MULTIFUNCTIONAL SELF-ASSEMBLING POLYMERIC NANOSYSTEMS

• US 20110244048A1
• Filed: 10/09/2009
• Published: 10/06/2011
• Est. Priority Date: 10/09/2008
• Status: Active Grant

• Current Assignee: Northeastern University
• Original Assignee: Northeastern University
• Inventors: Amiji, Mansoor M., Iyer, Arun K.
• Granted Patent: US 9,173,840 B2
• Time in Patent Office: Days
• US Class Current: 424/493
• CPC Class Codes: A61K 9/1273 Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances polymers grafted or coated on phosphatidyl liposomes A61K9/1271, on non-phosphatidyl liposomes A61K9/1272
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Libraries of nanoparticles comprising therapeutic agents and/or imaging agents are disclosed, as well as methods of making, customizing, and using such libraries of nanoparticles.

Claims

1. A method of making a customized nanoparticle library, the method comprising:

a) solubilizing a hydrophobic therapeutic agent in an aqueous solution;

b) providing a first water-soluble derivatized polymer comprising polyethylene glycol (PEG) and a C₁₄-C₂₂ fatty acid;

c) combining the solubilized therapeutic agent and the first derivatized polymer, the solubilized therapeutic agent and the first derivatized polymer self-assembling to form a first nanoparticle;

d) providing a second water-soluble derivatized polymer comprising PEG and a C₁₄-C₂₂ fatty acid that differs from the fatty acid of the first derivatized polymer; and

e) repeating step c) to form a second nanoparticle, thereby making a customized nanoparticle library.

2. The method of claim 1, wherein the hydrophobic therapeutic agent has a partition coefficient greater than about 1,000.

3. The method of claim 1, wherein the PEG comprises a reactive group at one terminus.

4. The method of claim 3, wherein the reactive group is an acid, amine, maleimide, acrylate, or a succinimidyl carboxy methyl ester.

5. The method of claim 3, further comprising linking a targeting agent to the reactive group.

6. The method of claim 1, wherein the first and the second water-soluble derivatized polymers form a hydrogel shell surrounding the solubilized therapeutic agent.

7. The method of claim 1, wherein the first and the second water-soluble derivatized polymers have a neutral charge.

8. The method of claim 7, wherein the first and the second water-soluble derivatized polymers are dextran, inulin, ficoll, starch, PEG, or poly(vinyl alcohol).

9. The method of claim 1, wherein the first and the second water-soluble derivatized polymers have a negative charge.

10. The method of claim 9, wherein the first and the second water-soluble derivatized polymers are alginate, hyaluronic acid, pectin, or a cellulose derivative.

11. The method of claim 1, further comprising adding a crosslinking agent to the first and the second water-soluble derivatized polymers, thereby enhancing the stability of the nanoparticles.

12. The method of claim 11, wherein the crosslinking agent is a disulfide bond-forming crosslinking agent.

13. The method of claim 12, wherein the disulfide bond-forming crosslinking agent is cystamine, 2-immunothiolane, aminothiolane, glutathione, lipoic acid, glyoxal, or epichlorohydrin.

14. The method of claim 11, wherein the crosslinking agent is a divalent cation.

15. The method of claim 14, wherein the divalent cation is Ca²⁺, Mg²⁺, Ba²⁺, or Fe²⁺.

16. The method of claim 11, wherein crosslinking agent is a trivalent cation.

17. The method of claim 16, wherein the trivalent cation is Al³⁺ or Fe³⁺.

18. The method of claim 1, wherein the first and the second water-soluble derivatized polymers are modified with thiol groups.

19. The method of claim 1, wherein the PEG is modified with thiol groups.

20. The method of claim 1, wherein the therapeutic agent is a chemotherapeutic agent.

21. The method of claim 20, wherein the chemotherapeutic agent is doxorubicin.

22. The method of claim 1, wherein the library comprises about 2 to about 5,000 different types of nanoparticles.

23. The method of claim 1, further comprising conjugating the first and the second water-soluble polymers with diethylene triamine pentaacetic acid (DTPA).

24. The method of claim 23, further comprising linking an imaging agent to the DTPA.

25. The method of claim 24, wherein the imaging agent is ⁶⁴Gd, ¹¹¹In, or ¹²⁵I.

26. A method of making a customized nanoparticle library, the method comprising:

a) solubilizing a hydrophilic therapeutic agent in an aqueous solution;

b) providing a first derivatized polymer comprising PEG and a C₂-C₁₄ fatty acid;

c) combining the solubilized therapeutic agent and the first derivatized polymer, the solubilized therapeutic agent and the first derivatized polymer self-assembling to form a first nanoparticle;

d) providing a second derivatized polymer comprising PEG and a C₂-C₁₄ fatty acid that differs from the fatty acid of the first derivatized polymer; and

e) repeating step c) to form a second nanoparticle,

thereby making a customized nanoparticle library.

27. The method of claim 26, wherein the therapeutic agent has a partition coefficient greater than about 1,000.

28. The method of claim 26, wherein the therapeutic agent is an siRNA.

29. The method of claim 26, further comprising conjugating the first and the second water-soluble polymers with DTPA.

30. The method of claim 29, further comprising linking an imaging agent to the DTPA.

31. The method of claim 30, wherein the imaging agent is iron oxide or a quantum dot.

32. A method of making a customized nanoparticle library, the method comprising:

a) determining the partition coefficient of a therapeutic agent;

b) solubilizing the therapeutic agent in an aqueous solution;

c) providing a first derivatized polymer comprising PEG and a fatty acid;

d) combining the solubilized therapeutic agent and the first derivatized polymer, the solubilized therapeutic agent and the first derivatized polymer self-assembling to form a first nanoparticle;

e) providing a second derivatized polymer comprising PEG and a fatty acid that differs from the fatty acid of the first derivatized polymer; and

f) repeating step d) to form a second nanoparticle,

thereby making a customized nanoparticle library.

33. The method of claim 32, wherein the therapeutic agent has a partition coefficient greater than about 1,000.

34. The method of claim 33, wherein the fatty acid is a C₁₄-C₂₂ fatty acid.

35. The method of claim 32, wherein the therapeutic agent has a partition coefficient less than about 100.

36. The method of claim 35, wherein the fatty acid is a C₂-C₁₄ fatty acid.

37. A method of making a customized nanoparticle library, the method comprising:

a) providing a first water-soluble derivatized polymer comprising (i) PEG, (ii) DTPA, and (iii) a C₁₄-C₂₂ fatty acid;

b) combining an imaging agent and the first derivatized polymer, the imaging agent and the first derivatized polymer self-assembling to form a first nanoparticle;

c) providing a second water-soluble derivatized polymer comprising (i) PEG, (ii) DTPA, and (iii) a C₁₄-C₂₂ fatty acid that differs from the fatty acid of the first derivatized polymer; and

d) repeating step b) to form a second nanoparticle,

thereby making a customized nanoparticle library.

38. The method of claim 37, wherein the imaging agent is ⁶⁴Gd, ¹¹¹In, or ¹²⁵I.

39. A method of making a customized nanoparticle library, the method comprising:

a) providing a first derivatized polymer comprising (i) PEG, (ii) DTPA, and (iii) a C₂-C₁₄ fatty acid;

b) combining an imaging agent and the first derivatized polymer, the imaging agent and the first derivatized polymer self-assembling to form a first nanoparticle;

d) providing a second derivatized polymer comprising (i) PEG, (ii) DTPA, and (iii) a C₂-C₁₄ fatty acid that differs from the fatty acid of the first derivatized polymer; and

e) repeating step c) to form a second nanoparticle, thereby making a customized nanoparticle library.

40. The method of claim 39, wherein the imaging agent is iron oxide or a quantum dot.

41. A method of treating a subject having a tumor, the method comprising administering to the subject a nanoparticle in an amount sufficient to reduce tumor size or number of tumor cells in the tumor, wherein the nanoparticle comprises:

a) a therapeutic agent;

b) a hydrogel shell surrounding the therapeutic agent, the hydrogel shell comprising a water-soluble derivatized polymer comprising (i) a C₁₄-C₂₂ fatty acid, (ii), PEG, and (iii) a crosslinking agent; and

c) a targeting agent bound to the PEG,

thereby treating the subject.

42. The method of claim 41, wherein the derivatized polymer comprises thiolated dextran.

43. A method of inhibiting expression of a target polypeptide in a subject, the method comprising administering to the subject a nanoparticle in an amount sufficient to inhibit expression of the target polypeptide, wherein the nanoparticle comprises:

a) an siRNA molecule;

b) a hydrogel shell surrounding the siRNA molecule, the hydrogel shell comprising a water-soluble derivatized polymer comprising (i) a C₂-C₁₄ fatty acid, (ii), PEG, and (iii) a crosslinking agent; and

c) a targeting agent bound to the PEG,

thereby inhibiting the expression of the target polypeptide.