Nanodroplets with improved properties

Abstract

Stable perfluorocarbon nanodroplet compositions with properties such as low-boiling points and small particle diameters are provided for improved performance in ultrasound imaging and therapeutic applications. Methods of producing stabilized nanodroplet compositions and methods of using the compositions are further provided to allow for improved performance in ultrasound imaging techniques and/or therapeutic applications.

1 - 29 . (canceled) 
     
     
         30 . A method of producing a liquid perfluorocarbon (PFC) nanodroplet composition, comprising the steps of:
 combining a PFC liquid with a surfactant and a co-surfactant to produce a fluid composition; and   emulsifying said PFC liquid with said surfactant and said co-surfactant within said fluid composition through direct microfluidization at a pressure of at least about 3,000 psi and no greater than about 13,000 psi to reduce the size of PFC droplets within said fluid composition to form nanodroplets having an average particle diameter of less than 300 nm,   wherein said surfactant comprises an amphiphilic phospholipid-based compound,   wherein said cosurfactant comprises a semi-fluorinated alkane,   wherein the PFC is decafluorobutane, and   wherein the emulsifying is carried out at less than about −15° C.   
     
     
         31 . The method of  claim 30 , wherein the emulsifying is carried out at a pressure of about 13,000 psi. 
     
     
         32 . The method of  claim 30 , wherein the emulsifying is carried out at a pressure of at least about 8,000 psi and no greater than about 13,000 psi. 
     
     
         33 . The method of  claim 30 , wherein the nanodroplet composition having an average particle diameter of less than 300 nm is
 stable at 4° C. for at least 18 days;   stable at 22° C. for at least one day;   stable upon heating to physiological temperature;   stable upon heating to 40° C.; and/or   stable upon heating to 45° C.   
     
     
         34 . The method of  claim 30 , wherein the semifluorinated alkane has a formula of C n F 2n+1 C m H 2m+1 . 
     
     
         35 . The method of  claim 30 , wherein the concentration of the surfactant in the composition is no greater than about 3.5 mg/mL, and wherein the amount of the co-surfactant in the composition is about equimolar to the amount of said surfactant in the composition. 
     
     
         36 . The method of  claim 30 , wherein the nanodroplet composition has a concentration of at least 10 11  nanodroplets/mL. 
     
     
         37 . The method of  claim 30 , further comprising fabricating the outer surface of a shell of the nanodroplet for coupling with a targeting ligand. 
     
     
         38 . A method of producing a liquid perfluorocarbon (PFC) nanodroplet composition, comprising the steps of:
 combining a PFC liquid with a surfactant and a co-surfactant to produce a fluid composition; and   emulsifying said PFC liquid with said surfactant and said co-surfactant within said fluid composition through direct microfluidization at a pressure of at least about 3,000 psi and no greater than about 13,000 psi to reduce the size of PFC droplets within said fluid composition to form nanodroplets having an average particle diameter of less than 300 nm,   wherein said surfactant comprises an amphiphilic phospholipid-based compound,   wherein said cosurfactant comprises a semi-fluorinated alkane,   wherein the PFC is octafluoropropane, and   wherein the emulsifying is carried out at less than about −35° C.   
     
     
         39 . The method of  claim 38 , wherein the emulsifying is carried out at a pressure of about 13,000 psi. 
     
     
         40 . The method of  claim 38 , wherein the emulsifying is carried out at a pressure of at least about 8,000 psi and no greater than about 13,000 psi. 
     
     
         41 . The method of  claim 38 , wherein the nanodroplet composition having an average particle diameter of less than 300 nm is substantially free of microbubbles at 37° C. 
     
     
         42 . The method of  claim 38 , wherein the semifluorinated alkane has a formula of C n F 2n+1 C m H 2m+1 . 
     
     
         43 . The method of  claim 38 , wherein the concentration of the surfactant in the composition is no greater than about 3.5 mg/mL, and wherein the amount of the co-surfactant in the composition is about equimolar to the amount of said surfactant in the composition. 
     
     
         44 . The method of  claim 38 , wherein the nanodroplet composition has a concentration of at least 10 11  nanodroplets/mL. 
     
     
         45 . A method of producing a liquid perfluorocarbon (PFC) nanodroplet composition, comprising the steps of:
 combining a PFC liquid with a surfactant and a co-surfactant to produce a fluid composition, wherein said PFC has a boiling point of less than about 0° C.; and   emulsifying said PFC liquid with said surfactant and said co-surfactant within said fluid composition through direct microfluidization to reduce the size of PFC droplets within said fluid composition to form nanodroplets having an average particle diameter of less than 300 nm,   wherein said surfactant comprises an amphiphilic phospholipid-based compound,   wherein said cosurfactant comprises a semi-fluorinated alkane,   wherein said emulsifying is performed at a temperature below 0° C., and   wherein said emulsifying is performed at about 13,000 psi.   
     
     
         46 . The method of  claim 45 , wherein the surfactant comprises one or more of 1,2-distearoyl-sn-glycero-3-phosphocoline (DSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene-glycol)-2000 (DSPE-PEG2000), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene-glycol)-5000 (DSPE-PEG5000), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene-glycol)-2000] (DSPE-PEG2000-Mal), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene-glycol)-5000] (DSPE-PEG5000-Mal), and 1,2-distearoyl-3-trimethylammonium propane (DSTAP); and wherein the concentration of said surfactant in the composition is no greater than about 3.5 mg/mL. 
     
     
         47 . The method of  claim 45 , wherein the semi-fluorinated alkane has a formula of C n F 2n+1 C m H 2m+1 . 
     
     
         48 . The method of  claim 45 , wherein the nanodroplet composition having an average particle diameter of less than 300 nm is substantially free of microbubbles at 37° C. 
     
     
         49 . The method of  claim 45 , wherein the nanodroplet composition has a concentration of at least 10 11  nanodroplets/mL.