Ligand-mediated controlled drug delivery

• US 8,128,952 B2
• Filed: 01/12/2005
• Issued: 03/06/2012
• Est. Priority Date: 01/12/2005
• Status: Active Grant

• Current Assignee: Clemson University
• Original Assignee: Clemson University
• Inventors: Metters, Andrew T., Chollangi, Srinivas
• Primary Examiner(s): Liu, Sue
• Assistant Examiner(s): SINGH, SATYENDRA K
• Application Number:
  US11/034,437
• Publication Number:
  US 20060153919A1
• Time in Patent Office: 2,610 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00

Abstract

Disclosed are systems and methods that can be utilized to define and control the delivery rate of a biological agent from a carrier matrix such as a biocompatible hydrogel. The carrier matrices of the present invention can include ligands incorporated within the matrix at a predetermined concentration level (C_LT). In addition, the ligands within the matrix can display a particular, predetermined affinity for the biologically active agents to be delivered by the system. In particular, the affinity between the ligand and the biologically active agent can have a known predetermined dissociation constant (K_D). When utilizing the system, the agent can be incorporated within the matrix due to association of the agent with the ligand. In addition, the agent can be protected from side reactions due to the association of the agent with the ligand. Through particular selection of the parameters C_LT and K_D, the rate of release of the biologically active agent from the matrix can be controlled. The disclosed methods and systems can be advantageously used in both in vivo clinical settings and ex vivo settings, such as tissue engineering applications.

Claims

1. A method for defining a controlled rate of release of a first biologically active agent from a polymeric carrier matrix comprising:

forming a polymeric carrier matrix;

loading an amount of a first polypeptide ligand into the polymeric carrier matrix, the first polypeptide ligand having an affinity for the first biologically active agent, the first biologically active agent being a protein; and

binding at least a portion of the first biologically active agent to at least a portion of the first polypeptide ligand with a reversible, non-covalent bond between the first polypeptide ligand and the first biologically active agent to form a first polypeptide ligand/first biologically active agent complex, wherein the complex is formed prior to loading the first polypeptide ligand into the polymeric matrix, the affinity of the first polypeptide ligand for the first biologically active agent being described by an equilibrium dissociation constant, K_D that is defined according to the equilibrium relationship;

2. The method according to claim 1, wherein the polymeric matrix is a degradable polymeric matrix.

3. The method according to claim 1, wherein the first polypeptide ligand is a fragment or a chimera of a naturally occurring protein.

4. The method according to claim 1, wherein the polymeric matrix defines a porosity that is larger than the size of the first biologically active agent.

5. The method according to claim 1, further comprising loading a second biologically active agent into the matrix.

6. The method according to claim 5, wherein the second biologically active agent is directly, reversibly, and non-covalently bound to the first ligand.

7. The method according to claim 5, further comprising loading a second ligand into the matrix, wherein the second biologically active agent is directly, reversibly, and non-covalently bound to the second ligand.

8. The method according to claim 1, further comprising encapsulating a living cell within the polymeric matrix.

9. The method according to claim 1, wherein the first biologically active agent is an unmodified protein therapeutic.

10. The method according to claim 1, wherein the polymeric matrix is a self-assembling matrix.

11. The method according to claim 1, further comprising locating the matrix adjacent a living cell.

12. The method according to claim 1, wherein the first polypeptide ligand is held within the polymeric matrix through hydrogen or ionic bonding.

13. The method according to claim 1, wherein the first polypeptide ligand is covalently bound within the polymeric matrix.

14. The method according to claim 1, wherein the complex is not bound to the polymeric matrix, the polymeric matrix defining a porosity that is less than the size of the complex, the complex being physically entrapped within the polymeric matrix.

15. The method according to claim 1, wherein the value of the equilibrium dissociation constant is less than about 1.0E+01 mM.

16. The method according to claim 15, wherein the value of the equilibrium dissociation constant is less than about 1.0E-05 mM.

17. The method according to claim 1, wherein the equilibrium dissociation constant is pH dependent.

18. A method for defining a controlled rate of release of a biologically active agent from a polymeric carrier matrix comprising:

combining multifunctional monomers or macromers with a polymerization initiator;

inducing the polymerization initiator to polymerize the multifunctional monomers or macromers to form a polymeric carrier matrix;

loading an amount of a polypeptide ligand into the polymeric carrier matrix, the polypeptide ligand having an affinity for the biologically active agent; and

binding at least a portion of the biologically active agent to at least a portion of the polypeptide ligand with a reversible, non-covalent bond between the polypeptide ligand and the biologically active agent to form a polypeptide ligand/biologically active agent complex, the biologically active agent being a protein, the affinity of the polypeptide ligand for the biologically active agent being described by an equilibrium dissociation constant, K_D that is defined according to the equilibrium relationship;

19. The method according to claim 18, wherein the polymerization initiator is a photoinitiator.

20. The method according to claim 18, wherein the polymerization initiator induces chemically activated polymerization.

21. The method according to claim 18, wherein the polymeric matrix is a degradable polymeric matrix.

22. The method according to claim 18, wherein the polymeric matrix defines a porosity that is larger than the size of the biologically active agent.

23. The method according to claim 18, further comprising encapsulating a living cell within the polymeric matrix.

24. The method according to claim 18, wherein the biologically active agent is an unmodified protein therapeutic.

25. The method according to claim 18, further comprising locating the matrix adjacent a living cell.

26. The method according to claim 18, wherein the polypeptide ligand is held within the polymeric matrix through hydrogen or ionic bonding.

27. The method according to claim 18, wherein the polypeptide ligand is covalently bound within the polymeric matrix.

28. The method according to claim 18, wherein the value of the equilibrium dissociation constant is less than about 1.0E+01 mM.

29. A method for defining a biphasic controlled rate of release of a biologically active agent from a polymeric carrier matrix comprising:

forming a polymeric carrier matrix;

loading an amount of a polypeptide ligand into the polymeric carrier matrix, the polypeptide ligand having an affinity for the biologically active agent, the biologically active agent being a protein;

loading an amount of the biologically active agent into the polymeric carrier matrix, wherein the ratio of the amount of the polypeptide ligand loaded into the polymeric carrier matrix to the amount of the biologically active agent loaded into the polymeric carrier matrix is less than unity;

binding at least a portion of the biologically active agent to at least a portion of the polypeptide ligand with a reversible, non-covalent bond between the polypeptide ligand and the biologically active agent to form a polypeptide ligand/biologically active agent complex, the affinity of the polypeptide ligand for the biologically active agent being described by an equilibrium dissociation constant, K_D that is defined according to the equilibrium relationship;

30. The method according to claim 29, wherein the polymeric matrix is a degradable polymeric matrix.

31. The method according to claim 29, wherein the polypeptide ligand is a fragment or a chimera of a naturally occurring protein.

32. The method according to claim 29, wherein the polymeric matrix defines a porosity that is larger than the size of the biologically active agent.

33. The method according to claim 29, further comprising encapsulating a living cell within the polymeric matrix.

34. The method according to claim 29, wherein the first biologically active agent is an unmodified protein therapeutic.

35. The method according to claim 29, wherein the polymeric matrix is a self-assembling matrix.

36. The method according to claim 29, further comprising locating the matrix adjacent a living cell.

37. The method according to claim 29, wherein the polypeptide ligand is held within the polymeric matrix through hydrogen or ionic bonding.

38. The method according to claim 29, wherein the polypeptide ligand is covalently bound within the polymeric matrix.

39. The method according to claim 29, wherein the complex is not bound to the polymeric matrix, the polymeric matrix defining a porosity that is less than the size of the complex, the complex being physically entrapped within the polymeric matrix.

40. The method according to claim 29, wherein the value of the equilibrium dissociation constant is less than about 1.0E+01 mM.

41. The method according to claim 29, wherein the value of the equilibrium dissociation constant is less than about 1.0E-05 mM.

42. The method according to claim 29, wherein the equilibrium dissociation constant is pH dependent.