Graduation Date

Fall 12-17-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupicky

Abstract

Cancer has been a major public health issue worldwide for years and is the second leading cause of death in the United States. Important barrier must be broken to extend the life expectancy in every country. The standard care for cancer causes severe side effects which affects patients’ physical health and quality of life. Polyamines are highly related with the cell proliferation and apoptosis. Dysregulated polyamine metabolism in cancer leads to increased polyamine concentration in neoplastic cells. Thus, polyamine metabolism for cancer therapy can be an intriguing target. However, the heterogeneity affecting key cancer pathways poses significant challenges for effective monotherapy. RNA interference (RNAi) can knock down upregulated oncogene expression with high specificity and selectivity. Among those, siRNA presents high potential as novel therapeutic modality for cancer when properly delivered. This dissertation hypothesized that polycation nanoparticles can be developed that regulate polyamine metabolism, while simultaneously serving as siRNA delivery systems to achieve enhanced combinational cancer therapy. An introduction on polyamines and RNAi with their connections to cancer is presented in chapter 1. Chapter 2 reports on the development of hyaluronic acid-coated fluoroalkyl-conjugated polyamine prodrugs as siRNA delivery systems (HA@F-PaP/siPLK1) for simultaneous targeting of polyamine metabolism and down-regulation of (polo-like kinase 1) PLK1 expression. The ternary complex achieved reduced toxicity to the membrane, improved gene silencing effect and selective targeting to tumor. The combination of N1,N11-Bis(ethyl)norspermine (BENSpm) and siPLK1 demonstrated superior apoptosis inducing effect in both colorectal cancer and pancreatic cancer. Finally, orthotopic pancreatic model was developed for the evaluation of HA@F-PaP/siPLK1. The biodistribution study showed selective tumor accumulation through CD44 targeting effect and HA@F-PaP/siPLK1 significantly inhibited the tumor growth. Chapter 3 reports on the folic acid conjugated, curcumin and siKras loaded cationic lipoplex (2FLPC/siKras) as drug/siRNA combinational therapy against colorectal cancer. The curcumin that targets multiple anti-cancer pathways is also involved in polyamine metabolism regulation. Curcumin-loaded liposomes showed similar toxicity and anti-migration effects as free curcumin. The folic acid on the lipoplex achieved enhanced siRNA delivery. Finally, the combination of curcumin and siKras demonstrated superior apoptosis inducing and anti-proliferation effect. Chapter 4 reports on the attempts to synthesize different GSH responsive polymeric norspermine prodrugs. Monomers were synthesized with methyl methacrylate group, vinyl group and methyl acrylamide group with the self-immolative linker conjugated with norspermine. The polymeric norspermine prodrug (PNP) were polymerized using reversible addition-fragmentation chain transfer (RAFT) polymerization. PNP showed excellent siRNA condensation ability with great siRNA cellular uptake. In chapter 5, summary and future directions are given.

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