Plasmonic Gold Nanoparticles: Combining Photoacoustic Imaging and Photothermal Therapy for New Cancer Treatments

Cancer is a complex disease with significant variability between cases, and as a result, is one of the leading causes of death worldwide. Lung cancer is a particularly difficult form of cancer to diagnose and treat, due largely to the inaccessibility of lung tumours and the limited available treatment options. There is a need for highly targeted, minimally invasive treatment options that facilitate the complete removal of cancer from a patient while minimising damage to non-malignant tissue. The development of plasmonic gold nanoparticles has lead to their potential use in a large range of disciplines, and in particular, they have shown great promise for application in biomedicine. Plasmonic gold nanoparticles possess many desirable characteristics, such as controllable size and shape during synthesis, the biocompatible and inert nature of gold, the potential functionalisation and surface modification prospects, and tunable surface plasmon resonances, that make them excellent candidates for biological use. These beneficial properties facilitate their use as contrast agents to further enhance existing light-based biomedical techniques, such as photoacoustic imaging and photothermal therapy, while possessing the ability to form new combined treatments. In this thesis, gold nanorods - a subset of gold nanoparticles - will be investigated as a means to mediate photoacoustic imaging and photothermal therapy for combined lung cancer theranostics, while demonstrating their ability to improve current clinical practice. Since gold nanorods can be synthesised to be almost any size, and their aspect ratio governs their peak surface plasmon resonance, there may be an optimal sized AuNR for use in biomedical modalities that absorbs light at a particular wavelength. Four different sized gold nanorods (widths of 10, 25, 40, and 50 nm) with similar aspect ratios and therefore similar surface plasmon resonances (815 ± 26 nm) were considered for use in photoacoustic imaging. It was shown that the larger gold nanorods produced the highest photoacoustic amplitude at an equivalent number of nanoparticles, but were the most toxic, while the smallest gold nanorods were optimal at an equivalent total mass. The results indicate the importance for determining the dependence of total mass or number of nanoparticles on cellular targeting and uptake in vivo. Gold nanorods can also be used as photoabsorbers for therapeutic modalities, such as photothermal therapy. Conventionally, continuous wave lasers are used to generate bulk heating in gold nanorods, that are situated in a target region, and the diseased tissue is destroyed via hyperthermia. However, there are potential negative side-effects of heat-induced cell death, such as the risk of damage to healthy tissue due to heat conducting tothe surrounding environment, and the development of heat and drug resistance. Therefore, the use of pulsed lasers for photothermal therapy was investigated and compared with continuous wave lasers. It was shown that, for continuous wave lasers, a larger number of gold nanorods in the absorbing region resulted in increased cell death, whereas with pulsed lasers, the location of the gold nanorods, with respect to the cells, was the most important factor governing laser-induced toxicity. Furthermore, gold nanorods targeted to lung cancer EGFR receptors showed enhanced therapeutic efficacy under pulsed laser illumination. Finally, the potential for gold nanorods to enhance endobronchial ultrasound - an existing clinical procedure for guiding lung cancer needle biopsies - was considered. This routine practice uses conventional B-mode ultrasound and a wide field of view to facilitate the locating of lymph nodes and guide the staging of lung cancer. This technique could be further improved with the use of gold nanorod mediated photoacoustic imaging with potentially minimal adaptation, since the underlying technology required to combine these modalities already exists. It was shown that inclusions of gold nanorods can be observed under pulsed laser illumination using imaging and transducer parameters comparable to that of endobronchial ultrasound. The potential for this promising new multimodality was demonstrated, with the aim of guiding future development. Overall, the work presented in this thesis provided valuable insights into the development of gold nanorods for biomedicine, and has demonstrated the potential for improving new and existing theranostic modalities