Novel Liposome Nanoparticles for Tumor Magnetic Resonance Imaging

Abstract

The present invention provides novel liposomes comprising Gd.DOTA.DSA (gadolinium(III)2-{4,7-bis-carboxymethyl-10-[(N,N-distearylamidomethyl-N′-amido-methyl]-1,4,7,10-tetra-azacyclododec-1-yl}-acetic acid), characterised in that said liposome further comprises a neutral, fully saturated phospholipid component (e.g. DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine]), which are of particular use in the preparation of magnetic resonance contrast agents for enhancing a magnetic resonance image of tumours in a mammal.

1 . A liposome comprising Gd.DOTA.D SA (gadolinium(III)2-{4,7-bis-carboxymethyl-10-[(N,N-distearylamidomethyl-N′-amido-methyl]-1,4,7,10-tetra-azacyclododec-1-yl}-acetic acid), characterised in that said liposome further comprises a neutral, fully saturated phospholipid component. 
     
     
         2 . A liposome according to  claim 1 , wherein said fully saturated phospholipid component is a 1,2-di(C12-C20 saturated lipid)-sn-glycero-3-phosphocholine, wherein the saturated lipid groups can be the same or different from each other. 
     
     
         3 . A liposome according to  claim 1 , wherein said fully saturated phospholipid component is DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine). 
     
     
         4 . A liposome according to any one of  claims 1  to  3 , wherein said liposome further comprises cholesterol. 
     
     
         5 . A liposome according to any one of  claims 1  to  3 , wherein said liposome further comprises a polyethylene glycol-phospholipid component. 
     
     
         6 . A liposome according to any one of  claims 1  to  3 , wherein said polyethylene glycol-phospholipid is DSPE-PEG(2000) [distearoylphosphatidylethanolamine-polyethylene glycol (2000)]. 
     
     
         7 . A liposome according to any one of  claims 1  to  3 , wherein the amount of Gd.DOTA.DSA in said liposome is from 29 to 31 mol % of the total liposome formulation. 
     
     
         8 . A liposome according to any one of  claims 1  to  3 , wherein the amount of Gd.DOTA.DSA in said liposome is 30 mol % of the total liposome formulation. 
     
     
         9 . A liposome according to any one of  claims 1  to  3 , wherein the amount of fully saturated phospholipid component in said liposome is from 32 to 34 mol % of the total liposome formulation. 
     
     
         10 . A liposome according to anyone of  claims 1  to  3 , wherein the amount of fully saturated phospholipid component in said liposome is 33 mol % of the total liposome formulation. 
     
     
         11 . A liposome according to anyone of  claims 1  to  3 , wherein the amount of cholesterol in said liposome is from 29 to 31 mol % of the total liposome formulation. 
     
     
         12 . A liposome according to anyone of  claims 1  to  3 , wherein the amount of cholesterol in said liposome is 30 mol % of the total liposome formulation. 
     
     
         13 . A liposome according to anyone of  claims 1  to  3 , wherein the amount of said polyethylene glycol-phospholipid component in said liposome is 5-8 mol % of the total liposome formulation. 
     
     
         14 . A liposome according to anyone of  claims 1  to  3 , wherein the amount of said polyethylene glycol-phospholipid component in said liposome is 7 mol % of the total liposome formulation. 
     
     
         15 . A liposome according to anyone of  claims 1  to  3 , wherein said liposome has an average particle size at 10× dilution in phosphate buffer solution of less than or equal to 100 nm. 
     
     
         16 . A liposome according to anyone of  claims 1  to  3 , wherein said liposome has an average particle size at 10× dilution in phosphate buffer solution of less than or equal to 80 nm. 
     
     
         17 . A liposome according to  claim 1 , wherein said liposome comprises Gd.DOTA.DSA, cholesterol, DSPC and DSPE-PEG(2000). 
     
     
         18 . A liposome according to  claim 17 , wherein Gd.DOTA.DSA, cholesterol, DSPC and DSPE-PEG(2000) are present in the ratio 30:33:30:7 mol % respectively in said liposome formulation. 
     
     
         19 . A liposome according to any one of  claims 1  to  3 , wherein said liposome further comprises a tumour targeting agent. 
     
     
         20 . A liposome according to  claim 19 , wherein said tumour targeting agent comprises a ligand for a receptor that is over-expressed in tumour cells relative to the expression of said receptors in the cells of non-tumourous tissue of mammals. 
     
     
         21 . A liposome according to  claim 19 , wherein said tumour targeting agent comprises a folate moiety. 
     
     
         22 . A liposome according to  claim 19 , wherein said tumour targeting agent is a phospholipid-polyethylene glycol-folate compound. 
     
     
         23 . A liposome according to  claim 19 , wherein said phospholipid-polyethylene glycol-folate compound is DSPE-PEG(2000)-Folate [distearoylphosphatidylethanolamine-polyethylene glycol (2000)-folate]. 
     
     
         24 . A liposome according to any one of  claims 21  to  23 , wherein the amount of said folate moiety present in said liposome is 1-2 mol % of the total liposome formulation. 
     
     
         25 . A liposome according to  claim 19 , wherein said liposome comprises Gd.DOTA.DSA, cholesterol, DSPC, DSPE-PEG(2000) and DSPE-PEG(2000)-Folate. 
     
     
         26 . A liposome according to  claim 25 , wherein Gd.DOTA.DSA, cholesterol, DSPC, DSPE-PEG(2000) and DSPE-PEG(2000)-Folate are present in the ratio 30:33:30:5.5:1.5 mol % respectively in said liposome formulation. 
     
     
         27 . A magnetic resonance contrast agent, comprising liposomes according to any one of  claims 1  to  26  and a pharmaceutically acceptable carrier. 
     
     
         28 . A magnetic resonance contrast agent according to  claim 27 , wherein said pharmaceutically acceptable carrier is an aqueous carrier. 
     
     
         29 . A magnetic resonance contrast agent according to  claim 27  or  claim 28  for use in medicine, e.g. in diagnosis. 
     
     
         30 . Use of a liposome according to any one of  claims 1  to  26  in the preparation of a magnetic resonance contrast agent for enhancing magnetic resonance images of organs and organ structures in a mammal. 
     
     
         31 . Use according to  claim 30  in the preparation of a magnetic resonance contrast agent for enhancing a magnetic resonance image of a tumour in a mammal. 
     
     
         32 . Use according to  claim 30  or  31 , wherein the concentration of said liposomes in said magnetic resonance contrast agent is 1-50 mg/mL, preferably 1-30 mg/mL. 
     
     
         33 . A method of magnetic resonance imaging of an organ or organ structure in a mammal, comprising the steps of:
 (a) administering the magnetic resonance contrast agent according to  claim 27  or  claim 28  to a patient; and   (b) taking images of the organ of interest in the patient.   
     
     
         34 . A method according to  33 , wherein said magnetic resonance contrast agent is used for enhancing a magnetic resonance image of a tumour in a mammal. 
     
     
         35 . A method according to  claim 33  or  claim 34 , wherein the concentration of liposomes in said magnetic resonance contrast agent is 1-50 mg/mL, preferably 1-30 mg/mL. 
     
     
         36 . A method of magnetic resonance imaging of an organ or organ structure in a mammal pre-administered with the magnetic contrast agent according to  claim 27  or  claim 28  comprising the step of:
 (i) taking images of the organ of interest in the patient. 
 
     
     
         37 . A method of making a liposome according to  claims 1  to  26  comprising mixing a solution of Gd.DOTA.DSA (gadolinium(III)2-{4,7-bis-carboxymethyl-10-[(N,N-distearylamidomethyl-N′-amido-methyl]-1,4,7,10-tetra-azacyclododec-1-yl}-acetic acid) and a solution of a neutral, fully saturated phospholipid. 
     
     
         38 . A method according to  claim 37  comprising the further step of drying the mixture (e.g. in vacuo) and optionally rehydrating the resulting liposome. 
     
     
         39 . A method of making a magnetic contrast agent according to  claim 27  or  claim 28  comprising mixing a liposome as defined in any one of  claims 1  to  26  and a pharmaceutically acceptable carrier.