Biocompatible polymeric system for targeted treatment of thrombotic and hemostatic disorders

Patent metadata

Field	Value
Publication number	US-2016263148-A1
Application number	US-201414392359-A
Country	US
Kind code	A1
Filing date	Jun 27, 2014
Priority date	Jun 27, 2013
Publication date	Sep 15, 2016
Grant date	—

Abstract

A biocompatible polymer to which a plurality of clot-modulating peptides (CMPs) are bound. The polymer comprises repeating units of hydrophilic monomers and display monomers to which the CMPs are bound. For example, the CMPs can be fibrin binding peptides (FBPs) that enhance clot formation by cross-linking that occurs within and between fibers by the plurality of fibrin-binding peptides during fibrin polymerization. The polymers of the invention can be used to modulate clotting in a variety of ways via multivalent display of fibrin-binding peptides and other clot-binding and clot-modulating moieties on polymer or co-polymer backbones. In addition to clot-modulating moieties, imaging agents and therapeutic agents can be conjugated to the polymers to facilitate imaging of blood flow and thrombosis, and for treatment of clotting-related disorders.

First claim

1 . A biocompatible polymer comprising repeating units that form a backbone, wherein the repeating units comprise:
(a) a hydrophilic monomer and a display monomer, and (b) a plurality of pendant clot-modulating peptides (CMPs) bound to the display monomer.

2 . The polymer of claim 1 , wherein the hydrophilic monomer comprises a polycarboxybetaine, polysulfobetaine, polyphosphobetaine, (hydroxyethyl)methacrylate (HEMA), or N-(2-hydroxypropyl)methacrylamide (HPMA).

3 . The polymer of claim 1 , wherein the hydrophilic monomer comprises (hydroxyethyl)methacrylate (HEMA).

4 . The polymer of claim 1 , wherein the display monomer is selected from the group consisting of N-hydroxysuccinimidyl ester methacrylate (NHSMA), pyridyl disulfide methacrylamide (PDSMA), N-(3-aminopropyl) methacrylamide hydrochloride (APMA), poly(propylacrylic acid) (PPAA), glycidyl methacrylate, 2-hydroxyethyl methacrylate, methacrylic acid N-hydroxysuccinimide, mono-2-(methacryloyloxy)ethyl maleate, 2-Carboxyethyl acrylate, propargyl acrylate, acrylate-PEG-maleimide, and amino acid-N-carboxyanhydride monomers.

5 . The polymer of claim 1 , wherein the repeating units are present at a ratio of 4 hydrophilic monomers to each display monomer.

6 . The polymer of claim 3 , wherein the display monomer comprises N-hydroxysuccinimidyl ester methacrylate (NHSMA), and wherein the NHSMA is present as a co-polymer with HEMA (p(HEMA-co-NHSMA)).

7 . The polymer of claim 1 , wherein the CMPs comprise fibrin-binding peptides (FBPs).

8 . The polymer of claim 1 , wherein the CMPs comprise platelet-binding peptides and/or Von Willebrand Factor binding peptides.

9 . The polymer of claim 7 , wherein the FBPs are cyclic and the FBPs comprise non-natural amino acids.

10 . The polymer of claim 7 , wherein the FBPs comprise the sequence Ac-Y(DGI)C(HPr)YGLCYIQGK, wherein Ac=acetylation of N-terminus, DGI=D-glutamic acid, HPr=hydroxyproline, cyclized via C3-C8 monodisulfide bond.

11 . The polymer of claim 6 , wherein the CMPs comprise FBPs conjugated to N-hydroxysuccinimidyl (NHS) reactive groups on the polymer via the ε-amine on the C-terminus lysine.

12 . The polymer of claim 1 , which has a degree of polymerization of 200.

13 . The polymer of claim 1 , which has a molecular weight of 50-60 kDa.

14 . The polymer of claim 6 , wherein the co-polymer is about 80% HEMA and about 20% NHSMA.

15 . The polymer of claim 1 , further comprising an imaging agent bound to the polymer.

16 . The polymer of claim 1 , which is synthesized by reversible addition-fragmentation chain-transfer (RAFT).

17 . A method of accelerating fibrin polymerization in a volume of blood, the method comprising contacting the volume of blood with the polymer of claim 7 , whereby cross-linking occurs within and between fibers by the plurality of fibrin-binding peptides during fibrin polymerization.

18 . The method of claim 17 , wherein the CMPs bound to the polymer further comprise an agent selected from the group consisting of thrombin, tissue factor, and clotting factors.

19 . A method of increasing fibrin stability in a volume of blood, the method comprising contacting the volume of blood with the polymer of claim 7 , whereby cross-linking occurs within and between fibers by the plurality of fibrin-binding peptides during fibrin polymerization.

20 . A method of increasing clot strength in a volume of blood, the method comprising contacting the volume of blood with the polymer of claim 1 , whereby cross-linking occurs within and between fibers by the plurality of fibrin-binding peptides during fibrin polymerization.

21 . The method of claim 17 , wherein the polymer further comprises one or more clot enhancing agents bound thereto, wherein the clot enhancing agents are selected from the group consisting of antifibrinolytic drugs, platelet binding peptides, adenosine diphosphate (ADP), collagen, and von Willebrand factor.

22 . A method of treating a patient suffering from a bleeding or thrombotic disorder, the method comprising administering to the subject a polymer of claim 1 .

23 . The method of claim 22 , wherein the bleeding disorder is selected from the group consisting of: acquired platelet function defects, congenital platelet function defects, congenital protein C or S deficiency, disseminated intravascular coagulation (DIC), Factor II deficiency, Factor V deficiency, Factor VII deficiency, Factor X deficiency, Factor XII deficiency, Hemophilia A, Hemophilia B, Idiopathic thrombocytopenic purpura (ITP), and Von Willebrand's disease (types I, II, and III).

Assignees

• Univ Washington Through Its Center For Commercialization

Inventors

• Pun Suzie H
• Chan Leslie
• White Nathan J

Classifications

• A61K31/787 Primary

  containing heterocyclic rings having nitrogen as a ring hetero atom · CPC title

• A61K38/36

  Blood coagulation or fibrinolysis factors · CPC title

• C07K14/00

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title