Amphiphilic Lipid-Substituted Cationic Polymers for Delivery of Gene Medicines

H. Uludag
University of Alberta,
Canada

Keywords: gene delivery, lipid, polymers

Summary:

Treating human diseases with gene-based agents is providing exciting opportunities to fullfill unmet medical needs. Gene medicines are implemented by the nucleic acids that can interface with the flow of genetic information inside cells. The unique features of nucleic acids, however, make them difficult to deliver in a clinical setting. While viral vectors are being explored in gene therapy trials, the unpredictable safety and immune responses are worrying the clinicians. As an alternative, synthetic biomaterials are being specifically designed to undertake effective delivery of nucleic acids in a safe manner. One such class of biomaterials, namely lipid-incorporating cationic polymers, are being extensively explored in the Uludag Lab. Such polymers can effectively assemble the nucleic acids (both RNA and DNA based) into nano-sized particles suitable for cellular uptake. Incorporating lipids in cationic polymers reduced the binding capability to nucleic acids, which needs to be compensated during nanoparticle assembly, but the lipids enhanced the delivery efficiency of nucleic acids into cells significantly. An inverse correlation between the ability of nanoparticles to dissociate and delivery into cells was noted, indicating the need for stable assembly for membrane crossing. We found the same amphiphilic materials to be functional for delivery of both siRNA and plasmid DNA into human cells. It was possible to express therapeutic proteins (e.g., BMPs) in primary bone marrow stromal cells, suitable for regenerative medicine. Silencing aberrant genes in cancer cell lines was also possible with lipid-substituted polymers and siRNA delivery, with desirable therapeutic responses. In particular, delivery of siRNA into patient derived attachment-independent cells (leukemic cells) was effectively implemented with the right choice of the lipid-modified polymer. Our studies indicate a close relationship between the molecular details of lipid-substitution and physicochemical properties of nanoparticles, and ultimately their physiological performance in biological systems. This presentation will emphasize the therapeutic potential and underlying operational basis of lipophilic polymers in delivery of gene medicines.