Thesis (Ph. D.)--Ohio State University, 2003. / Title from first page of PDF file. Document formatted into pages; contains xx, 168 p.; also includes graphics (some col.). Includes abstract and vita. Advisor: Clay B. Marsh, Biochemistry Program. Includes bibliographical references (p. 150-168).

Thesis (M.Med.Sc.)--University of Hong Kong, 2003. / Includes bibliographical references (leaves 49-59). Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 120-145).

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Thesis (M.S.)--University of Michigan. / Includes bibliographical references.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Tumour angiogenesis, the formation of new blood vessels within a tumour, is a hallmark of cancers, that allows them to grow beyond a critical size and to metastasize to other organs. As the key driver of tumour angiogenesis, αvβ3 integrin is both an established therapeutic target for anti-angiogenic drugs and a biomarker for imaging agents. Accurate detection of αvβ3 integrin in angiogenic tumours impacts patient prognosis and could report on therapy response. Over the last twenty years, novel αvβ3 integrin-targeted radiotracers have been developed for PET imaging of tumour angiogenesis. While most radiotracers have shown their utility as diagnostic tools, only a few focussed on evaluating response to treatment, partly due to complex biology of the integrin receptors. The aim of this project was the in-vitro biological testing of a novel αvβ3-targeted radiotracer, [3H]ZMPZAT71, and the corresponding unlabelled compound for targeted delivery of a cytotoxic drug, paclitaxel (PTX). Firstly, this piece of work involved validation of this radiotracer to assess expression of αvβ3 integrin. Secondly, [3H]ZMPZAT71 was investigated as a biomarker for assessing response to pharmacological inhibitors of cell signalling pathways. Thirdly, the targeting moiety (ZMPZAT71) conjugated with paclitaxel was studied for integrinmediated drug delivery. The results presented herein demonstrate that radiotracer binding to αvβ3 integrin is dependent not only on the expression levels, but also on the activation status of αvβ3 integrin. Furthermore, this piece of information was used to explain radiotracer binding in response to various pharmacological inhibitors of key cell signalling pathways. Additionally, the integrin-targeted chemotherapeutic exhibited selective cytotoxic effect, explained by enhanced apoptosis of cancer cells compared to PTX alone, together with anti-migratory and anti-invasive effects from the targeting moiety. This study provides valuable information about the molecular mechanisms regulated by αvβ3 integrin, supporting the development of integrin-targeted therapeutics and imaging.

Age-related macular degeneration (ARMD) is the leading cause for visual impairment and blindness in the elder population of developed countries. The primary underlying cause for significant visual loss is the choroidal neovascularization (CNV). CNV is also generated in high myopia ; angioid streaks and some inflammatory diseases and rarely after laser photocoagulation. Current treatment strategies for ARMD include laser photocoagulation , photodynamic therapy , but neither treatment addresses underlying stimuli for blood vessel growth. Therefore, recurrent disease is a problem of clinical significant relevance. Surgical excision of submacular neovascular membrane lead to the additional damage of the retinal pigment epithelium (RPE). Consequently, use of therapeutic agents that directly inhibit the angiogenic stimuli may be able to provide a more effective and permanent treatment. Vasostatin (VS) , the N-terminal domain (amino acid 1-180) of a calcium-binding protein , is a potent angiogenesis inhibitor , isolated from culture supernatants of an Epstein-Barr virus-immortalized cell line. In previous studies, we demonstrated that gene delivery of angiogenesis inhibitor vasostatin attenuated the corneal neovascularization in animals. The recombinant vasostatin also prevented or apparently reduced growth of human Burkitt lymphoma and human colon carcinoma in animal model. The primary objective of this study was to vasostatin attenuated the choroidal neovascularization in animals. Retinal and visual function will be evaluated. The above experiments would enable us to test the hypothesis that the topical application of VS delivery might be a promising strategy for the treatment of ARMD and other retinal disorders. Furthermore, the results from animal studies might be extrapolated for future clinical application.

Thesis (M. Orth.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 122-142).

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy