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Abstract
Hydrodynamic gene delivery was developed as an efficient and safe method for gene transfer into hepatocytes in mice via tail vein injection. The method then evolved into a versatile procedure to deliver various entities, including genes, proteins, and even living cells into various target organs in various animal models. In this dissertation, a series of studies on the application of hydrodynamics-based delivery method in cancer research and anti-obesity gene drug discovery are presented. In cancer research, the method was utilized to deliver tumor cells into mice liver, lungs, and kidneys for modeling of tumor metastasis. We have successfully established a multi-organ tumor growth model in mice using melanoma and colon carcinoma cell lines. The model was used for quantitative assessment of differential behavior of tumors growing in different organs. Our findings revealed that initial survival and growth rates of tumors vary in different organs. In addition, tumors respond to given chemo- and immunotherapies differently in different organs. The hydrodynamic method was also used deliver genes to overexpress the interferon beta (IFN1) gene in mice to assess the anti-obesity effects in mice. Our findings showed that IFN1 attenuates adipose tissue inflammation and blocks development of obesity and its related pathologies, such as insulin resistance. This dissertation comprises five chapters. Chapter one introduces the layout of the entire dissertation and provides a comprehensive overview of hydrodynamics-based delivery. Chapter two reviews theories and applications ofdifferent methods of gene transfer in biomedical research. Chapter three details the use of hydrodynamics-based procedure for modeling cancer metastasis and assessing differential behavior of tumors growing in different organs. Chapter four details the use of the hydrodynamic method for the assessment of therapeutic activities of interferon beta gene in blockage of development of obesity and its related complications upon high fat-diet feeding. Chapter five provides a discussion of conclusions and future perspectives of hydrodynamics-based delivery, with a focus on remaining challenges and its applications in modern drug discovery.