MULTICOMPONENT ASSEMBLIES HAVING ENHANCED BINDING PROPERTIES FOR DIAGNOSIS AND THERAPY

• US 20060269511A1
• Filed: 08/04/2006
• Published: 11/30/2006
• Est. Priority Date: 08/17/2001
• Status: Active Grant

• Current Assignee: Liebel Flarsheim Co LLC (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Cantrell, Gary L., Burleigh, B. Daniel
• Granted Patent: US 7,713,514 B2
• Time in Patent Office: Days
• US Class Current: 424/78.370
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

An organized mobile multicomponent conjugate (OMMC) and method of using to enhance binding of weakly binding compounds to a target. A lamellar structure containing at least two binding compounds is assembled under conditions in which the binding compounds self-regulate in or on the lamellar structure, forming a cooperative ensemble that is capable of binding with enhanced affinity to a complementary affinity site on a target. Each binding compound is bound to the lamellar surface, and may be connected by a linker. The OMMC may contain an effector molecule, such as a diagnostic or therapeutic agent, for administration to a patent who is then diagnosed or treated using the effector molecule.

Claims

1. A method of enhancing binding of a binding compound to a target site:

in a patient comprising

providing to said patient an effective amount of a physiologically acceptable organized mobile multicomponent conjugate (OMMC) assembly comprising a lamellar structure defining a void and having incorporated at least first and second binding compounds capable of binding to at least first and second affinity sites in said target site, wherein a position of said first and second binding compounds relatively self-adjust to form an OMMC ensemble resulting in enhanced binding of said binding compounds to said affinity sites.

2. The method of claim 1 wherein said assembly further comprises an agent.

3. The method of claim 2 wherein said agent is selected from the group consisting of a diagnostic agent and a therapeutic agent.

4. The method of claim 2 wherein said agent is attached to the assembly.

5. The method of claim 2 wherein said agent is contained within the assembly.

6. The method of claim 1 wherein said target site is a cell selected from the group consisting of tumor cells, macrophages, endothelial cells, myocardial cells, hepatocytes, leukocytes, platelets and combinations thereof.

7. The method of claim 3 further comprising thereafter performing a procedure on said patent.

8. The method of claim 1 wherein said binding compound is a ligand.

9. The method of claim 8 wherein the ligand is selected from the group consisting of a selectin, a selectin mimetic, a glycan binding protein, and combinations thereof.

10. The method of claim 1 wherein said first and second binding compounds are different.

11. A physiologically acceptable target binding composition comprising an organized mobile multicomponent conjugate (OMMC) assembly and a physiologically acceptable carrier or excipient, said assembly comprising a lamellar structure defining a void and having at least first mobile and second mobile binding compounds complementary to affinity sites on a target, said first and second binding compounds bound to said lamellar structure at first and second structure binding sites, said first and second structure binding sites being relatively adjustable within said lamellar structure.

12. The composition of claim 11 further comprising a linker between said first structure binding site and said first binding compound and said second structure binding site and said second binding compound.

13. The composition of claim 11 further comprising an agent.

14. The composition of claim 13 wherein said agent is selected from the group consisting of a therapeutic agent and a diagnostic agent.

15. The composition of claim 11 wherein said binding compounds are selected from the group consisting of an anionic compound, a saccharide, and combinations thereof.

16. The composition of claim 12 wherein said linker is a polyhydroxylated compound.

17. The composition of claim 11 having a size less than five microns.

18. A method of enhancing the affinity of binding compounds to a target site in a patient comprising

providing to said patient an effective amount of a physiologically acceptable organized mobile multicomponent conjugate (OMMC) assembly comprising a lamellar structure defining a void and having incorporated at least two binding compounds B¹ and B² bound to said structure at regions A¹ and A² via linkers L¹ and L², B¹ and B² capable of binding to at least first and second affinity sites in said target site, wherein a position of B¹ and B² relatively self-adjust to form an OMMC ensemble resulting in enhanced binding of B¹ and B² to said affinity sites.

19. The method of claim 18 wherein said target is selected from the group consisting of tumor cells, thrombi, monocytes, macrophages, eosinophils, neutrophils, lymphocytes, vascular endothelium, myocardial cells, hepatocytes, and an extracellular matrix surrounding any of these cells.

20. The method of claim 18 wherein A¹ and A² may be the same or different and are selected from the group consisting of CH₃(CH₂)_a—

W, CH₃(CH₂)_a—

O—

(CH₂)_b—

W, CH₃(CH₂)_a—

S—

(CH₂)_b—

W, and R¹O₂CCH₂(CW)CO₂R¹, wherein a and b range from 16 to 24, W is —

O—

, —

O₂C—

, —

CO₂—

, and —

NHCO—

.

21. The method of claim 18 wherein B¹ and B² may be the same or different and are selected from the group consisting of glucose, galactose, fucose, sialic acid, and carminic acid.

22. The method of claim 18 wherein L¹ and L² may be the same or different and are selected from the group consisting of polyethylene glycol having a molecular weight in the range of 1,000 to 4,000.

23. The method of claim 18 wherein the lamellar structure is selected from the group consisting of CH₃—

(CH₂)_e—

X, CH₃—

(CH₂)_fCONH(CH₂)_g—

X, CH₃—

(CH₂)_fNHCONH(CH₂)_g—

X, CH₃—

(CH₂)_fOCONH(CH₂)_g—

X, CH₃—

(CH₂)_fNH(CH₂)_g—

X, R²O₂CCH₂(CY)CO₂R², and R²O₂CCH₂CH₂(CY)CO₂R² where X is selected from the group consisting of carboxylate, sulfate, or phosphate;

Y is selected from the group consisting of —

(CH₂)_k—

X, —

NHCO(CH₂)_k—

X, and CH₂OCO(CH₂)₂—

CO₂⁻

;

R² is a normal alkyl radical containing 16-24 carbon atoms, and e, f, g, and k range from 1 to 5.

24. The method of claim 18 wherein the binding compounds have an affinity equal to or less than about 100 nM for the target.

25. The method of claim 18 wherein A¹ and A² may be the same or different and are selected from the group consisting of CH₃(CH₂)_a—

W, CF₃(CH₂)_a—

W, CF₃(CF₂)_a—

W, CF₃(CF₂)_aCH₂CH₂—

W, CH₃(CH₂)_a—

O—

(CH₂)_b—

W, CF₃(CF₂)_a—

O—

(CH₂)_b—

W, CH₃(CH₂)_a—

S—

(CH₂)_b—

W, CH₃(CH₂)_a—

S—

S—

(CH₂)_b—

W and R¹O₂CCH₂(CW)CO₂R¹, wherein a and b range from 16 to 32;

W is a connector unit selected from the group consisting of —

O—

, —

CO—

, —

CO₂—

, —

O₂C—

, —

O₂CO—

, —

NHCO—

, —

S—

, —

SO—

, —

SO₂—

, —

OSO—

, —

OSO₂—

, —

NHSO₂—

, —

PO₂—

, and —

OPO₂—

; and

R¹ is a normal alkyl radical containing 16-24 carbon atoms.

26. The method of claim 18 where B¹ and B² may be the same or different and are selected from the group consisting of amino acids;

peptides containing 1-20 amino acid residues;

flavenoids;

isoflavones;

C- or O-monosaccharides and glycosides selected from the group consisting of glucose, mannose, fucose, galactose, glucosamine, mannosamine, galactosamine, and sialic acid;

oligosaccharides containing 1-10 furanose or pyranose units;

C- or O-glucosides selected from the group consisting of rutin, neohesperidin dihydrochalone, phloridizin, hesperidin, hesperidin methyl chalcone, naringenin, and esculin; and

carminic acids selected from the group consisting of carmine and 18b-glycyrrhetinic acid.

27. The method of claim 18 where L¹ and L² may be the same or different neutral polymers or copolymers with a molecular weight in the range of 1,000 to 10,000 daltons selected from the group consisting of polyethyleneglycols, polysorbates, polyglycerols, polyvinylalcohols, polyglycolates, and polylactates.

28. The method of claim 18 where the lamellar structure is selected from the group consisting of CH₃—

(CH₂)_e—

X, CH₃—

(CF₂)_e—

X, CF₃—

(CF₂)_e—

X, CF₃—

(CF₂)_f—

O—

(CH₂)_g—

X, CH₃—

(CH₂)_f—

S—

(CH₂)_g—

X, CH₃—

(CH₂)_f—

S—

S—

(CH₂)_g—

X, CH₃—

—

(CH₂)_gCO₂(CH₂)_h—

X, CH₃—

(CH₂)_fCONH(CH₂)_g—

X, CH₃—

(CH₂)_fNHCONH(CH₂)_g—

X, CH₃—

(CH₂)_fOCONH(CH₂)_g—

X, CH₃—

(CH₂)_fNH(CH₂)_g—

X, CH₃—

(CH₂)_fN[(CH₂)_g]₂—

X, CH₃—

(CH₂)_fSO(CH₂)_g—

X, CH₃—

(CH₂)_fSO₂(CH₂)_g—

X, CH₃—

(CH₂)_mNH(CH₂)_fCO₂(CH₂)_g—

X, CH₃—

[(CH₂)_f]₂N(CH₂)_gCONH(CH₂)_h—

X, R²O₂CCH₂(CY)CO₂R², R²O₂CCH₂CH₂(CY)CO₂R², where X is selected from the group consisting of carboxylate, sulfonate, sulfate, phosphate, and phosphonate;

Y is —

(CH₂)_k—

X, —

NHCO(CH₂)_k—

X, —

OCO(CH₂)_k—

X, —

CH₂OCO(CH₂)₂—

CO₂⁻

;

e=16-32;

f, g, h=1-15;

R² is a normal alkyl radical containing 16-24 carbon atoms; and

k=1-6.

29. A method of performing a diagnostic or a therapeutic procedure on a patient using a target binding composition comprising

providing to said patient an effective amount of a physiologically acceptable composition comprising an organized mobile multicomponent conjugate (OMMC) assembly comprising a lamellar structure defining a void and having incorporated at least two binding compounds B¹ and B² bound to said structure by anchor regions A¹ and A² via linkers L¹ and L², and an effector molecule, said B¹ and B² capable of binding to at least first and second affinity sites in said target site, wherein a position of B¹ and B² relatively self-adjust to form an OMMC ensemble resulting in enhanced binding of B¹ and B² to said affinity sites, and

performing said diagnostic or said therapeutic procedure on said patient.

30. The method of claim 29 wherein A¹ and A² may be the same or different and are selected from the group consisting of CH₃(CH₃)_a—

W, CF₃(CH₂)_a—

W, CF₃(CF₂)_a—

W, CF₃(CF₂)_aCH₂CH₂—

W, CH₃(CH₂)_a—

O—

(CH₂)_b—

W, CF₃(CF₂)_a—

O—

(CH₂)_b—

W, CH₃(CH₂)_a—

S—

(CH₂)_b—

W, or CH₃(CH₂)_a—

S—

S—

(CH₂)_b—

W, wherein a and b range from 16 to 32 and W is a connector unit selected from the group consisting of —

O—

, —

CO₂—

, —

O₂C—

, —

O₂CO—

, —

CO—

, —

NHCO—

, —

S—

, —

SO—

, —

SO₂, —

OSO—

, —

OSO₂—

, —

NHSO₂—

, —

PO₂—

, and —

OPO₂—

.

31. The method of claim 29 wherein B¹ and B² may be the same or different C- or O-monosaccharides and glycosides selected from the group consisting of glucose, mannose, fucose, galactose, glucosamine, mannosamine, galactosamine, and sialic acid, oligosaccharides containing 1 to 10 furanose or pyranose units, amino acids, peptides containing 1 to 20 amino acid residues, flavonoids and isoflavonones C- or O-glucosides selected from the group consisting of rutin, neohesperidin dihydrochalone, phloridizin, hesperidin, hesperidin methyl chalcone, naringenin, and esculin, carminic acids selected from the group consisting of carmine, and 18b-glycyrrhetinic acid.

32. The method of claim 29 wherein L¹ and L² may be the same or different neutral polymers or copolymers selected from the group consisting of polyethyleneglycol, polysorbates, polyglycerols, polyvinylalcohols, polyglycolate, and polylactate wherein the molecular weight of the said polymer and copolymer range from 1,000 to 10,000.

33. The method of claim 29 wherein said lamellar structure is selected from the group consisting of CH₃—

(CH₂)_e—

X, CH₃—

(CF₂)_e—

X, CF₃—

(CF₂)_e—

X, CF₃—

(CF₂)_f—

O—

(CH₂)_g—

X, CH₃—

(CH₂)_f—

S—

(CH₂)_g—

X, CH₃—

(CH₂)_f—

S—

S—

(CH₂)_g—

X, CH₃—

(CH₂)_gCO₂(CH₂)_h—

X, CH₃—

(CH₂)_fCONH(CH₂)_g—

X, CH₃—

(CH₂)_fNHCONH(CH₂)_g—

X, CH₃—

(CH₂)_fOCONH(CH₂)_g—

X, CH₃—

(CH₂)_fNH(CH₂)_g—

X, CH₃—

(CH₂)_fNH(CH₂)_g)₂—

X, CH₃—

(CH₂)_fSO₂(CH₂)_g—

X, CH₃—

(CH₂)_fSO₂(CH₂)_g—

X, CH₃—

(CH₂)_fN[CH₂)_g]₂—

X, CH₃—

(CH₂)_mNH(CH₂)_fCO₂(CH₂)_g—

X, CH₃—

((CH₂)_f)₂N(CH₂)_gCONH(CH₂)_h—

, RO₂CCH₂(CY)CO₂R, wherein f, g, and h range from 1 to 5;

X is selected from the group consisting of carboxylate, sulfonate, sulfate, phosphate, and phosphonate;

Y is selected from the group consisting of —

(CH₂)_k—

X, —

NHCO(CH₂)_k—

X, —

OCO(CH₂)_k—

X, —

CH₂OCO(CH₂)₂—

CO⁻

₂;

R is a normal alkyl radical containing 16 to 24 carbon atoms; and

k varies from 2 to 6.

34. The method of claim 29 wherein A¹ and A² may be the same or different and are selected from the group consisting of CH₃(CH₂)_a—

W, CH₃(CH₂)_a—

O—

(CH₂)_b—

W, CH₃(CH₂)_a—

S—

(CH₂)_b—

W, and R¹O₂CCCH₂(CW)CO₂R¹, wherein a and b range from 16 to 24, W is —

O—

, —

O₂C—

, —

CO₂—

, and —

NHCO—

.

35. The method of claim 29 wherein B¹ and B² may be the same or different and are selected from the group consisting of glucose, galactose, fucose, sialic acid and carminic acid.

36. The method of claim 29 wherein L¹ and L² may be the same or different and is polyethylene glycol having a molecular weight in the range of 1,000 to 4,000.

37. The method of claim 29 wherein said lamellar structure is a compound selected from the group consisting of CH₃—

(Ch₂)_e—

X, CH₃—

(CH₂)_fCONH(CH₂)_g—

X, CH₃—

(CH₂)_fNHCONH(CH₂)_g—

X, CH₃—

(CH₂)_fOCONH(CH₂)_g—

, CH₃—

(CH₂)_fNH(CH₂)_g—

, R₂O₂CCH₂(CY)CO₂R², and R²O₂CCH₂CH₂(CY)CO₂R²;

R² is a normal alkyl radical containing 16 to 24 carbon atoms;

X is selected from the group consisting of carboxylate, sulfate, or phosphate;

Y is selected from the group consisting of —

(CH₂)_k—

X, —

NHCO(CH₂)_k—

X and CH₂OCO(CH₂)₂—

CO⁻

₂;

e ranges from 16 to 32, and f, g, and k range from 1 to 5.

38. The method of claim 29 wherein said effector molecule is selected from the group consisting of an echogenic agent, a radionuclide, a paramagnetic agent, an optical agent, and a cytotoxic agent.

39. The method of claim 38 wherein said effector molecule is an echogenic agent selected from the group consisting of perfluoropropane, perfluorobutane, sulfur hexafluoride, tetrafluoromethane, hexafluoroethane, octafluoropropane, decafluorobutane, dodecafluoropentane, and perfluorohexane.

40. The method of claim 38 wherein said effector molecule is a radionuclide selected from the group consisting of I-123, I-131, Tc-99m, Re-186, Re-188, SM-152, Ho-155, Bi-202, and Lu-157.

41. The method of claim 38 wherein said effector molecule is a paramagnetic agent selected from the group consisting of Gd-DTPA, Gd-DOTA, Gd-DTPA-bis(methoxyethyl)amide, and Mn-EDTA.

42. The method of claim 38 wherein said effector molecule is an optical agent selected from the group consisting of a fluorophore that absorbs light in the range of 300-1200 nm, and a chromophore that absorbs light in the range of 300-1200 nm.

43. The method of claim 38 wherein said effector molecule is a cytotoxic agent selected from the group consisting of fluorouracil, fluorouridine, sulfisoxazole, N′

-(w-thiazolyl)sulfanilamide, sulfmethoxazole, and sulfisomidine.

44. The method of claim 38 wherein said effector molecule is an optical agent selected from the group consisting of fluorescein and indocyanine green.

45. The method of claim 38 wherein said effector molecule is perfluorobutane.

46. The method of claim 38 wherein said effector molecule is I-131 or Tc-99m.

47. The method of claim 38 wherein said target is selected from the group consisting of tumor cells, thrombi, monocytes, macrophages, eosinophils, neutrophils, lymphocytes, vascular endothelium, myocardial cells, hepatocytes, and an extracellular matrix surrounding any of the said cells.