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 the liposome further comprises a neutral, fully saturated phospholipid component (e.g. DSPC (1,2-distearoyl-sn-glycero-3-phospocholine]), 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.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), wherein the amount of Gd.DOTA.DSA in said liposome is from 29 to 31 mol % of the total liposome formulation, a neutral, fully saturated phospholipid component, wherein said neutral, fully saturated phospholipid component is a 1,2-di(C 12 -C 20 saturated lipid)-sn-glycero-3-phosphocholine, wherein the saturated lipid groups can be the same or different from each other, wherein the amount of neutral, fully saturated phospholipid component in said liposome is from 32 to 34 mol % of the total liposome formulation;
a polyethylene glycol-phospholipid component, wherein the amount of the polyethylene glycol-phospholipid component is from 6 to 7 mol % of the total liposome formulation; wherein
(a) average size of the liposomes is at or less than 100 nm;
(b) the liposomes are of low size polydispersity; and
(a) and (b) in combination provide for gradual accumulation within tumor tissue, image enhancement and reduced toxicity.
2. A liposome according to claim 1 , wherein said neutral, fully saturated phospholipid component is DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine).
3. A liposome according to claim 1 , wherein said liposome further comprises cholesterol.
4. A liposome according to claim 3 , wherein the amount of cholesterol in said liposome is from 29 to 31 mol % of the total liposome formulation.
5. A liposome according to claim 1 , wherein said polyethylene glycol-phospholipid component is DSPE-PEG(2000) [distearoylphosphatidylethanolamine-polyethylene glycol (2000)].
6. A liposome according to claim 1 , wherein said liposome has an average particle size of less than or equal to 80 nm.
7. A liposome according to claim 1 , wherein said liposome comprises Gd.DOTA.DSA, cholesterol, DSPC and DSPE-PEG(2000).
8. A liposome according to claim 1 , wherein said liposome further comprises a tumor targeting agent.
9. A liposome according to claim 8 , wherein said tumor targeting agent comprises a ligand for a receptor that is over-expressed in tumor cells relative to the expression of said receptors in the cells of non-tumorous tissue of mammals.
10. A liposome according to claim 9 , wherein said tumor targeting agent comprises a folate moiety.
11. A liposome according to claim 10 , wherein the amount of said folate moiety present in said liposome is 1-2 mol % of the total liposome formulation.
12. A liposome according to claim 9 , wherein said tumor targeting agent is a phospholipid-polyethylene glycol-folate compound.
13. A liposome according to claim 12 , wherein said phospholipid-polyethylene glycol-folate compound is DSPE-PEG(2000)-Folate [distearoylphosphatidylethanolamine-polyethylene glycol (2000)-folate].
14. A liposome according to claim 8 , wherein said liposome comprises Gd.DOTA.DSA, cholesterol, DSPC, DSPE-PEG(2000) and DSPE-PEG(2000)-Folate.
15. A magnetic resonance contrast agent, comprising a liposome according to claim 1 and a pharmaceutically acceptable carrier.
16. A magnetic resonance contrast agent according to claim 15 , wherein said pharmaceutically acceptable carrier is an aqueous carrier.
17. 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 15 to the mammal; and (b) taking images of the organ or organ structure in the mammal.
18. A method according to claim 17 , wherein said magnetic resonance contrast agent enhances a magnetic resonance image of a tumor in the mammal.
19. A method according to claim 17 , wherein the concentration of the liposome in said magnetic resonance contrast agent is 1-50 mg/mL.
20. 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 15 comprising the step of: (i) taking images of the organ or organ structure in the mammal.
21. A method of making a magnetic contrast agent according to claim 15 comprising mixing said liposome and said pharmaceutically acceptable carrier.