Novel Liposome Nanoparticles for Tumor Magnetic Resonance Imaging
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.