Nucleic acid coating compositions and methods

• US 6,596,699 B2
• Filed: 01/22/2002
• Issued: 07/22/2003
• Est. Priority Date: 09/22/1998
• Status: Expired due to Term

• Current Assignee: Biosurface Engineering Technologies, Inc. (Ferring Holding SA)
• Original Assignee: Biosurface Engineering Technologies, Inc. (Ferring Holding SA)
• Inventors: Osaki, Shigemasa, Zamora, Paul O., Tsang, Ray
• Primary Examiner(s): FONDA, KATHLEEN KAHLER
• Application Number:
  US10/054,091
• Publication Number:
  US 20020160098A1
• Time in Patent Office: 546 Days
• Field of Search: 514/44, 514/54, 514/56, 514/55, 514/62, 536/21, 536/3, 536/112, 536/23.1, 536/123.1, 523/112, 604/266, 427/2.1, 427/2.24, 427/2.25, 427/2.3
• US Class Current: 514/44.00R
• CPC Class Codes: A61L 27/28 Materials for coating prostheses
• CPC Class Codes: A61L 31/08 Materials for coatings
• CPC Class Codes: A61L 33/0011 Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
• CPC Class Codes: A61L 33/0029 using an intermediate layer of polymer
• CPC Class Codes: A61L 33/08 Polysaccharides
• CPC Class Codes: C08B 37/0063 Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08G 77/60 in which all the silicon atoms are connected by linkages other than oxygen atoms
• CPC Class Codes: C08L 83/00 Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
• CPC Class Codes: C09D 105/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C09D 105/10 Heparin; Derivatives thereof

Abstract

A nucleic acid coating composition including a polyanion bound, directly or through one or more intermediates, to a medical device surface, with a condensate comprising a polycation and nucleic acid bound to the polyanion, devices incorporating such coating compositions, and methods for making. In one embodiment, a silyl-heparin complex is provided, bound to a medical device surface by hydrophobic interaction with the silyl moiety, with a polycation and nucleic acid condensate bound to the heparin by electrostatic interaction.

Claims

1. A nucleic acid-containing coating composition for contacting surfaces of medical devices, said composition comprising a polyanion substrate having bound thereto by non-covalent means a condensate comprising a polycation and nucleic acid.

2. The composition according to claim 1 wherein the polyanion substrate is a glycosaminoglycan.

3. The composition according to claim 1 wherein the polyanion substrate is heparin.

4. The composition according to claim 3 wherein the heparin comprises heparan sulfate, hyaluronic acid, amino dextran, dextran sulfate, chondroitin sulfate, dermatan sulfate, a molecule including a mixture of variably sulfated polysaccharide chains composed of repeating units of D-glucosamine and either L-iduronic or D-glucuronic acids, or salts or derivatives of any of the foregoing.

5. The composition according to claim 1 wherein the polyanion substrate comprises collagen, negatively charged chitosan derivatives, polyacrylic acid, chemically-modified dextans, sulfated polysaccharides, sodium alginate or albumin.

6. The composition according to claim 1 wherein the polyanion complex binds to the contacting surfaces.

7. The composition according to claim 6 wherein the polyanion complex binds to the contacting surfaces via hydrophobic bonding interactions.

8. The composition according to claim 1 wherein said nucleic acid is double-stranded DNA, single-stranded DNA, or RNA.

9. The composition according to claim 1 wherein said polycation is a histone protein, polyornithine, polylysine, polyarginine or polyethylenimine.

10. The composition according to claim 1 wherein said condensate is directly bound to the polyanion substrate by electrostatic interaction.

11. A coating composition for contacting surfaces of medical device, said composition comprising a molecule of Formula I:

wherein

R₁ is an C_1-18 alkyl or C_6-32 aryl group,

each R₂ is independently selected from the group consisting of C_1-18 alkyl and C_6-32 aryl

R₃ is N or O,

n is a number from 1 to 10, and

x is a number from 1 to about 30,

bound to a heparin-activity molecule via a covalent bond, thereby forming a silyl-heparin covalent complex, with a condensate comprising a polycation and nucleic acid directly and non-covalently bound to the heparin-activity molecule.

12. The composition according to claim 11 wherein the silyl-heparin covalent complex binds to the contacting surf aces via hydrophobic bonding interactions.

13. The composition according to claim 11 wherein the silyl-heparin covalent complex has a disassociation rate from the contacting surface determined by the value of n and x.

14. The composition according to claim 11 wherein the heparin-activity molecule comprises heparin, heparan sulfate, hyaluronic acid, dextran, dextran sulfate, chondroitin sulfate, dermatan sulfate, or a molecule including a mixture of variably sulfated polysaccharide chains composed of repeating units of D-glucosamine and either L-iduronic or D-glucuronic acids or salts or derivatives of any of the foregoing.

15. The composition according to claim 11 wherein said nucleic acid is double-stranded DNA, single-stranded DNA, or RNA.

16. The composition according to claim 11 wherein said polycation is a histone protein, polyornithine, polylysine, polyarginine or polyethylenimine.

17. The composition according to claim 11 wherein said condensate is directly bound to the heparin-activity molecule by electrostatic interaction.

18. The composition according to claim 11 wherein the silyl-heparin covalent complex comprises [benzyl-bis(dimethylsilylmethyl)]-(N-heparinyl)-carbamate or [benzyl-tris(dimethylsilylmethyl)]-(N-heparinyl)-carbamate.

19. A medical device with at least one contacting surface for contacting bodily fluids, the surface having coated thereon a coating composition comprising a molecule of Formula I:

wherein

R₁ is an C_1-18 alkyl or C_6-32 aryl group,

each R₂ is independently selected from the group consisting of C_1-18 alkyl and C_6-32 aryl,

R₃ is N or O,

n is a number from 1 to 10, and

x is a number from 1 to about 30,

directly bound to a heparin-activity molecule via covalent bonding, thereby forming a silyl-heparin covalent complex, with a condensate comprising a polycation and nucleic acid directly and non-covalently bound to the heparin-activity molecule.

20. The device according to claim 19 wherein the silyl-heparin covalent complex binds to the surface via hydrophobic bonding interactions.

21. The device according to claim 19 wherein the silyl-heparin covalent complex has a disassociation rate from the surface determined by the value of n and x.

22. The device according to claim 19 wherein the heparin-activity molecule is heparin, heparan sulfate, hyaluronic acid, dextran, dextran sulfate, chondroitin sulfate, dermatan sulfate, or a molecule including a mixture of variably sulfated polysaccharide chains composed of repeating units of D-glucosamine and either L-iduronic or D-glucuronic acids, or salts or derivatives of any of the foregoing.

23. The device according to claim 19 wherein said nucleic acid is double-stranded DNA, single-stranded DNA, or RNA.

24. The device according to claim 19 wherein said polycation is a histone protein, polyornithine, polylysine, polyarginine or polyethylenimine.

25. The device according to claim 19 wherein said condensate is directly bound to the heparin-activity molecule by electrostatic interaction.

26. The device according to claim 19 wherein the silyl-heparin covalent complex comprises [benzyl-bis(dimethylsilylmethyl)]-(N-heparinyl)-carbamate or [benzyl-tris(dimethylsilylmethyl)]-(N-heparinyl)-carbamate.

27. The device according to claim 19 wherein the device is a blood gas exchange device, blood filter, artificial blood vessel, artificial valve, prosthetic, blood shunt, catheter, bone replacement, cartilage replacement, suture, graft, catheter or nerve growth guide.

28. A method for coating a contacting surface of a medical device with a nucleic acid-containing coating composition, comprising:

providing a hydrophobic silyl moiety of Formula I

wherein

R₁ is an C_1-18 alkyl or C_6-32 aryl group,

each R₂ is independently selected from the group consisting of C_1-18 alkyl and C_6-32 aryl,

R₃ is N or O, and

n is a number from 1 to 10

binding said silyl moiety to a heparin-activity molecule via covalent bonding, wherein x is from 1 to about 30 for each heparin-activity molecule, thereby forming a silyl-heparin complex,

attaching the silyl-heparin complex to the contacting surface by hydrophobic interaction, and

attaching a condensate comprising a polycation and a nucleic acid to the heparin-activity molecule.

29. The method of claim 28 wherein the silyl-heparin complex has a disassociation rate from the contacting surface determined by the value of n and x.

30. The method of claim 28 wherein the heparin-activity molecule is heparin, heparan sulfate, hyaluronic acid, dextran, dextran sulfate, chondroitin sulfate, dermatan sulfate, or a molecule including a mixture of variably sulfated polysaccharide chains composed of repeating units of D-glucosamine and either L-iduronic or D-glucuronic acids, or salts or derivatives of any of the foregoing.

31. The method of claim 28 wherein said polycation is a histone protein, polyornithine, polylysine, polyarginine or polyethylenimine.

32. The method of claim 28 wherein said condensate is directly bound to the heparin-activity molecule by electrostatic interaction.

33. The method of claim 28 wherein the silyl-heparin covalent complex comprises [benzyl-bis(dimethylsilylmethyl)]-(N-heparinyl)-carbamate or[benzyl-tris(dimethylsilylmethyl)]-(N-heparinyl)-carbamate.