Abstract: The present invention embodies a multi-disciplinary approach to validate or identify targets involved in any given biological process or pathway, such as an immune response, or progression or regression of disease. By introducing a target(s) with, e.g., gene delivery vector(s) or other foreign substance(s) to an in vivo system and by integrating, for example, pathological, pharmacological, bioassay, microarray and bioinformatics data obtained from the in vivo system, the present inventors are able to (1) identify one or more targets, e.g., genes, that are involved in a biological pathway of interest, (2) implement these identified targets for further analysis of the biological process or pathway and (3) provide a scalable approach in vivo for potential large quantities of target(s) discovery and validation. This process can be used in any number of applications, including the identification of agonists and antagonists to a biological process or pathway, which can lead to drugs and vaccine discovery.

Abstract: A liposome composition comprising small, surface-bound effector molecules is disclosed. The liposomes have a surface layer of hydrophilic polymer chains, for enhanced circulation time in the bloodstream. The effector molecules are attached to the distal ends of the polymer chains. In one embodiment, the effector is polymyxin B, for treatment of septic shock.

Abstract: Non-naturally occurring vector for gene therapy are provided, comprised of chemically defined reagents, where the vector is self-assembling and where the vector comprises (1) a core complex comprising a nucleic acid and (2) at least one complex forming reagent, where the vector has fusogenic activity. The vector optionally may contain reagents permitting fusion with cell membranes and nuclear uptake. The vector also may contain an outer shell moiety that is anchored to the core complex, whereby the outer shell stabilizes the complex, protects it from unwanted interactions and enhances delivery of the nucleic acid into a target tissue or cell. The outer shell optionally may be sheddable, that is, it may be designed such that it dissociates from the vector upon entry into the target cell or tissue.

Abstract: It has been found that certain synthetic vectors and nucleic acid sequences that encode viral genomic sequences can, for example, be administered to a subject repeatedly as a vehicle for effectively delivering one or more therapeutic nucleic acid molecules or polypeptides to a cell or tissue. Accordingly, the disclosed nucleic acid delivery vehicles can be used, for instance, as part of a therapeutic regimen that involves an ongoing use of a therapeutic nucleic acid molecule or polypeptide.

Abstract: A liposome composition comprising small, surface-bound effector molecules is disclosed. The liposomes have a surface layer of hydrophilic polymer chains, for enhanced circulation time in the bloodstream. The effector molecules are attached to the distal ends of the polymer chains. In one embodiment, the effector is polymyxin B, for treatment of septic shock.

Abstract: A liposome composition for localizing an anti-tumor compound to a solid tumor via the bloodstream. The liposomes, which contain the agent in entrapped form, are composed of vesicle-forming lipids and between 1-20 mole percent of a vesicle-forming lipid derivatized with hydrophilic biocompatible polymer, and have sizes in a selected size range between 0.07 and 0.12 microns. After intravenous administration, the liposomes are taken up by the tumor within 24-48 hours, for site-specific release of entrapped compound into the tumor. In one composition for use in treating a solid tumor, the compound is an anthracycline antibiotic drug which is entrapped in the liposomes at a concentration of greater than about 50 &mgr;g agent/&mgr;mole liposome lipid. The method results in regression of solid colon and breast carcinomas which are refractory to anthracycline antibiotic drugs administered in free form or entrapped in conventional liposomes.

Abstract: A liposome composition for localizing an anti-tumor compound to a solid tumor via the bloodstream. The liposomes, which contain the agent in entrapped form, are composed of vesicle-forming lipids and between 1-20 mole percent of a vesicle-forming lipid derivatized with hydrophilic biocompatible polymer, and have sizes in a selected size range between 0.07 and 0.12 microns. After intravenous administration, the liposomes are taken up by the tumor within 24-48 hours, for site-specific release of entrapped compound into the tumor. In one composition for use in treating a solid tumor, the compound is an anthracycline antibiotic drug which is entrapped in the liposomes at a concentration of greater than about 50 &mgr;g agent/&mgr;mole liposome lipid. The method results in regression of solid colon and breast carcinomas which are refractory to anthracycline antibiotic drugs administered in free form or entrapped in conventional liposomes.

Abstract: A liposome composition comprising small, surface-bound effector molecules is disclosed. The liposomes have a surface layer of hydrophilic polymer chains, for enhanced circulation time in the bloodstream. The effector molecules are attached to the distal ends of the polymer chains. In one embodiment, the effector is polymyxin B, for treatment of septic shock.

Abstract: A liposome composition comprising small, surface-bound effector molecules is disclosed. The liposomes have a surface layer of hydrophilic polymer chains, for enhanced circulation time in the bloodstream. The effector molecules are attached to the distal ends of the polymer chains. In one embodiment, the effector is polymyxin B, for treatment of septic shock.

Abstract: A liposome composition comprising small, surface-bound effector molecules is disclosed. The liposomes have a surface layer of hydrophilic polymer chains, for enhanced circulation time in the bloodstream. The effector molecules are attached to the distal ends of the polymer chains. In one embodiment, the effector is polymyxin B, for treatment of septic shock.

Abstract: A method of treating a site of systemic infection which includes administering a therapeutic compound entrapped in liposomes. Also included is a liposomal composition and a method of preparing a liposomal composition for use in concentrating a therapeutic compound to an infected region via the bloodstream. The liposomes, which contain the agent in entrapped form, are composed of vesicle-forming lipids, a vesicle-forming lipid derivatized with hydrophilic biocompatible polymer, and have sizes in a selected size range between 0.07 and 0.2 microns. After parenteral administration, the liposomes are selectively taken up by the infected region within 24-48 hours, for release of entrapped compound into the infected region.

Abstract: A lipid-polymer conjugate for use in forming long-circulating liposomes is disclosed. The conjugate includes a vesicle-forming lipid having covalently attached to its polar head group, one of the polymers: polyvinylpyrrolidone, polyvinylmethylether, polyhydroxypropyl methacrylate, polyhydroxypropylmethacrylamide, polyhydroxyethyl acrylate, polymethacrylamide, polydimethylacrylamide, polymethyloxazoline, polyethyloxazoline, polyhydroxyethyloxazoline, polyhydroxypropyloxazoline, or polyaspartamide. A method for preparing liposomes containing the lipid-polymer conjugate is also disclosed.

Abstract: A lipid-polymer conjugate for use in forming long-circulating liposomes is disclosed. The conjugate includes a vesicle-forming lipid having covalently attached to its polar head group, one of the polymers: polyvinylpyrrolidone, polyvinylmethylether, polyhydroxypropyl methacrylate, polyhydroxypropylmethacrylamide, polyhydroxyethyl acrylate, polymethacrylamide, polydimethylacrylamide, polymethyloxazoline, polyethyloxazoline, polyhydroxyethyloxazoline, polyhydroxypropyloxazoline, or polyaspartamide. A method for preparing liposomes containing the lipid-polymer conjugate is also disclosed.

Abstract: A method of and composition for concentrating a therapeutic agent in an inflamed dermal region are disclosed. The composition, which is also used in the method, is a liposomal composition. The liposomes contain the therapeutic agent in entrapped form and are composed of vesicle-forming lipids including a vesicle-forming lipid derivatized with hydrophilic biocompatible polymer. After intravenous administration, the liposomes are taken up by the inflamed region within 24-48 hours, for site-specific release of entrapped compound into the inflamed region.

Abstract: A liposome composition for extended release of a therapeutic compound into the bloodstream. The liposomes are composed of vesicle-forming lipids and between 1-20 mole percent of a vesicle-forming lipid derivatized with hydrophilic polymer, have sizes in a selected size range between 0.1 and 0.4 microns, and contain the therapeutic compound in liposome-entrapped form. The dosage form of the composition contains at least about three times the dose of the compound required for intravenous injection in free form. Also disclosed in a method for extending to at least 24 hours the period in which an intravenously administered therapeutic compound is therapeutically active in the bloodstream, and novel liposomes compositions for practicing the method.

Abstract: A liposome composition for localizing an anti-tumor compound to a solid tumor via the bloodstream. The liposomes, which contain the agent in entrapped form, are composed of vesicle-forming lipids and between 1-20 mole percent of a vesicle-forming lipid derivatized with hydrophilic biocompatible polymer, and have sizes in a selected size range between 0.07 and 0.12 microns. After intravenous administration, the liposomes are taken up by the tumor within 24-48 hours, for site-specific release of entrapped compound into the tumor. In one composition for use in treating a solid tumor, the compound is an anthracycline antibiotic drug which is entrapped in the liposomes at a concentration of greater than about 50 .mu.g agent/.mu.mole liposome lipid. The method results in regression of solid colon and breast carcinomas which are refractory to anthracycline antibiotic drugs administered in free form or entrapped in conventional liposomes.

Abstract: A liposome composition which contains between 1-20 mole percent of an amphipathic lipid derivatized with a polyalkylether, as exemplified by phosphatidylethanolamine derivatized with polyethyleneglycol. The derivatized lipid enchances the circulation time of the liposomes severalfold, and this enhancement is achieved with either fluid or membrane-rigidifying liposome components. Also disclosed are methods for delivering a drug for slow release from the bloodstream, and for targeting a selected tissue or cells with liposomes, via the bloodstream.