Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors

• US 6,261,537 B1
• Filed: 10/29/1997
• Issued: 07/17/2001
• Est. Priority Date: 10/28/1996
• Status: Expired due to Fees

• Current Assignee: GE Healthcare As (GE Healthcare Technologies, Inc.)
• Original Assignee: Nycomed A/S (Takeda Pharmaceutical Company Limited)
• Inventors: Rongved, Pål, Klaveness, Jo, Hoff, Lars, Cuthbertson, Alan, Solbakken, Magne, Høgset, Anders, Tolleshaug, Helge, Hellebust, Halldis, Nævestad, Anne, Løvhaug, Dagfinn
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US08/960,054
• Time in Patent Office: 1,357 Days
• Field of Search: 424/9.52, 424/9.51, 424/489, 424/490, 424/498, 424/502, 424/450, 424/9.3, 424/9.32, 424/9.4, 424/1.29, 424/9.6, 264/4, 264/4.1, 264/5, 427/213, 427/213.3, 427/213.36, 428/402, 428/402.21, 530/300, 530/326, 530/328, 600/458, 600/441
• US Class Current: 424/9.52
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0047 Green fluorescent protein [GFP]
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61K 49/0058 Antibodies
• CPC Class Codes: A61K 49/0091 Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61K 51/1227 Micelles, e.g. phospholipidic or polymeric micelles
• CPC Class Codes: A61K 51/1255 Granulates, agglomerates, microspheres
• CPC Class Codes: Y10S 977/928 X-ray agent

Abstract

Targetable diagnostic and/or therapeutically active agents, e.g. ultrasound contrast agents, having reporters comprising gas-filled microbubbles stabilised by monolayers of film-forming surfactants, the reporter being coupled or linked to at least one vector.

Claims

1. A targetable ultrasound diagnostic active agent comprising a suspension in an aqueous carrier liquid of a reporter comprising gas-filled microbubbles stabilised by monolayers of film-forming surfactant material, at least 75% of said film-forming surfactant material comprising phospholipid molecules bearing a net overall charge and said film-forming surfactant material including a positively charged peptide linker element comprising two or more lysine residues and wherein said linker element is anchored through electrostatic interaction with the reporter material, said peptide linker coupling to one or more vector molecules selected from the group consisting of angiogenesis-specific binding vectors, atherosclerotic plaque-binding peptides and thrombus-binding peptides.

2. An agent as claimed in claim 1 wherein the gas is air, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, selenium hexafluoride, a low molecular weight hydrocarbon, a ketone, an ester, a halogenated low molecular weight hydrocarbon or a mixture of any of the foregoing.

3. An agent as claimed in claim 2 wherein the gas is a perfluorinated ketone, perfluorinated ether or perfluorocarbon.

4. An agent as claimed in claim 2 wherein the gas is sulphur hexafluoride, perfluoropropane, perfluorobutane or perfluoropentane.

5. An agent as claimed in claim 1 wherein the film-forming surfactant material is one or more phospholipids selected from the group consisting of phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids and cardiolipins.

6. An agent as claimed in claim 5 wherein at least 80% of said phospholipids are phosphatidylserines.

7. An agent as claimed in claim 1 which further contains moieties which are radioactive or are effective as X-ray contrast agents, light imaging probes or spin labels.

8. An agent as claimed in claim 1 further comprising a therapeutic compound.

9. An agent as claimed in claim 8 wherein said therapeutic compound is an antineoplastic agent, blood product, biological response modifier, antifungal agent, hormone or hormone analogue, vitamin, enzyme, antiallergic agent, tissue factor inhibitor, platelet inhibitor, coagulation protein target inhibitor, fibrin formation inhibitor, fibrinolysis promoter, antiangiogenic, circulatory drug, metabolic potentiator, antitubercular, antiviral, vasodilator, antibiotic, antiinflammatory, antiprotozoan, antirheumatic, narcotic, opiate, cardiac glycoside, neuromuscular blocker, sedative, local anaesthetic, general anaesthetic or genetic material.

10. An agent as claimed in claim 8 wherein said therapeutic compound is covalently coupled or linked to the reporter through disulphide groups.

11. An agent as claimed in claim 8 wherein a lipophilic therapeutic compound is linked to the surfactant monolayers stabilizing the gas-filled microbubbles of the reporter through hydrophobic interactions.

12. An agent as claimed in claim 1 wherein the vector(s) is one or more atherosclerotic plaque-binding peptides selected from the group consisting of YRALVDTLK, YAKFRETLEDTRDRMY and RALVDTEFKVKQEAGAK.

13. An agent as claimed in claim 12 wherein the vector molecule is an atherosclerotic plaque-binding peptide having the sequence YRALVDTLK.

14. An agent as claimed in claim 1 wherein the vector molecule is a thrombus-binding peptide.

15. An agent as claimed in claim 1 wherein the angiogenesis-specific binding vector is α

₂-antiplasmin.

16. An agent as claimed in claim 1 wherein the vector molecule is an angiogenesis-specific binding vector.

17. An agent as claimed in claim 16 wherein the vector binds to an integrin.

18. An agent as claimed in claim 17 wherein the vector is an RGD-peptide.

19. An agent as claimed in claim 17 wherein the vector is a non-peptide RGD analogue.

20. An agent as claimed in claim 17 wherein the vector is selected from the group consisting of vectors binding to one or more of the following angiogenesis targets:

integrins β

₁, β

₃ and β

₅, α

_vβ

₃, α

₆β

₁, α

₂β

₁, α

_vβ

₅, α

₆ and α

₅.

21. An agent as claimed in claim 20 wherein the vector is a vector which binds to the integrin α

_vβ

₃.

22. An agent as claimed in claim 1 wherein the vector is a urokinase-type vector.