Functionalization of polyglycolides by "click" chemistry

• US 20090054619A1
• Filed: 08/25/2008
• Published: 02/26/2009
• Est. Priority Date: 08/24/2007
• Status: Active Grant

• Current Assignee: The Board of Trustees of Michigan State University (Michigan State University)
• Original Assignee: The Board of Trustees of Michigan State University (Michigan State University)
• Inventors: Jiang, Xuwei, Smith, Milton R. III, Baker, Gregory L., Vogel, Erin B.
• Granted Patent: US 8,927,682 B2
• Time in Patent Office: Days
• US Class Current: 528/354
• CPC Class Codes: C08G 63/08 Lactones or lactides
• CPC Class Codes: C08G 63/823 for the preparation of polylactones or polylactides

Abstract

Poly(glycolide) polymers are disclosed. The polymers generally include a polymerized alkynyl-substituted glycolide having a polymer backbone with one or more alkynyl groups appended thereto. The alkynyl groups provide reactive sites for further functionalization of the polymer, for example by reaction with azide derivatives (e.g., azide-substituted organic compounds). Alkynyl and azide groups react via the “click” chemistry mechanism to form functional groups covalently bonded to the polymer via a triazole link. The polymers are biodegradable and can be used to deliver drugs or other therapeutic substances (e.g., large biomolecules such as single strand RNA) at targeted locations in a patient'"'"'s body and/or at controlled release rates.

Claims

1. A poly(glycolide) polymer comprising:

a polymerized alkynyl-substituted glycolide, the alkynyl-substituted glycolide comprising an alkynyl group.

2. The poly(glycolide) polymer of claim 1, wherein the alkynyl group contains 3 to 12 carbon atoms.

3. The poly(glycolide) polymer of claim 2, wherein the alkynyl group comprises a propargyl group having a terminal alkynyl group.

4. The poly(glycolide) polymer of claim 1, wherein the polymerized alkynyl-substituted glycolide comprises one or more repeating units according to Formula I

wherein:

(i) R₁ comprises one or more moieties selected from a hydrogen, an alkyl group, an aryl group, and the alkynyl group;

(ii) R₂ comprises the alkynyl group; and

,

(iii) x is between 0 and 1.

5. The poly(glycolide) polymer of claim 4, further comprising lactide repeating units, thereby forming a copolymer selected from the group consisting of a random copolymer, a block copolymer, and combinations thereof.

6. The poly(glycolide) polymer of claim 1, wherein the polymerized alkynyl-substituted glycolide comprises one or more polymeric chains according to Formula II

wherein:

(i) R₁ comprises one or more moieties selected from a hydrogen, an alkyl group, an aryl group, and the alkynyl group;

(ii) R₂ comprises the alkynyl group;

(iii) R comprises a terminal group;

(iv) x ranges from 0 to less than 1; and

,

(v) n ranges from about 10 to about 1000.

7. The poly(glycolide) polymer of claim 1, wherein the alkynyl-substituted glycolide comprises one or more monomers according to Formula III

wherein:

(i) R₁, R₂, R₃, and R₄ are independently selected from a hydrogen, an alkyl group, an aryl group, and the alkynyl group; and

(ii) at least one of R₁, R₂, R₃, and R₄ is the alkynyl group.

8. The poly(glycolide) polymer of claim 7, wherein the alkynyl-substituted glycolide is represented by Formula IIIa.

9. A functionalized poly(glycolide) polymer, comprising:

a triazole reaction product of (a) a poly(glycolide) polymer comprising a polymerized alkynyl-substituted glycolide, the alkynyl-substituted glycolide comprising an alkynyl group and (b) an azide-substituted organic compound.

10. The functionalized poly(glycolide) polymer of claim 9, wherein the azide-substituted organic compound is selected from the group consisting of an azide-substituted polyoxyalkylene, an azide-substituted organic amine, an azide-substituted organic ammonium salt, an azide-substituted organic imine, an azide-substituted organic amide, an azide-substituted carboxylic acid, an azide-substituted carboxylate salt, an azide-substituted ester, an azide-substituted alkyl polyoxyalkylene, an azide-substituted alcohol, an azide-substituted alkane, an azide-substituted alkene, a diazido alkane, and combinations thereof.

11. The functionalized poly(glycolide) polymer of claim 9, wherein:

(i) the azide-substituted organic compound comprises an azide-substituted alkane and an azide-substituted polyoxyalkylene; and

(ii) the functionalized poly(glycolide) polymer has a lower critical solution temperature (LCST) ranging from about 25°

C. to about 65°

C. and an LCST transition range of about 5°

C. or less.

12. A process for preparing a functionalized polyester polymer, the process comprising:

(a) providing a polyester polymer comprising backbone-pendant alkynyl groups; and

(b) forming a functionalized polyester polymer by reacting an azide-substituted organic compound with the p polymer in the presence of a copper salt and a reducing agent in a non-reactive solvent at about room temperature, thereby (i) generating Cu(I) in situ and (ii) covalently grafting the organic compound to the polyester polymer via a triazole reaction product of the alkynyl group and the azide-substituted organic compound.

13. The process of claim 12, wherein the polyester polymer comprises a poly(glycolide) polymer comprising:

a polymerized alkynyl-substituted glycolide, the alkynyl-substituted glycolide comprising an alkynyl group containing 3 to 12 carbon atoms.

14. The process of claim 12, wherein the azide-substituted organic compound is selected from the group consisting of an azide-substituted polyoxyalkylene, an azide-substituted organic amine, an azide-substituted organic ammonium salt, an azide-substituted organic imine, an azide-substituted organic amide, an azide-substituted carboxylic acid, an azide-substituted carboxylate salt, an azide-substituted ester, an azide-substituted alkyl polyoxyalkylene, an azide-substituted alcohol, an azide-substituted alkane, an azide-substituted alkene, a diazido alkane, and combinations thereof.

15. The process of claim 12, wherein:

(i) the azide-substituted organic compound comprises an azide-substituted alkane and an azide-substituted polyoxyalkylene; and

(ii) the functionalized polyester polymer has a lower critical solution temperature (LCST) ranging from about 25°

C. to about 65°

C.

16. The process of claim 12, wherein the polyester polymer comprises at least one terminal hydroxyl group.

17. The process of claim 12, wherein the functionalized polyester polymer has a degree of polymerization that is substantially the same as that of the polyester polymer.

18. The process of claim 12, wherein the copper salt comprises copper (II) sulfate, the reducing agent comprises sodium ascorbate, the non-reactive solvent comprises dimethyl formamide (DMF), and the temperature ranges from about 0°

C. to about 50°

C.

19. The process of claim 13, wherein step (a) further comprises reacting an alkynyl-substituted glycolide in the presence of an initiator and a metal catalyst at a polymerization temperature ranging from about 30°

C. to about 180°

C., thereby forming the poly(glycolide) polymer.

20. The process of claim 19, wherein the initiator comprises t-butylbenzyl alcohol, the metal catalyst comprises Sn(2-ethylhexanoate)₂, and the polymerization temperature ranges from about 110°

C. to about 150°

C.

21. The process of claim 19, wherein step (a) further comprises copolymerizing the alkynyl-substituted glycolide with a lactide, thereby forming a copolymer.

22. The process of claim 19, wherein the alkynyl-substituted glycolide comprises one or more monomers according to Formula III

wherein:

(i) R₁, R₂, R₃, and R₄ are independently selected from a hydrogen, an alkyl group, an aryl group, and the alkynyl group; and

(ii) at least one of R₁, R₂, R₃, and R₄ is the alkynyl group.