Surfactant microbubbles and process for preparing and methods of using the same

Abstract

The invention relates to an ultrasound contrast agent (UCA) comprising an outer shell and a gas core. The gas core is filled with oxygen, and the outer shell comprises a first surfactant and a second surfactant. The invention also relates to a method of making an oxygen-filled UCA and delivering oxygen to a local area of a subject's body. The method comprises injecting a composition comprising an oxygen-filled UCA of the invention into the subject's body; directing ultrasound radiation to the local area in an intensity sufficient to rupture the UCA.

1 . An ultrasound contrast agent (UCA) comprising an outer shell and a gas core, wherein said gas core is filled with substantially pure oxygen, and
 wherein said outer shell comprises a first surfactant and a second surfactant.   
     
     
         2 . The UCA of  claim 1 , wherein the gas core is filled with about 100% pure oxygen. 
     
     
         3 . The UCA of  claim 1 , wherein the gas core is filled with at least about 90% pure oxygen. 
     
     
         4 . The UCA of  claim 1 , wherein the first surfactant is d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). 
     
     
         5 . The UCA of  claim 1 , wherein the first surfactant is polyoxyethylene sorbitan monooleate. 
     
     
         6 . The UCA of  claim 1 , wherein the second surfactant is selected from the group consisting of: sorbitan esters, alkylphenol ethoxylate-based surfactants, alcohol ethoxylate-based surfactants, silicone-based surfactants, alkyl poly(ethylene oxide), alkylphenol poly(ethylene oxide), copolymers of poly(ethylene oxide) and poly(propylene oxide), alkyl polyglucosides, fatty alcohols, cocamide MEA, cocamide DEA, and polysorbates. 
     
     
         7 . The UCA of  claim 1 , wherein the mean diameter of the UCA is in the range of 1 μm to 10 μm. 
     
     
         8 . The UCA of  claim 1 , wherein the mean diameter of the UCA is in the range of 2 μm to 7 μm. 
     
     
         9 . The UCA of  claim 1 , wherein the mean diameter of the UCA is about 3 μm. 
     
     
         10 . The UCA of  claim 1 , wherein the half-life of the UCA under 5 MHz ultrasound is in the range of 1 to 20 minutes. 
     
     
         11 . The UCA of  claim 1 , wherein the half-life of the UCA under 5 MHz ultrasound is in the range of 5 to 20 minutes. 
     
     
         12 . The UCA of  claim 1 , wherein the half-life of the UCA under 5 MHz ultrasound is in the range of 10 to 20 minutes. 
     
     
         13 . The UCA of  claim 1 , wherein the half-life of the UCA under 5 MHz ultrasound is about 15 minutes. 
     
     
         14 . The UCA of  claim 1 , wherein:
 the first surfactant is TGPS;   the second surfactant is sorbitan monostearate; and   the gas core is filled with about 100% pure oxygen.   
     
     
         15 . The UCA of  claim 14 , wherein the mean diameter of the UCA is about 3 μm. 
     
     
         16 . A method of making an oxygen-filled UCA, said method comprising the steps of:
 a. mixing a first surfactant and a second surfactant in phosphate buffered saline;   b. heating the mixture until both surfactants are dissolved;   c. cooling said mixture to room temperature while stirring;   d. placing the mixture in a vessel in an ice bath, purging said mixture using a gas while sonicating said mixture;   e. separating microbubbles;   f. adding a lyoprotectant to the microbubbles;   g. freeze-drying the microbubbles;   h. sealing the microbubbles under vacuum; and   i. refilling the microbubbles with substantially pure oxygen.   
     
     
         17 . The method of  claim 16 , wherein:
 the first surfactant is TPGS;   the second surfactant is sorbitan monostearate;   the gas is octafluoropropane; and   the lyoprotectant is glucose.   
     
     
         18 . A method of delivering oxygen to a local area of a subject's body, comprising
 a. injecting a composition comprising a UCA of  claim 1  into the subject's body; and   b. directing ultrasound radiation to the local area in an intensity sufficient to rupture the UCA.   
     
     
         19 . A method of improving effectiveness of radiotherapy and chemotherapy against cancer, comprising the steps of:
 a. injecting a composition comprising a UCA of  claim 1  into a subject suffering from cancer;   b. directing ultrasound radiation to a location of said cancer in an intensity sufficient to rupture the UCA; and   c. applying radiotherapy and/or chemotherapy.   
     
     
         20 . A method of delivering a drug to a subject, comprising the steps of:
 a. preparing a drug-containing UCA;   b. injecting the UCA into the circulatory system of the subject; and   c. directing ultrasound radiation to a location of interest with an intensity sufficient to rupture the drug-containing UCA.