Date of Award

Fall 12-16-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupicky

Abstract

Metastasis is the main cause of cancer mortality and morbidity, leading to several million deaths every year. Less than 20% of pancreatic cancer (PC) patients are candidates for surgery due to spread beyond the pancreas. Desmoplasia presents substantial barriers to perfusion, diffusion, and convection of antitumor therapeutics into the PC tissues. We focus on developing novel therapies that regulates tumor microenvironment, chemosensitizing tumor to therapeutics and preventing metastasis.

Gene therapy is emerging as a promising new therapeutic agents for cancer treatment. A targeted, systemic, effective and safe gene delivery system should be developed. CXCR4/SDF-1 axis plays a crucial role in the crosstalk between cancer cells and their microenvironment, and is involved in tumor progression, angiogenesis, metastasis and survival. We successfully designed dual-function polymeric CXCR4 inhibitors (PCX) as gene delivery vectors.

To enhance the CXCR4 antagonism, we reported synthesis of novel monocyclam monomers and their polymerization to PCX. In order to improve the physical properties and safety of PCX, it was modified by PEGylation. The negative effect of PEG on transfection activity of PEG-PCX polyplexes could be overcome by using polyplexes formulated with a mixture of PCX and PEG-PCX. Moreover, modification of PCX with cholesterol, the enzymatic stability against RNase and siRNA delivery efficiency were enhanced dramatically. NCOA3 silencing can downregulate mucin expression and regulate tumor microenvironment. Using a series of PCX, we optimized formulation of PCX/siNCOA3 polyplexes to simultaneously target CXCR4 and NCOA3 in PC. Cholesterol-modified PCX showed maximum CXCR4 antagonism, NCOA3 silencing and inhibition of PC cell migration in vitro. The optimized PCX/siNCOA3 polyplexes were used in evaluating antitumor and antimetastatic activity in orthotopic mouse model of metastatic PC. The polyplexes displayed significant inhibition of primary tumor growth, which was accompanied by a decrease in tumor necrosis and increased tumor perfusion. These dual-function polyplexes also showed significant antimetastatic effect and effective suppression of metastasis to distant organs. Overall, dual-function PCX/siNCOA3 polyplexes can effectively regulate the tumor microenvironment to decrease progression and dissemination of PC.

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