Novel Liposome Nanoparticles for Tumor Magnetic Resonance Imaging

Patent metadata

Field	Value
Publication number	US-2017348440-A1
Application number	US-201715463964-A
Country	US
Kind code	A1
Filing date	Mar 20, 2017
Priority date	Nov 20, 2009
Publication date	Dec 7, 2017
Grant date	—

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-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.

First claim

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), 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(C 12 -C 20 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-phospocholine).

4 . A liposome according to claim 1 , wherein said liposome further comprises cholesterol.

5 . A liposome according to claim 1 , wherein said liposome further comprises a polyethylene glycol-phospholipid component.

6 . A liposome according to claim 5 , wherein said polyethylene glycol-phospholipid is DSPE-PEG(2000) [di stearoylphosphatidylethanolamine-polyethylene glycol (2000)].

7 . A liposome according to claim 1 , wherein the amount of Gd.DOTA.DSA in said liposome is from 29 to 31 mol % of the total liposome formulation.

8 . (canceled)

9 . A liposome according to claim 1 , wherein the amount of fully saturated phospholipid component in said liposome is from 32 to 34 mol % of the total liposome formulation.

10 . (canceled)

11 . A liposome according to claim 4 , wherein the amount of cholesterol in said liposome is from 29 to 31 mol % of the total liposome formulation.

12 . (canceled)

13 . A liposome according to claim 5 , wherein the amount of said polyethylene glycol-phospholipid component in said liposome is 5-8 mol % of the total liposome formulation.

14 . (canceled)

15 . A liposome according to claim 1 , 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 claim 1 , 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 . (canceled)

19 . A liposome according to claim 1 , 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 20 , wherein said tumour targeting agent comprises a folate moiety.

22 . A liposome according to claim 20 , wherein said tumour targeting agent is a phospholipid-polyethylene glycol-folate compound.

23 . A liposome according to claim 22 , wherein said phospholipid-polyethylene glycol-folate compound is DSPE-PEG(2000)-Folate [distearoylphosphatidylethanolamine-polyethylene glycol (2000)-folate].

24 . A liposome according to claim 21 , 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 . (canceled)

27 . A magnetic resonance contrast agent, comprising a liposome according to claim 1 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 . (canceled)

30 . (canceled)

31 . (canceled)

32 . (canceled)

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 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 , wherein the concentration of liposomes in said magnetic resonance contrast agent is 1-50 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 comprising the step of:
taking images of the organ of interest in the patient.

37 . A method of making a liposome according to claim 1 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 and optionally rehydrating the resulting liposome.

39 . A method of making a magnetic contrast agent according to claim 27 comprising mixing said liposome and said pharmaceutically acceptable carrier.

Assignees

• Medical Res Council
• Imperial Innovations Ltd

Inventors

• Kamaly Nazila
• Kalber Tammy Louise
• Kenny Gavin David
• Thanou Maya
• Miller Andrew David
• Bell Jimmy

Classifications

• A61K49/1812 Primary

  liposomes, polymersomes, e.g. immunoliposomes · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title

• Y10S977/773

  Nanoparticle, i.e. structure having three dimensions of 100 nm or less · CPC title