Goud Nanodeeltjes als Gerichte Behandeling van het Hoofd en Hals Plaveiselcelcarcinoom

A key challenge in modern radiation therapy remains the localization of its toxicity relative to the tumor. The limitations in this cancer treatment lie in the creation of side effects in healthy cells located in the vicinity of the beam track. An interdisciplinary solution is presented offering new possibilities for an increased localization of the treatment. A targeted approach is proposed in a novel combination with low-energy irradiation for the treatment of squamous cell carcinoma of the head and neck. Coating gold nanoparticles with functionalizing surface layers is observed to interact with specific protein ligands on the surface of the SQD9 culture cell. This necessary cell differentiation for head and neck squamous cell carcinomas is offered by their expression of the Epidermal Growth Factor Receptor on its cell surface. The latter allows for the increased selectivity of the cancer cell due to enhanced affinity by the monoclonal antibody Cetuximab grafted on the gold nanoparticles. After the synthesis of various gold nanoparticles, the supplementary features that the functionalizing coatings of polyethylene glycol and Cetuximab offer are examined. By means of different characterization methods the final nanostructures are systematically adapted and the most effective gold nanoparticle complexes are then chosen for further irradiation experiments on supercoiled DNA and the SQD9 cell lines. With DNA damage by gold nanoparticle radiosensitization as the main goal of the presented approach, the experiments with supercoiled DNA are especially relevant as experimental supplement to biophysical simulations. The subsequent experiments on cell cultures evaluate the gold nanoparticle radiosensitization on the next stage towards potential clinical use. As increased damage of the DNA remains the key target, supplementary biochemical parameters defined by the cellular environment are simultaneously accounted for in order to achieve successful application of the gold nanoparticles. Gold nanoparticles functionalized with polyethylene glycol of different chain lengths are intercalated in supercoiled DNA to determine the influence of the capping layer thickness on the radiosensitizing effect of the particles. Size variations in the polyethylene glycol coating and the relaxation pattern of the DNA after irradiation allow an unprecedented evaluation of the decrease in dose enhancement percentages caused by the gold nanoparticles at different radial distances from their surface. It could be concluded that on average up to 58 % of the radiosensitizing efficiency was lost when the radial dimensions of the functionalizing layer were increased from 4.1 to 15.3 nm. The subsequent addition of Cetuximab enables the targeting function of the presented gold nanoparticles. The eventual functionalization with the final coating layer, improving colloidal stability and molecular targeting, allows subsequent administration to the SQD9 cell lines. The cellular uptake by endocytosis and the eventual intracellular localization is confirmed. These visualizations of internalization and the absence of gold nanoparticle-specific cytotoxicity confirm the presence of specific pathophysiological characteristics on the cell surface of the solid tumors that allow specific targeting by enhanced gold nanoparticles. Finally, evaluations of the cell survival reveal radiosensitizing enhancement factors in the range of 1.3 to 2.1 for 15 and 30 nm gold nanoparticles. Reported without precedent for head and neck squamous cell carcinoma, experimental evidence is presented for an improved localization on the cellular level and an enhanced reduction of cell survival induced by the radiosensitizing effect of gold nanoparticles under low-energy irradiation. In parallel, by lowering the incoming beam energy and improving the localized energy deposition a reduction of side effects caused in the surrounding healthy cells can be achieved. The results generated throughout this study serve as an experimental supplement for biophysical simulations. They also demonstrate the influence of important parameters in the development of, and further confirm the large potential of radiosensitizing nanomaterials for targeted therapies in cancer radiotherapy.status: publishe