MRI imageable liposomes for the evaluation of treatment efficacy, thermal distribution, and demonstration of dose painting

• US 20070197904A1
• Filed: 12/29/2006
• Published: 08/23/2007
• Est. Priority Date: 09/11/2002
• Status: Active Grant

• Current Assignee: Duke University
• Original Assignee: Duke University
• Inventors: Dewhirst, Mark, Viglianti, Benjamin, Ponce, Ana
• Granted Patent: US 7,769,423 B2
• Time in Patent Office: Days
• US Class Current: 600/420
• CPC Class Codes: A61B 5/055 involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 49/1812 liposomes, polymersomes, e.g. immunoliposomes
• CPC Class Codes: A61K 51/1234 Liposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Abstract

Methods and compositions useful for detecting an in vivo blood pool, monitoring the distribution of a compound of interest to a desired site in an organism by magnetic resonance imaging, monitoring the accumulation of a compound of interest at a desired site in vivo by magnetic resonance imaging, and monitoring the release of liposomal contents to an external stimulus at a desired site in vivo by magnetic resonance imaging are disclosed. Some compositions comprise envirosensitive or non-sensitive liposomes. Contrast agents, such as manganese-based compounds, are also disclosed.

Claims

1. A method of predicting efficacy of a treatment in a subject, the method comprising:

monitoring accumulation of a compound of interest at a desired site in vivo by magnetic resonance imaging; and

predicting efficacy of treatment based on accumulation of a compound of interest at the desired site.

2. The method of claim 1, wherein the compound of interest is a chemotherapeutic agent.

3. The method of claim 1, comprising:

administering to a subject a non-sensitive liposome composition comprising;

(i) a contrast agent;

(ii) a compound of interest; and

(iii) a non-sensitive liposome encapsulating the contrast agent and the compound of interest; and

monitoring the accumulation of the compound of interest at the desired site by magnetic resonance imaging.

4. The method of claim 1, wherein the non-sensitive liposome comprises DSPC/Cholesterol (55:

45, mol;

mol).

5. The method of claim 4, wherein the contrast agent comprises a element selected from the group consisting of Gd, Cu, Cr, Fe, Co, Er, Ni, Eu, Dy, Zn, Mg, Mo, Li, Ta, and Mn.

6. The method of claim 1, comprising:

administering an envirosensitive liposome composition to a subject, the composition comprising;

(i) a contrast agent;

(ii) a compound of interest; and

(iii) an envirosensitive liposome encapsulating the contrast agent and the compound of interest; and

monitoring the accumulation of the compound of interest at the desired site by magnetic resonance imaging.

7. The method of claim 6, wherein the envirosensitive liposome is a liposome selected from the group consisting of a thermosensitive liposome, a pH-sensitive liposome, a chemosensitive liposome and a radiation-sensitive liposome.

8. The method of claim 7, wherein the thermosensitive liposome comprises a formulation selected from the group consisting of DPPC-PEG₂₀₀₀, DPPC-DSPE-PEG₂₀₀₀ (95:

5, mol;

mol), and DPPC-MSPC-DSPE-PEG₂₀₀₀ (90;

10;

4, mol;

mol).

9. The method of claim 6, wherein the contrast agent comprises a element selected from the group consisting of Gd, Cu, Cr, Fe, Co, Er, Ni, Eu, Dy, Zn, Mg, Mo, Li, Ta, and Mn.

10. The method of claim 6, further comprising exposing the envirosensitive liposome at the desired site to a non-physiological environmental condition.

11. The method of claim 10, wherein the environmental condition is selected from the group consisting of hyperthermia, electromagnetic radiation, a chemical agent and non-physiological pH.

12. The method of claim 1, wherein the desired site is selected from the group consisting of a tumor, an embolism, an injury site, an ischemia, and a tissue edema.

13. The method of claim 1, wherein the monitoring the accumulation of the compound of interest at the desired site by magnetic resonance imaging comprises making a pixel density determination.

14. The method of claim 1, wherein the predicting efficacy comprises predicting efficacy of treatment based on a location of accumulation at the desired site, a rate of accumulation at the desired site, or both location and rate of accumulation at the desired site.

15. A method of enhancing efficacy of a treatment at a desired site in a subject, the method comprising:

administering to the subject a composition comprising a compound of interest; and

targeting the composition to a desired location at a desired site in the subject, at a desired rate of accumulation at the desired site, or both a desired location and desired rate of accumulation at the desired site, to thereby enhance efficacy of treatment provided by the compound of interest.

16. The method of claim 15, wherein the compound of interest is a chemotherapeutic agent.

17. The method of claim 15, wherein the composition comprises a non-sensitive liposome composition comprising:

(i) the compound of interest; and

(ii) a non-sensitive liposome encapsulating the compound of interest.

18. The method of claim 17, wherein the non-sensitive liposome comprises DSPC/Cholesterol (55:

45, mol;

mol).

19. The method of claim 17, wherein the composition further comprises a contrast agent.

20. The method of claim 19, wherein the contrast agent comprises a element selected from the group consisting of Gd, Cu, Cr, Fe, Co, Er, Ni, Eu, Dy, Zn, Mg, Mo, Li, Ta, and Mn.

21. The method of claim 15, wherein the composition comprises an envirosensitive liposome composition comprising:

(i) the compound of interest; and

(ii) an envirosensitive liposome encapsulating the compound of interest.

22. The method of claim 21, wherein the envirosensitive liposome is a liposome selected from the group consisting of a thermosensitive liposome, a pH-sensitive liposome, a chemosensitive liposome and a radiation-sensitive liposome.

23. The method of claim 22, wherein the thermosensitive liposome comprises a formulation selected from the group consisting of DPPC-PEG₂₀₀₀, DPPC-DSPE-PEG₂₀₀₀ (95:

5, mol;

mol), and DPPC-MSPC-DSPE-PEG₂₀₀₀ (90;

10;

4, mol;

mol).

24. The method of claim 21, wherein the composition further comprises a contrast agent.

25. The method of claim 24, wherein the contrast agent comprises a element selected from the group consisting of Gd, Cu, Cr, Fe, Co, Er, Ni, Eu, Dy, Zn, Mg, Mo, Li, Ta, and Mn.

26. The method of any one of claims 15, 17 and 21, wherein a non-physiological environmental condition is present at the desired site, and the composition is targeted to a desired location at the desired site in the subject, at a desired rate of accumulation at the desired site, or both a desired location and desired rate of accumulation at the desired site by the presence of the non-physiological environmental condition.

27. The method of claim 26, wherein the non-physiological environmental condition is selected from the group consisting of hyperthermia, electromagnetic radiation, a chemical agent and non-physiological pH.

28. The method of claim 27, wherein the hyperthermia is provided by a natural process or by a method selected from the group consisting of contacting a heated material with the desired site, applying RF energy to the desired site, applying ultrasonic energy to the desired site and applying a laser beam to the desired site.

29. The method of claim 26, wherein the desired site is exposed to a non-physiological environmental condition before, after, or both before and after administering the composition.

30. The method of claim 26, comprising administering the composition in one or more partial doses before, after, or both before and after the desired site is exposed to a non-physiological environmental condition.

31. The method of claim 15, wherein the desired site is selected from the group consisting of a tumor, an embolism, an injury site, an ischemia, and at a tissue edema.

32. The method of one of claims 19 and 24, further comprising monitoring accumulation of the compound of interest at the desired site in vivo by magnetic resonance imaging.

33. The method of claim 32, wherein the monitoring the accumulation of the compound of interest at the desired site by magnetic resonance imaging comprises making a pixel density determination.

34. The method of claim 15, further comprising predicting efficacy of treatment based on a location of accumulation at the desired site, a rate of accumulation at the desired site, or both the location and the rate of accumulation at the desired site.

35. A method of targeting delivery of a compound of interest at a desired site in vivo, the method comprising:

administering to a subject a composition comprising a compound of interest, wherein a non-physiological environmental condition is present at the desired site, and the composition is targeted to a desired location at the desired site in the subject, at a desired rate of accumulation at the desired site, or both a desired location and desired rate of accumulation at the desired site by the presence of the non-physiological environmental condition.

36. The method of claim 35, wherein the compound of interest is a chemotherapeutic agent.

37. The method of claim 35, wherein the composition comprises a non-sensitive liposome composition comprising:

(i) the compound of interest; and

(ii) a non-sensitive liposome encapsulating the compound of interest.

38. The method of claim 37, wherein the non-sensitive liposome comprises DSPC/Cholesterol (55:

45, mol;

mol).

39. The method of claim 37, wherein the composition further comprises a contrast agent.

40. The method of claim 39, wherein the contrast agent comprises a element selected from the group consisting of Gd, Cu, Cr, Fe, Co, Er, Ni, Eu, Dy, Zn, Mg, Mo, Li, Ta, and Mn.

41. The method of claim 35, wherein the composition comprises an envirosensitive liposome composition comprising:

(i) the compound of interest; and

(ii) an envirosensitive liposome encapsulating the compound of interest.

42. The method of claim 41, wherein the envirosensitive liposome is a liposome selected from the group consisting of a thermosensitive liposome, a pH-sensitive liposome, a chemosensitive liposome and a radiation-sensitive liposome.

43. The method of claim 42, wherein the thermosensitive liposome comprises a formulation selected from the group consisting of DPPC-PEG₂₀₀₀, DPPC-DSPE-PEG₂₀₀₀ (95:

5, mol;

mol), and DPPC-MSPC-DSPE-PEG₂₀₀₀ (90;

10;

4, mol;

mol).

44. The method of claim 41, wherein the composition further comprises a contrast agent.

45. The method of claim 44, wherein the contrast agent comprises a element selected from the group consisting of Gd, Cu, Cr, Fe, Co, Er, Ni, Eu, Dy, Zn, Mg, Mo, Li, Ta, and Mn.

46. The method of claim 35, wherein the non-physiological environmental condition is selected from the group consisting of hyperthermia, electromagnetic radiation, a chemical agent and non-physiological pH.

47. The method of claim 46, wherein the hyperthermia is provided by a natural process or a method selected from the group consisting of contacting a heated material with the desired site, applying RF energy to the desired site, applying ultrasonic energy to the desired site and applying a laser beam to the desired site.

48. The method of one of claims 35 and 46, wherein the desired site is exposed to a non-physiological environmental condition before, after, or both before and after administering the composition.

49. The method of one of claims 35 and 46, comprising administering the composition in one or more partial doses before, after, or both before and after the desired site is exposed to a non-physiological environmental condition.

50. The method of claim 35, wherein the desired site is selected from the group consisting of a tumor, an embolism, an injury site, an ischemia, and at a tissue edema.

51. The method of one of claims 39 and 44, further comprising monitoring accumulation of the compound of interest at the desired site in vivo by magnetic resonance imaging.

52. The method of claim 51, wherein the monitoring the accumulation of the compound of interest at the desired site by magnetic resonance imaging comprises making a pixel density determination.

53. The method of claim 35, further comprising predicting efficacy of treatment based on a location of accumulation at the desired site, a rate of accumulation at the desired site, or both location and rate of accumulation at the desired site.