Acid-degradable and bioerodible modified polyhydroxylated materials

Patent metadata

Field	Value
Publication number	US-9644039-B2
Application number	US-98767911-A
Country	US
Kind code	B2
Filing date	Jan 10, 2011
Priority date	Mar 24, 2006
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

Compositions and methods of making a modified polyhydroxylated polymer comprising a polyhydroxylated polymer having reversibly modified hydroxyl groups, whereby the hydroxyl groups are modified by an acid-catalyzed reaction between a polydroxylated polymer and a reagent such as acetals, aldehydes, vinyl ethers and ketones such that the modified polyhydroxylated polymers become insoluble in water but freely soluble in common organic solvents allowing for the facile preparation of acid-sensitive materials. Materials made from these polymers can be made to degrade in a pH-dependent manner. Both hydrophobic and hydrophilic cargoes were successfully loaded into particles made from the present polymers using single and double emulsion techniques, respectively. Due to its ease of preparation, processability, pH-sensitivity, and biocompatibility, of the present modified polyhydroxylated polymers should find use in numerous drug delivery applications.

First claim

What is claimed is:

1. A composition comprising
a modified polyhydroxylated polymer comprising pendant hydroxyl groups, wherein at least 20% of the pendant hydroxyl groups are directly linked to a functional group selected from the group consisting of acetal, aromatic acetal, and ketal, wherein said functional group renders the modified polyhydroxylated polymer acid-degradable and pH sensitive and substantially insoluble in water; and
a bioactive material conjugated to or entrapped within the modified polyhydroxylated polymer, wherein the bioactive material is a drug or agent.

2. The composition of claim 1 , wherein at least 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or 100% of the hydroxyl groups in the polymer are directly linked to a functional group.

3. The composition of claim 1 , wherein the functional group is an acetal.

4. The composition of claim 1 , wherein said polymers form particles, sutures, bulk materials, tissue engineering scaffolds, or implants.

5. The composition of claim 1 , wherein the polyhydroxylated polymers are preformed polymers or hydroxyl-containing polymers selected from the group consisting of, multiply-hydroxylated polymers, polysaccharides, carbohydrates, polyols, polyvinyl alcohol, poly amino acids, polyserine, and 2-(hydroxyethyl)methacrylate.

6. The composition of claim 5 , wherein the polyhydroxylated polymers are polysaccharides.

7. The composition of claim 6 , wherein the polysaccharides are selected from the group consisting of dextran, mannan, pullulan, maltodextrin, starches, cellulose and cellulose derivatives, xanthan gum, locust bean gum, and pectin.

8. The composition of claim 7 , wherein the polysaccharides are dextran or mannan.

9. The composition of claim 1 , wherein the modified polyhydroxylated polymers are modified polysaccharides with pendant acetals, thus providing acetal-derivatized polysaccharides.

10. The composition of claim 9 , wherein the acetal-derivatized polysaccharides are acetal-derivatized dextran, acetal-derivatized mannan or acetal-derivatized polyvinyl alcohols.

11. The composition of claim 4 , wherein the modified polyhydroxylated polymers release the bioactive material conjugated or entrapped therein after exposure to mildly acidic conditions.

12. The composition of claim 1 , wherein the bioactive material drug or agent is selected from the group consisting of polynucleotides, polypeptides, proteins, peptides, antibodies, vaccines, antigens, small molecule drugs, ribonucleotides, amino acids, oligopeptides, peptoids, proteins, plasmid DNA, growth factors and hormones, interleukins, immunostimulatory agents, neurotransmitters, neurostimulatory agents, adrenergic agents, neuromodulatory agents, enzymes, proteases, anticancer agents, antitumor agents, imaging agents, diagnostic agents, antiviral agents, antibacterial agents and therapeutic agents.

13. The composition of claim 12 , wherein the bioactive material is a polynucleotide.

14. The composition of claim 12 , wherein the bioactive material is a therapeutic agent.

15. The composition of claim 12 , wherein the bioactive material is a vaccine.

16. An acid-degradable modified polyhydroxylated polymer comprising a polyhydroxylated polymer having modified pendant hydroxyl groups, wherein the hydroxyl groups are directly linked to acid degradable, pH-sensitive functional groups, whereby the functional groups remain stable in plasma at pH of about 7.4, and degrade by hydrolysis at about pH 5.0-6.0, thereby resulting in degradation upon hydrolysis, wherein the modified polyhydroxylated polymer is substantially insoluble in water.

17. The acid-degradable modified polyhydroxylated polymer of claim 16 wherein the polyhydroxylated polymer is a polysaccharide.

18. The composition of claim 17 , wherein the polysaccharides are dextran or mannan.

19. The acid-degradable modified polyhydroxylated polymer of claim 17 , wherein the polymer is a bioactive material, whereupon the bioactive material is released in response to mildly acidic conditions, found in the body in tumors, inflammatory tissues and in cellular compartments, lysosomes and phagolysosomes of antigen presenting cells.

20. The acid-degradable modified polyhydroxylated polymer of claim 19 , wherein the bioactive material is selected from the group comprising of antigens, proteins, polynucleotides, polypeptides, small drug molecules and other bioactive material having a physiological effect on a cell.

21. The acid-degradable modified polyhydroxylated polymer of claim 19 , wherein the polymer forms particles for delivery to a cell.

22. The acid-degradable modified polyhydroxylated polymer of claim 21 , wherein the particle size is 10 nm to 50 μm.

23. The acid-degradable modified polyhydroxylated polymer of claim 22 , wherein the particle size is 10 nm to 2000 nm.

24. The acid-degradable modified polyhydroxylated polymer of claim 23 , wherein the particle size is 40 to 300 nm.

25. The acid-degradable modified polyhydroxylated polymer of claim 21 , wherein the polymer forms or coats sutures, scaffolds, stents and other implantable polymer materials.

26. The acid-degradable modified polyhydroxylated polymer of claim 19 , wherein the bioactive materials are encapsulated in or conjugated to the polymer in bulk materials, scaffolds, coated stents and other implantable devices.

27. A composition comprising a modified polyhydroxylated polymer comprising a polyhydroxylated polymer having (a) modified pendant hydroxyl groups, whereby at least 20% to 85%, of the hydroxyl groups are directly linked to acid degradable, pH-sensitive functional groups, and (b) a bioactive material conjugated or entrapped therein, wherein the bioactive material is a drug or agent, wherein the polyhydroxylated polymer forms a drug-delivery material that delivers said drug or agent, and wherein the modified polyhydroxylated polymer is substantially insoluble in water.

28. The composition of claim 27 wherein the polyhydroxylated polymer is a polysaccharide.

29. The composition of claim 28 wherein the polysaccharide is selected from the group consisting of dextran, mannan, pullulan, maltodextrin, starches, cellulose and cellulose derivatives, xanthan gum, locust bean gum, and pectin.

30. The composition of claim 29 , wherein the polysaccharide is dextran.

31. The composition of claim 27 , wherein said polymers form particles, bulk materials, tissue engineering scaffolds, or implants.

32. The acid-degradable modified polyhydroxylated polymer of claim 30 , whereupon the bioactive material is released in response to mildly acidic conditions found in the body in tumors, inflammatory tissues and in cellular compartments, lysosomes and phagolysosomes of antigen presenting cells, and the polymer is degraded.

33. A composition comprising an acetal modified polyhydroxylated processed polymer and a bioactive material conjugated to or entrapped therein, said processed polymer comprising a polyhydroxylated polymer having about 75-85% of its hydroxyl groups directly linked to acetals, whereby said acetals allows said composition to be soluble in organic solvents and insoluble in water and to form excretable and degradable products, wherein said modified polyhydroxylated polymer forms particles in the presence of a bioactive materi

Assignees

• Frechet Jean M J
• Bachelder Eric M
• Beaudette Tristan T
• Broaders Kyle E
• Univ California

Inventors

• Frechet Jean M J
• Bachelder Eric M
• Beaudette Tristan T
• Broaders Kyle E

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P37/04

  Immunostimulants · CPC title

• C08B37/14

  Hemicellulose; Derivatives thereof (not used) · CPC title

• C08L1/02

  Cellulose; Modified cellulose · CPC title