Methods and devices for detection and therapy of atheromatous plaque

Abstract

The present invention relates to devices for detection and therapy of active atheromatous plaque and/or thin-capped fibro-atheroma (“vulnerable plaque”), using selectively targeted fluorescent, radiolabeled, or fluorescent and radiolabeled compositions. The present invention further relates to methods and devices for detection and therapy of active atheromatous plaques and/or vulnerable plaques, using selectively targeted beta-emitting compositions, optionally comprising fluorescent compositions.

1 - 124 . (canceled)  
   
   
       125 . A method of detecting and treating a vulnerable plaque in a subject comprising the steps of: 
 a) administering a beta-emitting composition;    b) localizing the composition to the vulnerable plaque;    c) administering a therapeutically effective amount of at least one photosensitizer composition, wherein the photosensitizer composition is localized to the vulnerable plaque;    d) detecting a signal from the beta-emitting composition;    e) identifying the vulnerable plaque;    f) light activating the photosensitizer composition at the site of the vulnerable plaque to produce a phototoxic species; and    g) stabilizing the vulnerable plaque against rupture, thereby treating the vulnerable plaque in the subject.    
   
   
       126 . The method of  claim 125 , wherein the vulnerable plaque comprises inflammatory components, a large lipid pool, and a thin fibrous cap.  
   
   
       127 . The method of  claim 126 , wherein the thin fibrous cap is less than about 150 microns thick.  
   
   
       128 . The method of  claim 127 , wherein the thin fibrous cap is less than about 100 microns thick.  
   
   
       129 . The method of  claim 126 , wherein inflammatory components are selected from the group consisting of inflammatory cells, lipids, procoagulants and agents that promote inhibition of extracellular matrix production or degradation of extracellular matrix.  
   
   
       130 . The method of  claim 129 , wherein the inflammatory cells are selected from the group consisting of smooth muscle cells, leukocytes, lymphocytes, monocytes, macrophages, foam cells, mast cells, endothelial cells, platelets, erythrocytes and polymorphonuclear cells.  
   
   
       131 . The method of  claim 130 , wherein the lymphocytes comprise B-lymphocytes and T-lymophocytes.  
   
   
       132 . The method of  claim 130 , wherein the polymorphonuclear cells comprise granulocytes and neutrophils.  
   
   
       133 . The method of  claim 130 , wherein the inflammatory cells comprise greater than about 10% macrophages and/or monocytes.  
   
   
       134 . The method of  claim 130 , wherein the inflammatory cells comprise greater than about 25% macrophages and/or monocytes.  
   
   
       135 . The method of  claim 129 , wherein the lipid content is greater than about 10%.  
   
   
       136 . The method of  claim 129 , wherein the lipid content is greater than about 25%.  
   
   
       137 . The method of  claim 125 , wherein the beta-emitting composition comprises a beta-emitting agent selected from the group consisting of  18 F-Fluorodeoxyglucose, I 131 , Re 186  and Re 188  coupled to a molecular carrier.  
   
   
       138 . The method of  claim 137 , wherein the molecular carrier targets inflammatory components selected from the group consisting of inflammatory cells, lipids, procoagulants and agents that promote inhibition of extracellular matrix production or degradation of extracellular matrix.  
   
   
       139 . The method of  claim 138 , wherein the inflammatory cells are selected from the group consisting of smooth muscle cells, leukocytes, lymphocytes, monocytes, macrophages, foam cells, mast cells, endothelial cells, platelets, erythrocytes and polymorphonuclear cells.  
   
   
       140 . The method of  claim 139 , wherein the lymphocytes comprise B-lymphocytes and T-lymophocytes.  
   
   
       141 . The method of  claim 139 , wherein the polymorphonuclear cells comprise granulocytes and neutrophils.  
   
   
       142 . The method of  claim 137 , wherein the molecular carrier is selected from the group consisting of serum proteins, receptor ligands, microspheres, liposomes, antibodies, growth factors, peptides, hormones and lipoproteins.  
   
   
       143 . The method of  claim 137 , wherein the molecular carrier binds to a scavenger receptor.  
   
   
       144 . The method of  claim 143 , wherein the molecular carrier is selected from the group consisting of maleylated albumin, daunorubicin, doxorubicin, oxidized low density lipoprotein, acetylated low density lipoprotein, oxidized high density lipoprotein, malondialdehyde treated proteins, formaldehyde treated albumin, glycated albumin, polyinosinic acid, glycated lipoproteins, dextran sulfate, anionic phospholipids, fucoidin, carrageenan, polyvinyl sulfate and monoclonal antibodies that recognize CD11b, CD11c, CD13, CD14, CD16a, CD32 or CD68.  
   
   
       145 . The method of  claim 144 , wherein the anionic phospholipid is phosphatidyl serine.  
   
   
       146 . The method of  claim 137 , wherein the molecular carrier targets the beta-emitting composition to a T lymphocyte.  
   
   
       147 . The method of  claim 146 , wherein the molecular carrier is selected from the group consisting of monoclonal antibodies that recognize CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD25, CD28, CD44 and CD71 and transferrin.  
   
   
       148 . The method of  claim 137 , wherein the molecular carrier targets the beta-emitting composition to lipids of the vulnerable plaque.  
   
   
       149 . The method of  claim 148 , wherein the molecular carrier comprises a hydrophobic vehicles selected from the group consisting of liposomes, cremaphor EL, PEG/solvent mixtures, iodized castor oil, nanoparticles and micellar preparations.  
   
   
       150 . The method of  claim 149 , wherein the liposomes contain cholesterol.  
   
   
       151 . The method of  claim 150 , wherein the liposomes contain cardiolipin.  
   
   
       152 . The method of  claim 137 , wherein the molecular carrier targets the beta-emitting composition to macrophages.  
   
   
       153 . The method of  claim 152 , wherein the molecular carrier targets the beta-emitting composition to a macrophage biomolecule selected from the group consisting of tenascin C, tissue factor, tissue inhibitor of MMP 1, tissue inhibitor of MMP 2, oxidized LDL receptor, heme oxygenase-1, human cartilage gp-39, IL-6, IL-6 receptor, IL-10, IL-10 receptor, lectin-like oxidized LDL-receptor, monocyte inflammatory protein-1, monocyte inflammatory protein-1 receptor and macrophage chemoattractant protein-1 receptor.  
   
   
       154 . The method of  claim 146 , wherein the molecular carrier targets the beta-emitting composition to a T cell biomolecule selected from the group consisting of IL-10, IL-10 receptor, monocyte inflammatory protein-1, monocyte inflammatory protein-1 receptor and transferrin.  
   
   
       155 . The method of  claim 137 , wherein the molecular carrier targets the beta-emitting composition to foam cells.  
   
   
       156 . The method of  claim 137 , wherein the molecular carrier targets the beta-emitting composition to a protease that degrades extracellular matrix.  
   
   
       157 . The method of  claim 156 , wherein the protease is a metalloproteinase.  
   
   
       158 . The method of  claim 157 , wherein the molecular carrier is a monoclonal antibody that binds to an epitope on a protease.  
   
   
       159 . The method of  claim 125 , wherein the photosensitizer is chlorin e6 .  
   
   
       160 . The method of  claim 125 , wherein the light is administered in a 20-500 J/cm dose.  
   
   
       161 . The method of  claim 125 , wherein the light is administered in a 50-300 J/cm dose.  
   
   
       162 . The method of  claim 125 , wherein the light is administered in a 100-200 J/cm dose.  
   
   
       163 . The method of  claim 125 , wherein the photosensitizer induces apoptosis and not necrosis of the cells comprising the vulnerable plaque.