Graduation Date

Fall 12-14-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupický

Abstract

Metastasis is the main contributor to cancer-associated deaths. Inhibition of CXCR4 emerged as one promising approach in metastatic cancer therapy. MiRNAs represent a new class of therapeutics for cancer treatment through RNA interference-mediated gene silencing. Polymeric CXCR4 antagonist (PCX) is a dual-functional polycation to inhibit CXCR4 and deliver nucleic acids. This dissertation hypothesized that blockade of CXCR4 by PCX combined with delivery of miRNA cooperatively enhances metastatic cancer therapy.

In chapter 1, an overview of CXCR4 inhibition, miRNA delivery and CXCR4 targeted nanomedicine in cancer therapy is given.

Chapter 2 reports that PCX can effectively deliver miR-200c mimic and that the combination treatment consisting of PCX and miR-200c results in cooperative antimigration activity by coupling the CXCR4 blockade with epithelial-to-mesenchymal transition inhibition in the cholangiocarcinoma (CCA) cells. The ability of the combined PCX/miR-200c treatment to obstruct two migratory pathways represents a promising antimetastatic strategy in CCA.

Chapter 3 describes that blockade of CXCR4 by PCX combined with the inhibition of hypoxia-inducible miR-210 can cooperatively enhance therapeutic efficacy in CCA. PCX had a broad inhibitory effect on cell migration, effectively delivered anti-miR-210, and downregulated miR-210 expression in CCA cells. PCX/anti-miR-210 nanoparticles showed cytotoxic activity towards CCA cells and reduced cancer stem-like cells. The nanoparticles reversed hypoxia-induced drug resistance and sensitized CCA cells to gemcitabine and cisplatin combination treatment. Systemic treatment with the nanoparticles in CCA xenograft model resulted in prominent combined antitumor activity.

In chapter 4, PCX effectively delivered both siKRAS and miR-210 inhibitor into pancreatic cancer (PC) cells and induced combined cell killing effect. IP injection of nanoparticles targeted to orthotopic PC tumor. The IP injected combination nanoparticles achieved improved survival in KPC-derived mice through inhibition both primary tumor growth and metastasis. The nanoparticles represent a promising dual-function delivery platform for siRNA/miRNA codelivery and provide safe and effective nanomedicines for metastatic PC therapy.

Results of this thesis and future directions are given in Chapter 5.

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