Therefore, we PF-4708671 price accomplished decreasing the overall charge of BIV complexes by adding the small neutral lipid, n-dodecyl-β-D-maltopyranoside, approximately 511 MW, just prior to iv injections [9](Templeton, N.S. US Patent no. 7,037,520 B2 issued May 2, 2006). By addition of ligands using the novel approaches that we developed, adequate

overall positive charge on the surface of complexes at the target site is preserved. In summary, we achieve optimal circulation time of the complexes, reach and deliver to the target organ, avoid uptake in nontarget tissues, and efficiently interact with the cell surface to produce optimal transfection. We have developed a multidisciplinary approach combining molecular biology, delivery technology, combinatorial chemistry, Inhibitors,research,lifescience,medical and reversible masking Inhibitors,research,lifescience,medical to create improved systemic, targeted delivery of plasmid DNA while avoiding nonspecific uptake in vivo. We applied this technology to efficiently target delivery to a human tumor-microenvironment model. We

achieved efficient, targeted delivery by attachment of specific targeting ligands to the surface of our BIV complexes in conjunction with reversible masking to bypass nonspecific tissues and organs. We identified ligands Inhibitors,research,lifescience,medical that target a human tumor-microenvironment created in vitro by coculturing primary human endothelial cells with human lung or pancreatic cancer cells. The model was confirmed by increased expression of tumor endothelial phenotypes including CD31 and VEGF-A and prolonged survival of endothelial capillary-like structures. The cocultures were used for high-throughput screening

of a specialized small-molecule peptidomimetic library to identify ligands specific for human tumor-associated endothelial cells in vitro. We identified small molecules Inhibitors,research,lifescience,medical that enhanced the transfection Inhibitors,research,lifescience,medical efficiency of tumor-associated endothelial cells, but not normal human endothelial cells or cancer cells. IV administration of our targeted, reversibly masked complexes into mice, bearing human pancreatic tumor and endothelial cells, specifically increased transfection to this tumor microenvironment about 200-fold. Efficacy studies using our optimized targeted delivery of a plasmid encoding thrombospondin-1 eliminated tumors completely after five intravenous injections administered once weekly. We plan to use our targeted, reversibly masked delivery system in the clinic to treat metastatic (-)-p-Bromotetramisole Oxalate cancer. Table 1 compares reversible masking versus the cleavable PEG systems. None of the cleavable PEG systems have shown the exceptionally high, 200-fold increased targeted delivery demonstrated by BIVs coated with small molecule B-turn mimics for specific delivery to the target cell and reversible masking to avoid nonspecific uptake described above. Furthermore, we achieve this high level of targeted delivery without the use of peptides that are known to be immunogenic when multimerized on the surface of delivery vehicles and then repeatedly injected iv.