Targeting microbubbles

Abstract

This invention related to manufactured microbubbles, as well as methods of using manufactured microbubbles, for example, in medicinal applications. The invention pertains to the physical structure and materials of the microbubbles, as well as to methods for manufacturing microbubbles, methods for targeting microbubbles for specific medicinal applications, and methods for delivering microbubbles in medical treatment.

What is claimed: 
     
         1 . A targeting microbubble comprising:
 (a) a core containing a fluid having a normal boiling point less than about 30° C.;   (b) an anchoring moiety comprising a bio-lipid, protein, surfactant, or synthetic polymer; and   (c) a targeting moiety comprising:
 (i) a chemical group having an affinity for a metal-containing material; or 
 (ii) a cell specific ligand. 
   
     
     
         2 . The targeting microbubble of  claim 1 , wherein the anchoring moiety and the targeting moiety are linked via a covalent, ionic, or hydrogen-bonding linkage. 
     
     
         3 . The targeting microbubbles of  claim 2 , wherein the anchoring moiety covalently attached to the targeting moiety. 
     
     
         4 . The targeting microbubble of  claim 1 , further comprising a polymeric linker that covalently attaches the anchoring moiety to the targeting moiety. 
     
     
         5 . The targeting microbubble of  claim 1 , wherein the fluid is air, CO 2 , a fluorinated or perfluorinated C 1-6  hydrocarbon, or a combination thereof. 
     
     
         6 . The targeting microbubble of  claim 5 , wherein the fluorinated hydrocarbon is perfluoropropane or perfluoropentane. 
     
     
         7 . The targeting microbubble of  claim 5 , wherein the targeting moiety comprises a chemical group having an affinity for a metal-containing material. 
     
     
         8 . The targeting microbubble of  claim 1 , wherein the chemical group comprises a chelant having at least two amino, carboxy, hydroxyl, phosphoryl, or thiol groups, or a combination thereof, said chelant having an affinity for the metal-containing material. 
     
     
         9 . The targeting microbubble of  claim 1 , wherein the targeting moiety comprises a chemical group having an affinity for a calcium-containing material 
     
     
         10 . The targeting microbubble of  claim 9 , wherein the chemical group comprises a bisphosphonate moiety. 
     
     
         11 . The targeting microbubble of  claim 9 , wherein the calcium-containing material is atheromatous plaque, biliary stone, a calcified tissue or plaque, a cancerous tumor, or a urinary stone. 
     
     
         12 . The targeting microbubbles of  claim 1 , wherein the targeting moiety is a cell specific ligand. 
     
     
         13 . The targeting microbubbles of  claim 12 , wherein the cell specific ligand is a cancer tumor cell specific ligand. 
     
     
         14 . The targeting microbubbles of  claim 13 , wherein the cancer tumor cell specific ligand is a folate. 
     
     
         15 . A solution comprising a plurality of the targeting microbubbles of  claim 1  dispersed in a solvent. 
     
     
         16 . The solution of  claim 15 , wherein the solvent is water. 
     
     
         17 . The solution of  claim 15 , wherein the solvent is a physiological fluid. 
     
     
         18 . The solution  claim 15 , wherein the plurality of targeting microbubbles have an average diameter in the solution in the range of about 1 micron to about 10 microns. 
     
     
         19 . A method for preparing a solution of microbubbles, the method comprising delivering energy to a solution comprising a bubble-forming material and a solvent, wherein:
 (a) the bubble-forming material comprises an anchoring moiety and a targeting moiety, said targeting moiety comprising:
 (i) a chemical group having an affinity for a metal-containing material; or 
 (ii) a cell specific ligand; and 
   (b) the energy is sufficient to cause the bubble-forming material to form microbubbles in the solvent.   
     
     
         20 . The method of  claim 19 , wherein the chemical group comprises a chelant having at least two amino, carboxy, hydroxyl, phosphoryl, or thiol groups, or a combination thereof, said chelant having an affinity for the metal-containing material. 
     
     
         21 . The method of  claim 19 , wherein the targeting moiety comprises a chemical group having an affinity for a calcium-containing material 
     
     
         22 . The method of  claim 21 , wherein the targeting moiety comprises a bisphosphonate moiety. 
     
     
         23 . The method of  claim 19 , wherein the energy is in the form of ultrasound, mechanical, or microwave energy. 
     
     
         24 . The method of  claim 19 , wherein the anchoring moiety comprises a bio-lipid, surfactant, synthetic polymer, protein, or combination thereof. 
     
     
         25 . The method of  claim 19 , wherein the anchoring moiety and the targeting moiety are chemically linked. 
     
     
         26 . The method of  claim 25 , wherein the chemical linkage is a covalent polymeric linking moiety. 
     
     
         27 . The method of  claim 19 , wherein the bubble-forming material further comprises a bio-lipid, surfactant, synthetic polymer, or protein, wherein the compound is not chemically linked to the targeting moiety. 
     
     
         28 . A method of treating a patient comprising applying energy to microbubbles disposed within the patient, wherein the microbubbles comprise a targeting moiety with a specific affinity to a target within the patient, and wherein the energy is effective to cause cavitation of the microbubbles. 
     
     
         29 . The method of  claim 28 , wherein the energy is in the form of ultrasound or electromagnetic energy. 
     
     
         30 . The method of  claim 28 , further comprising administering the microbubbles to the patient prior to applying the energy. 
     
     
         31 . The method of  claim 30 , wherein the administering is via injection, inhalation, or implantation. 
     
     
         32 . The method of  claim 28 , wherein the target is a calcium-containing mass, a cancerous cell, a tumor, or a tissue. 
     
     
         33 . The method of  claim 28 , wherein the target is a calcium-containing mass, and where the cavitation causes damage to the target. 
     
     
         34 . The method of  claim 33 , wherein the target is a renal or urinary stone, biliary stone, blood clot, fibroid, cancerous tumor, or atheromatous plaque. 
     
     
         35 . The method of  claim 28 , wherein the target is a cancerous cell, and where the cavitation causes lysis of the target. 
     
     
         36 . The method of  claim 28 , wherein the targeting moiety is chemically attached to an anchoring moiety. 
     
     
         37 . The method of  claim 36 , wherein the anchoring moiety comprises a bio-lipid, synthetic polymer, protein, or surfactant, or combination thereof. 
     
     
         38 . The method of  claim 36 , wherein the chemical attachment is via a linking polymeric moiety. 
     
     
         39 . The method of  claim 28 , wherein the microbubbles further comprise a bio-lipid, synthetic polymer, protein, or surfactant, wherein the compound is lacking a targeting moiety. 
     
     
         40 . The method of  claim 28 , wherein the microbubbles are attached to the target. 
     
     
         41 . The method of  claim 28 , wherein the microbubbles are in proximity to the target, but are not attached to the target. 
     
     
         42 . A method of treating a patient, the method comprising:
 (a) delivering a solution comprising microbubbles to a site within the patient; and   (b) applying energy to the microbubbles, wherein the energy is in the form of electromagnetic or ultrasound energy and is sufficient to cause cavitation of the microbubbles, and wherein the cavitation releases sufficient energy to cause destruction of cell, tissue, or calcium-containing mass at the site within the patient.   
     
     
         43 . The method of  claim 42 , wherein the solution is delivered directly to the site via implantation or via a catheter. 
     
     
         44 . The method of  claim 42 , wherein the solution is delivered to the patient via injection or inhalation, and wherein the microbubbles comprise a targeting moiety having an affinity for a cell, tissue, or calcium-containing mass at the site within the patient.