Graduation Date

Summer 8-14-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupický, Ph.D.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a growing medical problem associated with extensive metastasis and high mortality. Late diagnosis and complexity of the tumor microenvironment (TME) with severe hypoxia, desmoplasia, and hypovascular nature contributes to poor effectiveness of conventional chemotherapies. RNA interference (RNAi) holds great potential in the treatment of multiple genetic and acquired diseases, including PDAC. CXCR4/CXCL12 chemokine axis plays a pivotal role in PDAC TME remodeling to promote tumor proliferation, angiogenesis, metastasis, and chemoresistance. This project developed polymeric AMD3100 (PAMD) derivatives as dual-function vectors capable of simultaneously delivering small RNAs and blocking CXCR4/CXCL12 signaling.

Administration route plays pivotal role in determining the fate of therapeutics in the body. This project first compared intravenous (IV) and intraperitoneal (IP) administration of the developed nanoparticles (PAMD-CHOL/siRNA) in a murine orthotopic PDAC model. IP administration greatly improved tumor accumulation by providing high local concentrations and prolonged residence time of the particles in the peritoneal cavity, while the efficiency of IV administration was severely compromised in part due to hypovascularity and dense desmoplastic stroma.

Triple combination therapy using PAMD-CHOL nanoparticles consisting of anti-miR-210 and siKRASG12D displayed improved therapeutic effect in the treatment of PDAC when compared with individual therapies as documented by delayed tumor growth, depletion of stroma, reduction of immunosuppression, inhibition of metastasis, and prolonged survival.

To further understand how physiochemical properties of the nanoparticles contribute to enhanced tumor accumulation, this project developed five formulations with different surface properties. Positively charged mPAMD-TFTA/siRNA nanoparticles displayed the highest tumor accumulation at 24 h after IP administration in orthotopic PDAC mice. Treatment of mPAMD-TFTA/siPLK1 nanoparticles with combination of CXCR4 inhibition and PLK1 downregulation in PDAC mice showed significant inhibition of both primary and metastatic tumors.

Overall, the studies demonstrated the benefits of local IP delivery for the treatment of PDAC. Our data provide insights into and guides the design of the nanoparticles for improved drug delivery in PDAC by IP administration.

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