COMPOSITIONS FOR DELIVERY OF THERAPEUTIC AGENTS

• US 20090232762A1
• Filed: 03/11/2008
• Published: 09/17/2009
• Est. Priority Date: 03/11/2008
• Status: Abandoned Application

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Bae, Younsoo, Xiong, May Pang, Kwon, Glen S., Kataoka, Kazunori
• Application Number:
  US12/046,287
• Publication Number:
  US 20090232762A1
• Time in Patent Office: Days
• US Class Current: 424/78.300
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/51 Nanocapsules; Nanoparticles; nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides

Abstract

The invention provides a polyamide compounds and compositions, in addition to methods for their preparation and methods for their use. The invention also provides micelle compositions that include encapsulated therapeutic agents, for example, nucleic acids or prodrugs, and methods for their preparation. The invention further provides methods of delivering therapeutic agents to cells and methods of activating therapeutic prodrugs.

Claims

1. A polyamide polymer comprising amino acid units derived from amino acids with side chains that can have positive, neutral, or negative charges;

wherein at least one side chain of an amino acid of the polyamide is covalently linked to a poly(ethylene glycol) chain through a hydrazide moiety, and

wherein the hydrazide moiety is linked to the poly(ethylene glycol) chain at the N′

nitrogen of the hydrazide through a hydrazone bond.

2. The polymer of claim 1 wherein the amino acid units comprise aspartic acid units, glutamic acid units, or both, and optionally lysine units, arginine units, or both.

3. The polymer of claim 2 wherein a plurality of aspartic acid or glutamic acid units are covalently linked to poly(ethylene glycol) chains;

the molecular weight of the poly(ethylene glycol) chains is each independently about 500 to about 10,000; and

the poly(ethylene glycol) chains each optionally terminate in methoxy, amino, or acetamide groups.

4. The polymer of claim 3 wherein the ratio of aspartic acid or glutamic acid units to polyethylene(glycol) chains is about 1:

1 to about 20;

1.

5. The polymer of claim 2 comprising poly(lysine) units wherein one or more of the lysine side chain amino groups is optionally protected with trifluoroacetate groups or carbonylbenzyloxy groups.

6. The polymer of claim 2 comprising about 5 to about 100 aspartic acid or glutamic acid units;

and about 10 to about 150 lysine or arginine units.

16. A micelle composition comprising the polymer of claim 1 and a therapeutic agent, wherein the polymer substantially encapsulates the therapeutic agent and the poly(ethylene glycol) chains of the polymer align toward the outside surface of the micelle.

17. The micelle composition of claim 16 wherein the therapeutic agent comprises a nucleic acid, a gene, a drug, a prodrug, or a combination thereof, and when the therapeutic agent comprises a nucleic acid, the nucleic acid is optionally a plasmid DNA encoding a gene product or RNAi.

18. The polymer of claim 1 comprising formula I:

19. The polymer of claim 18 wherein m is about 30 to about 50, n is about 40 to about 60, p is selected such that the molecular weight of the poly(ethylene glycol) chain is about 2,000 to about 10,000;

and R² is —

NHR³ wherein R³ is an acetyl group.

20. The polymer of claim 1 comprising formula II:

21. A method of activating a therapeutic prodrug comprising:

contacting the micelle composition of claim 16 and a cell, wherein the micelle composition contains a gene or vector that encodes a therapeutic protein that converts the prodrug to an active drug; and

introducing the prodrug to the vicinity of the cell after the cell has synthesized the therapeutic protein so that the therapeutic protein activates the prodrug to the active drug;

wherein the therapeutic protein is optionally an enzyme.

22. The method of claim 21 wherein amino acid side chain protecting groups have been removed from the polymer of the micelle composition prior to forming the micelle that encapsulates the therapeutic agent.

23. A method of providing RNAi to a cell comprising:

contacting the micelle composition of claim 16 and a cell, wherein the micelle composition contains a gene or vector that encodes RNAi that silences or reduces the expression of a gene in the cell;

wherein the gene or vector is incorporated into the cell and the cell then synthesizes the RNAi thereby silencing or reducing the expression of a gene.

24. A method of delivering a gene, vector, RNAi, or plasmid that encodes a gene product or RNAi, to a cell comprising encapsulating the gene or vector in a micelle comprising the polymer of claim 1;

and contacting a cell with the micelle.

7. A polyamide block polymer comprising a first block and a second block;

wherein

the first block comprises amino acid units derived from amino acid units with side chains that can have neutral or negative charges;

the second block comprises amino acid units with side chains that can have positive charges;

wherein at least one side chain of an amino acid of the first block is covalently linked to a poly(ethylene glycol) chain through a hydrazide moiety, and

wherein the hydrazide moiety is linked to the poly(ethylene glycol) chain at the N′

nitrogen of the hydrazide through a hydrazone bond.

8. The polymer of claim 7 wherein the first block comprises aspartic acid or glutamic acid units, and the second block comprises lysine or arginine units.

9. The polymer of claim 8 wherein a plurality of aspartic acid or glutamic acid units are covalently linked to poly(ethylene glycol) chains;

the molecular weight of the poly(ethylene glycol) chains is each independently about 500 to about 10,000; and

the poly(ethylene glycol) chains each optionally terminate in methoxy, amino, or acetamide groups.

10. The polymer of claim 9 wherein the ratio of aspartic acid or glutamic acid units to polyethylene(glycol) chains is about 1:

1 to about 20;

1.

11. The polymer of claim 8 comprising poly(lysine) units wherein one or more of the lysine side chain amino groups is optionally protected with trifluoroacetate groups or carbonylbenzyloxy groups.

12. The polyamide block polymer of claim 7 comprising at least one block of poly(aspartic acid) or poly(glutamic acid) units and at least one block of poly(lysine) or poly(arginine) units;

wherein at least one side chain of an aspartic acid unit or a glutamic acid units is covalently linked to a poly(ethylene glycol) chain through a hydrazide moiety, and

wherein the hydrazide moiety is linked to the poly(ethylene glycol) chain at the N′

nitrogen of the hydrazide through a hydrazone bond.

13. The polymer of claim 12 wherein a plurality of aspartic acid or glutamic acid units are covalently linked to poly(ethylene glycol) chains;

the molecular weight of the poly(ethylene glycol) chains is each independently about 500 to about 10,000; and

the poly(ethylene glycol) chains each optionally terminate in methoxy, amino, or acetamide groups.

14. The polymer of claim 12 wherein the ratio of aspartic acid or glutamic acid units to polyethylene(glycol) chains is about 1:

1 to about 20;

1.

15. The polymer of claim 12 comprising poly(lysine) units wherein one or more of the lysine side chain amino groups is optionally protected with trifluoroacetate groups or carbonylbenzyloxy groups.