Novel therapeutic delivery systems

Abstract

Targeted therapeutic delivery systems comprising gas- or gaseous precursor-filled lipid microspheres comprising a therapeutic are described. Methods for employing such microspheres in therapeutic delivery applications are also provided. Targeted therapeutic delivery systems comprising gas- or gaseous precursor-filled liposomes having a drug encapsulated therein are preferred. Methods of and apparatus for preparing such liposomes and methods for employing such liposomes in therapeutic delivery applications are also disclosed.

1 - 40 . (canceled) 
     
     
         41 . A method for preparing a targeted therapeutic delivery system comprising temperature activated gaseous precursor-filled liposomes, the method comprising shaking an aqueous solution, comprising a lipid and a therapeutic compound, in the presence of a gaseous precursor, at a temperature below the gel to liquid crystalline phase transition temperature of the lipid, and at the activation temperature of the gaseous precursor or below the activation temperature. 
     
     
         42 . The method of  claim 41 , wherein the method is carried out at the activation temperature of the gaseous precursor. 
     
     
         43 . The method of  claim 41 , wherein the shaking comprises vortexing. 
     
     
         44 . The method of  claim 41 , further comprising filtering and heat sterilizing the aqueous lipid solution. 
     
     
         45 . The method of  claim 41 , further comprising extruding the gaseous precursor-filled liposomes through at least one filter of a selected pore size. 
     
     
         46 . The method of  claim 45 , wherein the pore size is about 10 μm or smaller. 
     
     
         47 . The method of  claim 41 , further comprising hydrating a dried lipid to form an aqueous solution comprising a lipid. 
     
     
         48 . A method for preparing a targeted therapeutic delivery system comprising gaseous precursor-filled liposomes, the method comprising:
 (a) shaking an aqueous solution, comprising a lipid, in the presence of a gaseous precursor, at a temperature below the gel to liquid crystalline phase transition temperature of the lipid, to form gaseous precursor-filled liposomes; and   (b) adding to the liposomes a therapeutic compound.   
     
     
         49 . The method of  claim 48 , wherein the method is carried out at the activation temperature of the gaseous precursor. 
     
     
         50 . The method of  claim 48 , wherein the shaking vortexing. 
     
     
         51 . The method of  claim 48 , further comprising filtering and heat sterilizing the aqueous lipid solution. 
     
     
         52 . The method of  claim 48 , further comprising extruding the liposomes through at least one filter of a selected pore size. 
     
     
         53 . The method of  claim 48 , wherein the pore size is about 10 μm or smaller. 
     
     
         54 . The method of  claim 48 , further comprising hydrating a dried lipid to form an aqueous solution comprising a lipid. 
     
     
         55 . A method for preparing a targeted therapeutic delivery system comprising gaseous precursor-filled liposomes, the method comprising:
 (a) shaking an aqueous solution, comprising a lipid and a therapeutic compound, in the presence of a gaseous precursor; and   (b) separating the resulting gaseous precursor-filled liposomes for therapeutic use.   
     
     
         56 . A method for preparing a targeted therapeutic delivery system comprising gaseous precursor-filled liposomes, the method comprising:
 (a) shaking an aqueous solution, comprising a lipid, in the presence of a gaseous precursor, at a temperature below the gel to liquid crystalline phase transition temperature of the lipid, to form gaseous precursor-filled liposomes;   (b) adding a therapeutic compound; and   (c) separating the resultant gaseous precursor-filled liposomes for therapeutic use.   
     
     
         57 . A method of making therapeutic containing gaseous precursor-filled liposome microspheres, comprising:
 (a) introducing an aqueous solution comprising a lipid and a therapeutic compound into a vessel;   (b) introducing a gaseous precursor into the vessel;   (c) shaking the aqueous lipid solution in the presence of the gaseous precursor so as to instill at least a portion of the gaseous precursor into the aqueous solution, the shaking being performed with sufficient intensity and duration to produce a gaseous precursor-filled-liposome-containing foam above the aqueous solution; and   (d) extracting at least a portion of the gaseous precursor-filled-liposome containing foam from the vessel.   
     
     
         58 . The method of  claim 57 , further comprising cooling the aqueous solution. 
     
     
         59 . The method of  claim 58 , wherein the cooling of the aqueous solution comprises cooling the aqueous solution below the gel to liquid crystalline phase transition temperature of the lipid in the aqueous solution. 
     
     
         60 . The method of  claim 57 , further comprising pressurizing the vessel. 
     
     
         61 . The method of  claim 57 , further comprising sizing the gaseous precursor-filled liposomes. 
     
     
         62 . The method of  claim 61 , wherein the sizing of the gaseous precursor-filled liposomes comprises controlling the size of the gaseous precursor-filled liposomes extracted from the vessel. 
     
     
         63 . The method of  claim 61 , wherein the size of the gaseous precursor-filled liposomes extracted from the vessel is controlled by extracting the gaseous precursor-filled liposomes through a filter. 
     
     
         64 . The method of  claim 61 , wherein the size of the gaseous precursor-filled liposomes extracted from the vessel is controlled by setting the location within the vessel from which the gaseous precursor-filled liposomes are extracted. 
     
     
         65 . The method of  claim 61 , wherein the size of the gaseous precursor-filled liposomes extracted from the vessel is controlled by adjusting the location within the vessel from which the gaseous precursor-filled liposomes are extracted during the extracting of the gaseous precursor-filled liposomes from the vessel. 
     
     
         66 . The method of  claim 61 , wherein the sizing of the gaseous precursor-filled liposomes comprises extruding the extracted gaseous precursor-filled liposomes through a filter. 
     
     
         67 . The method of  claim 61 , wherein the sizing of the gaseous precursor-filled liposomes comprises controlling the intensity of the shaking. 
     
     
         68 . The method of  claim 57 , further comprising the flowing of the gaseous precursor-filled liposomes extracted from the vessel into a syringe without further processing. 
     
     
         69 . The method of  claim 57 , wherein the shaking of the aqueous solution comprises shaking at a frequency of at least about 60 shaking motions per minute. 
     
     
         70 . The method of  claim 57 , wherein the shaking the aqueous solution comprises vortexing of the aqueous solution. 
     
     
         71 . The method of  claim 57 , wherein the shaking of the aqueous solution comprises the shaking of the vessel. 
     
     
         72 . The method of  claim 57 , wherein the shaking of the aqueous solution comprises shaking the aqueous solution with sufficient intensity to create the gaseous precursor-filled-liposomes-containing foam in less than about 30 minutes. 
     
     
         73 . The method of  claim 57 , wherein the shaking of the aqueous solution comprises controlling the duration of the shaking based on the detection of the gaseous precursor-filled-liposome-containing foam. 
     
     
         74 . The method of  claim 73 , wherein the controlling the duration of the shaking based on the detection of the gaseous precursor-filled-liposome-containing foam comprises shaking until the presence of a pre-determined volume of the foam has been detected. 
     
     
         75 . The method of  claim 57  wherein the method is carried out at the activation temperature of the gaseous precursor. 
     
     
         76 . A method for preparing drug delivery systems comprising:
 (a) placing under negative pressure liposomes having encapsulated therein a drug;   (b) incubating the liposomes under the negative pressure for a time sufficient to remove substantially all water from the liposomes; and   c) instilling gas into the liposomes until ambient pressures are achieved, wherein the gas is provided by a gaseous precursor.   
     
     
         77 . The method of  claim 76 , further comprising allowing the liposomes to cool prior to and during step (a) to a temperature between about −10° C. and about −20° C., allowing the liposomes to warm during step (b) to a temperature between about 10° C. and about 20° C., and allowing the liposomes to warm during step (c) to ambient temperatures. 
     
     
         78 . The method of  claim 76 , wherein the negative pressure is between about 700 mm Hg and about 760 mm Hg and is applied for about 24 to about 72 hours. 
     
     
         79 . The method of  claim 76 , where the gas is instilled into the liposomes over a period of about 4 to about 8 hours. 
     
     
         80 . The method of  claim 76 , where the gas is selected from the group consisting of fluorine, perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, hexafluoropropylene, bromochlorofluoromethane, octafluoropropane, 1,1 dichloro, fluoro ethane, hexa fluoroethane, hexafluoro-2-butyne, perfluoropentane, perfluorobutane, octafluoro-2-butene, hexafluorobuta-1,3-diene, octafluorocyclopentene, hexafluoroacetone, isopropyl acetylene, allene, tetrafluoro allene, boron trifluoride, 1,2-butadiene, 1,3-butadiene, 1,2,3-trichloro,2-fluoro-1,3-butadiene, 2-methyl,1,3-butadiene, hexafluoro-1,3-butadiene, butadiene, 1-fluoro-butane, 2-methyl-butane, decafluoro butane, 1-butene, 2-butene, 2-methyl-1-butene, 3-methyl-1-butene, perfluoro-1-butene, perfluoro-2-butene, 4-phenyl-3-butene-2-one, 2-methyl-1-butene-3-yne, butyl nitrate, 1-butyne, 2-butyne, 2-chloro-1,1,1,4,4,4-hexafluoro-butyne, 3-methyl-1-butyne, perfluoro-2-butyne, 2-bromo-butyraldehyde, carbonyl sulfide, crotononitrile, cyclobutane, methyl-cyclobutane, octafluoro-cyclobutane, perfluoro-cyclobutene, 3-chloro-cyclopentene, cyclopropane, 1,2-dimethyl-cyclopropane, 1,1-dimethyl-cyclopropane, 1,2-dimethyl cyclopropane, ethyl cyclopropane, methyl cyclopropane, diacetylene, 3-ethyl-3-methyl diaziridine, 1,1,1-trifluoro-diazoethane, dimethyl amine, hexafluoro-dimethyl amine, dimethylethylamine, bis-(dimethyl phosphine)amine, 2,3-dimethyl-2-norbornane, perfluoro-dimethylamine, dimethyloxonium chloride, 1,3-dioxolane-2-one, 4-methyl, 1,1,1,2-tetrafluoro ethane, 1,1,1 trifluoroethane, 1,1,2,2-tetrafluoroethane, 1,1,2-trichloro-1,2,2-trifluoroethane, 1,1 dichloro ethane, 1,1-dichloro-1,2,2,2-tetrafluoro ethane, 1,2-difluoro ethane, 1-chloro-1,1,2,2,2-pentafluoro ethane, 2-chloro,1,1-difluoroethane, 1-chloro-1,1,2,2-tetrafluoro ethane, 2-chloro,1,1-difluoro ethane, chloroethane, chloropentafluoro ethane, dichlorotrifluoroethane, fluoro-ethane, hexafluoro-ethane, nitro-pentafluoro ethane, nitroso-pentafluoro ethane, perfluoro ethane, perfluoro ethylamine, ethyl vinyl ether, 1,1-dichloro ethylene, 1,1-dichloro-1,2-difluoro ethylene, 1,2-difluoro ethylene, methane, methane-sulfonyl chloride-trifluoro, methane-sulfonyl fluoride-trifluoro, methane-(pentafluorothio)trifluoro, methane-bromo difluoro nitroso, methane-bromo fluoro, methane-bromo chloro-fluoro, methane-bromo-trifluoro, methane-chloro difluoro nitro, methane-chloro dinitro, methane-chloro fluoro, methane-chloro trifluoro, methane-chloro-difluoro, methane-dibromo difluoro, methane-dichloro difluoro, methane-dichloro-fluoro, methane-difluoro, methane-difluoro-iodo, methane-disilano, methane-fluoro, methane-iodo-trifluoro, methane-nitro-trifluoro, methane-nitroso-trifluoro, methane-tetrafluoro, methane-trichlorofluoro, methane-trifluoro, methanesulfenylchloride-trifluoro, 2-methyl butane, methyl ether, methyl isopropyl ether, methyl lactate, methyl nitrite, methyl sulfide, methyl vinyl ether, neon, neopentane, nitrogen, nitrous oxide, 1,2,3-nonadecane tricarboxylic acid-2-hydroxytrimethylester, 1-nonene-3-yne, oxygen, 1,4-pentadiene, n-pentane, pentane-perfluoro, 2-pentanone-4-amino-4-methyl, 1-pentene, 2-pentene{cis}, 2pentene{trans}, 1-pentene-3-bromo, 1-pentene-perfluoro, phthalic acid-tetrachloro, piperidine-2,3,6-trimethyl, propane, propane-1,1,1,2,2,3-hexafluoro, propane-1,2-epoxy, propane-2,2 difluoro, propane-2-amino, propane-2-chloro, propane-heptafluoro-1-nitro, propane-heptafluoro-1-nitroso, propane-perfluoro, propene, propyl-1,1,1,2,3,3-hexafluoro-2,3 dichloro, propylene-1-chloro, propylene-chloro-{trans}, propylene-2-chloro, propylene-3-fluoro, propylene-perfluoro, propyne, propyne-3,3,3-trifluoro, styrene-3-fluoro, sulfur hexafluoride, sulfur(di)-decafluoro(S 2 F 10 ), toluene-2,4-5 diamino, trifluoroacetonitrile, trifluoromethyl peroxide, trifluoromethyl sulfide, tungsten hexafluoride, vinyl acetylene, vinyl ether, and xenon. 
     
     
         81 . The method of  claim 76 , where the gas is 1-fluorobutane. 
     
     
         82 . The method of  claim 76 , further comprising, after step (c), extruding the liposomes through at least one filter of a selected pore size. 
     
     
         83 . A method for preparing drug delivery systems comprising:
 (a) allowing liposomes having encapsulated therein a drug to cool to a temperature between about −10° C. and about −20° C.;   (b) placing the liposomes under a negative pressure of between about 700 mm Hg to about 760 mm Hg;   (c) incubating the liposomes under the negative pressure for about 24 to about 72 hours to remove substantially all water from the liposomes, while allowing the liposomes to warm to a temperature between about 10° C. and about 20° C.; and   (d) instilling gas into the liposomes over a period of about 4 to about 8 hours until ambient pressures are achieved, while allowing the liposomes to warm to ambient temperature, wherein the gas is provided by a gaseous precursor.   
     
     
         84 . The method of  claim 83 , where the gas is selected from the group consisting of fluorine, perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, hexafluoropropylene, bromochlorofluoromethane, octafluoropropane, 1,1 dichloro, fluoro ethane, hexa fluoroethane, hexafluoro-2-butyne, perfluoropentane, perfluorobutane, octafluoro-2-butene, hexalluorobuta-1,3-diene, octafluorocyclopentene, hexafluoroacetone, isopropyl acetylene, allene, tetrafluoro allene, boron trifluoride, 1,2-butadiene, 1,3-butadiene, 1,2,3-trichloro,2-fluoro-1,3-butadiene, 2-methyl,1,3-butadiene, hexafluoro-1,3-butadiene, butadiene, 1-fluoro-butane, 2-methyl-butane, decafluorobutane, 1-butene, 2-butene, 2-methyl-1-butene, 3-methyl-1-butene, perfluoro-1-butene, perfluoro-2-butene, 4-phenyl-3-butene-2-one, 2-methyl-1-butene-3-yne, butyl nitrate, 1-butyne, 2-butyne, 2-chloro-1,1,1,4,4,4-hexafluoro-butyne, 3-methyl-1-butyne, perfluoro-2-butyne, 2-bromo-butyraldehyde, carbonyl sulfide, crotononitrile, cyclobutane, methyl-cyclobutane, octafluoro-cyclobutane, perfluoro-cyclobutene, 3-chloro-cyclopentene, cyclopropane, 1,2-dimethyl-cyclopropane, 1,1-dimethyl-cyclopropane, 1,2-dimethyl cyclopropane, ethyl cyclopropane, methyl cyclopropane, diacetylene, 3-ethyl-3-methyl diaziridine, 1,1,1-trifluoro-diazoethane, dimethyl amine, hexafluoro-dimethyl amine, dimethylethylamine, bis-(dimethyl phosphine)amine, 2,3-dimethyl-2-norbornane, perfluoro-dimethylamine, dimethyloxonium chloride, 1,3-dioxolane-2-one, 4-methyl, 1,1,1,2-tetrafluoro ethane, 1,1,1 trifluoroethane, 1,1,2,2-tetrafluoroethane, 1,1,2-trichloro-1,2,2-trifluoroethane, 1,1 dichloro ethane, 1,1-dichloro-1,2,2,2-tetrafluoro ethane, 1,2-difluoro ethane, 1-chloro-1,1,2,2,2-pentafluoro ethane, 2-chloro,1,1-difluoroethane, 1-chloro-1,1,2,2-tetrafluoroethane, 2-chloro,1,1-difluoro ethane, chloroethane, chloropentafluoro ethane, dichlorotrifluoroethane, fluoroethane, hexafluoro-ethane, nitro-pentafluoro ethane, nitroso-pentafluoro ethane, perfluoro ethane, perfluoro ethylamine, ethyl vinyl ether, 1,1-dichloro ethylene, 1,1-dichloro-1,2-difluoro ethylene, 1,2-difluoro ethylene, methane, methane-sulfonyl chloride-trifluoro, methane-sulfonyl fluoride-trifluoro, methane-(pentafluorothio)trifluoro, methane-bromodifluoro nitroso, methane-bromo fluoro, methane-bromo chloro-fluoro, methane-bromo-trifluoro, methane-chloro difluoro nitro, methane-chloro dinitro, methane-chloro fluoro, methane-chloro trifluoro, methane-chloro-difluoro, methane-dibromo difluoro, methane-dichloro difluoro, methane-dichloro-fluoro, methane-difluoro, methane-difluoro-iodo, methane-disilano, methane -fluoro, methane-iodo-trifluoro, methane-nitro-trifluoro, methane-nitroso-trifluoro, methane-tetrafluoro, methane-trichlorofluoro, methane-trifluoro, methanesulfenylchloride-trifluoro, 2-methyl butane, methyl ether, methyl isopropyl ether, methyl lactate, methyl nitrite, methyl sulfide, methyl vinyl ether, neon, neopentane, nitrogen, nitrous oxide, 1,2,3-nonadecane tricarboxylic acid-2-hydroxytrimethylester, 1-nonene-3-yne, oxygen, 1,4-pentadiene, n-pentane, pentane-perfluoro, 2-pentanone-4-amino-4-methyl, 1-pentene, 2-pentene{cis}, 2-pentene{trans}, 1-pentene-3-bromo, 1-pentene-perfluoro, phthalic acid-tetrachloro, piperidine-2,3,6-trimethyl, propane, propane-1,1,1,2,2,3-hexafluoro, propane-1,2-epoxy, propane-2,2 difluoro, propane-2-amino, propane-2-chloro, propane-heptafluoro-1-nitro, propane-heptafluoro-1-nitroso, propane-perfluoro, propene, propyl-1,1,1,2,3,3-hexafluoro-2,3 dichloro, propylene-1-chloro, propylene-chloro-{trans}, propylene-2-chloro, propylene-3-fluoro, propylene-perfluoro, propyne, propyne-3,3,3-trifluoro, styrene-3-fluoro, sulfur hexafluoride, sulfur(di)-decafluoro(S 2 F 10 ), toluene-2,4-diamino, trifluoroacetonitrile, trifluoromethyl peroxide, trifluoromethyl sulfide, tungsten hexafluoride, vinyl acetylene, vinyl ether, and xenon. 
     
     
         85 . The method of  claim 83 , where the gas is 1-fluorobutane. 
     
     
         86 . The method of  claim 83 , further comprising, after step (d), extruding the liposomes through at least one filter of a selected pore size. 
     
     
         87 . A product produced by the method of  claim 76 . 
     
     
         88 . A product produced by the method of  claim 83 . 
     
     
         89 . A drug delivery system prepared by a method comprising:
 (a) placing under negative pressure liposomes having encapsulated therein a drug;   (b) incubating the liposomes under the negative pressure for a time sufficient to remove substantially all water from the liposomes; and   (c) instilling gas into the liposomes until ambient pressures are achieved, wherein the gas is provided by a gaseous precursor.   
     
     
         90 . The method of  claim 89 , wherein the method is carried out at the activation temperature of the gaseous precursor. 
     
     
         91 . A method of imaging ischemic and diseased tissues comprising:
 (a) administering to a target site of a patient a drug delivery system comprising gas-filled microspheres having encapsulated therein a drug, wherein the gas is provided by a gaseous precursor having an activation temperature of about body temperature;   (b) monitoring the microspheres using energy to determine the accumulation of microspheres at the target site and the phase transition of the gaseous precursor from a liquid to a gas and to determine the presence of the microspheres in the region; and   (c) rupturing the microspheres using energy to release the drugs in the region.   
     
     
         92 . A method for preparing a drug delivery system comprising gas-filled liposomes, the method comprising shaking an aqueous solution comprising a lipid and a therapeutic compound, in the presence of a fluorinated gas, at a temperature below the gel to liquid crystalline phase transition temperature of the lipid. 
     
     
         93 . The method of  claim 92 , wherein the fluorinated gas is selected from the group consisting of fluorine gas, 1-fluorobutane, hexafluoro acetone, tetrafluoroallene, boron trifluoride, 1,2,3-trichloro, 2-fluoro-1,3-butadiene, hexafluoro-1,3-butadiene, 1-fluoro-butane, 1,2,3-trichloro, 2-fluoro-1,3-butadiene; hexafluoro-1,3-butadiene; 1-fluoro-butane; decafluoro butane; perfluoro-1-butene; perfluoro-1-butene; perfluoro-2-butene; 2-chloro-1,1,1,4,4,4-hexafluoro-butyne; perfluoro-2-butyne; octafluoro-cyclobutane; perfluoro-cyclobutene; perfluoroethane; perfluoropropane; perfluorobutane; perfluoropentane; perfluorohexane; 1,1,1-trifluorodiazoethane; hexafluoro-dimethyl amine; perfluorodimethylamine; 4-methyl-1,1,1,2-tetrafluoro ethane; 1,1,1-trifluoroethane; 1,1,2,2-tetrafluoroethane; 1,1,2-trichloro-1,2,2-trifluoroethane; 1,1-dichloro-1,2,2,2-tetrafluoro ethane; 1,2-difluoro ethane; 1-chloro-1,1,2,2,2-pentafluoro ethane; 2-chloro, 1,1-difluoroethane; 1-chloro-1,1,2,2-tetrafluoro ethane; 2-chloro,1,1-difluoroethane; chloropentafluoro ethane; dichlorotrifluoroethane; fluoro-ethane; hexafluoro-ethane; nitro-pentafluoro ethane; nitroso-pentafluoro ethane; perfluoro ethane; perfluoro ethylamine; 1,1-dichloro-1,2-difluoro ethylene; 1,2-difluoro ethylene; methane-sulfonyl chloride-trifluoro; methanesulfonyl fluoride-trifluoro; methane-(pentafluoro-thio)trifluoro; methane-bromo difluoro nitroso; methane-bromo fluoro; methane-bromo chloro-fluoro; methanebromo-trifluoro; methane-chloro difluoro nitro; methanechloro fluoro; methane-chloro trifluoro; methane-chloro-difluoro; methane dibromo difluoro; methane-dichloro difluoro; methane-dichloro-fluoro; methanedifluoro; methane-difluoro-iodo; methane-fluoro; methane-iodo-trifluoro; methane-nitro-trifluoro; methane-nitroso-trifluoro; methane-tetrafluoro; methane-trichlorofluoro; methane-trifluoro; methanesulfenylchloride-trifluoro; pentane-perfluoro; 1-pentane-perfluoro; propane-1,1,1,2,2,3-hexafluoro; propane-2,2 difluoro; propane-heptafluoro-1-nitro; propane-heptafluoro-1-nitroso; propane-perfluoro; propyl-1,1,1,2,3,3-hexafluoro-2,3 dichloro; propylene-3-fluoro; propylene-perfluoro; propyne-3,3,3-trifluoro; styrene-3-fluoro; sulfur hexafluoride; sulfur(di)-decafluoro; trifluoroacetonitrile; trifluoromethyl peroxide; trifluoromethyl sulfide; tungsten hexafluoride; pentafluoro octadecyl iodide, perfluorooctylbromide, perfluorodecalin, perfluorododecalin, perfluorooctyliodide; perfluorotripropylamine; perfluorotributylamine; hexafluoropropylene; bromochlorofluoromethane; octafluoropropane, 1,1 dichloro, fluoro ethane; hexafluoroethane; hexafluoro-2-butyne; perfluoropentane; perfluorobutane; octafluoro-2-butene, hexafluorobuta-1,3-diene; and octafluorocyclopentene. 
     
     
         94 . The method of  claim 93 , wherein the fluorinated gas is selected from the group consisting of fluorine gas, perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, hexafluoropropylene, octafluoropropane, perfluorocyclobutane, octafluorocyclopentene, dodecafluoropentane, and octafluorocyclobutane. 
     
     
         95 . The method of  claim 93 , wherein the fluorinated gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, and sulfur hexafluoride. 
     
     
         96 . The method of  claim 95 , wherein the fluorinated gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane. 
     
     
         97 . The method of  claim 92 , wherein the fluorinated gas is perfluoropropane. 
     
     
         98 . The method of  claim 92 , wherein the fluorinated gas is a perfluorocarbon gas. 
     
     
         99 . The method of  claim 98 , wherein the perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, and perfluorocyclobutane. 
     
     
         100 . The method of  claim 99 , wherein the perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane. 
     
     
         101 . The method of  claim 100 , wherein the perfluorocarbon gas is perfluoropropane. 
     
     
         102 . A method for preparing a targeted therapeutic delivery system comprising gas-filled liposomes, the method comprising:
 (a) shaking an aqueous solution comprising a lipid, in the presence of a fluorinated gas, at a temperature below the gel to liquid crystalline phase transition temperature of the lipid, to form gas-filled liposomes; and   (b) adding to the liposomes a therapeutic compound.   
     
     
         103 . The method of  claim 102 , wherein the fluorinated gas is selected from the group consisting of fluorine gas, 1-fluorobutane, hexafluoro acetone, tetrafluoroallene, boron trifluoride, 1,2,3-trichloro, 2-fluoro-1,3-butadiene, hexafluoro-1,3-butadiene, 1-fluoro-butane, 1,2,3-trichloro, 2-fluoro-1,3-butadiene; hexafluoro-1,3-butadiene; 1-fluoro-butane; decafluoro butane; perfluoro-1-butene; perfluoro-1-butene; perfluoro-2-butene; 2-chloro-1,1,1,4,4,4-hexafluoro-butyne; perfluoro-2-butyne; octafluoro-cyclobutane; perfluoro-cyclobutene; perfluoroethane; perfluoropropane; perfluorobutane; perfluoropentane; perfluorohexane; 1,1,1-trifluorodiazoethane; hexafluoro-dimethyl amine; perfluorodimethylamine; 4-methyl,1,1,1,2-tetrafluoro ethane; 1,1,1-trifluoroethane; 1,1,2,2-tetrafluoroethane; 1,1,2-trichloro-1,2,2-trifluoroethane; 1,1-dichloro-1,2,2,2-tetrafluoro ethane; 1,2-difluoro ethane; 1-chloro-1,1,2,2,2-pentafluoro ethane; 2-chloro, 1,1-difluoroethane; 1-chloro-1,1,2,2-tetrafluoro ethane; 2-chloro,1,1-difluoroethane; chloropentafluoro ethane; dichlorotrifluoroethane; fluoro-ethane; hexafluoro-ethane; nitro-pentafluoro ethane; nitroso-pentafluoro ethane; perfluoro ethane; perfluoro ethylamine; 1,1-dichloro-1,2-difluoro ethylene; 1,2-difluoro ethylene; methane-sulfonyl chloride-trifluoro; methanesulfonyl fluoride-trifluoro; methane-(pentafluoro-thio)trifluoro; methane-bromo difluoro nitroso; methane-bromo fluoro; methane-bromo chloro-fluoro; methanebromo-trifluoro; methane-chloro difluoro nitro; methanechloro fluoro; methane-chloro trifluoro; methane-chloro-difluoro; methane dibromo difluoro; methane-dichloro difluoro; methane-dichloro-fluoro; methanedifluoro; methane-difluoro-iodo; methane-fluoro; methane-iodo-trifluoro; methane-nitro-trifluoro; methane-nitroso-trifluoro; methane-tetrafluoro; methane-trichlorofluoro; methane-trifluoro; methanesulfenylchloride-trifluoro; pentane-perfluoro; 1-pentane-perfluoro; propane-1,1,1,2,2 3-hexafluoro; propane-2,2 difluoro; propane-heptafluoro-1-nitro; propane-heptafluoro-1-nitroso; propane-perfluoro; propyl-1,1,1,2,3,3-hexafluoro-2,3 dichloro; propylene-3-fluoro; propylene-perfluoro; propyne-3,3,3-trifluoro; styrene-3-fluoro; sulfur hexafluoride; sulfur(di)-decafluoro; trifluoroacetonitrile; trifluoromethyl peroxide; trifluoromethyl sulfide; tungsten hexafluoride; pentafluoro octadecyl iodide; perfluorooctylbromide; perfluorodecalin; perfluorododecalin; perfluorooctyliodide; perfluorotripropylamine; perfluorotributylamine; hexafluoropropylene; bromochlorofluoromethane; octafluoropropane, 1,1 dichloro, fluoro ethane; hexafluoroethane; hexafluoro-2-butyne; perfluoropentane; perfluorobutane; octafluoro-2-butene; hexafluorobuta-1,3-diene; and octafluorocyclopentene. 
     
     
         104 . The method of  claim 103 , wherein the fluorinated gas is selected from the group consisting of fluorine gas, perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, hexafluoropropylene, octafluoropropane, perfluorocyclobutane, octafluorocyclopentene, dodecafluoropentane, and octafluorocyclobutane. 
     
     
         105 . The method of  claim 104 , wherein the fluorinated gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, and sulfur hexafluoride. 
     
     
         106 . The method of  claim 105 , wherein the fluorinated gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane. 
     
     
         107 . The method of  claim 106 , wherein the fluorinated gas is perfluoropropane. 
     
     
         108 . The method of  claim 102 , wherein the fluorinated gas is a perfluorocarbon gas. 
     
     
         109 . The method of  claim 102 , wherein the perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, and perfluorocyclobutane. 
     
     
         110 . The method of  claim 109 , wherein the perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane. 
     
     
         111 . The method of  claim 110 , wherein the perfluorocarbon gas is perfluoropropane. 
     
     
         112 . A method for preparing a targeted therapeutic delivery system comprising gas-filled liposomes, the method comprising:
 (a) shaking an aqueous solution comprising a lipid and a therapeutic compound, in the presence of a fluorinated gas; and   (b) separating the resulting gas-filled liposomes for therapeutic use.   
     
     
         113 . The method of  claim 112 , wherein the fluorinated gas is selected from the group consisting of fluorine gas, 1-fluorobutane, hexafluoro acetone, tetrafluoroallene, boron trifluoride, 1,2,3-trichloro, 2-fluoro-1,3-butadiene, hexafluoro-1,3-butadiene, 1-fluoro-butane, 1,2,3-trichloro, 2-fluoro-1,3-butadiene; hexafluoro-1,3-butadiene; 1-fluoro-butane; decafluoro butane; perfluoro-1-butene; perfluoro-1-butene; perfluoro-2-butene; 2-chloro-1,1,1,4,4,4-hexafluoro-butyne; perfluoro-2-butyne; octafluoro-cyclobutane; perfluoro-cyclobutene; perfluoroethane; perfluoropropane; perfluorobutane; perfluoropentane; perfluorohexane; 1,1,1-trifluorodiazoethane; hexafluoro-dimethyl amine; perfluorodimethylamine; 4-methyl,1,1,1,2-tetrafluoro ethane; 1,1,1-trifluoroethane; 1,1,2,2-tetrafluoroethane; 1,1,2-trichloro-1,2,2-trifluoroethane; 1,1-dichloro-1,2,2,2-tetrafluoro ethane; 1,2-difluoro ethane; 1-chloro-1,1,2,2,2-pentafluoro ethane; 2-chloro, 1,1-difluoroethane; 1-chloro-1,1,2,2-tetrafluoro ethane; 2-chloro,1,1-difluoroethane; chloropentafluoro ethane; dichlorotrifluoroethane; fluoro-ethane; hexafluoro-ethane; nitro-pentafluoro ethane; nitroso-pentafluoro ethane; perfluoro ethane; perfluoro ethylamine; 1,1-dichloro-1,2-difluoro ethylene; 1,2-difluoro ethylene; methane-sulfonyl chloride-trifluoro; methanesulfonyl fluoride-trifluoro; methane-(pentafluoro-thio)trifluoro; methane-bromo difluoro nitroso; methane-bromo fluoro; methane-bromo chloro-fluoro; methanebromo-trifluoro; methane-chloro difluoro nitro; methanechloro fluoro; methane-chloro trifluoro; methane-chloro-difluoro; methane dibromo difluoro; methane-dichloro difluoro; methane-dichloro-fluoro; methanedifluoro; methane-difluoro-iodo; methane-fluoro; methane-iodo-trifluoro; methane-nitro-trifluoro; methane-nitroso-trifluoro; methane-tetrafluoro; methane-trichlorofluoro; methane-trifluoro; methanesulfenylchloride-trifluoro; pentane-perfluoro; 1-pentane-perfluoro; propane-1,1,1,2,2,3-hexafluoro; propane-2,2 difluoro; propane-heptafluoro-1-nitro; propane-heptafluoro-1-nitroso; propane-perfluoro; propyl-1,1,1,2,3,3-hexafluoro-2,3 dichloro; propylene-3-fluoro; propylene-perfluoro; propyne-3,3,3-trifluoro; styrene-3-fluoro; sulfur hexafluoride; sulfur(di)-decafluoro; trifluoroacetonitrile; trifluoromethyl peroxide; trifluoromethyl sulfide; tungsten hexafluoride; pentafluoro octadecyl iodide; perfluorooctylbromide; perfluorodecalin; perfluorododecalin; perfluorooctyliodide; perfluorotripropylamine; perfluorotributylamine; hexafluoropropylene; bromochlorofluoromethane; octafluoropropane; 1,1 dichloro, fluoro ethane; hexafluoroethane; hexafluoro-2-butyne; perfluoropentane; perfluorobutane; octafluoro-2-butene; hexafluorobuta-1,3-diene; and octafluorocyclopentene. 
     
     
         114 . The method of  claim 113 , wherein the fluorinated gas is selected from the group consisting of fluorine gas, perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, hexafluoropropylene, octafluoropropane, perfluorocyclobutane, octafluorocyclopentene, dodecafluoropentane, and octafluorocyclobutane. 
     
     
         115 . The method of  claim 114 , wherein the fluorinated gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, and sulfur hexafluoride. 
     
     
         116 . The method of  claim 115 , wherein the fluorinated gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane. 
     
     
         117 . The method of  claim 116 , wherein the fluorinated gas is perfluoropropane. 
     
     
         118 . The method of  claim 112 , wherein the fluorinated gas is a perfluorocarbon gas. 
     
     
         119 . The method of  claim 118 , wherein the perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, and perfluorocyclobutane. 
     
     
         120 . The method of  claim 119 , wherein the perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane. 
     
     
         121 . The method of  claim 120 , wherein the perfluorocarbon gas is perfluoropropane. 
     
     
         122 . A method for preparing a targeted therapeutic delivery system comprising gas-filled liposomes, the method comprising:
 (a) shaking an aqueous solution comprising a lipid, in the presence of a fluorinated gas, at a temperature below the gel to liquid crystalline phase transition temperature of the lipid, to form gas-filled liposomes;   (b) adding a therapeutic compound; and   (c) separating the resultant gas-filled liposomes for therapeutic use.   
     
     
         123 . The method of  claim 122 , wherein the fluorinated gas is selected from the group consisting of fluorine gas, 1-fluorobutane, hexafluoro acetone, tetrafluoroallene, boron trifluoride, 1,2,3-trichloro, 2-fluoro-1,3-butadiene, hexafluoro-1,3-butadiene, 1-fluoro-butane, 1,2,3-trichloro, 2-fluoro-1,3-butadiene; hexafluoro-1,3-butadiene; 1-fluoro-butane; decafluoro butane; perfluoro-1-butene; perfluoro-1-butene; perfluoro-2-butene; 2-chloro-1,1,1,4,4,4-hexafluoro-butyne; perfluoro-2-butyne; octafluoro-cyclobutane; perfluoro-cyclobutene; perfluoroethane; perfluoropropane; perfluorobutane; perfluoropentane; perfluorohexane; 1,1,1-trifluorodiazoethane; hexafluoro-dimethyl amine; perfluorodimethylamine; 4-methyl-1,1,1,2-tetrafluoro ethane; 1,1,1-trifluoroethane; 1,1,2,2-tetrafluoroethane; 1,1,2-trichloro-1,2,2-trifluoroethane; 1,1-dichloro-1,2,2,2-tetrafluoro ethane; 1,2-difluoro ethane; 1-chloro-1,1,2,2,2-pentafluoro ethane; 2-chloro, 1,1-difluoroethane; 1-chloro-1,1,2,2-tetrafluoro ethane; 2-chloro, 1,1-difluoroethane; chloropentafluoro ethane; dichlorotrifluoroethane; fluoro-ethane; hexafluoro-ethane; nitro-pentafluoro ethane; nitroso-pentafluoro ethane; perfluoro ethane; perfluoro ethylamine; 1,1-dichloro-1,2-difluoro ethylene; 1,2-difluoro ethylene; methane-sulfonyl chloride-trifluoro; methanesulfonyl fluoride-trifluoro; methane-(pentafluoro-thio)trifluoro; methane-bromo difluoro nitroso; methane-bromo fluoro; methane-bromo chloro-fluoro; methanebromo-trifluoro; methane-chloro difluoro nitro; methanechloro fluoro; methane-chloro trifluoro; methane-chloro-difluoro; methane dibromo difluoro; methane-dichloro difluoro; methane-dichloro-fluoro; methanedifluoro; methane-difluoro-iodo; methane-fluoro; methane-iodo-trifluoro; methane-nitro-trifluoro; methane-nitroso-trifluoro; methane-tetrafluoro; methane-trichlorofluoro; methane-trifluoro; methanesulfenylchloride-trifluoro; pentane-perfluoro; 1-pentane-perfluoro; propane-1,1,1,2,2,3-hexafluoro; propane-2,2 difluoro; propane-heptafluoro-1-nitro; propane-heptafluoro-1-nitroso; propane-perfluoro; propyl-1,1,1,2,3,3-hexafluoro-2,3 dichloro; propylene-3-fluoro; propylene-perfluoro; propyne-3,3,3-trifluoro; styrene-3-fluoro; sulfur hexafluoride; sulfur(di)-decafluoro; trifluoroacetonitrile; trifluoromethyl peroxide; trifluoromethyl sulfide; tungsten hexafluoride; pentafluoro octadecyl iodide; perfluorooctylbromide; perfluorodecalin; perfluorododecalin; perfluorooctyliodide; perfluorotripropylamine; perfluorotributylamine; hexafluoropropylene; bromochlorofluoromethane; octafluoropropane; 1,1 dichloro, fluoro ethane; hexa fluoroethane; hexafluoro-2-butyne; perfluoropentane; perfluorobutane; octafluoro-2-butene; hexafluorobuta-1,3-diene; and octafluorocyclopentene. 
     
     
         124 . The method of  claim 123 , wherein the fluorinated gas is selected from the group consisting of fluorine gas, perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, hexafluoropropylene, octafluoropropane, perfluorocyclobutane, octafluorocyclopentene, dodecafluoropentane, and octafluorocyclobutane. 
     
     
         125 . The method of  claim 124 , wherein the fluorinated gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, and sulfur hexafluoride. 
     
     
         126 . The method of  claim 125 , wherein the fluorinated gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane. 
     
     
         127 . The method of  claim 126 , wherein the fluorinated gas is perfluoropropane. 
     
     
         128 . The method of  claim 122 , wherein the fluorinated gas is a perfluorocarbon gas. 
     
     
         129 . The method of  claim 128 , wherein the perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, and perfluorocyclobutane. 
     
     
         130 . The method of  claim 129 , wherein the perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane. 
     
     
         131 . The method of  claim 130 , wherein the perfluorocarbon gas is perfluoropropane.