Entrapment of Radionuclides in Nanoparticle Compositions

Abstract

The present invention is directed to the technical field of imaging compositions useful for diagnosing cancer and other diseases in a subject. In particular, the invention relates to a class of diagnostic compounds comprising a novel liposome composition with encapsulated metal entities such as radionuclides, for example 61 Cu and 64 Cu copper isotopes. The invention further relates to a novel method for loading delivery systems, such as liposome compositions, with metal entities such as radionuclides, and the use of liposomes for targeted diagnosis and treatment of a target site, such as cancerous tissue and, in general, pathological conditions associated with leaky blood vessels. The present invention provides a new diagnostic tool for the utilization of positron emission tomography (PET) imaging technique.

1 - 38 . (canceled) 
     
     
         39 . A kit of parts for preparation of a liposome loaded with a metal cation, said kit comprising:
 a) a liposome composition comprising a vesicle forming component and a non-lipophilic chelator enclosed by the vesicle forming component; and   a metal cation-containing composition for loading into the liposome,   wherein the kit of parts does not comprise an ionophore capable of transporting the metal cation across a lipid bilayer.   
     
     
         40 . (canceled) 
     
     
         41 . The kit of parts of  claim 39 , wherein the metal cation-containing composition comprises two or more copper radionuclides ( 61 Cu,  64 Cu, and  67 Cu). 
     
     
         42 - 46 . (canceled) 
     
     
         47 . The kit of parts of  claim 39 , wherein the vesicle forming component comprises one or more amphiphatic compounds selected from the group consisting of HSPC, DSPC, POPC, DPPC, CHOL, DSPE-PEG-2000 and DSPE-PEG-2000-TATE. 
     
     
         48 . (canceled) 
     
     
         49 . The kit of parts of  claim 39 , wherein said chelator is 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. 
     
     
         50 . (canceled) 
     
     
         51 . The kit of parts of  claim 39 , wherein the metal cations are two or more 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. 
     
     
         52 . The kit of parts of  claim 39 , wherein the liposome composition further comprises a targeting moiety. 
     
     
         53 . (canceled) 
     
     
         54 . The kit of parts of  claim 39 , wherein the interior pH of the liposome is within the range of 4 to 8.5. 
     
     
         55 - 61 . (canceled) 
     
     
         62 . The kit of parts of  claim 39 , wherein said cation is a divalent cation or a trivalent cation. 
     
     
         63 . The kit of parts of  claim 39 , wherein the metal cation-containing composition comprises one or more radionuclides selected from the group consisting of Copper ( 61 Cu,  64 Cu, and  67 Cu), Indium ( 111 In), Technetium ( 99m Tc), Rhenium ( 186 Re,  188 Re), Gallium ( 67 Ga,  68 Ga), Strontium ( 89 Sr), Samarium ( 153 Sm), Ytterbium ( 169 Yb) Thallium ( 201 Tl) Astatine ( 211 At), Lutetium ( 177 Lu), Actinium ( 225 Ac), Yttrium ( 90 Y), Antimony ( 119 Sb), Tin ( 117 Sn,  113 Sn), Dysprosium ( 159 Dy), Cobalt ( 56 Co), Iron ( 59 Fe), Ruthenium ( 97 Ru,  103 Ru), Palladium ( 103 Pd), Cadmium ( 115 Cd), Tellurium ( 118 Te,  123 Te), Barium ( 131 Ba,  140 Ba), Gadolinium ( 149 Gd,  151 Gd), Terbium ( 160 Tb), Gold ( 198 Au,  199 Au), Lanthanum ( 140 La), and Radium ( 223 Ra,  224 Ra). 
     
     
         64 . The kit of parts of  claim 39 , wherein the metal cation is a radionuclide selected from the group consisting of  61 Cu,  64 Cu,  67 Cu,  177 Lu,  67 Ga,  68 Ga,  225 Ac,  90 Y,  186 Re,  188 Re,  119 Sb, and  111 In. 
     
     
         65 . The kit of parts of  claim 39 , wherein the metal cation is a radionuclide selected from the group consisting of  61 Cu,  64 Cu,  67 Cu,  111 In, and  177 Lu. 
     
     
         66 . The kit of parts of  claim 39 , wherein the metal cation is a radionuclide selected from the group consisting of  61 Cu,  64 Cu, and  67 Cu. 
     
     
         67 . The kit of parts of  claim 39 , wherein the metal cation is selected from the group consisting of Gd, Dy, Ti, Cr, Mn, Fe, Co, and Ni, including divalent or trivalent ions thereof. 
     
     
         68 . The kit of parts of  claim 39 , wherein the metal cation-containing composition comprises a combination of cations selected from the group consisting of  64 Cu and Gd(III),  64 Cu and Dy(III),  64 Cu and Ti(II),  64 Cu and Cr(III),  64 Cu and Mn(II),  64 Cu and Fe(II),  64 Cu and Fe(III),  64 Cu and Co(II),  64 Cu and Ni(II),  68 Ga and Gd(III),  68 Ga and Dy(III),  68 Ga and Ti(II),  68 Ga and Cr(III),  68 Ga and Mn(II),  68 Ga and Fe(II),  68 Ga and Fe(III),  68 Ga and Co(II),  68 Ga and Ni(II),  111 In and Gd(III),  111 In and Dy(III),  111 In and Ti(II),  111 In and Cr(III),  111 In and Mn(II),  111 In and Fe(II),  111 In and Fe(III),  111 In and Co(II),  111 In and Ni(II),  99m Tc and Gd(III),  99m Tc and Dy(III),  99m Tc and Ti(II),  99m Tc and Cr(III),  99m Tc and Mn(II),  99m Tc and Fe(II),  99m Tc and Fe(III),  99m Tc and Co(II),  99m Tc and Ni(II),  177 Lu and Gd(III),  177 Lu and Dy(III),  177 Lu and Ti(II),  177 Lu and Cr(III),  177 Lu and Mn(II),  177 Lu and Fe(II),  177 Lu and Fe(III),  177 Lu and Co(II),  177 Lu and Ni(II),  67 Ga and Gd(III),  67 Ga and Dy(III),  67 Ga and Ti(II),  67 Ga and Cr(III),  67 Ga and Mn(II),  67 Ga and Fe(II),  67 Ga and Fe(III),  67 Ga and Co(II),  67 Ga and Ni(II),  201 Tl and Gd(III),  201 Tl and Dy(III),  201 Tl and Ti(II),  201 Tl and Cr(III),  201 Tl and Mn(II),  201 Tl and Fe(II),  201 Tl and Fe(III),  201 Tl and Co(II),  201 Tl and Ni(II),  90 Y and Gd(III),  90 Y and Dy(III),  90 Y and Ti(II),  90 Y and Cr(III),  90 Y and Mn(II),  90 Y and Fe(II),  90 Y and Fe(III),  90 Y and Co(II), and  90 Y and Ni(II), wherein said isotope of metal radionuclide appears in any of the existing oxidation states for the metal including monovalent cations, divalent cations, trivalent cations, tetravalent cations, pentavalent cations, hexavalent cations and heptavalent cations. 
     
     
         69 . The kit of parts of  claim 41 , wherein the two or more copper radionuclides are selected from the group consisting of  61 Cu and  64 Cu;  61 Cu and  67 Cu;  64 Cu and  67 Cu; and  61 Cu,  64 Cu and  67 Cu. 
     
     
         70 . The kit of parts of  claim 39 , wherein said vesicle-forming component comprises one or more of the compounds selected from the group consisting of lipids, ceramides, sphingolipids, phospholipids, and pegylated phospholipids. 
     
     
         71 . The kit of parts of  claim 39 , wherein said chelator is selected from the group consisting of 1,4,7,10-tetraazacyclododecane ([12]aneN4); 1,4,7,10-tetraazacyclotridecane ([13]aneN4); 1,4,8,11-tetraazacyclotetradecane ([14]aneN4); 1,4,8,12-tetraazacyclopentadecane ([15]aneN4); 1,5,9,13-tetraazacyclohexadecane ([16]aneN4); ethylene-diamine-tetraacetic-acid (EDTA); and diethylene-triamine-penta-acetic acid (DTPA). 
     
     
         72 . The kit of parts of  claim 39 , wherein said chelator is selected from the group consisting of 1,4-ethano-1,4,8,11-tetraazacyclotetradecane (et-cyclam); 1,4,7,11-tetraazacyclotetradecane (iso-cyclam); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2-(1,4,7,10-tetraazacyclododecan-1-yl)acetate (DO1A); 2,2′-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (DO2A); 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanephosphonic acid) (DOTP); 1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphonic acid) (DO2P); 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P); 1,4,8,11-15 tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A); 2,2′-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A); ethylene-diamine-tetraacetic-acid (EDTA), and diethylene-triamine-penta-acetic acid (DTPA). 
     
     
         73 . The kit of parts of  claim 39 , wherein the interior of the liposome has an osmolarity 10-100 mOsm/L higher than the osmolarity of the exterior. 
     
     
         74 . The kit of parts of  claim 39 , wherein the metal cation is a freeze dried salt or an aqueous solution of said cation.