Biodegradable organic radical-functionalized polycarbonates for medical applications

• US 9,718,957 B2
• Filed: 01/30/2015
• Issued: 08/01/2017
• Est. Priority Date: 01/30/2015
• Status: Expired due to Fees

• Current Assignee: Agency For Science Technology and Research (Government of Singapore), International Business Machines Corporation
• Original Assignee: Agency For Science Technology and Research (Government of Singapore), International Business Machines Corporation
• Inventors: Chan, Julian M. W., Hedrick, James L., Lee, Ashlynn L. Z., Wojtecki, Rudy J., Yang, Yi Yan
• Primary Examiner(s): ROGERS, JAMES WILLIAM
• Application Number:
  US14/609,778
• Publication Number:
  US 20160220705A1
• Time in Patent Office: 914 Days
• Field of Search: None
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61K 49/1809 Micelles, e.g. phospholipidic or polymeric micelles
• CPC Class Codes: A61K 49/20 containing free radicals , e.g. trityl radical for overhauser
• CPC Class Codes: C08G 64/0241 containing nitrogen
• CPC Class Codes: C08G 64/183 containing polyether sequences
• CPC Class Codes: C08L 69/00 Compositions of polycarbonates; Compositions of derivatives of polycarbonates

Abstract

Paramagnetic, amphiphilic, biocompatible polymers were prepared comprising a carbonate repeat unit bearing a paramagnetic organic radical, more specifically a nitroxyl radical. The radical polymers can be produced in one step from a precursor polymer bearing an active ester side chain by treating the precursor polymer with a radical-bearing nucleophile. The precursor polymer can be prepared by organocatalyzed catalyzed ring opening polymerization (ROP) of a cyclic carbonate monomer bearing an active ester side chain. The radical polymers can be non-toxic and partially biodegradable. The radical polymers have utility as contrast enhancing agents in a medical imaging application and/or as therapeutic agents for treating a medical condition. The radical polymers can also serve as carriers for therapeutic agents (e.g., drugs) and/or medical image enhancing agents (e.g., NIRF dyes).

Claims

1. A polymer comprising:

a radical repeat unit having a structure according to formula (1);

2. The polymer of claim 1, wherein the nitroxide radical is

3. The polymer of claim 1, wherein the nitroxide radical is

4. The polymer of claim 1, wherein the nitroxide radical is

5. The polymer of claim 1, wherein each R″

is hydrogen (H—

*).

6. The polymer of claim 1, wherein W′

is selected from the group consisting of

7. The polymer of claim 1, wherein the radical repeat unit is selected from the group consisting of

22. A method, comprising:

contacting living tissue with the polymer of claim 1, thereby enhancing contrast in a medical imaging application used to view the tissue and/or administering a therapeutic treatment to the tissue, wherein the polymer is water soluble, non-toxic, biodegradable, and paramagnetic.

23. The method of claim 22, wherein the polymer is a block polymer of formula (4):

24. The method of claim 22, wherein the polymer is administered to a medical patient.

25. The method of claim 22, wherein said contacting living tissue with the polymer enhances contrast in a medical imaging application used to view the tissue.

26. The method of claim 25, wherein the polymer is bound by non-covalent interactions to a near infrared fluorescent (NIRF) dye.

27. The method of claim 26, wherein the NIRF dye is 1,1′

-dioctadecyltetramethyl indotricarbocyanine iodide (DiR).

28. The method of claim 22, wherein said contacting living tissue with the polymer administers a therapeutic treatment to the tissue.

8. A block polymer of formula (4):

9. The block polymer of claim 8, wherein n′

has an average value of about 50 to about 200, and m′

has an average value of about 1 to about 20.

10. The block polymer of claim 8, wherein Z′

is an alkoxy or aryloxy group comprising 1 to 15 carbons, X′

is oxygen (*—

O—

*), and Z″

is hydrogen (H—

*).

11. A composition, comprising:

water; and

the block polymer of claim 8;

wherein

the composition is suitable for enhancing contrast in a medical imaging application.

12. The composition of claim 11, wherein the composition comprises micelles of the block polymer.

13. The composition of claim 11, wherein the composition is suitable for intravenous injection.

14. The composition of claim 11, wherein the composition further comprises a drug.

15. The composition of claim 11, wherein the composition further comprises a contrast enhancing dye.

16. The composition of claim 15, wherein the contrast enhancing dye fluoresces at a wavelength in the range of about 700 nm to about 900 nm.

17. A method, comprising:

forming a first mixture comprising water and the block polymer of claim 8;

forming a second mixture comprising i) a solvent selected from the group consisting of organic solvents, water, and combinations thereof and ii) a medically useful material;

combining the first mixture and the second mixture, thereby forming a third mixture; and

removing organic solvent from the third mixture, thereby forming a composition comprising particles, the particles comprising the block polymer and the medically useful material bound by non-covalent interactions.

18. The method of claim 17, wherein the medically useful material is a contrast enhancing dye suitable for a medical imaging application.

19. The method of claim 18, wherein the medical imaging application is magnetic resonance imaging.

20. The method of claim 17, wherein the medically useful material is a drug.

21. The method of claim 17, wherein an aqueous mixture of the particles is suitable for intravenous injection.