Lipid-based systems for targeting diagnostic agents

• US 20030175205A1
• Filed: 02/11/2003
• Published: 09/18/2003
• Est. Priority Date: 04/12/2000
• Status: Active Grant

• Current Assignee: LiPlasome Pharma A/S
• Original Assignee: LiPlasome Pharma A/S
• Inventors: Jorgensen, Kent, Mouritsen, Ole G., Vermehren, Charlotte, Davidsen, Jesper, Frokjer, Sven
• Granted Patent: US 7,368,254 B2
• Time in Patent Office: Days
• US Class Current: 424/1.11
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• 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: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/04 Amoebicides
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to targeting of diagnostic agents by use of lipid-based compositions. The invention is useful in the diagnosis of various disorders which are associated with or resulting from increased levels of extracellular PLA₂ activity in the diseased tissue, e.g. cancer, infectious, and inflammatory conditions.

Claims

1. Use of lipid-based system comprising a lipid derivative and a label, said lipid derivative having (a) an aliphatic group of a length of at least 7 carbon atoms and an organic radical having at least 7 carbon atoms, and (b) a hydrophilic moiety, said lipid derivative furthermore being a substrate for extracellular PLA₂ to the extent that the organic radical can be hydrolytically cleaved off, whereas the aliphatic group remains substantially unaffected, whereby lipid derivative from which the organic radical has been cleaved off is liberated in the form of a lysolipid derivative which is not a substrate for lysophospholipase, said system having included therein lipopolymers or glycolipids so as to present hydrophilic chains on the surface of the system, for the preparation of a diagnostic composition for detecting and/or quantifying diseases or conditions associated with a localised increase in extracellular PLA₂ activity in mammalian tissue.

2. Use according to any of the preceding claims, wherein the label is selected from the group consisting of ¹¹¹In, ^99mTc, ⁶⁷Ga, ¹¹C;

Gd, Mn, iron oxide, argon, nitrogen, Iodine, bromine and barium.

3. Use according to any of the preceding claims, wherein the lipid derivative has the following formula:

4. Use according to claim 3, wherein R² is an aliphatic group of a length of at least 7 carbon atoms.

5. Use according to claim 4, wherein R² is a group of the formula Y¹Y².

6. Use according to any of the preceding claims, wherein the prodrug constitutes 15-100 mol % of the total dehydrated lipid-based system.

7. Use according to any of the preceding claims, wherein the lipid-based system is in the form of liposomes wherein a second drug substance is incorporated.

8. Use according to any of the preceding claims, wherein the label is covalently linked to the lipid derivative.

9. Use according to any of the preceding claims, wherein the disease or condition characterised by having an elevated PLA₂ level in a mammal is caused by malignant tissue, e.g. selected from the group consisting of brain cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, lymphoma, sarcoma and carcinoma.

10. Use according to claim 9, wherein the malignant tissue is the primary tumour.

11. Use according to any one of claims 9 or 10, wherein the malignant tissue is metastatic cells originating from the primary tumour.

12. Use according to any of the preceding claims, wherein the label is detectable and/or quantified by a method selected from the group consisting of positron emission tomography (PET), X-ray, gamma-scintigraphy, magnetic resonance (MR) imaging, computed tomography (CT) imaging and ultrasonography.

13. A method for identifying and optionally quantifying malignant tissue in a mammal, comprising

a) administering a lipid-based system comprising a lipid derivative and a label, said lipid derivative having (a) an aliphatic group of a length of at least 7 carbon atoms and an organic radical having at least 7 carbon atoms, and (b) a hydrophilic moiety, said lipid derivative furthermore being a substrate for extracellular PLA₂ to the extent that the organic radical can be hydrolytically cleaved off, whereas the aliphatic group remains substantially unaffected, whereby lipid derivative from which the organic radical has been cleaved off is liberated in the form of a lysolipid derivative which is not a substrate for lysophospholipase, said system having included therein lipopolymers or glycolipids so as to present hydrophilic chains on the surface of the system, to an individual suspected of having a malignant disease characterised by having an elevated PLA₂ level whereby a label is released from the lipid derivative to the malignant tissue,

b) detecting and optionally quantifying the label.

14. A method according to claim 13, wherein the label is selected from the group consisting of ¹¹¹In, ^99mTc, ⁶⁷Ga, ¹¹C;

Gd, Mn, iron oxide, argon, nitrogen, Iodine, bromine and barium.

15. A method according to claim 13, wherein the lipid derivative has the following formula:

16. A method according to claim 15, wherein R² is an aliphatic group of a length of at least 7 carbon atoms.

17. A method according to claim 16, wherein R²is a group of the formula Y¹Y².

18. A method according to claim 13, wherein the prodrug constitutes 15-100 mol % of the total dehydrated lipid-based system.

19. A method according to claim 13, wherein the-lipid-based system is in the form of liposomes wherein a second drug substance is incorporated.

20. A method according to claim 13, wherein the label is covalently linked to the lipid derivative.

21. A method according to claim 13, wherein the disease or condition characterised by having an elevated PLA₂ level in a mammal is caused by malignant tissue, e.g. selected from the group consisting of brain cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, lymphoma, sarcoma and carcinoma.

22. A method according to claim 21, wherein the malignant tissue is the primary tumour.

23. A method according to claim 21, wherein the malignant tissue is metastatic cells originating from the primary tumour.

24. A method according to claim 13, wherein the label is detected and/or quantified by a method selected from the group consisting of positron emission tomography (PET), X-ray, gamma-scintigraphy, magnetic resonance (MR) imaging, computed tomography (CT) imaging and ultrasonography.