Encapsulation of microbubbles within the aqueous core of microcapsules

Abstract

The present invention includes a construct that comprises at least one microbubble encapsulated within the aqueous core of a microcapsule. The present invention also includes a pharmaceutical composition comprising a construct comprising at least one microbubble encapsulated within the aqueous core of a microcapsule. The present invention further includes a method of imaging a tissue or organ in a subject, a method of delivering a therapeutic cargo to a tissue or organ in a subject, and a method of treating a disease or disorder in a subject.

1 - 75 . (canceled) 
     
     
         76 . A method of preparing a triple emulsion composition, the method comprising:
 dissolving a lipid mixture in an aqueous phase to provide a first mixture, wherein the lipid mixture comprises a first phospholipid;   dispersing a gas into the first mixture to provide a microbubble suspension;   emulsifying a second mixture comprising the microbubble suspension, an organic solvent, and at least one of a polymer and a second phospholipid, to provide a first emulsion;   emulsifying a third mixture comprising the first emulsion and polyvinyl alcohol (PVA) to provide a second emulsion; and   emulsifying a fourth mixture comprising the second emulsion and PVA, to provide the triple emulsion composition.   
     
     
         77 . The method of  claim 76 , wherein the aqueous phase comprises a therapeutic agent. 
     
     
         78 . The method of  claim 76 , wherein the aqueous phase comprises phosphate buffered saline (PBS). 
     
     
         79 . The method of  claim 76 , wherein the first phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), egg phosphatidylcholine (Egg PC), or dimyristoylphosphatidylcholine (DMPC). 
     
     
         80 . The method of  claim 76 , wherein the first mixture further comprises a stabilizing agent, wherein the stabilizing agent is 1,2-disteroyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000] (mPEG 2000 DPPE). 
     
     
         81 . The method of  claim 76 , wherein the polymer is poly-lactic-co-glycolic acid or poly-L-lactic acid (PLA). 
     
     
         82 . The method of  claim 76 , wherein the gas is sulfur hexafluoride or a fluorinated compound. 
     
     
         83 . The method of  claim 76 , wherein the gas is sulfur hexafluoride, octafluoropropane, or perfluorobutane. 
     
     
         84 . The method of  claim 76 , wherein the second mixture further comprises an oil. 
     
     
         85 . The method of  claim 76 , wherein the second mixture further comprises from about 0.001% to about 10% of an oil. 
     
     
         86 . A method of preparing a construct for delivering a therapeutic cargo, the method comprising:
 dissolving a lipid mixture in an aqueous phase to provide a first mixture, wherein the lipid mixture comprises a first phospholipid;   dispersing a gas into the first mixture to provide a microbubble suspension;   emulsifying a second mixture comprising the microbubble suspension, an organic solvent, and at least one of a polymer and a second phospholipid, to provide a first emulsion;   emulsifying a third mixture comprising the first emulsion and polyvinyl alcohol (PVA) to provide a second emulsion;   emulsifying a fourth mixture comprising the second emulsion and PVA to provide a triple emulsion; and   removing at least a fraction of the organic solvent, to provide the construct.   
     
     
         87 . The method of  claim 86 , wherein the aqueous phase comprises a therapeutic agent. 
     
     
         88 . The method of  claim 86 , wherein the aqueous phase comprises phosphate buffered saline (PBS). 
     
     
         89 . The method of  claim 86 , wherein the first phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), egg phosphatidylcholine (Egg PC), or dimyristoylphosphatidylcholine (DMPC). 
     
     
         90 . The method of  claim 86 , wherein the first mixture further comprises a stabilizing agent, wherein the stabilizing agent is mPEG 2000 DPPE. 
     
     
         91 . The method of  claim 86 , wherein the polymer is poly-lactic-co-glycolic acid or PLA. 
     
     
         92 . The method of  claim 86 , wherein the gas is sulfur hexafluoride, perfluoropropane, or perfluorobutane. 
     
     
         93 . The method of  claim 86 , where the second mixture further comprises an oil. 
     
     
         94 . The method of  claim 86 , wherein the second mixture further comprises from about 0.001% to about 10% of an oil. 
     
     
         95 . A construct for delivering a therapeutic cargo, wherein the construct is prepared by a process comprising:
 dissolving a lipid mixture in an aqueous phase to provide a first mixture, wherein the lipid mixture comprises a first phospholipid;   dispersing a gas into the first mixture to provide a microbubble suspension;   emulsifying a second mixture comprising the microbubble suspension, an organic solvent, and at least one of a polymer and a second phospholipid, to provide a first emulsion;   emulsifying a third mixture comprising the first emulsion and polyvinyl alcohol (PVA) to provide a second emulsion;   emulsifying a fourth mixture comprising the second emulsion and PVA to provide a triple emulsion; and   removing at least a fraction of the organic solvent to provide the construct.