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As of 2010, cancer remains the leading cause of death in Canada, and second in the United States of America. This is despite decades of research into development of chemotherapeutics and diagnostics. A number of major challenges have prevented new discoveries from translating into a reduction in mortality rates. One challenge is the poor efficiency with which anti-cancer agents (diagnostic contrast agents and therapeutics) reach deregulated cells in the body. Therefore, development of new methods and technologies for improving efficiency of delivery has been a focus of research. Nanoparticles are leading candidates for improving the efficiency of delivery because they can act as payload vehicles for anti-cancer agents, because it is possible to mediate their interaction with biological systems and thus their pharmaockinetics, and because they can exploit inherent vulnerabilities of tumours. This thesis describes the results from a series of research projects designed to progress our understanding of how nanoparticles behave in vivo, and how their design can be optimized to improve tumour targeting.

In radionuclide therapy it is still common to administer standard activities or to scale administered activity with blunt parameters such as body weight or surface area. This is not ideal because, due to considerable variation in kinetics, large safety margins have to be applied to avoid radiation damage to healthy organs, which causes under-treatment of many patients. To base the administered activity on individual dosimetry, as in other therapy modalities using ionizing radiation, will essentially solve this problem. However, dosimetry in radionuclide therapy is resource-demanding and debilitating for the patient because it involves a number of measurements to determine the kinetics of the therapy radionuclide and needs to be optimized for clinical feasibility. First, the ability to measure radioactivity distributions of radionuclides for therapy was investigated. SPECT measurements of 177Lu, which was later used clinically, showed good spatial resolution and a reasonable quantitative accuracy. A new method to calculate absorbed dose to solid risk organs and tumours was developed and applied in the clinic. Kinetic data were obtained by repeated SPECT measurements. Radiation concentration determined in small volumes of interest could then be multiplied by a constant to obtain absorbed dose because it was shown that cross-fire was negligible in organs with high activity concentration. The new dosimetry method, compared to other methods, was found to give better results with less effort. In addition, a method to calculate absorbed dose to bone marrow was developed and clinically implemented. In 200 patients, individual kinetics and absorbed dose were studied and variations were found to be large. Kidney was the dose-limiting organ in almost all patients (98.5%). Keeping the kidney dose < 23Gy, about half of the patients could receive 5, or up to 10 treatments instead of the stipulated 4.

For the treatment of cancer, Auger-electron emitting radionuclides are strongly dependent on their close proximity to DNA to utilize the local therapeutic potential of the Auger electrons. This thesis investigates a two-step targeting approach that uses targeting liposomes for the delivery of an Auger-electron emitter, 125I, coupled to a DNA-binding compound, Comp1, to the tumour-cell DNA. In the first step the liposome targets overexpressed cell-surface receptors. Receptors belonging to epidermal growth factor receptor (EGFR) family are overexpressed in a number of different cancers and are therefore suitable targets. The second step is transportation of the radionuclide to the cell nucleus utilizing a DNA-binding compound. The DNA-binder used in this thesis is a daunorubicin derivative called Comp1. Papers I and II are in vitro characterizations of the targeting liposomes. Both EGFR- and HER2-targeting liposomes delivered 125I-Comp1 receptor specifically to tumour cells, and were efficient in decreasing growth of cultured tumour cells. Paper II also included a biodistribution of 125I-Comp1 delivered by HER2-targeting liposomes in tumour-bearing mice. The results gave a time-dependent uptake in tumours differed from when non-targeting liposomes encapsulating 125I-Comp1 were given. Paper III investigates the therapeutic effect of 125I-Comp1 delivered by HER2-targeting liposomes, in an animal model that mimics a situation of disseminated tumour cells in the abdomen. 125I-Comp1 delivered by HER2-targeting liposomes effectively prolonged survival of the mice in a dose-dependent relation. Several mice in the groups receiving the highest doses were tumour-free at the end of the study. Paper IV compares different lipid compositions of the liposomes with respect to leakage, cellular uptake and therapeutic efficacy of delivered 125I-Comp1on cultured cells. Liposomes containing sphingomyelin or dihydrosphingomyelin retained drug more efficiently and exhibited more receptor specific delivery properties than distearoylglycerophosphatidylcholine (DSPC) containing liposomes. However, it was the DSPC-containing liposomes that displayed best growth inhibition on cultured tumour cells. The thesis concludes that 125I-Comp1 delivered by targeting liposomes is a promising candidate for effective radionuclide therapy.

This manuscript presents an investigation and application of the medical radiographic technique of Dynamic Contrast-enhanced Computed Tomography with an emphasis on its application to the measurement of tissue perfusion using the techniques of CT Perfusion. CT Perfusion was used in association with Fluoro- Deoxy Glucose Positron Emission Tomography (FDG PET) to investigate altered blood flow due to the angiogenic effects of tumour in the clinical setting of medical imaging for cancer diagnosis and staging. CT perfusion, CT enhancement and Doppler ultrasound studies were compared in a series of patient studies performed for the assessment of metastatic liver disease. There was good correlation between all techniques for the arterial phase but not between Doppler measurements of the portal phase and any CT measurement. A new method was developed for quantifying CT perfusion and enhancement values, the Standardised Perfusion Value (SPV) and the Standardised Enhancement Value (SEV). The SPV was shown to correlate with FDG uptake in a series of 16 patient studies of lung nodules, an unexpected and potentially important finding that if confirmed in a larger study may provide an additional diagnostic role for CT in the assessment of lung nodules. Investigation of a commercially available package for the determination of CT Perfusion, CT Perfusion GE Medical Systems, was undertaken in a small series of brain studies for assessment of acute stroke. This data set showed the technique to positively identify patients with non-hemorrhagic stroke in the presence of a normal conventional CT, to select those cases where thrombolysis is appropriate, and to provide an indication for prognosis. An investigation of the accuracy and cost-effectiveness of FDG PET in solitary pulmonary nodules using Australian data was carried out. FDG PET was found to be accurate, cost saving and cost effective for the characterisation of indeterminate solitary pulmonary nodules in Australia. This work was expanded to include the impact of quantitative contrast enhancement CT (QECT) on the cost-effectiveness of FDG PET. The addition of QECT is a cost effective approach, however whether QECT is used alone or in combination with FDG PET will depend on local availability of PET, the cost of PET with respect to surgery and the prior probability of malignancy. A published review of CT perfusion, clinical applications and techniques, is included in the body of the work. Dynamic contrast-enhanced CT and FDG PET were used to investigate blood flow, expressed as SPV, and metabolic relationships in non-small cell lung cancers (NSCLC) of varying size and stage. A significant correlation between SPV and FDG uptake was only found for tumours smaller than 4.5 cm2. Blood flow-metabolic relationships are not consistent in NSCLC but depend on tumour size and stage. Dynamic contrast-enhanced CT as an adjunct to an FDG study undertaken using integrated PET-CT offers an efficient way to augment the assessment of tumour biology with possible future application as part of clinical care. In summary the work has developed a method for standardizing the results of dynamic contrast-enhanced CT and investigated its potential when applied with FDG PET to improve the diagnosis and staging of cancers.