Delivering genes of a bioactive protein, in contrast to delivering the actual protein itself, has the potential to induce a more lasting therapeutic effect; upon successful gene delivery, a bioactive protein may be continuously produced by a host at a site where it is able to exert its effect. Gene delivery is effectively achieved by using viral carriers, where therapeutic genes are incorporated into designer viruses. The viruses, however, are associated with significant side-effects; they could be immunogenic and inflammatory, and sometimes cause irreparable damage to the patients cells when they integrate into the genome. Non-viral to transfer genes into a patient’s cells will greatly facilitate therapeutic approaches based on gene delivery. Towards this goal, novel biomaterials are being synthesized in our group that bind to plasmid DNA and transport it into cells. Our intent is to design 'nano'-engineered vesicles, based on architecterally-controlled polymers, to facilitate cellular uptake of DNA as well as to ensure its nuclear delivery and expression. Since the structural features of DNA molecules are similar to siRNA molecules, the same biomaterials have the potential to deliver siRNA in order to down-regulate expression of specific molecules implicated in diseases processes

Specific projects currently underway in the lab include:

Engineering Lipophilic Polycations

Cationic polymers are ideal for binding of plasmid DNA and condensing it into nano-sized complexes suitable for cellular uptake. Imparting a lipophilic character to these polymers was considered beneficial to facilitate DNA delivery into the cells, since the plasma membrane is lipophilic in nature. Towards this end, cationic polymers (such as polyethyleneimine and polylysine) are being modified with endogenous fatty acids. We are now exploring the ideal properties of a lipophilic, cationic polymer that will maximize DNA transfer into the cells and allow its sustained expression. Read more about this line of research in Abbasi et al., 2008 and Hsu et al., 2008.

Designing Biomaterials with Bioactive Moieties

Synthetic biomaterials that interact with cellular features are expected to facilitate trafficking of exogenous nucleic acids. Bioactive moieties that can impart a given functionality to the carriers are indispensibel in this endeavor. As the starting point, we synthesized biomaterials with RGD-mofits capable of binding to cell surface integrins. Although our first attempts were not successful (Clements et al., 2006), we are now pursuing studies to with other types of bioactive moieties. Our goal is to discover means to facilitate cellular update, improve cell specificity of delivery systems, enhance endosomal escape, prolong intracellular persistence and, if necessary, enhance nuclear trafficking of exogenous molecules.

Exploring siRNA Delivery for Cancer Therapy

Lipophilic biomaterials synthesized in this lab were shown to be effective for delivery of short interfering RNA (siRNA). Given the potential of siRNA to down-regulate aberrant molecules in cells, we are exploring the potential of gene carriers to deliver siRNA for cancer therapy. Several aberrant targets, for example multidrug resistance transporters, integrins responsible for increased resistance to chemotherapy and STAT3 expression, were identified and their down-regulation is currently explored to assess their potential for therapy. Read more about this line of research in Alshamsan et al. 2008.