Method For Ultrasound Triggered Drug Delivery Using Hollow Microbubbles With Controlled Fragility

Abstract

A method is provided for site specific delivering therapeutic or diagnostic agents to a region in a fluid-filled cavity, vessel or tissue using an agent-loaded microbubble population. The population has controlled fragility characterized by a uniform wall thickness to diameter ratio which defines the discrete threshold intensity value of ultrasonic power where microbubble rupture occurs in the population. The location of the microbubble population may be monitored by ultrasound to determine its presence at the region prior to application of the ultrasonic power to rupture to microbubbles.

1 . A composition comprising a microbubble population, wherein said microbubble population comprises a plurality of microbubbles, wherein each of said microbubbles comprise the same wall thickness to diameter ratio. 
   
   
       2 . The composition of  claim 1 , wherein said ratio ranges between approximately 0.016-0.049. 
   
   
       3 . The composition of  claim 1 , wherein said wall thickness ranges between approximately 25 nm to 1000 nm. 
   
   
       4 . The composition of  claim 1 , wherein said diameter ranges between approximately 1 to 10 microns. 
   
   
       5 . The composition of  claim 1 , wherein each of said microbubbles comprise a single layer shell. 
   
   
       6 . The composition of  claim 1 , wherein each of said microbubbles comprise a bi-layer shell. 
   
   
       7 . The composition of  claim 1 , wherein each of said microbubbles comprise a biodegradable polymer. 
   
   
       8 . The composition of  claim 7 , wherein said biodegradable polymer is biocompatible. 
   
   
       9 . The composition of  claim 6 , wherein said bi-layer shell comprises an outer layer of an amphiphilic material. 
   
   
       10 . The composition of  claim 9 , wherein said amphiphilic material comprises a protein. 
   
   
       11 . The composition of  claim 10 , wherein said protein is selected from the group consisting of collagen, gelatin, albumin, and globulin. 
   
   
       12 . The composition of  claim 7 , wherein said biodegradable polymer is selected from the group consisting of polycaprolactone, polylactide, polyglycolide, polyhydroxyvalerate, polyhydroxybutyrate, or copolymers thereof. 
   
   
       13 . The composition of  claim 1 , wherein each of said microbubbles further comprise at least one therapeutic agent. 
   
   
       14 . The composition of  claim 13 , wherein said therapeutic agent comprises a cardiovascular drug. 
   
   
       15 . The composition of  claim 13 , wherein said therapeutic agent comprises an anti-restenosis drug. 
   
   
       16 . The composition of  claim 14 , wherein said cardiovascular drug is selected from the group consisting of a fibrinolytic agent, vasodilator, calcium channel blocker, angiogenesis agent, antiplatelet agent, anti-white cell agent, endocardium acting agent, free radical scavenging agent, or anti-restenosis agent. 
   
   
       17 . The composition of  claim 13 , wherein said therapeutic agent is selected from the group consisting of adeno sine, adeno sine monophosphate, adeno sine diphosphate, adenosine triphosphate or chemical derivatives of adenosine.