MULTICOMPONENT ASSEMBLIES HAVING ENHANCED BINDING PROPERTIES FOR DIAGNOSIS AND THERAPY

• US 20100041827A1
• Filed: 10/23/2009
• Published: 02/18/2010
• Est. Priority Date: 08/17/2001
• Status: Active Grant

• Current Assignee: Liebel-Flarsheim Company (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Cantrell, Gary L., Burleigh, B. Daniel
• Granted Patent: US 8,246,930 B2
• Time in Patent Office: Days
• US Class Current: 525/56
• 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 biocompatible organized mobile multicomponent conjugate (OMMC) comprising:

(A) a lamellar structure comprising R²O₂CCH₂CH₂(CY)CO₂R², wherein;

(1) R² is an alkyl radical containing 16-24 carbon atoms;

(2) Y is selected from the group consisting of —

(CH₂)_k—

X, —

NHCO(CH₂)_k—

X, —

OCO(CH₂)_k—

X, and —

CH₂OCO(CH₂)₂—

CO₂⁻

;

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

(4) k is 1-6; and

(B) a first binding compound and a second binding compound, each of which is bound to the lamellar structure, the first binding compound capable of binding to an exogenous first affinity site, and the second binding compound capable of binding to an exogenous second affinity site, wherein the first and second binding compounds are mobile and self-adjust relative to the lamellar structure to allow for cooperative binding of the first and second binding compounds to said first and second affinity sites, respectively, wherein each binding compound independently comprises;

(1) an anchor region that connects the binding compound to the lamellar structure, the anchor region being selected from the group consisting of CH₃(CH₂)_a—

W, CH₃(CH₂)_a—

O—

(CH₂)_b—

W, CH₃(CH₂)_a—

S—

(CH₂)_b—

W, R¹O₂CCH₂(CW)CO₂R¹, CF₃(CH₂)_a—

W, CF₃(CF₂)_a—

W, CF₃(CF₂)_aCH₂CH₂—

W, CF₃(CF₂)_a—

O—

(CH₂)_b—

W, and CH₃(CH₂)_a—

S—

S—

(CH₂)_b—

W, wherein;

(a) each of a and b ranges from 16 to 32;

(b) W is selected from the group consisting of —

O—

, —

CO—

, —

CO₂—

, —

OCO—

, —

O₂CO—

, —

S—

, —

SO—

, —

SO₂—

, —

OPO₂H—

, —

NH—

, —

NHCO—

, —

NHCS—

, —

NHSO₂—

, —

PO₂H—

, —

OPO₂H—

, —

PO₂—

, and —

OPO₂—

; and

(c) R¹ is an alkyl radical containing 16 to 24 carbon atoms; and

(2) a binding region selected from the group consisting of amino acids, peptides, peptidomimics, monosaccharides, disaccharides, oligosaccharides, sialic acid, carminic acid, and anionic compounds of —

(CH₂)_d—

CO₂⁻

, —

(CH₂)_d—

SO₃⁻

, —

(CH₂)_d—

OSO₃⁻

, —

(CH₂)_d—

PO₃⁼, —

(CH₂)_d—

OPO₃⁼, —

Ar—

SO₃⁻

, DTPA, EDTA, DOTA, and EGTA, wherein d ranges from 1 to 10, inclusive; and

(3) a linker that connects the anchor region to the binding region, the linker being selected from the group consisting of polysorbates, polyglycerols, polypeptides, polynucleotides, polysaccharides, polyvinylpyrrolidones, polyvinylalcohols, polyethyleneglycols, polyglycolate, polylactate, and copolymers of any of the members of this group.

2. The conjugate of claim 1, wherein at least one of the first and second binding compounds is bound to R²O₂CCH₂CH₂(CY)CO₂R² of the lamellar structure.

3. The conjugate of claim 1, wherein Y is NHCO(CH₂)_k—

X.

4. The conjugate of claim 3, wherein X is carboxylate.

5. The conjugate of claim 1, wherein X is carboxylate.

6. The conjugate of claim 1, wherein the anchor region of each of the first and second binding compounds is independently 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.

7. The conjugate of claim 1, wherein the anchor region of the first binding compound, the second binding compound, or the first and second binding compounds is CH₃(CH₂)_a—

W.

8. The conjugate of claim 7, wherein W is —

O—

.

9. The conjugate of claim 7, wherein W is —

CO—

.

10. The conjugate of claim 7, wherein W is —

CO₂—

.

11. The conjugate of claim 7, wherein W is —

OCO—

.

12. The conjugate of claim 7, wherein W is —

O₂CO—

.

13. The conjugate of claim 7, wherein W is —

NHCO—

.

14. The conjugate of claim 1, wherein the anchor region of the first binding compound, the second binding compound, or the first and second binding compounds is R¹O₂CCH₂(CW)CO₂R¹.

15. The conjugate of claim 14, wherein W is —

NH—

.

16. The conjugate of claim 14, wherein W is —

NHCO—

.

17. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is an amino acid.

18. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is a monosaccharide.

19. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is a disaccharide.

20. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is sialic acid.

21. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is selected from the group consisting of C or O monosaccharides and glycosides.

22. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is selected from the group consisting of mannose, glucose, fucose, and galactose.

23. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is selected from the group consisting of glucosamine, mannosamine, and galactosamine.

24. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is selected from the group consisting of selectin mimics.

25. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is DTPA.

26. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is DOTA.

27. The conjugate of claim 1, wherein the binding region of the first binding compound, the second binding compound, or the first and second binding compounds is a peptide.

28. The conjugate of claim 1, wherein the linker of the first binding compound, the second binding compound, or the first and second binding compounds is a polyvinylpyrrolidone.

29. The conjugate of claim 1, wherein the linker of the first binding compound, the second binding compound, or the first and second binding compounds is a polyethyleneglycol.

30. The conjugate of claim 1, wherein the polyethyleneglycol has a molecular weight in the range of 1,000 to 4,000.

31. The conjugate of claim 1, wherein the linker of the first binding compound, the second binding compound, or the first and second binding compounds is polyglycolate.

32. The conjugate of claim 1, wherein the linker of the first binding compound, the second binding compound, or the first and second binding compounds is polylactate.

33. The conjugate of claim 1, wherein the linker of the first binding compound, the second binding compound, or the first and second binding compounds is a copolymer of polyglycolate and polylactate.

34. The conjugate of claim 1, wherein the first binding compound, the second binding compound, or the first and second binding compounds has a dissociation constant (K_d) value greater than about 100 nM.

35. The conjugate of claim 1, wherein each of the first and second binding compounds has a dissociation constant (K_d) value greater than about 100 nM.

36. The conjugate of claim 1, further comprising:

an effector molecule attached to the lamellar structure.

37. The conjugate of claim 1, wherein the lamellar structure has a void defined therein, and the conjugate further comprises an effector molecule located in the void of the lamellar structure.

38. The conjugate of claim 1, further comprising:

an effector molecule incorporated within the lamellar structure.

39. The conjugate of any one of claims 36-38, wherein the effector molecule comprises a radiopharmaceutical agent.

40. The conjugate of any one of claims 36-38, wherein the effector molecule is a cytotoxic agent.

41. The conjugate of any one of claims 36-38, wherein the effector molecule is a paramagnetic agent.

42. The conjugate of any one of claims 36-38, wherein the effector molecule is an optical agent.

43. The conjugate of any one of claims 36-38, wherein the effector molecule is a sulfa antibiotic.

44. The conjugate of claim 39 wherein the radiopharmaceutical agent is a radionuclide, or a radionuclide chelate covalently attached to an antibody, a hormone, a peptide, and/or a peptidomimetic.

45. The conjugate of claim 39 wherein the radiopharmaceutical is radioactive molecule emitting alpha, beta, or gamma radiation.

46. The conjugate of claim 39 wherein the radiopharmaceutical is a chelate of a beta emitting isotope or a chelate of a gamma emitting isotope.

47. The conjugate of claim 39 wherein the radiopharmaceutical comprises Lu, Sm, In, Ru, or Tc.

48. The conjugate of claim 39 wherein the radiopharmaceutical comprises I-123, I-131, Tc-99m, Re-186, Re-188, Sm-152, Ho-155, Bi-202, or Lu-157.

49. The conjugate of claim 39 wherein the radiopharmaceutical is diethylenetriamine pentaacetic acid (DTPA) or 1,4,7,10-tetraazacyclododecane-N,N′

,N″

,N′

″

-tetraacetic acid (DOTA).

50. The conjugate of claim 40 wherein the cytotoxic agent comprises a chemotherapeutic agent.

51. The conjugate of claim 40 wherein the cytotoxic agent is fluorouracil or fluorouridine.

52. The conjugate of claim 41 wherein the paramagnetic agent is Gd-DTPA, Gd-DOTA, Gd-DTPA-bis(methoxyethyl)amide, or Mn-EDTA.

53. The conjugate of claim 42 wherein the optical agent is a fluorophore that absorbs light in the range of 300-1200 nm or a chromophore that absorbs light in the range of 300-1200 nm.

54. The conjugate of claim 42 wherein the optical agent is selected from the group consisting of fluoresceins, rhodamines, cyanines, indocyanines, squaraines, phenothiazines, porphyrins, and azo compounds.

55. The conjugate of claim 42 wherein the optical agent is fluorescein or indocyanine green.

56. The conjugate of claim 43 wherein the sulfa antibiotic is sulfisoxazole, N′

-(w-thiazolyl)sulfanilamide, sulfinethoxazole, or sulfisomidine.