Branched gold nanoparticles for specific photothermal therapy of cancer.

Despite significant investments and advances in cancer research, this disease is still a leading cause of mortality, currently responsible for a fourth of all deaths. Current strategies for cancer therapy, such as surgical excision, chemotherapy and radiotherapy, suffer from high invasiveness, toxicity and too many side effects. There is a pressing need for more sensitive, accurate and cost-effective methods for the treatment of cancer.Gold nanoparticles have tremendous potential for the development of novel methods in the field of biology and medicine, including cancer therapy. Due to their unique optical and thermal properties, they become useful agents for hyperthermia therapy, a promising non-invasive approach for cancer treatment. In this therapy, a lethal dose of heat is transferred to the tumor tissue with as little damage as possible to intervening and surrounding normal tissue. Gold nanoparticles efficiently convert absorbed light into localized heat, which can be exploited for the selective laser photothermal therapy of cancer.First of all, it is desirable to use nanoparticles that absorb light in the near infrared region (NIR) of the electromagnetic spectrum since light from this region provides maximal penetration through tissue due to minimal absorption by intrinsic chromophores (hemoglobin and water). Current NIR absorbing nanoparticles, such as nanoshells and nanorods, suffer from too large sizes and toxicity issues. This calls for the development of new NIR absorbing gold nanoparticles, which is the first major aim of this thesis. Branched gold nanoparticles with a plasmon resonance band in the NIR were developed by optimizing the synthesis procedure and electroless plating with gold. Stabilization of these nanoparticles was achieved by chemical functionalization with alkanethiols or disulfides. Secondly, the nanoparticles need to convert the absorbed light energy into sufficient heat to destruct the tumor cells. The presence of sharp edges and tips allows exceptional enhancements of the electric field around branched gold nanoparticles leading to high absorption cross sections and consequently high heating efficiencies. In this thesis, their heating upon laser illumination was evaluated at the nanoparticle level using X-ray extended absorption fine structure spectroscopy and in suspension using a thermocouple. A detailed comparison with gold nanorods was performed and the effect of the nanoparticles and their heating on cells was investigated. Finally, a major bottleneck in photothermal therapy is the achievement of selective tumor targeting, which allows preferential destruction of the cancer cells. The nanoparticles should be linked with tumor specific ligands to target cancer specific receptors on tumor cells with high affinity and precision. Small antibody fragments, such as nanobodies, have unique properties suitable for tumor targeting. In this thesis, an efficient biofunctionalization method was developed and specific cell targeting was demonstrated in vitro using different techniques. Photothermal cell destruction was achieved in vitro using these specific nanobody conjugated branched gold nanoparticles.This study clearly demonstrates the effectiveness of bioconjugated branched gold nanoparticles as antigen-targeting photothermal therapeutic agents for cancer treatment. Hence, this multidisciplinary research has made a significant contribution to the field of nanomedicine.nrpages: 196status: publishe