Methods of making and using surfactant polymers

• US 7,276,474 B2
• Filed: 04/13/2004
• Issued: 10/02/2007
• Est. Priority Date: 04/29/1998
• Status: Expired due to Term

• Current Assignee: Nanomimetics, Inc., Roger E. Marchant
• Original Assignee: Nanomimetics, Inc.
• Inventors: Qiu, Yongxing, Ruegsegger, Mark A., Marchant, Roger E., Zhang, Tianhong
• Primary Examiner(s): Campell; Bruce R.
• Assistant Examiner(s): TELLER, ROY R
• Application Number:
  US10/823,218
• Publication Number:
  US 20050008603A1
• Time in Patent Office: 1,267 Days
• Field of Search: 514/8, 514/2, 530/300
• US Class Current: 514/14.9
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 33/0017 using a surface active agent
• CPC Class Codes: A61L 33/08 Polysaccharides
• CPC Class Codes: A61L 33/128 Other specific proteins or polypeptides not covered by A61L33/122 - A61L33/126
• CPC Class Codes: C07K 5/0817 the first amino acid being Arg
• CPC Class Codes: C07K 5/1019 with the first amino acid being basic
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C08B 37/0021 Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
• CPC Class Codes: C08F 16/06 Polyvinyl alcohol ; Vinyl alcohol
• CPC Class Codes: C08F 26/02 by a single or double bond to nitrogen
• CPC Class Codes: C08F 8/00 Chemical modification by after-treatment graft polymers, block polymers, crosslinking with unsaturated monomers or with polymers C08F251/00 - C08F299/00; of conjugated diene rubbers C08C

Abstract

Comblike, surfactant polymers for changing the surface properties of biomaterials are provided. Such surfactant polymers comprise a polymeric backbone of repeating monomeric units having functional groups for coupling with side chains, a plurality of hydrophobic side chains linked to said backbone via the functional groups, and a plurality of hydrophilic side chains linked to said backbone via the functional groups. The hydrophobic side chains comprise an alkyl group comprising from 2 to 18 methylene groups. The alkyl groups are linked to the polymeric backbone through ester linkages, secondary amine linkages, or, preferably, amide linkages. The hydrophilic side chain is selected from the group consisting of: a neutral oligosaccharide, which, preferably, has weight average molecular weight of less than 7000; a charged oligosaccharide, preferably a negatively charged oligosaccharide having a weight average molecular weight of less than 10,000; an oligopeptide of from about 3 to about 30 amino acid residues, said oligopeptide having an amino acid sequence which interacts with protein receptors on the surface of cells; and combinations thereof. Methods of making the surfactant polymers and using the surfactant polymers to alter the surface properties of a biomaterial are also provided.

Claims

1. A method of reducing the thrombogenicity of a hydrophobic surface of a substrate comprising:

a) providing a comblike surfactant polymer comprising;

i) a polymeric backbone of repeating monomeric units,

ii) a plurality of hydrophobic side chains comprising from about 2 to about 18 methylene groups, said plurality of hydrophobic side chains being linked to said polymeric backbone by ester linkages, secondary amine linkages, amide linkages;

or combinations thereof and

iii) a plurality of hydrophilic side chains linked to said polymeric backbone by ester linkages, secondary amine linkages, amide linkages, or combinations thereof;

said hydrophilic side chains selected from the group consisting of;

neutral oligosaccharide side chains having a weight average molecular weight of less than 7000;

charged oligosaccharide side chains having a weight average molecular weight of less than 10,000, polyethylene oxide; and

combinations thereof,

b) attaching the comblike surfactant polymer to the hydrophobic substrate to provide a substrate with reduced thrombogenicity.

2. The method of claim 1 wherein said surfactant polymer is attached to said surface by immersing said surface into an aqueous solution containing said surfactant polymer.

3. A method of promoting attachment of endothelial cells to the surface of a hydrophobic surface comprising:

a) providing a comblike surfactant polymer comprising;

i) a polymeric backbone of repeating monomeric units,

ii) a plurality of hydrophobic side chains comprising from about 2 to about 18 methylene groups, said plurality of hydrophobic side chains being linked to said polymeric backbone by secondary amine linkages, amide linkages;

or combinations thereof and

iii) a plurality of hydrophilic side chains linked to said polymeric backbone by secondary amine linkages said hydrophilic side chains comprising an oligopeptide of from about 3 to 30 amino acid residues and having an amino acid sequence which interacts with protein receptors on the surface of endothelial cells

b) attaching the comblike surfactant polymer to the hydrophobic substrate.

4. The method of claim 3 wherein said oligopeptide side chains comprise an amino acid sequence selected from the group consisting of:

SEQ ID NO;

1 (RGD), SEQ ID NO;

4 (RRAR), SEQ ID NO;

5 (RRRKRR), SEQ ID NO;

6 (PPRRARVT), and SEQ ID NO;

7 (PPREVVPRPRP).

5. A method of preparing a surfactant polymer for changing the surface properties of a biomaterial comprising the following steps:

a) providing a polymer comprising a plurality of side groups selected from the group consisting of OH groups, COOH groups and NH₂ groups;

b) reacting said polymer with

i) an alkanoyl or an alkanal having an end for reacting with the side groups of said polymer; and

ii) a hydrophilic compound selected from the group consisting of neutral oligosaccharide chains having an end for reacting with the side groups of said polymer, charged oligosaccharide chains having an end for reacting with the side groups of said polymer, oligopeptides having an end for reacting with the side groups of said polymer, and combinations thereof;

wherein said alkanal and said alkanoyl comprise from 2 to 18 methylene groups;

wherein said neutral oligosaccharide chains have a weight average molecular weight of less than 7000;

wherein said charged oligosaccharide chains have a weight average molecular weight of less than 10,000; and

wherein said oligopeptides comprise from about 3 to 30 amino acid residues and a sequence which interact with protein receptors on the surface of endothelial cells.

6. The method of claim 5 wherein said polymer is selected from the group consisting of poly(vinyl amine), poly(vinyl alcohol), and poly(lysine).

7. The method of claim 5 wherein said polymer is simultaneously reacted with said alkanal or said alkanoyl and said hydrophilic compound.

8. The method of claim 5 wherein the molar feed ratio of said hydrophilic compound to said alkanal or said alkanoyl is from 3:

1 to 1;

6.

9. The method of claim 5 further comprising the step of capping any unreacted amine groups.