However, their efficiency measured in vitro did not correlate with their ability to deliver DNA after administration in animals. Functional properties defined in vitro do not assess the stability of the complexes in plasma or their pharmacokinetics and biodistribution, all of which are essential for optimal activity in vivo. Colloidal properties of the complexes, in addition to the physicochemical properties of their component lipids, also determine these parameters. In particular, in addition to efficient transfection

of target cells, nucleic acid-liposome complexes must be able Inhibitors,research,lifescience,medical to traverse tight barriers in vivo and penetrate throughout the target tissue to produce efficacy Inhibitors,research,lifescience,medical for the treatment of disease, that is, countercurrent to increased intratumoral pressure gradients for the treatment of cancer. These are not issues for achieving efficient transfection of cells in culture with the exception of polarized tissue culture cells. Therefore, we are not enough surprised that optimized liposomal delivery vehicles for use in vivo may be different than those used for efficient

delivery to Inhibitors,research,lifescience,medical some cells in culture. In summary, in vivo nucleic acid-liposome complexes that produce efficacy in animal models of disease have extended half-life in the circulation, are stable in serum, have broad biodistribution that can be focused, efficiently encapsulate various sizes of nucleic acids, are targetable to specific organs and cell types, penetrate across tight barriers in several organs, penetrate evenly throughout the target tissue, are optimized for nucleic acid:lipid Inhibitors,research,lifescience,medical ratio and colloidal suspension in vivo, can be size

fractionated to produce a homogenous population of complexes prior to injection, and can be repeatedly administered. Recently, we demonstrated efficacy of a robust liposomal delivery system in small and large animal models for lung [18], Imatinib PDGFR inhibitor breast [19], head and neck, and pancreatic cancers [20–22], and for Hepatitis B and Inhibitors,research,lifescience,medical C [23]. Based on efficacy in these animal studies, this liposomal delivery system has been used successfully in phase I clinical trials to treat end-stage nonsmall cell lung carcinoma patients who have failed to respond to chemotherapy [6] and hereditary inclusion body myopathy [7, 8]. The nonsmall cell lung carcinoma patients have prolonged life spans and have Drug_discovery demonstrated objective responses including tumor regression. Efficacy was also demonstrated for the single patient trials for hereditary inclusion body myopathy. The BIV delivery system will also be used in upcoming clinical trials to treat other types of cancer including pancreatic, breast, and head and neck cancers. Our studies have demonstrated broad efficacy in the use of liposomes to treat disease and have dispelled several myths that exist concerning the use of liposomal systems. 3.