Engineered Therapeutic Plasmids and Nanoparticle Delivery Vehicles for Targeted Treatment of Hepatocellular Carcinoma

Nucleic acid-based therapies can be used to target the genetic basis of a disease and have been explored for the treatment of wide range of medical conditions, including cancer. However, many of these therapies have largely been ineffective in the clinic due to off-target toxicities and poor targeting properties, resulting in poor safety and efficacy outcomes. To address these challenges, there has been a strong effort over the past decades to develop delivery vehicles for targeted nucleic acid delivery. A high degree of targeting is particularly critical when delivering cytotoxic therapies for cancer cell killing, as off-target toxicities can lead to dangerous or deadly adverse events. In the case of liver cancer, off-target toxicity has a high risk of liver failure due to the prevalence of severe underlying liver disease in these patients. The aim of this thesis is to investigate multiple methods for targeted DNA delivery to hepatocellular carcinoma, the most common form of liver cancer. Polyplex nanoparticles (NPs) synthesized using poly(beta-amino ester) (PBAE) serve as a delivery vehicle to deliver plasmid DNA to target cells. This thesis uses PBAE NPs to explore multimodal targeting using (1) anatomical targeting of tissues, specifically HCC tumor vasculature, (2) optimization of delivery vehicle biomaterials for HCC cell-specific transfection, and (3) an HCC-specific promoter to restrict therapeutic gene expression. These methodologies are explored independently and in combination to specifically deliver DNA to HCC cells in vitro and in vivo. Importantly, these targeting principles are applied to develop two targeted therapeutics for HCC, which show therapeutic efficacy in preclinical rodent models of HCC. Altogether, these results highlight the clinical potential of PBAE NPs for targeted therapy for HCC