Loading Technique for Preparing Radionuclide Containing Nanoparticles

Abstract

The present invention relates to a novel composition and method for loading delivery systems such as liposome compositions with radionuclides useful in targeted diagnostic and/or therapy of target site, such as cancerous tissue and, in general, pathological conditions associated with leaky blood vessels. The composition and methods of the invention find particular use in diagnosing and imaging cancerous tissue and, in general, pathological conditions associated with leaky blood vessels in a subject. The present invention provides a new diagnostic tool for the utilization of positron emission tomography (PET) imaging technique. One specific aspect of the invention is directed to a method of producing nanoparticles with desired targeting properties for diagnostic and/or radio-therapeutic applications.

1 - 45 . (canceled) 
     
     
         46 . A nanoparticle composition loaded with radionuclides comprising:
 a) a vesicle forming component,   b) an agent-entrapping component enclosed by said vesicle-forming component;   c) a copper radionuclide entrapped on the interior side of the nanoparticle composition.   
     
     
         47 . The nanoparticle composition of  claim 46 , wherein the vesicle-forming component comprises one or more amphiphatic compounds. 
     
     
         48 . The nanoparticle composition of  claim 47 , wherein the vesicle forming component comprises one or more amphiphatic compounds selected from the group of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), CHOL (Cholesterol), DSPE-PEG-2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]), POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), and DSPE-PEG 2000 -TATE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]-TATE). 
     
     
         49 . The nanoparticle composition of  claim 46 , wherein said agent-entrapping component is a chelator. 
     
     
         50 . The nanoparticle composition of  claim 46 , wherein said agent-entrapping component is a chelator selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,8,11-15 tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanephosphonic acid) (DOTP), cyclam and cyclen. 
     
     
         51 . The nanoparticle composition of  claim 46 , wherein the entrapped copper isotope is an ion. 
     
     
         52 . The nanoparticle composition of  claim 51 , wherein said ion is selected from the group consisting of Cu(I) and Cu(II). 
     
     
         53 . The nanoparticle composition of  claim 46 , wherein said Copper radionuclide is selected from the group consisting of  61 Cu,  64 Cu, and  67 Cu. 
     
     
         54 . The nanoparticle composition of  claim 46 , wherein nanoparticle further comprise one or more radionuclides selected from the group consisting of  177 Lu,  67 Ga,  68 Ga,  225 Ac,  90 Y,  186 Re,  188 Re, and  119 Sb. 
     
     
         55 . The nanoparticle composition of  claim 54 , wherein said radionuclides comprise two radionuclides selected from the group consisting of  64 Cu and  67 Cu,  61 Cu and  67 Cu,  64 Cu and  90 Y,  64 Cu and  119 Sb,  64 Cu and  225 Ac,  64 Cu and  188 Re,  64 Cu and  186 Re,  64 Cu and  211 At,  64 Cu and  67 Ga,  61 Cu and  177 Lu,  61 Cu and  90 Y,  61 Cu and  119 Sb,  61 Cu and  225 Ac,  61 Cu and  188 Re,  61 Cu and  186 Re,  61 Cu and  211 At,  61 Cu and  67 Ga,  67 Cu and  177 Lu,  67 Cu and  90 Y,  67 Cu and  119 Sb,  67 Cu and  225 Ac,  67 Cu and  188 Re,  67 Cu and  186 Re,  67 Cu and  211 At,  68 Ga and  177 Lu,  68 Ga and  90 Y,  68 Ga and  119 Sb,  68 Ga and  225 Ac,  68 Ga and  188 Re,  68 Ga and  186 Re,  68 Ga and  211 At, and  68 Ga and  67 Cu. 
     
     
         56 . The nanoparticle composition of  claim 46 , further comprising a targeting moiety selected from the group consisting of antibodies, affibodies, and peptide components. 
     
     
         57 . The nanoparticle composition of  claim 46 , further comprising a compound with intracellular targeting properties which is conjugated to the agent-entrapping component. 
     
     
         58 . The nanoparticle composition of  claim 46 , comprising a controlled interior pH, thereby inducing effective encapsulation of the entrapping agent. 
     
     
         59 . The nanoparticle composition of  claim 46 , wherein the interior pH of the nanoparticle is within the range of 3 to 8. 
     
     
         60 . The nanoparticle composition of  claim 46 , wherein the diameter of the nanoparticle is in the range of 30 nm to 300 nm. 
     
     
         61 . The nanoparticle composition of  claim 46 , wherein the stability of the radiolabeled nanoparticles is such that less than 20% leakage of radioactivity is observed following 24 hours incubation in human serum at 37° C. followed by a purification step such as size exclusion chromatography (SEC), ion-exchange chromatography or dialysis to separate the radiolabeled nanoparticles from leaked radionuclide. 
     
     
         62 . The nanoparticle composition of  claim 46 , wherein the entrapped agent has been loaded into the nanoparticle composition using an ionophore.