Antisense and triple helix-forming oligonucleotides (TFOs) have great potential as therapeutic agents to specifically block the expression of deleterious genes. We will develop novel delivery vehicles, to improve the cellular internalization and membrane permeability of oligonucleotides. These compounds are polyaminolipids that contain both cationic and lipophilic moieties, and they are designed to be biodegradable and relatively nontoxic to cells and animals. The utility of the potential uptake enhancers will be validated in a quantitative, anti-oncogene assay system. Specifically, we have established sensitive in vitro assays to measure the inhibition of Epidermal Growth Factor Receptor (EGFR) expression in glioblastoma cells. The candidate uptake enhancers will be coadministered with anti-EGFR TFOs to cells, and any gain in the biological efficacy of the TFOs will be quantified. A varied of TFO and polyaminolipid formulations will be tested. The toxicity and pharmacokinetic properties of the most effective formulation will be monitored in animal studies. The most promising uptake enhancers will be tested for in vivo pharmacological activity in Phase II of these studies. In principle, the approach should be of utility in optimizing the cellular delivery of not only oligonudeotides but also longer pieces of DNA for gene therapy.National Cancer Institute (NCI)
