Multicomponent assemblies having enhanced binding properties for diagnosis and therapy

• US 7,087,212 B2
• Filed: 08/17/2001
• Issued: 08/08/2006
• Est. Priority Date: 08/17/2001
• Status: Expired due to Term

• Current Assignee: Liebel Flarsheim Co LLC (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Cantrell, Gary L., Burleigh, B. Daniel
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/932,291
• Publication Number:
  US 20030039683A1
• Time in Patent Office: 1,817 Days
• Field of Search: 424/1.11, 424/9.1, 424/9.3, 424/9.321, 424/9.322, 424/9.323, 424/9.341, 424/9.363, 424/450, 424/489, 424/1.69, 424/1.65
• US Class Current: 424/9.1
• 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 targeting an effector molecule to a target site in a patient, said method 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 selected from at least one of salts of docosanoic acid or salts of octacosanoic acid;

said lamellar structure defining a void and having incorporated at least two binding compounds B¹ and B² independently selected from at least one of amino acids, peptides (1–

20 amino acids), peptidomimics, monosaccharides, oligosaccharides (1–

10), glycomimics, glycopeptides, anionic compounds, C- or O-monosaccharides and glycosides, flavonoids, isoflavonones, or C- or O-glucosides;

B¹ bound to said structure by anchor region A¹ and B¹ and A¹ linked via linker L¹ wherein A¹ is a succinic acid ester of PEG[50] stearate L¹ and B² bound to said structure by anchor region A² and B² and A² linked via linker L² wherein A² is a fucosuccinamide ester of a PEG[50] stearate L², and

an effector molecule selected from an echogenic agent selected from the group consisting of perfluoropropane, perfluorobutane, sulfur hexafluoride, tetrafluoromethane, hexafluoroethane, octafluoropropane, decafluorbutane , dodecafluorpentane, and perfluorohexane;

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;

a paramagnetic agent selected from the group consisting of Gd-DTPA, Gd-DOTA, Gd-DTPA-bis(methoxyethyl)amide, and Mn-EDTA;

a cytotoxcic agent selected from the group consisting of fluorouracil, fluorouridine, sulfisoxazole, N′

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

an optical agent selected from the group consisting of fluorescein and indocyanine green,

said B¹ and B² 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 OMMO ensemble resulting in cooperative binding of B¹ and B² to said affinity sites, wherein said effector molecule is provided to the target site.

2. The method of claim 1 wherein B¹ and B² are 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.

3. The method of claim 1 wherein B¹ and B² are the same or different and are selected from the group consisting of glucose, galactose, fucose, sialic acid and carminic acid.

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

5. The method of claim 1 wherein said effector molecule is perfluorobutane.

6. The method of claim 1 wherein said effector molecule is I-131 or Tc-99m.

7. The method of claim 1 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.

8. The method of claim 1 wherein B¹ is at least one saccharide and B² is at least one anionic component.

9. The method of claim 1 wherein B² is selected from the group consisting of a carboxylate, a sulfate, and combinations thereof.

10. The method of claim 1 wherein B¹ is selected from the group consisting of a —

C—

or an —

O—

saccharide, a saccharosamine, sialic acid, lactose, sucrose, maltose, and salts thereof, and B² is selected from the group consisting of —

(CH₂)_d—

CO₂⁻

, —

(CH₂)_d—

SO₃⁻

, —

(CH₂)_d—

OSO₃⁻

and —

(CH₂)_d—

OPO₃<sup>−

2</sup> wherein d=1–

10;

—

ArylSO₃⁻

;

DTPA, EDTA, DOTA, EGTA, amino acids, succinic acid, maleic acid, polypeptides, and salts thereof.

11. The method of claim 10 wherein the —

C—

or —

O—

saccharide is selected from the group consisting of glucose, mannose, fucose, and galaotose.

12. The method of claim 10 wherein the saccharosamine is selected from the group consisting of glucosamine, galactosamine, fucosamine, and mannosamine.

13. The method of claim 1 wherein L¹, L² are bound to A¹, A² and B¹, B² through an amide bond, an ester bond, an ether bond, or a thioether bond.

14. The method of claim 1 wherein L¹, L² are bound to B¹, B² through an activated succinylated linker.

15. The method of claim 1 wherein at least one of B¹, B² has an anionic functional group.

16. The method of claim 1 wherein B¹ is selected from the group consisting of an oligosaccharide, a monosaccharide, and a disaccharide;

and B² is selected from the group consisting of —

O(CH2)₁ or ₂CO₂⁻

, —

O(CH2)_{1 or 2}SO₃⁻

;

—

O(CH2), _{1 or 2} SO₄⁻

, and —

O(CH2)_{1 or 2}PO₄⁻

.

17. The method of claim 1 wherein the anionic compound is selected from at least one of —

(CH₂)_d—

CO₂⁻

, —

(CH₂)_d—

SO₃⁻

, —

(CH₂)_d—

OSO₃⁻

, —

(CH₂)_d—

PO₃^═

, —

(CH₂)_d—

OPO₃^═

where d=1–

10, —

Ar—

SO₃⁻

, DTPA, EDTA, DOTA, or EGTA.

18. The method of claim 1 wherein the monosaccharides and glycosides are selected from at least one of glucose, mannose, fucose, galactose, glucosamine, mannosamine, galactosamine, or sialic acid.

19. The method of claim 1 wherein the C- or O-glucosides are selected from at least one of rutin, neohesperidin dihydrochalone, phloridizin, hesperidin, hesperidin methyl chalcone, naringenin, esculin, or carminic acid family.

20. The method of claim 19 wherein the carminic acid family is selected from the group consisting of carmine, 18b-glycyrrhetinic acid, or a salt thereof.