amount of photosensitizer loaded with chemisorption was a 1000 times higher than with physisorption. The cell killing of these photosensitizers was tested in vitro. The photosensitizer loaded via physisorption did not show any cell killing while the other one had an IC50 value of 200 mg/ml.
The second objective was to destroy cancer cells. Nanoparticles can be the silver bullet that science has been looking for in treatment of cancer.  In gold nanoparticle (GNP) aided radiotherapy, one uses gold nanoparticles to enhance the dose during radiation therapy. The  dose  enhancements  caused  by  the  presence  of  gold nanoparticles in irradiated  organic  material  were  experimentally assessed as a function of their radial distance to DNA. The distance between the GNP and the DNA was controlled by the use of a PEG-SH molecule. These molecules, attached to the GNP, formed a shell around the GNP which effectively kept the DNA at a distance. We first looked at neutral charged PEG (m-PEG-SH). This yielded a strong decrease of radio enhancement in function of the molecular weight of the m-PEG-SH. The enhancement decreased with 18% at 5 Gy and decrease with 5% at 15 Gy over a distance of 12 nm. However some residual negative charge remained on the GNP. In order to have a better control on the radial distance, it was decided to use NH2-PEG-SH to have an attraction between the GNPs and the DNA. We saw a very low enhancement due the GNPs. The decrease in enhancement due to increasing PEG size was 50%  larger for 5 Gy and for 15 Gy it was 300% larger than for m-PEG-SH. This indicates that a too thick functionalization shell around the GNP can be detrimental for the gold nanoparticle aided radiotherapy.