Targeted diagnostic/therapeutic agents having more than one different vectors

• US 6,331,289 B1
• Filed: 10/28/1997
• Issued: 12/18/2001
• 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: Cuthbertson, Alan, Høgset, Anders, Tolleshaug, Helge, Hellebust, Halldis, Bryn, Klaus, Rongved, Pål, Klaveness, Jo, Hoff, Lars, Solbakken, Magne
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US08/959,206
• Time in Patent Office: 1,512 Days
• Field of Search: 424/9.52, 424/9.51, 424/9.5, 424/450, 424/489, 424/498, 424/499, 424/502, 424/1.21, 424/9.4, 424/9.6, 424/9.1, 530/300, 530/324, 530/326, 530/327, 514/14
• 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 51/065 conjugates with carriers being macromolecules
• 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
• CPC Class Codes: Y10S 977/929 Ultrasound contrast agent
• CPC Class Codes: Y10S 977/93 MRI contrast agent

Abstract

Targetable diagnostic and/or therapeutically active agents, e.g. ultrasound contrast agents, comprising a suspension in an aqueous carrier liquid of a reporter comprising gas-containing or gas-generating material, said agent being capable of forming at least two types of binding pairs with a target.

Claims

1. A targetable diagnostic and/or therapeutically active agent comprising a suspension in an aqueous carrier liquid of a reporter comprising gas-containing material in the form of phospholipid-stabilized gas microbubbles, said reporter being conjugated to more than one type of vector, the vectors binding to different targets on the same or different cells.

2. An agent as claimed in claim 1 wherein the gas is selected from the group consisting of 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 selected from the group consisting of a perfluorinated ketone, perfluorinated ether and a perfluorocarbon.

4. An agent as claimed in claim 2 wherein the gas is selected from the group consisting of sulphur hexafluoride, perfluoropropane, perfluorobutane and perfluoropentane.

5. An agent as claimed in claim 1 wherein at least 75% of the phospholipid comprises phospholipid molecules individually bearing net overall charge.

6. An agent as claimed in claim 5 wherein at least 75% of the phospholipids are selected from the group consisting of phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids and cardiolipins.

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

8. An agent as claimed in claim 1, wherein said gas-containing material further comprises moieties capable of binding to a receptor system so as to induce a therapeutic response.

9. An agent as claimed in claim 1 wherein the vectors are selected from the group consisting of antibodies;

cell adhesion molecules;

cell adhesion molecule receptors;

cytokines;

growth factors;

peptide hormones;

non-bioactive binders of receptors for cell adhesion molecules, cytokines, growth factors and peptide hormones;

oligonucleotides and modified oligonucleotides;

DNA-binding drugs;

protease substrates/inhibitors; and

proteins and peptides which bind to cell-surface proteoglycans.

10. An agent as claimed in claim 1 wherein the vectors have affinity for targets at a level such that the agent interacts with but does not fixedly bind to said targets.

11. An agent as claimed in claim 10 wherein the vectors are selected from ligands for cell adhesion proteins and cell adhesion proteins which have corresponding ligands on endothelial cell surfaces.

12. An agent as claimed in claim 1 wherein the vectors are sited such that they are not readily exposed to the target.

13. An agent as claimed in claim 1 wherein the vectors are coupled or linked to the reporter by means of avidin-biotin and/or streptavidin-biotin interactions.

14. An agent as claimed in claim 1 wherein the vectors may be covalently or non-covalently coupled or linked to the reporter.

15. An agent as claimed in claim 1 wherein the vectors are coupled or linked to the reporter by means of electrostatic charge interaction.

16. 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.

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

18. An agent as claimed in claim 17 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.

19. An agent as claimed in claim 17 wherein said therapeutic compound is covalently coupled or linked to the reporter through disulphide groups.

20. An agent as claimed in claim 17 wherein a lipophilic or lipophilically-derivatised therapeutic compound is linked to the reporter through hydrophobic interactions.

21. A process for the preparation of a targetable diagnostic and/or therapeutically active agent as defined in claim 1 which comprises coupling or linking more than one type of vector to the reporter comprising gas-containing material wherein the vectors bind to different targets on the same or different cells.

22. A process as claimed in claim 21 wherein a therapeutic compound is also combined with the reporter.