Polyethylene Oxide Polymers Including Anti-Inflammatory Glycodendrons

• US 20080268013A1
• Filed: 02/10/2006
• Published: 10/30/2008
• Est. Priority Date: 02/10/2005
• Status: Abandoned Application

• Current Assignee: Emory University, Regents of the University of California (University of California)
• Original Assignee: Emory University, University of California San Diego (University of California)
• Inventors: Cui, Wanxing, Esko, Jeffrey D., Gnanou, Yves, Chaikof, Elliot Lorne, Rele, Shyam Mohan
• Application Number:
  US11/815,993
• Publication Number:
  US 20080268013A1
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 31/77 of oxiranes
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C08G 65/2606 containing hydroxyl groups
• CPC Class Codes: C08G 65/3314 cyclic
• CPC Class Codes: C08G 65/3356 having nitrogen in addition to phosphorus
• CPC Class Codes: C08L 2203/02 for biomedical use
• CPC Class Codes: C08L 2666/22 Macromolecular compounds not provided for in C08L2666/16 - C08L2666/20
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: C08L 85/02 containing phosphorus

Abstract

Poly(ethylene oxide) (PEO) glycodendrimers can serve as multivalent inhibitors of selectin-mediated leukocyte recruitment regulating inflammatory response. Disclosed are compounds and methods relating to functionalized branched glycopolymers. In embodiments, the compounds are capable of modifying cell adhesion events and inflammatory conditions. In a particular embodiment, a multi-arm PEO polymer with sulfated lactose end groups can specifically inhibit interactions involving L-selectin. Also disclosed are methods of synthetic preparation and use.

Claims

1. A branched glycopolymer comprising the formula:

L-[A_m]_n-X;

wherein L is lactose or a lactose derivative;

A is a polymeric arm comprising a poly(alkylene oxide) where m is a number of monomeric units;

n is a number of branching arms where n=2 to about 100; and

X is a polymer core.

2. The branched glycopolymer of claim 1 wherein L is a sulfated lactose.

3. The branched glycopolymer of any of claims 1-2 wherein A comprises polyethylene oxide.

4. The branched glycopolymer of any of claims 1-3 wherein X is the core selected from the group consisting of alkyl and a phosphazene group.

5. The branched glycopolymer of claim 4 wherein X is alkyl.

6. The branched glycopolymer of claim 4 wherein X is neopentyl.

7. The branched glycopolymer of claim 4 wherein X is a phosphazene group.

8. The branched glycopolymer of claim 7 wherein the phosphazene group is a cyclolinear phosphazene.

9. The branched glycopolymer of claim 8 wherein the cyclolinear phosphazene is a cyclic trimer.

10. The branched glycopolymer of any of claims 1-3 wherein there is a single branch generation.

11. The branched glycopolymer of any of claims 1-3 wherein there is a plurality of branch generations.

12. The branched glycopolymer of claim 11 wherein there are two branch generations.

13. The branched glycopolymer of claim 12 wherein there is a first branch generation of six arms and a second branch generation of two arms from each of the first generation, and wherein the total number of arms is 12.

14. The branched glycopolymer of claim 5 wherein n=3 or 4.

15. The branched glycopolymer of claim 7 wherein n=12.

16. The branched glycopolymer of claim 4 wherein n is from about 6 to about 96.

17. The branched glycopolymer of claim 4 wherein n is from about 12 to about 48.

18. The branched glycopolymer of claim 4 wherein m=from about 2 to about 600.

19. The branched glycopolymer of any of claims 1-3 wherein a value for n is selected from the group consisting of n=2, 3, 4, and 12.

39. A medical device, cell, tissue, or organ further comprising a film, gel, or other coating with the compound of any of claims 1-19.

45. The branched glycopolymer of claim 1 wherein m is from about 20 to about 50.

46. The branched glycopolymer of claim 1 wherein m is from about 30 to about 45.

47. The branched glycopolymer of claim 1 wherein m is from about 20 to about 50 and n is 3 or 4.

20. A method of preparing a branched glycopolymer composition of a structural formula represented by L-[A_m]_n-X;

wherein L is a saccharide or a saccharide derivative;

A is a polymeric arm comprising a poly(alkylene oxide) where m is a number of monomeric units;

n is a number of branching arms where n=2 to about 100; and

X is a polymer core.

21. The method of claim 20 comprising the steps of providing an imidated lactose donor group and performing a Schmidt glycosidation coupling.

22. The method of claim 20 comprising anionic polymerization using a core-first approach.

23. The method of claim 20 comprising synthesis of a first generation of PEO arms on a phosphazene core using an arm-first approach.

24. The method of claim 23 further comprising synthesis of a second generation of PEO arms, wherein the second generation is directly polymerized onto the first generation.

25. The method of claim 23 further comprising synthesis of multiple further generations of PEO arms, wherein each further generation is directly polymerized onto the previous generation.

26. The method of claim 25 wherein a total number of generations is from about 3 to about 8.

27. A method of modifying an inflammatory condition comprising administering to a patient in need a compound of the formula L-[A_m]_n-X;

wherein L is lactose or a lactose derivative;

A is a polymeric arm comprising a poly(alkylene oxide) where m is a number of monomeric units;

n is a number of branching arms where n=2 to about 100; and

X is a polymer core.

28. A method of modifying a cell adhesion event comprising administering to a patient in need a compound of the formula L-[A_m]_n-X;

wherein L is lactose or a lactose derivative;

A is a polymeric arm comprising a poly(alkylene oxide) where m is a number of monomeric units;

n is a number of branching arms where n=2 to about 100; and

X is a polymer core.

33. The method of claim 28 or 29 wherein said modifying occurs in vivo, in vitro, or ex vivo.

34. The method of claim 28 or 29 wherein said modifying occurs in vitro.

35. The method of claim 28 or 29 wherein said modifying occurs in vitro under hemodynamic flow conditions.

29. A method of modifying a selectin-mediated interaction comprising administering to a patient in need a compound of the formula L-[A_m]_n-X;

wherein L is lactose or a lactose derivative;

A is a polymeric arm comprising a poly(alkylene oxide) where m is a number of monomeric units;

n is a number of branching arms where n=2 to about 100; and

X is a polymer core.

30. The method of claim 29 wherein the selectin-mediated interaction involves a selectin selected from the group consisting of L-selectin, P-selectin, and E-selectin.

31. The method of claim 29 wherein the selectin-mediated interaction involves a selectin selected from the group consisting of L-selectin.

32. The method of claim 29 wherein L is the lactose derivative which is a sulfated lactose.

36. A method of therapy for abdominal aortic aneurysm comprising administering to a patient in need a compound of the formula L-[A_m]_n-X;

wherein L is lactose or a lactose derivative;

A is a polymeric arm comprising a poly(alkylene oxide) where m is a number of monomeric units;

n is a number of branching arms where n=2 to about 100; and

X is a polymer core.

38. The medical device of claim 36 selected from the group consisting of a stent, embolization coil, vascular graft, or other biomedical device capable of exposure to a patient.

37. A medical device treated with a compound of formula L-[A_m]_n-X;

wherein L is lactose or a lactose derivative;

A is a polymeric arm comprising a poly(alkylene oxide) where m is a number of monomeric units;

n is a number of branching arms where n=2 to about 100; and

X is a polymer core;

wherein said treated device has at least a portion of a surface that is capable of contacting a patient.

40. A branched glycopolymer comprising the formula:

L-[A2_m2]_n2-[A1_m1]_n1-X;

wherein L is lactose or a lactose derivative;

A1 and A2 are polymeric arms comprising a poly(alkylene oxide) where m1 and m2 are numbers of monomeric units;

n1 and n2 are numbers of branching arms where n1=2 to about 100 and n2=2 to about 100; and

X is a polymer core.

41. The branched glycopolymer of claim 40 wherein m1 is from about 2 to about 400 and m2 is from about 2 to about 100.

42. The branched glycopolymer of claim 40 wherein m1 is from about 100 to about 150 and m2 is from about 10 to about 25.

43. The branched glycopolymer of claim 40 wherein A1 and A2 are each poly(ethylene oxide);

m1 is from about 100 to about 150;

n1 is 6;

m2 is from about 10 to about 30;

n2 is 2, and L is selected from the group consisting of lactose, sulfated lactose, and other derivatized lactose.

44. A branched glycopolymer comprising the formula:

S-[A_m2]_n2-[A_m1]_n1-X;

wherein S is a saccharide or a saccharide derivative;

A is a polymeric arm comprising a poly(alkylene oxide) where m1 and m2 are numbers of monomeric units;

n1 and n2 are numbers of branching arms where n1=2 to about 100 and n2=2 to about 100; and

X is a polymer core.

48. The invention substantially as herein described and illustrated.

49. A new compound, substantially as herein described.

50. A new use of a compound, substantially as herein described.

51. A substance or composition for a new use in a method of treatment, substantially as herein described.

52. A new process for preparing a compound, substantially as herein described.