Graft copolymer polyelectrolyte complexes for drug delivery

Patent metadata

Field	Value
Publication number	US-9789194-B2
Application number	US-201615056386-A
Country	US
Kind code	B2
Filing date	Feb 29, 2016
Priority date	Nov 27, 2007
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

Graft copolymer polyelectrolyte complexes are disclosed for the efficient delivery of anionic, cationic or polyelectrolyte therapeutic agents into biological cells, and for maintaining the biological activity of these molecules while in serum and other aqueous environments are provided. Such complexes comprise (1) an anionic graft copolymer containing an anionic polymer backbone, with pendent carboxylic acid groups and pendant chains containing amphipathic or hydrophilic polymers covalently bonded to a portion of the pendant carboxylic acid groups, (2) one or more anionic, cationic or polyelectrolyte therapeutic agents, and (3) optionally a liposome optionally containing an additional therapeutic agent. Also disclosed are functional nanoparticles containing the complexes.

First claim

What is claimed is:

1. A graft copolymer-polyelectrolyte complex comprising:
(1) an anionic graft copolymer comprising:
(i) a backbone comprising a poly(alkylacrylic acid) or copolymer thereof; and
(ii) one or more polyetheramine pendent chains covalently attached to said copolymer backbone as amides of acrylic acid groups, wherein said pendent chains predominantly comprise ethylene oxide repeating units;

wherein said copolymer has a graft density between about 0.1 and about 25 mole percent;
(2) one or more anionic, cationic or polyelectrolyte therapeutic agents; and
(3) optionally, a liposome which optionally comprises a further therapeutic agent;

provided that when said anionic, cationic or polyelectrolyte therapeutic agent comprises a polynucleotide molecule, said liposome, optionally comprising said further therapeutic agent, is also present.

2. The complex of claim 1 , wherein the copolymer backbone comprises poly(propyl acrylic acid) or copolymer thereof, or poly(methacrylic acid) or copolymer thereof.

3. The complex of claim 1 , wherein said copolymer has a graft density between about 0.5 and about 5 mole percent.

4. The complex of claim 1 , wherein said liposome is present.

5. The complex of claim 1 , wherein said pendent chains further comprise one or more ligands that target a specific cell, tissue or surface.

6. The complex of claim 1 , wherein said anionic, cationic or polyelectrolyte therapeutic agent is selected from the group consisting of cationic peptides, peptide nucleic acids, aminoglycoside antibiotics, oligonucleotides, nucleic acids, plasmid DNA-encoding genes, and ribozymes.

7. The complex of claim 6 , wherein said aminoglycoside antibiotic is selected from the group consisting of neomycin, gentamicin and tobramycin.

8. The complex of claim 1 , wherein said further therapeutic agent is selected from the group consisting of small molecule therapeutic agents, imaging agents, fluorescent dyes and quantum dots.

9. The complex of claim 8 , wherein said small molecule therapeutic agents are selected from the group consisting of anticancer agents, wound healing agents, tissue regeneration agents, antibiotic agents, and pain control agents.

10. The complex of claim 1 , wherein said anionic, cationic or polyelectrolyte therapeutic agent comprises a cationic peptide.

11. The complex of claim 10 , wherein said cationic peptide comprises a compound selected from the group consisting of KSL-W, colistin and polymyxin B.

12. The complex of claim 1 , wherein said anionic, cationic or polyelectrolyte therapeutic agent is stabilized toward biological degradation in vivo.

13. A functional nanoparticle comprising the complex of claim 1 , wherein said nanoparticle provides in vivo delivery of the anionic, cationic or polyelectrolyte therapeutic agent.

14. A method of preparing a graft copolymer-polyelectrolyte complex of claim 1 comprising the steps of:
(1) providing an aqueous mixture of an anionic graft copolymer comprising:
(i) a backbone comprising a poly(alkyl acrylic acid) or copolymer thereof; and
(ii) one or more polyetheramine pendent chains covalently attached to said copolymer backbone as amides of the acrylic acid groups, wherein said pendent chains predominantly comprise ethylene oxide repeating units;

wherein said copolymer has a graft density between about 0.1 and about 25 mole percent;
(2) adding one or more polyelectrolytes to form a polyelectrolyte-copolymer mixture;
(3) optionally adding an aqueous mixture containing a liposome which optionally comprises a further therapeutic agent, to form a liposome-containing polyelectrolyte-copolymer mixture; and
(4) allowing said polyelectrolyte-copolymer mixture or said liposome-containing polyelectrolyte-copolymer mixture to self-assemble in the aqueous medium to form said complex, which further forms nanoparticles.

15. A method of treating a patient in need thereof with a polyelectrolyte therapeutic agent comprising the steps of:
(1) formulating the complex of claim 1 with one or more pharmaceutically acceptable carriers to provide a pharmaceutical composition; and
(2) administering said pharmaceutical composition to said patient in an amount effective to treat said patient.

16. The method of claim 15 , wherein said anionic, cationic or polyelectrolyte therapeutic agent is selected from the group consisting of antibacterial agents, anticancer agents, wound treatment agents and tissue regeneration agents.

17. The method of claim 15 , wherein the administration is via oral, enteral, parenteral or topical delivery.

18. The method of claim 15 , wherein said pharmaceutical composition is selected from the group consisting of injectable aqueous solutions, injectable aqueous dispersions, emulsions, gels, pastes, aerosols, sprays, coatings, hydrogels, topical creams, topical ointments, natural polymeric fibers, synthetic polymeric fibers, porous ceramics, polymeric composites, ceramic composites, and wound treatment compositions.

19. The method of claim 14 , wherein said copolymer has a graft density between about 0.5 and about 5 mole percent.

Assignees

• Univ Rutgers
• Us Army Secretary Of The Army

Inventors

• Devore David
• Roth Charles

Classifications

• C08G81/025

  containing polyether sequences · CPC title

• C08F265/02

  on to polymers of acids, salts or anhydrides · CPC title

• A61K47/6911

  the form being a liposome · CPC title

• A61K31/70 Primary

  Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047) · CPC title

• A61K9/1272

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title