Without these events, therapeutic efficacy is highly compromised for any treatment including gene and drug therapies. Achieving this goal is difficult due to the many tight barriers that exist in animals and people. Furthermore, many of these barriers become tighter in the transition from neonates to becoming adults. Penetration throughout an entire tumor is further hindered due to the increased

interstitial pressure within most tumors [35–37]. We believe that nonviral systems can play a pivotal role in achieving target organ extravasation and penetration needed to treat or cure certain diseases. Our preliminary studies have shown that extruded Inhibitors,research,lifescience,medical BIV DOTAP:Chol nucleic acid:liposome Inhibitors,research,lifescience,medical complexes can extravasate across tight barriers and penetrate evenly throughout entire target organs, whereas viral vectors cannot cross identical barriers. As stated above, these barriers include the endothelial cell barrier in a normal mouse [18, 38], the posterior blood retinal barrier in adult mouse eyes [38], complete and homogeneous diffusion throughout large tumors [18, 38], and penetration through several tight layers of smooth muscle cells in the arteries of pigs [38]. Diffusion throughout large tumors was measured by expression of ß-galactosidase or the proapoptotic Inhibitors,research,lifescience,medical gene p53 in about half of the p53-null tumor cells after

a single injection of BIV DOTAP:Chol-DNA liposome complexes into the center of a tumor. Transfected cells were evenly spread throughout the tumors. Tumors injected with complexes encapsulating plasmid DNA Olaparib supplier encoding p53 showed apoptosis in almost all of the tumor cells by Inhibitors,research,lifescience,medical TUNEL staining. Tumor cells expressing p53 mediate a bystander effect on neighboring cells perhaps due to upregulation by Fas ligand that causes nontransfected tumor Inhibitors,research,lifescience,medical cells to undergo apoptosis.

7. Charge versus Delivery Our delivery system is efficient because we have optimized the overall charge of complexes to produce the highest delivery into cells, that is approximately 45.5mV measured by a zeta potential analyzer [9]. Our complexes deliver DNA into cells by fusion with the cell membrane and thereby avoid the endocytic pathway (Figure 6). Cells are negatively charged on the surface, and specific cell types vary in their density of negative charge. These differences in charge density can influence the ability of Thalidomide cells to be transfected. Cationic complexes have nonspecific ionic charge interactions with cell surfaces. Efficient transfection of cells by cationic complexes is, in part, contributed by adequate charge interactions. In addition, other publications report that certain viruses have a partial positive charge around key subunits of viral proteins on the virus surface responsible for binding to and internalization through target cell surface receptors [39–44]. Therefore, this partial positive charge is required for virus entry into the cell.