Controlled release polymer nanoparticle containing bound nucleic acid ligand for targeting

• US 7,550,441 B2
• Filed: 06/04/2004
• Issued: 06/23/2009
• Est. Priority Date: 06/06/2003
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Farokhzad, Omid C., Langer, Robert S., Jon, Sangyong
• Primary Examiner(s): Naff; David M
• Application Number:
  US10/860,918
• Publication Number:
  US 20050037075A1
• Time in Patent Office: 1,845 Days
• Field of Search: None
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 48/0041 the non-active part being polymeric
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
• CPC Class Codes: Y10S 530/817 Entrapped within the carrier, e.g. gel, hollow fibre

Abstract

The present invention relates to a conjugate that includes a nucleic acid ligand bound to a controlled release polymer system, a pharmaceutical composition that contains the conjugate, and methods of treatment using the conjugate. The controlled release polymer system includes an agent such as a therapeutic, diagnostic, prognostic, or prophylactic agent. The nucleic acid ligand that is bound to the controlled release polymer system, binds selectively to a target, such as a cell surface antigen, and thereby delivers the controlled release polymer system to the target.

Claims

1. A controlled release polymer nanoparticle, comprising;

a therapeutic or diagnostic agent incorporated in the controlled release polymer nanoparticle; and

a nucleic acid ligand comprising an oligonucleotide bound to the surface of the controlled release polymer nanoparticle that selectively binds to a target cell or tissue, and thereby delivers the controlled release polymer nanoparticle to the target cell or tissue;

wherein the controlled release polymer nanoparticle carries a neutral to negative charge on its surface; and

wherein the bound oligonucleotide has a folded three-dimensional conformation resulting from intramolecular interactions.

2. The controlled release polymer nanoparticle of claim 1, wherein the nucleic acid ligand is prepared using L-enantiomeric nucleosides.

3. The controlled release polymer nanoparticle of claim 1, wherein one or more internal nucleotides at the 3′

-end, 5′

-end, or both at the 3′

- and 5′

-end of the nucleic acid ligand are inverted to yield a 3′

-3′

or a 5′

-5′

nucleotide linkage.

4. The controlled release polymer nanoparticle of claim 1, wherein one or more of the nucleotides of the nucleic acid ligand are bound to another nucleotide by a hydrocarbon linker or a polyether linker.

5. The controlled release polymer nanoparticle of claim 1, wherein the nucleic acid ligand binds to a protein, a carbohydrate, a lipid or a nucleic acid.

6. The controlled release polymer nanoparticle of claim 5, wherein the nucleic acid ligand binds to a protein selected from the group consisting of tumor-markers, integrins, cell surface receptors, transmembrane proteins, ion channels, membrane transport protein, enzymes, antibodies, and chimeric proteins.

7. The controlled release polymer nanoparticle of claim 5, wherein the nucleic acid ligand binds to a nucleic acid selected from the group consisting of DNA, RNA, modified DNA, modified RNA, and combinations thereof.

8. The controlled release polymer nanoparticle of claim 1, further comprising an agent for localization.

9. The controlled release polymer nanoparticle of claim 8, wherein the localizing agent is a magnetic particle.

10. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle releases a therapeutic agent.

11. The controlled release polymer nanoparticle of claim 10, wherein the therapeutic agent is selected from the group consisting of small molecule drugs, protein drugs, radionuclides, nucleic acid based drugs, and combinations thereof.

12. The controlled release polymer nanoparticle of claim 11, wherein the therapeutic agent is a small molecule drug selected from the group consisting of an antibiotic, an antiviral agent, an antiparasitic agent, an anti-cancer agent, a radionuclide, an anticoagulant, an analgesic agent, an anesthetic agent, an ion channel potentiator, and ion channel inhibitor, an anti-inflammatory agent, and combinations thereof.

13. The controlled release polymer nanoparticle of claim 11, wherein the therapeutic agent is a nucleic acid based drug selected from the group consisting of DNA, RNA, modified DNA, modified RNA, antisense oligonucleotides, expression plasmid systems, intact genes, intact or partially complementary DNA promoter regions of gene expression, intact or partially complementary DNA repressor regions of gene expression, intact or partially complementary DNA enhancer regions of gene expression, nucleotides, modified nucleotides, nucleosides, modified nucleosides, nucleic acid ligands, and combinations thereof.

14. The controlled release polymer nanoparticle of claim 1, wherein the diagnostic agent is an iron oxide particle.

15. The controlled release polymer nanoparticle of claim 1, wherein the diagnostic agent is a gadolinium complex.

16. The controlled release polymer nanoparticle of claim 1, wherein the controlled release nanoparticle releases a prophylactic agent.

17. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises poly(lactic acid).

18. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises poly(lactic acid) with a terminal carboxylic acid group or a terminal maleimide group.

19. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises PEG-poly(lactic acid) co-polymer.

20. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises poly(lactic-co-glycolic acid).

21. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises poly(lactic-co-glycolic acid) with a terminal carboxylic acid group or a terminal maleimide group.

22. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises PEG-poly(lactic-co-glycolic acid) co-polymer.

23. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises poly(glycolic acid).

24. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises PEG-poly(glycolic acid) co-polymer.

25. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises poly(caprolactone).

26. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises a polyanhydride.

27. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle is attached to the nucleic acid ligand by a linker.

28. The controlled release polymer nanoparticle of claim 27, wherein the linker comprises an alkylene chain, a hydrocarbon chain, or a polyether chain.

29. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises poly(lactic acid)-PEG- maleimide and poly(lactic acid)-PEG.

30. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle has a zeta potential ranging between −

17 and −

100 mV.

31. The controlled release polymer nanoparticle of claim 1, wherein the nucleic acid ligand is a spiegelmer.

32. The controlled release polymer nanoparticle of claim 1, wherein the controlled release polymer nanoparticle comprises a polymer that is biologically degradable, chemically degradable, or both biologically and chemically degradable.

33. The controlled release polymer nanoparticle of claim 32, wherein the controlled release polymer nanoparticle comprises a polymer selected from the group consisting of poly(lactic acid), derivatives of poly(lactic acid), PEGylated poly(lactic acid), poly(lactic-co-glycolic acid), derivatives of poly(lactic-co-glycolic acid), PEGylated poly(lactic-co-glycolic acid), a polyanhydride, poly(ortho esters), derivaties of poly(ortho esters), PEGylated poly(ortho esters), poly(caprolactone), derivatives of poly(caprolactone), PEGylated poly(caprolactone), poly(acrylic acid), derivatives of poly(acrylic acid), poly(urethane), derivatives of poly(urethane), and combinations thereof.

34. A composition comprising the controlled release polymer nanoparticle of claim 1 and a lipid.

35. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a controlled release polymer nanoparticle of claim 1.

36. A method of delivering an agent to a target cell, comprising contacting a target cell or tissue with the controlled release polymer nanoparticle of claim 1.

37. A method of treating a patient with cancer, comprising administering to the patient a controlled release polymer nanoparticle system of claim 1.