Branched histidine copolymers and methods for using same

• US 7,070,807 B2
• Filed: 04/25/2002
• Issued: 07/04/2006
• Est. Priority Date: 12/29/1999
• Status: Expired due to Term

• Current Assignee: Mixson A. James
• Original Assignee: Mixson A. James
• Inventors: Mixson, A. James
• Primary Examiner(s): PRIEBE, SCOTT DAVID
• Application Number:
  US10/131,909
• Publication Number:
  US 20030165567A1
• Time in Patent Office: 1,531 Days
• Field of Search: 514/44, 435/320.1, 435/458, 424/450, 424/484, 424/486
• US Class Current: 424/484
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 14/00 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• CPC Class Codes: C07K 14/001 by chemical synthesis
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle

Abstract

The invention provides a branched transport polymer characterized as having at least 10 amino acids and a ratio of histidine to non-histidine amino acids greater than 1.5, said branched transport polymer comprising one or more backbones, one or more terminal branches, and optionally, one or more non-terminal branches. The branched transport polymer may be associated with a pharmaceutical agent to form a pharmaceutical agent delivery composition useful for in vivo therapies based on local injection.

Claims

1. A branched transport polymer characterized as having at least 10 amino acids and a ratio of histidine to non-histidine amino acids greater than 1.5 and less than 10, said branched transport polymer comprising one or more backbones, one or more terminal branches, and optionally, one or more non-terminal branches.

2. The branched transport polymer of claim 1, wherein said branched transport polymer is further characterized as having synthetic monomer and/or synthetic oligomer covalently incorporated therein.

3. The branched transport polymer of claim 1, said branched transport polymer further characterized as having between 40 and 300 amino acids.

4. The branched transport polymer of claim 1, wherein the ratio of histidine to non-histidine amino acids is between 1.75 and 6.

5. The branched transport polymer of claim 4, wherein the ratio of histidine to non-histidine amino acids is between 2 and 4.

6. The branched transport polymer of claim 1, wherein a sufficient portion of the non-histidine amino acids are selected so as to permit the branched transport polymer to non-covalently associate with a pharmaceutical agent having an overall negative charge.

7. The branched transport polymer of claim 1, wherein said backbones, said terminal branches or said non-terminal branches is characterized as having a histidine to non-histidine ratio less than 1.5.

8. The branched transport polymer of claim 1, wherein at least one of said backbones and/or one of said terminal branches and/or one of said non-terminal branches comprises a subsegment of amino acid residues having the sequence X-H-H-H or the reverse thereof, where X is independently selected from the group of non-histidine hydrophilic amino acids.

9. The branched transport polymer of claim 1, wherein said branched transport polymer does not comprise a non-terminal branch.

10. The branched transport polymer of claim 9, wherein said branched transport polymer is characterized by the formula

[K-H-H-H-K-H-H-H-K-H-H-H-K-H-H-H-K]_x+1K_x

where x is equal to 1 to 30.

11. The branched transport polymer of claim 10, wherein x is equal to at least 3.

12. A pharmaceutical agent delivery composition for in vivo therapies based on local injection, said pharmaceutical agent delivery composition comprising the branched transport polymer of claim 1;

and a pharmaceutical agent associated with said branched transport polymer.

13. The pharmaceutical agent delivery composition of claim 12, wherein a sufficient portion of the non-histidine amino acids are selected so as to permit the branched transport polymer to non-covalently associate with a pharmaceutical agent having an overall negative charge.

14. The pharmaceutical agent delivery composition of claim 13, wherein said portion of non-histidine amino acids are selected from the group consisting of lysine, ornithine, and arginine.

15. The pharmaceutical agent delivery composition of claim 13, wherein said pharmaceutical agent is a therapeutic agent selected from the group consisting of a protein, an oligopeptide, a nucleic acid, a cancer chemotherapeutic agent, an infectious disease chemotherapeutic agent, and any combination of two or more of the above.

16. The pharmaceutical agent delivery composition of claim 15, wherein said therapeutic agent is nucleic acid.

17. The pharmaceutical agent delivery composition of claim 12, wherein said branched transport polymer is characterized by the formula [K-H-H-H-K-H-H-H-K-H-H-H-K-H-H-H-K]₄K₃.

18. A method of in vivo therapy based on local injection comprising the steps of:

preparing a pharmaceutical agent delivery composition comprising the branched transport polymer of claim 1; and

a therapeutic agent associated with said transport polymer; and

administering the pharmaceutical agent delivery composition by local injection to a patient in need thereof.

19. The method of claim 18, wherein at least one of said backbones and/or one of said terminal branches and/or one of said non-terminal branches comprises a subsegment of amino acid residues having the sequence X-H-H-H or the reverse thereof, where X is independently selected from the group of non-histidine hydrophilic amino acids.

20. The transport polymer of claim 1, wherein the content of histidine and non-histidine amino acids renders the transport polymer soluble in water.