Synthetic conjugates and uses thereof

• US 8,940,690 B2
• Filed: 01/27/2010
• Issued: 01/27/2015
• Est. Priority Date: 01/28/2009
• Status: Active Grant

• Current Assignee: SmartCells, Inc. (Merck & Co., Inc.)
• Original Assignee: National Institutes of Health (NIH) (Government of the United States of America), The United States of America As Represented By The Secretary of Agriculture
• Inventors: Zion, Todd C., Lancaster, Thomas M.
• Primary Examiner(s): Lukton, David
• Application Number:
  US13/145,534
• Publication Number:
  US 20110275560A1
• Time in Patent Office: 1,826 Days
• Field of Search: 514/5.9, 530/396, 530/345, 424/488
• US Class Current: 514/5.9
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/6415 Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present disclosure provides a cross-linked material comprising conjugates which include two or more separate affinity ligands bound to a non-polymeric framework, wherein the molecular weight of the non-polymeric framework is less than 10,000 Da; and multivalent cross-linking agents that non-covalently bind the affinity ligands of the conjugates and thereby cross-link the conjugates to form a cross-linked material, wherein the non-covalent bonds between the multivalent cross-linking agents and the affinity ligands are competitively dissociated in the presence of excess amounts of a target molecule. The present disclosure also provides methods of making and methods of using these materials. In other aspects, the present disclosure provides exemplary conjugates including conjugates for use in glucose responsive cross-linked materials.

Claims

1. A cross-linked material comprising:

conjugates which include an anti-diabetic drug and two or more separate affinity ligands bound to a non-polymeric framework, wherein the molecular weight of the non-polymeric framework is less than 10,000 Da; and

multivalent cross-linking agents that non-covalently bind the affinity ligands of the conjugates and thereby cross-link the conjugates to form a cross-linked material, wherein the non-covalent bonds between the multivalent cross-linking agents and the affinity ligands are competitively dissociated in the presence of excess amounts of a target molecule.

2. The material of claim 1, wherein the target molecule is glucose and the two or more separate affinity ligands comprise a saccharide.

3. The material of claim 2, wherein the two or more separate affinity ligands comprise a saccharide selected from the group consisting of glucose, mannose, glucosamine, mannosamine, methylglucose, methylmannose, ethylglucose, and ethylmannose.

4. The material of claim 2, wherein the two or more separate affinity ligands comprise aminoethylglucose (AEG), aminoethylmannose (AEM), aminoethylbimannose (AEBM) or aminoethyltrimannose (AETM).

5. The material of claim 1, wherein the conjugate has the general formula (I):

6. The material of claim 5, wherein the conjugate is of the formula (VIa):

7. The material of claim 6, wherein the conjugate is of the formula (VIa-1):

8. The material of claim 5, wherein the conjugate is of the formula (VIb):

9. The material of claim 8, wherein the conjugate is of the formula (VIb-1):

10. The material of claim 5, wherein the conjugate is of the formula (VIc):

11. The material of claim 10, wherein the conjugate is of the formula (VIc-1):

12. The material of claim 1, wherein the anti-diabetic drug is an insulin molecule.

13. The material of claim 12, wherein the insulin molecule is conjugated to the non-polymeric framework via the A1 amino acid residue of the insulin molecule.

14. The material of claim 12, wherein the insulin molecule is conjugated to the non-polymeric framework via the B1 amino acid residue of the insulin molecule.

15. The material of claim 12, wherein the insulin molecule is conjugated to the non-polymeric framework via the B29 amino acid residue of the insulin molecule.

16. The material of claim 1, wherein the multivalent cross-linking agent includes a lectin.

17. The material of claim 16, wherein the lectin is covalently bonded to a recognition element, wherein the recognition element competes with the target molecule and affinity ligands of the conjugate for binding to the lectin, and the lectin has a higher affinity for the affinity ligands of the conjugate than for the recognition element.

18. The material of claim 17, wherein the target molecule is glucose and both the affinity ligands of the conjugate and the recognition element include a saccharide.