(324f) Polymer-Virus Hybrids for Enhanced Transgene Delivery and Cancer Cell Apoptosis

Viruses are the vehicles of choice for transgene delivery in several applications. Viruses are attractive vectors for cancer gene therapy, but suffer from low efficacies in advanced cases where expression of viral receptors is often lost. A cationic polymer library was screened in order to identify candidates that enhanced adenoviral transduction in advanced bladder cancer cells. The polymer library was generated using ring opening polymerization between diglycidyl ethers and polyamines. Polymers were screened for enhacing adenoviral infectivity in human and murine bladder cancer cells that demonstrated poor levels of transgene expression following adenoviral infection. Lead polymers that resulted in high levels of exogenous green fluorescent protein were investigated using an expanded dose response, and were conjugated with fluorescent dyes in order to investigate the uptake and localization of the resulting polymer-virus hybrids. Lead polymers were selected for enhancing the expression and delivery of TNF-alpha Related Apoptosis Inducing Ligand (TRAIL) in bladder cancer cells. Increased TRAIL expression following delivery of polymer-adenovirus hybrids resulted in increased apoptosis of bladder cancer cells compared to cells treated with adenoviruses without polymers. These studies have set the stage for investigating the efficacy of polymer-virus hybrids for the ablation of bladder cancer tumors in vivo. As part of related studies, we have also investigated the use of polymeric vectors for viral production and for enhancing virus-mediated gene silencing. Taken together, our results indicate that polymer libraries can be rapidly synthesized and lead polymers can be interfaced with viruses for enhancing cancer cell ablation and gene silencing, and can also be used to enhance virus production.