Compositions comprising multivalent synthetic ligands of surface nucleolin and glycosaminoglycans

Patent metadata

Field	Value
Publication number	US-9487559-B2
Application number	US-201113877490-A
Country	US
Kind code	B2
Filing date	Oct 4, 2011
Priority date	Oct 4, 2010
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

The present invention relates to a composition comprising a Nucant multivalent synthetic compound and a glycosaminoglycan, the admixture of both compounds forming microspheres comprising both compounds, as well as their use for the treatment or prevention of diseases associated with deregulation of proliferation and/or angiogenesis, such as cancer, inflammatory disease, or for promoting wound healing.

First claim

The invention claimed is:

1. A composition comprising:
a) a polyvalent synthetic compound comprising a linear peptide support on which at least 3 pseudopeptide units are grafted, said pseudopeptide units being of formula:
Y 1 -ψ-Z—Y 2 ,

wherein:
Y 1 and Y 2 are selected independently from amino acids having a basic side chain;
Z is selected from: proline or derivatives thereof; and
ψ represents a reduced bond (—CH 2 NH—), a retro-inverso bond (—NHCO—), a methyleneoxy bond (—CH 2 O—), a thiomethylene bond (—CH 2 —S—), a carba bond (—CH 2 CH 2 —), a ketomethylene bond (—CO—CH 2 —), a hydroxyethylene bond (—CHOH—CH 2 —), a (—N—N) bond, an E-alkene bond or a (—CH═CH—) bond; and

b) a glycosaminoglycan (GAG).

2. The composition of claim 1 , wherein said support comprises:
a) a cyclic hexapeptide consisting of alternating alkaline (A) residues of configuration D and Lysine (K) residues of configuration L; or
b) 5 lysine residues linked by amide bonds at the c amino group of each Lysine residue or
c) a linear peptide of sequence SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 22 and SEQ ID NO: 24.

3. The composition of claim 1 , wherein said pseudopeptide units are grafted directly on said support.

4. The composition of claim 1 , wherein the compound comprises between 3 and 15 pseudopeptide units.

5. The composition of claim 1 , wherein Z is proline (P).

6. The composition of claim 1 , wherein Y 1 and Y 2 are independently selected from arginine (R) and lysine (K).

7. The composition of claim 1 , wherein the compound is selected from compounds of formula:

8. The composition of claim 1 , wherein the lysine residues in the pseudopeptide units are all in D configuration or all in L configuration.

9. The composition of claim 1 or 7 , wherein the GAG is selected from heparin, chondroitin sulfate A, chondroitin sulfate B, chondroitin sulfate C, and combinations thereof.

10. The composition of claim 1 , wherein the composition comprises at least 1 μM of the polyvalent synthetic compound.

11. The composition of claim 1 , wherein the weight ratio of the polyvalent synthetic compound to the GAG is comprised between 0.01 and 24.

12. The composition of claim 1 , wherein the polyvalent synthetic compound is admixed with the GAG.

13. The composition of claim 12 , wherein another active compound such as but not limited to a cytotoxic agent is admix to it.

14. A method of treating a disease involving deregulation of cell proliferation and/or angiogenesis, comprising administering the composition of claim 1 to a patient in need thereof.

15. A method of treating an inflammatory disease, comprising administering the composition of claim 1 to a patient in need thereof.

16. A method of improving wound healing, comprising administering the composition of claim 1 to a patient in need thereof.

17. A method of inhibiting proliferation, comprising administering the composition of claim 1 to a patient in need thereof, wherein the inhibition is mediated by inhibiting nucleolin through nucleolin binding.

Assignees

• Zimmer Robert
• Courty José
• Elro Pharma Sarl
• Centre Nat De La Rech Scient (Cnrs)
• Univ Paris 12—Val De Marne

Inventors

• Zimmer Robert
• Courty José

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/00

  Antineoplastic agents · CPC title