Methods for using annexin for detecting cell death in vivo and treating associated conditions

Abstract

The present invention provides methods and compositions for imaging cell death in vivo, as well as methods and compositions for tumor radiotherapy.

What is claimed is:  
     
         1 . A magnetic reasonance imaging composition comprising an annexin coupled to a contrast agent.  
     
     
         2 . The composition of  claim 1 , wherein the contrast agent is a paramagnetic agent.  
     
     
         3 . The composition of  claim 2 , wherein the contrast agent is a gadolinium-chelating group complex.  
     
     
         4 . The composition of  claim 3 , wherein the contrast agent is a gadolinium-diethylenetriamine penta-acetic acid.  
     
     
         5 . The composition of  claim 1 , wherein the contrast agent is a superparamagnetic agent.  
     
     
         6 . The composition of  claim 5 , wherein the contrast agent is a metal oxide.  
     
     
         7 . The composition of  claim 6 , wherein the contrast agent is an iron oxide.  
     
     
         8 . The composition of  claim 6 , wherein the contrast agent is a polymer coated metal oxide.  
     
     
         9 . The composition of  claim 8 , wherein the contrast agent is a dextran coated iron oxide.  
     
     
         10 . The composition of  claim 1 , wherein the annexin is annexin V.  
     
     
         11 . A composition comprising an annexin coupled to a contrast agent and a radioisotope.  
     
     
         12 . The composition of  claim 11 , wherein the radioisotope is a therapeutic radioisotope.  
     
     
         13 . The composition of  claim 12 , wherein the therapeutic radioisotope is selected from the group consisting of  103 Pd,  186 Re,  188 Re,  90 Y,  153 Sm,  159 Gd, and  166 Ho.  
     
     
         14 . The composition of  claim 11 , wherein the annexin is annexin V.  
     
     
         15 . The composition of  claim 11 , wherein the contrast agent is a polymer coated metal oxide.  
     
     
         16 . A method for imaging cell death in a mammalian subject in vivo, comprising 
 administering to the subject a magnetic reasonance imaging composition comprising annexin coupled to a contrast agent; and    obtaining a magnetic reasonance image, wherein said image is a representation of cell death in said mammalian subject.    
     
     
         17 . The method of  claim 16 , wherein the magnetic reasonance image is obtained between about 5 minutes and about 2 hours after the administration of the magnetic reasonance imaging composition.  
     
     
         18 . The method of  claim 16 , wherein the magnetic reasonance image is obtained between about 12-30 hours after the administration of the magnetic reasonance imaging composition.  
     
     
         19 . The method of  claim 16 , wherein the cell death is caused by apoptosis.  
     
     
         20 . The method of  claim 16 , further comprising obtaining a magnetic reasonance image at a plurality of time points, thereby monitoring changes in the number of cells undergoing cell death.  
     
     
         21 . The method of  claim 16 , further comprising obtaining a magnetic reasonance image at a plurality of time points, thereby monitoring changes in the location of cells undergoing cell death.  
     
     
         22 . The method of  claim 16 , wherein the magnetic reasonance imaging composition is administered at a concentration of 1-500 μg protein/kg.  
     
     
         23 . The method of  claim 16 , wherein the magnetic reasonance imaging composition is administered at a concentration of 1-400 μg protein/kg.  
     
     
         24 . The method of  claim 16 , wherein the magnetic reasonance imaging composition is administered at a concentration of 1-200 μg protein/kg.  
     
     
         25 . The method of  claim 16 , wherein the magnetic reasonance imaging composition is administered intravenously.  
     
     
         26 . The method of  claim 16 , wherein the magnetic reasonance imaging composition is administered via a method selected from the group consisting of intraperitoneally, intrathecally, intrapleurally, intralymphatically and intramuscularly.  
     
     
         27 . The method of  claim 16 , wherein cell death is imaged in an organ of a subject or a portion thereof.  
     
     
         28 . The method of  claim 16 , wherein cell death is imaged in the brain of a subject or a portion thereof.  
     
     
         29 . The method of  claim 16 , wherein cell death is imaged in the heart of a subject or a portion thereof.  
     
     
         30 . The method of  claim 16 , wherein cell death is imaged in the liver of a subject or a portion thereof.  
     
     
         31 . An optical imaging composition comprising an annexin coupled to an optically active molecule.  
     
     
         32 . The composition of  claim 31 , wherein the optically active molecule is a fluorescent dye.  
     
     
         33 . The composition of  claim 32 , wherein the fluorescent dye is Fluorescein.  
     
     
         34 . The composition of  claim 31 , wherein the optically active molecule is a luminescent molecule.  
     
     
         35 . The composition of  claim 34 , wherein the luminescent molecule is luminol.  
     
     
         36 . The composition of  claim 31 , wherein the optically active molecule is a bioluminescent molecule.  
     
     
         37 . The composition of  claim 36 , wherein the bioluminescent molecule is selected from the group consisting of luciferase, luciferin, and aequorin.  
     
     
         38 . The composition of  claim 31 , wherein the annexin is annexin V.  
     
     
         39 . A method for imaging cell death in a mammalian subject in vivo, comprising 
 administering to the subject an optical imaging composition comprising annexin coupled to an optically active molecule;    illuminating the subject with a light source; and    visually monitoring the presence of the optical imaging composition in the subject, thereby obtaining an image, wherein said image is a representation of cell death in said mammalian subject.    
     
     
         40 . The method of  claim 39 , wherein the image is obtained between about 5 minutes and about 2 hours after the administration of the optical imaging composition.  
     
     
         41 . The method of  claim 39 , wherein the image is obtained between about 12-30 hours after the administration of the optical imaging composition.  
     
     
         42 . The method of  claim 39 , wherein the cell death is caused by apoptosis.  
     
     
         43 . The method of  claim 39 , further comprising obtaining an image at a plurality of time points, thereby monitoring changes in the number of cells undergoing cell death.  
     
     
         44 . The method of  claim 39 , further comprising obtaining an image at a plurality of time points, thereby monitoring changes in the location of cells undergoing cell death.  
     
     
         45 . The method of  claim 39 , wherein the optical imaging composition is administered at a concentration of 1-500 μg protein/kg.  
     
     
         46 . The method of  claim 39 , wherein the optical imaging composition is administered at a concentration of 1-400 μg protein/kg.  
     
     
         47 . The method of  claim 39 , wherein the optical imaging composition is administered at a concentration of 1-200 μg protein/kg.  
     
     
         48 . The method of  claim 39 , wherein the magnetic reasonance imaging composition is administered via a method selected from the group consisting of intraperitoneally, intrathecally, intrapleurally, intralymphatically and intramuscularly.  
     
     
         49 . The method of  claim 39 , wherein cell death is imaged in an organ of a subject or a portion thereof.  
     
     
         50 . The method of  claim 39 , wherein cell death is imaged in the head of a subject or a portion thereof.  
     
     
         51 . The method of  claim 39 , wherein cell death is imaged in the heart of a subject or a portion thereof.  
     
     
         52 . The method of  claim 39 , wherein cell death is imaged in the liver of a subject or a portion thereof.  
     
     
         53 . The method of  claim 39 , wherein cell death is imaged in the eye of a subject or a portion thereof.  
     
     
         54 . A method of tumor radiotherapy, comprising 
 administering to a subject bearing a tumor an optical imaging composition comprising annexin coupled to an optically active molecule; and    illuminating the subject with a light source in the presence of oxygen, thereby creating a toxic form of oxygen capable of destroying the tumor.    
     
     
         55 . The method of  claim 54 , wherein the optically active molecule is selected from the group consisting of PHOTOFRIN®, Lutrin, ANTRIN®, FOSCAN®, aminolevulinic acid, aluminum (III) phthalocyanine tetrasulfonate, Hypericin, verteporfin, and methylene blue dye.  
     
     
         56 . The method of  claim 54 , wherein the toxic form of oxygen is singlet oxygen.  
     
     
         57 . The method of  claim 54 , wherein the tumor is selected from the group consisting of a brain tumor, a head tumor, a neck tumor, a breast tumor, an esophagus tumor, a lung tumor, a pleural cavity tumor, an ovary tumor, an abdominal cavity tumor, a bladder tumor, a prostate tumor, a cervix tumor, and a skin tumor.