1. COMBINATORIAL DISCOVERY OF POLYMERIC GENE DELIVERY AGENTS
We employ combinatorial synthesis and parallel screening methods for the rapid generation and identification of polymers capable of delivering transgenes to cancer cells with high efficacies.
2. CHEMOTHERAPEUTIC ENHANCERS OF POLYMER-MEDIATED TRANSGENE EXPRESSION
Several intracellular barriers of intracellular trafficking limit the efficacy of polymer-mediated transgene expression. As seen in the figure below, polymer:plasmid DNA complexes (green fluorescence) are localized to the microtubule organizing complex (MTOC) just outside the nucleus (stained blue; lamin in the nuclear envelope is stained red). This limits nuclear import and therefore, transgene expression.
We employ chemotherapeutic mediators to enable polymeric vectors overcome such barriers with an eye towards enhancing transgene expression. For example, we recently demonstrated that inhibiting cytoplasmic histone deacetylase 6 (HDAC 6) using tubacin resulted in enhancement of transgene expression in prostate cancer cell lines (Biomaterials, 2010).
3. POLYMER-VIRUS HYBRIDS FOR ENHANCING TRANSDUCTION AND APOPTOSIS OF CANCER CELLS
While viruses typically demonstrate higher efficacies for delivering genetic material to cells, advanced cancer cells downregulate viral receptors. We employ polymers from our combinatorial library in order to restore the infectivity of cancer cells resistant to viral infection. We are currently employing this strategy to enhance infection, transgene expression, and apoptosis in bladder cancer cells that downregulate the Coxsackie-Adenovirus Receptor (CAR). We are extending these approaches towards re-engineering the tropism of these viruses as well as using different polymers for enhancing the efficacy of additional viral vectors.