Multicomponent assemblies having enhanced binding properties for diagnosis and therapy
View Patent ↗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.
1. A biocompatible organized mobile multicomponent conjugate (OMMC) comprising:
(A) a lamellar structure comprising R 2 O 2 CCH 2 (CHY)CO 2 R 2 , wherein:
(1) R 2 is an alkyl radical containing 16-24 carbon atoms;
(2) Y is selected from —(CH 2 ) k —X, —NHCO(CH 2 ) k —X, —OCO(CH 2 ) k —X, and —CH 2 OCO(CH 2 ) 2 —CO 2 —;
(3) X is selected from carboxylate, sulfonate, sulfate, and phosphate, and phosphonate; and
(4) k is 1-6; and
(B) a first binding compound and a second binding compound, each of which is anchored 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 anchors the binding compound to the lamellar structure, the anchor region being selected from CH 3 (CH 2 ) a —W, CH 3 (CH 2 ) a —O—(CH 2 ) b —W, CH 3 (CH 2 ) a —S—(CH 2 ) b —W, R 1 O 2 CCH 2 (CHW)CO 2 R 1 , CF 3 (CH 2 ) a —W, CF 3 (CF 2 ) a —W, CF 3 (CF 2 ) a CH 2 CH 2 —W, CF 3 (CF 2 ) a —O—(CH 2 ) b —W, and CH 3 (CH 2 ) a —S—S—(CH 2 ) b —W, wherein:
(a) each of a and b ranges from 16 to 32, inclusive;
(b) W is selected from —O—, —CO—, —CO 2 —, —OCO—, —O 2 CO—, —S—, —SO—, —SO 2 —, —NH—, —NHCO—, —NHCS—, —NHSO 2 —, —PO 2 H—, —OPO 2 H—, —PO 2 —, and —OPO 2 —; and
(c) R 1 is an alkyl radical containing 16 to 24 carbon atoms; and
(2) a binding region selected from amino acids, peptides, peptidomimics, monosaccharides, disaccharides, oligosaccharides, sialic acid, carminic acid, and anionic compounds selected from —(CH 2 ) d —CO 2− , —(CH 2 ) d —SO 3− , —(CH 2 ) d —OSO 3− , —(CH 2 ) d —PO 3 ═, —(CH 2 ) d —OPO 3 ═, —Ar—SO 3− , 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 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 Y is NHCO(CH 2 ) k —X.
3. The conjugate of claim 2 , wherein X is carboxylate.
4. The conjugate of claim 1 , wherein X is carboxylate.
5. The conjugate of claim 1 , wherein the anchor region of the first binding compound, the second binding compound, or each of the first and second binding compounds is CH 3 (CH 2 ) a —W.
6. The conjugate of claim 5 , wherein W is —O—.
7. The conjugate of claim 5 , wherein W is —CO—.
8. The conjugate of claim 5 , wherein W is —CO 2 —.
9. The conjugate of claim 5 , wherein W is —NH—.
10. The conjugate of claim 5 , wherein W is —O 2 CO—.
11. The conjugate of claim 5 , wherein W is —NHCO—.
12. The conjugate of claim 5 , wherein W is —S—.
13. The conjugate of claim 1 , wherein the anchor region of the first binding compound, the second binding compound, or each of the first and second binding compounds is R 1 O 2 CCH 2 (CHW)CO 2 R 1 .
14. The conjugate of claim 13 , wherein W is —O—.
15. The conjugate of claim 13 , wherein W is —CO—.
16. The conjugate of claim 13 , wherein W is —CO 2 —.
17. The conjugate of claim 13 , wherein W is —NH—.
18. The conjugate of claim 13 , wherein W is —O 2 CO—.
19. The conjugate of claim 13 , wherein W is —NHCO—.
20. The conjugate of claim 13 , wherein W is —S—.
21. The conjugate of claim 1 , wherein the anchor region of the first binding compound, the second binding compound, or each of the first and second binding compounds is CH 3 (CH 2 ) a —O—(CH 2 ) b —W.
22. The conjugate of claim 21 , wherein W is —O—.
23. The conjugate of claim 21 , wherein W is —CO—.
24. The conjugate of claim 21 , wherein W is —CO 2 —.
25. The conjugate of claim 21 , wherein W is —NH—.
26. The conjugate of claim 21 , wherein W is —O 2 CO—.
27. The conjugate of claim 21 , wherein W is —NHCO—.
28. The conjugate of claim 21 , wherein W is —S—.
29. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is an amino acid.
30. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is a monosaccharide.
31. The conjugate of claim 30 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is selected from C monosaccharides and O monosaccharides.
32. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is a disaccharide.
33. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is sialic acid.
34. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is a glycoside of a monosaccharide or sialic acid.
35. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is a monosaccharide selected from mannose, glucose, fucose, and galactose.
36. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is a monosaccharide selected from glucosamine, mannosamine, and galactosamine.
37. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is DTPA.
38. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is DOTA.
39. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is a peptide.
40. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is independently selected from —(CH 2 ) d —CO 2− , —(CH 2 ) d —SO 3− , —(CH 2 ) d —OSO 3− , —(CH 2 ) d —PO 3 ═, —(CH 2 ) d —OPO 3 ═, and —Ar—SO 3− .
41. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is —(CH 2 ) d —CO 2− .
42. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is —(CH 2 ) d —OSO 3− .
43. The conjugate of claim 1 , wherein the binding region of the first binding compound, the second binding compound, or each of the first and second binding compounds is —(CH 2 ) d —OPO 3 ═.
44. The conjugate of claim 1 , wherein the linker of the first binding compound, the second binding compound, or each of the first and second binding compounds is a polyvinylpyrrolidone.
45. The conjugate of claim 1 , wherein the linker of the first binding compound, the second binding compound, or each of the first and second binding compounds is a polyethyleneglycol.
46. The conjugate of claim 45 , wherein the polyethyleneglycol has a molecular weight in the range of 1,000 to 4,000.
47. The conjugate of claim 45 , wherein the linker of the first binding compound, the second binding compound, or each of the first and second binding compounds is poly(ethyleneglycol) p , wherein p is from 40 to 150.
48. The conjugate of claim 1 , wherein the linker of the first binding compound, the second binding compound, or each of the first and second binding compounds is polyglycolate.
49. The conjugate of claim 1 , wherein the linker of the first binding compound, the second binding compound, or each of the first and second binding compounds is polylactate.
50. The conjugate of claim 1 , wherein the linker of the first binding compound, the second binding compound, or each of the first and second binding compounds is a copolymer of polyglycolate or a copolymer of polylactate or a copolymer of polyglycolate and polylactate.
51. The conjugate of claim 1 , wherein the first binding compound or the second binding compound has a dissociation constant (K d ) value equal to or greater than about 100 nM.
52. The conjugate of claim 1 , wherein each of the first and second binding compounds has a dissociation constant (K d ) value equal to or greater than about 100 nM.
53. The conjugate of claim 1 , wherein the first binding compound or the second binding compound has a dissociation constant (K d ) value of at least about 100 nM.
54. The conjugate of claim 1 , wherein each of the first and second binding compounds has a dissociation constant (K d ) value of at least about 100 nM.
55. The conjugate of claim 1 , wherein the first binding compound is the same as the second binding compound.
56. The conjugate of claim 1 , further comprising:
an effector molecule attached to the lamellar structure.
57. The conjugate of claim 1 , wherein the lamellar structure has a void defined therein, and the conjugate further comprises an effector molecule contained within the void of the lamellar structure.
58. The conjugate of claim 1 , further comprising:
an effector molecule incorporated within the lamellar structure.
59. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a cytotoxic agent.
60. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a cytotoxic agent selected from fluorouracil and fluorouridine.
61. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a paramagnetic agent.
62. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a paramagnetic agent selected from Gd-DTPA, Gd-DOTA, Gd-DTPA-bis(methoxyethyl)amide, and Mn-EDTA.
63. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is an optical agent.
64. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is an optical agent selected from fluorophores that absorb light in the range of 300- 1200 nm and chromophores that absorb light in the range of 300-1200 nm.
65. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is an optical agent selected from fluoresceins, rhodamines, cyanines, indocyanines, squaraines, phenothiazines, porphyrins, and azo compounds.
66. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is an optical agent selected from fluorescein and indocyanine green.
67. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a sulfa antibiotic.
68. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a sulfa antibiotic selected from sulfisoxazole, N′-(w-thiazolyl)sulfanilamide, sulfmethoxazole, and sulfisomidine.
69. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a radiopharmaceutical agent.
70. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a radioactive molecule emitting alpha, beta, or gamma radiation.
71. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a radiopharmaceutical agent that comprises a chelate of a beta emitting isotope or a chelate of a gamma emitting isotope.
72. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a radiopharmaceutical agent that comprises Lu, Sm, In, Ru, or Tc.
73. The conjugate of any one of claims 56 - 58 , wherein the effector molecule comprises a radionuclide selected from l-123, l-131, Tc-99m, Re-186, Re-188, Sm-152, Ho-155, Bi-202, and Lu-177.
74. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a radiopharmaceutical agent selected from diethylenetriamine pentaacetic acid (DTPA) or 1,4,7,10-tetraazacyclododecane-N, N′, N″, N′″- tetraacetic acid (DOTA).
75. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is a chemotherapeutic agent.
76. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is selected from hyaluronic acid and heparin.
77. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is an X-ray opacification agent.
78. The conjugate of any one of claims 56 - 58 , wherein the effector molecule is an echogenic agent.
79. The conjugate of claim 1 , wherein the lamellar structure comprises a micelle.
80. The conjugate of claim 1 , wherein the lamellar structure comprises a liposome.
81. The conjugate of claim 1 , wherein the lamellar structure comprises a microparticle.
82. The conjugate of claim 1 , wherein the lamellar structure comprises a nanoparticle.
83. The conjugate of any one of claims 1 - 43 , 51 - 58 , and 79 - 82 , wherein the linker of the first binding compound, the second binding compound, or each of the first and second binding compounds is a polynucleotide.
84. The conjugate of any one of claims 1 - 43 , 51 - 58 , and 79 - 82 , wherein the linker of the first binding compound, the second binding compound, or each of the first and second binding compounds is a copolymer of a polynucleotide.