Graduation Date

Spring 5-5-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupický

Abstract

Pancreatic ductal adenocarcinoma is a deadly disease with limited treatment options due to late diagnosis and resistance to conventional chemotherapy. Moreover, with the decreased survival rate in the past several years, pancreatic cancer may become the second leading cause of cancer-related death by surpassing breast cancer in 2030. CXCR4/CXCL12 pathway is crucial in tumor-supporting microenvironment, tumor progression, angiogenesis, metastasis and chemotherapy resistance. Small interfering RNA (siRNA) is one of the interfering RNA (RNAi), which targets mRNA specifically then knockdowns the overexpressed oncogene. Thus, siRNA has been widely used as a therapeutic strategy for various diseases including PDAC. In the research described in this dissertation, we synthesized and modified polymeric AMD3100, which is a CXCR4 antagonist, as siRNA delivery vectors to treat PDAC.

In Chapter 1, an introduction about PDAC, siRNA and CXCR4/CXCL12 chemokine axis is given.

In Chapter 2, we combined CXCR4 inhibition by a polymeric CXCR4 antagonist PAMD-CHOL with PLK1 knockdown by siRNA (PAMD-CHOL/siPLK1 nanoparticles) in order to enhance the therapeutic effect of gemcitabine (GEM) in the orthotopic model of metastatic pancreatic cancer. We found PAMD-CHOL/siPLK1 nanoparticles showed strong synergism when combined with GEM treatment in vitro in both murine and human pancreatic cancer cell lines. The biodistribution of the nanoparticles in orthotopic pancreatic cancer models revealed strong accumulation in primary and metastatic tumors, with limited hepatic disposition. The cholesterol-containing nanoparticles showed not only more tumor accumulation than the cholesterol-lacking control but also deeper penetration into the tumors. In a therapeutic study in vivo, the triple combination of PAMD-CHOL/siPLK1 and GEM showed superior anticancer activity when compared with single and dual combination controls.

In Chapter 3, we developed a α-tocopherol conjugated polymeric CXCR4 antagonist (PAMD-TOC) to deliver therapeutic STAT3 siRNA to treat PDAC. The α- tocopherol modified PAMD-TOC/siSTAT3 polyplexes showed anti-tumor and anti- migration performance superior to the non-modified PAMD/siSTAT3 polyplexes in murine and human PDAC cell lines. The biodistribution of the polyplexes in orthotopic mouse KPC8060 and human PANC-1 PDAC models indicated that PAMD-TOC/siRNA polyplexes greatly improved tumor accumulation compared with PAMD/siRNA control. The improved cellular uptake, penetration and tumor accumulation of PAMD-TOC/siSTAT3 polyplexes then contributed to the suppression of tumor growth and metastasis in both animal models of PDAC.

Overall, all the studies indicated that the modifications of polymeric AMD3100 could enhance the siRNA delivery efficacy and thereby improve the treatment effect against PDAC.

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