Prompted by the successful clinical application of cisplatin in cancer therapy, worldwide efforts have been devoted to develop new metal-based drugs for anticancer treatment. Gold(III) complexes at first received attention as anti-cancer drug candidates because of their square-planar geometry which resembles that of platinum(II) complexes. Subsequent studies revealed that various gold(III) complexes displayed promising anti-cancer activities with different biological mechanisms. Although some achievements have been obtained in the development of anti-cancer gold(III) complexes, challenges including the improvement of bioavailability, stability and selectivity, elucidation of the action mechanisms, and the development of novel delivery approaches of gold(III) complexes to reduce systematic toxicity, remain to be exploited. A panel of anti-cancer complexes [AuIII(R-C^N)(L)]n+ (wherein HC^N is 2-phenylpyridine, L is biguanide or biuret) have been identified and described in Chapter 3. Biguanide or biuret have been employed to improve the solubility of the complexes in aqueous solutions. Meanwhile, the lipophilicity could readily be adjusted by varying the R group to obtain a balance between lipophilicity and aqueous solubility. Among the synthesized complexes, the cationic complexes, [AuIII(butyl-C^N)biguanide]Cl (3.1) and [AuIII(C^N)biguanide]Cl (3.2) are soluble in aqueous solutions with solubility over 5 mg/mL. Besides, introduction of butyl groups to 3.1 and [AuIII(butyl-C^N)biuret] (3.3) resulted in higher cellular uptake of gold, which might enhance their cytotoxic activities (IC50 values: 1.5–17 μM) compared with 3.2 and [AuIII(C^N)biuret] (3.4) (IC50 values: 9.4–47.3 μM). Moreover, 3.1 was also found to induce cell cycle arrest in S-phase and endoplasmic reticulum (ER) damage in human cervical epithelial carcinoma (HeLa) cells, and display significant anti-angiogenic activity at its sub-cytotoxic concentrations. In Chapter 4, a series of gold(III) complexes with dithiocarbamate and 2-phenylpyridine ligands to target deubiquitinases (DUBs), have been designed. These complexes achieved significant inhibition on purified DUBs. Notably, [AuIII(2-(4-nbutylphenyl) pyridyl)(diethyldithiocarbamate)]PF6 (4.1) inhibited both the purified (IC50 values: 46–223 nM) and cell-based DUBs activities with high efficiency. Its interaction with DUB UCHL1 and peptides which are present in several types of DUBs and contain active cysteine residue were confirmed by mass spectrometric analysis. All complexes displayed significant cytotoxicities, and those containing diethyldithiocarbamate ligand displayed specific cytotoxicity on breast cancer cells. Accumulation of a tumor suppressor p53, cell-cycle arrest, and apoptotic cell death were induced in breast cancer cells by 4.1. Besides, 4.1 also showed anti-angiogenic effects. These biological activities might be related with DUBs inhibition. In Chapter 5, a cytotoxic complex [AuIII(C^N^C)(4-dpt)](CF3SO3) (5.1, HC^N^CH = 2,6-diphenylpyridine; 4-dpt = 2,4-diamino-6-(4-pyridyl)-1,3,5-triazine) has been designed to self-assemble into supramolecular polymers (5.1-SP) in acetonitrile. In physiologically relevant solutions, 5.1-SP displayed a sustained-release property of the anti-angiogenic ligand 4-dpt, and in the presence of glutathione (GSH), [AuIII(C^N^C)-GSH] adduct(s) were also gradually released. The supramolecular polymers 5.1-SP also showed selective cytotoxicity toward cancerous cells, and could act as drug-carriers of other cytotoxic agents to achieve sustained-release behavior. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

In a 6-week rat model it was demonstrated that a small dose of peri-implant zoledronic acid (ZA) increased local bone formation 3-fold compared with controls. Ancillary in vitro studies using 14C-labeled ZA implant doses demonstrated biphasic elution profiles for implants coated with hydroxyapatite; complete ZA release occurred within one to three weeks in serum compared with only 60% ZA release after 12 weeks in water. Implants without hydroxyapatite coating showed more burst-type release profiles and full ZA elution within 24 hours of hydration in serum or water. Canine studies at 6 weeks using implants with 14C-labeled ZA showed that the compound remained localized, with the greatest ZA concentration immediately adjacent to the implant. Although there was evidence of skeletal ZA distribution via diffusion into the circulation, the levels were two orders of magnitude less than at the implant site.

This thesis is a step forward in evaluating insulin therapy and defining its role in cardiac surgery first described as Glucose-Insulin-Potassium (GIK) solution 40 years ago. / Chapter (I) includes a review of the literature on insulin therapy in cardiac surgery and illustrates the scientific bases and controversies in this therapy. / Chapter (II) entitled: "Myocardial Protection During Elective Coronary Artery Bypass Grafting Using High Dose Insulin Therapy" represents a manuscript that was presented in the following meetings: (A) Local meetings: (1) McGill cardiovascular research day, February 1/2007, Montreal, Canada. (2) Fraser Gurd annual research day, McGill surgery department, May 31/2007, Montreal, Canada. (B) National meetings: (1) 11th Annual Terrence Donnelly research day for Canadian cardiac surgery residents, May 26/2007, Toronto, Canada. (C) International meetings: (1) 43rd Annual meeting of the Society of thoracic surgeons (STS), January 30/2007, San Diego, United States. A full manuscript was submitted to "The Annals of Thoracic Surgery" for review. / Chapter (III) entitled: "High Dose Insulin Therapy Attenuates Systemic Inflammatory Response in Patients Undergoing Elective Coronary Artery Bypass Grafting" represents a manuscript that was presented in the following meetings: (A) Local meetings: (1) Fraser Guard McGill Surgery department annual research day, May 3/2006, Montreal, Canada. (B) National meetings: (1) 10th Annual Terrence Donnelly research day for Canadian cardiac surgery residents, May 26/2007, Toronto, Canada. (2) Young investigator forum, Canadian Society of Clinical Investigators (CSCI), September 28/2006, Ottawa, Canada. (3) 59 th annual meeting of Canadian Cardiovascular Society (CCS), October 21/2006, Vancouver, Canada. (C) International meetings: (1) American Heart Association (AHA), November 12/2006, Chicago, United states. / Abstracts from this work were published in the following journals: (1) Clinical and Investigative Medicine, Vol. 29, No. 4, August 2006. (2) The Canadian Journal of Cardiology, Vol. 22 supp D, October 2006 (3) Circulation, Vol. 114 supp, No. 18, October 2006. / A full manuscript was submitted to "the journal of thoracic and cardiovascular surgery" for review.

The high performance of bone implants depends on the positive response of osteoblasts to the surface of the materials manufactured for the implant. Cell response in turn strongly depends on the nature of the initial interaction of macromolecules involved in cell adhesion and proliferation with the atomic structure of the surface of the material used for the implant. The initial interaction between bone specific extracellular matrix proteins and the solid substrate influences cell response at the cell-implant interface. This interaction is crucial for implant stability, long-term durability, and osseointegration. Despite extensive research undertaken to develop high-quality material for implants in order to improve the cell-substrate interaction, little is known about the significance of the atomic structure of the substrate and the role of molecular machinery involved in cell-substrate interaction. Using a combined approach involving material sciences and cell and molecular biology, the objectives of this research are to evaluate the response of pre-osteoblast and fibroblast cell lines to novel bulk polycrystalline and single crystal titanium based material and assess the role of crystal size and orientation. / Novel bulk nano-structured titanium substrates were produced by the process of high-pressure torsion (HPT). These materials have a significant advantage compared to conventional titanium-based materials by having higher surface wettablity, mechanical properties as well as a distinct surface oxide layer and atomic structure. A co-culture system was adapted to investigate the differential response of pre-osteoblast and fibroblast cell lines to titanium and titanium dioxide single-crystal substrates. / The results of this study provide clear evidence that crystal size and specific crystallographic orientation can be used to improve cell adhesion and proliferation. The nanostructured titanium substrates show strong interaction with pre-osteoblast cells as evident by the higher expression of fibronectin and the formation of extensive focal adhesion. Differential cell behaviour of pre-osteoblasts and fibroblasts are observed in cultures grown on the substrates with specific crystallographic orientations. The degree of cell attachment of the pre-osteoblasts is considerably higher on Ti-(1120) crystal face compared with the fibroblasts. These findings have profound implications for the improved osseointegration and inhibition of fibrosis leading to long-term implant consolidation and stability.

Title page, contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / The growth plate is a cartilaginous structure located at the proximal and distal ends of immature long bones, which contributes to longitudinal growth through the process of endochondral ossification. Cartilage has a limited ability to regenerate and in children, injury to the the growth plate can result in limb length discrepancies and angular deformity, due to formation of a bone bridge at the damaged site which disturbs structure and function of the growth plate. Current treatments of the abnormalities arising from growth plate arrest involve surgical correction once the deformities have manifested. To date, there is no biological based therapy for the repair of injured/damaged growth plate cartilage. Mesenchymal stem cells (MSC) are self renewable mulitpotential progenitor cells with the capacity to differentiate toward the chondrogenic lineage. Since their discovery, significant interest has been generated in the potential application of these cells for cartilage regeneration. In this study, the ability of autologous bone marrow mesenchymal stem cells to regenerate growth plate cartilage in a sheep model was examined. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1330837 / Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2008

Title page, contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / The growth plate is a cartilaginous structure located at the proximal and distal ends of immature long bones, which contributes to longitudinal growth through the process of endochondral ossification. Cartilage has a limited ability to regenerate and in children, injury to the the growth plate can result in limb length discrepancies and angular deformity, due to formation of a bone bridge at the damaged site which disturbs structure and function of the growth plate. Current treatments of the abnormalities arising from growth plate arrest involve surgical correction once the deformities have manifested. To date, there is no biological based therapy for the repair of injured/damaged growth plate cartilage. Mesenchymal stem cells (MSC) are self renewable mulitpotential progenitor cells with the capacity to differentiate toward the chondrogenic lineage. Since their discovery, significant interest has been generated in the potential application of these cells for cartilage regeneration. In this study, the ability of autologous bone marrow mesenchymal stem cells to regenerate growth plate cartilage in a sheep model was examined. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1330837 / Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2008