Injectable preformed macroscopic 3-dimensional scaffolds for minimally invasive administration

• US 10,045,947 B2
• Filed: 04/27/2012
• Issued: 08/14/2018
• Est. Priority Date: 04/28/2011
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Bencherif, Sidi A., Mooney, David J., Edwards, David, Sands, Roger Warren
• Primary Examiner(s): Thakor, Devang K
• Application Number:
  US14/112,096
• Publication Number:
  US 20140112990A1
• Time in Patent Office: 2,300 Days
• CPC Class Codes: A61K 2039/55522 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/64 characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/258 Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
• CPC Class Codes: A61L 2300/64 Animal cells
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 2400/16 Materials with shape-memory or superelastic properties
• CPC Class Codes: A61L 2430/34 for soft tissue reconstruction
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: C08L 5/04 Alginic acid; Derivatives thereof

Abstract

The invention provides polymer compositions for cell and drug delivery.

Claims

1. An injectable cell-compatible highly crosslinked cryogel composition comprising open interconnected pores,

wherein said cryogel composition comprises at least 75% pores, and wherein said cryogel composition is characterized by shape memory following deformation by compression through a needle, such that said cryogel composition returns to its original undeformed three-dimensional shape less than one second after compression through the needle, and

wherein said cryogel composition comprises a cryo-crosslinked alginate polymer, wherein said alginate is methacrylated.

2. The cryogel composition of claim 1, comprising at least 90% pores.

3. The cryogel composition of claim 1, comprising at least 90% water when water is within said pores such that said cryogel is in a fully hydrated state.

4. The cryogel composition of claim 1, comprising less than 25% water when compressed.

5. The cryogel composition of claim 1, comprising a cell adhesion composition covalently attached to said polymer.

6. The cryogel composition of claim 5, wherein said cell adhesion composition comprises a peptide comprising an RGD amino acid sequence.

7. The cryogel composition of claim 1, comprising a eukaryotic cell in one or more of said open interconnected pores.

8. The cryogel composition of claim 7, wherein said eukaryotic cell comprises a live attenuated cancer cell.

9. The cryogel composition of claim 1, comprising a biomolecule in one or more of said open interconnected pores.

10. The cryogel composition of claim 9, wherein said biomolecule comprises a small molecule, nucleic acid, or protein.

11. The cryogel composition of claim 10, wherein said protein comprises granulocyte macrophage-colony stimulating factor (GM-CSF).

12. The cryogel composition of claim 10, wherein said nucleic acid comprises a CpG nucleic acid oligonucleotide.

13. The cryogel composition of claim 1, which is injectable through a hollow needle.

14. The cryogel composition of claim 1, wherein upon compression, said cryogel composition maintains structural integrity and shape memory properties.

15. The cryogel composition of claim 1, further comprising gelatin, heparin, dextran, carob gum, PEG, a PEG derivative, collagen, chitosan, carboxymethylcellulose, pullulan, PVA, PHEMA, PNIPAAm, or PAAc.

16. The cryogel composition of claim 1, comprising the shape of a disc, cylinder, square, rectangle, or string.

17. The cryogel composition of claim 1, which is between 100 μ

m³ to 100 mm³ in size.

18. A method for delivering genetic material to a tissue, comprising administering the cryogel composition of claim 1, wherein said cryogel composition further comprises a nucleic acid.

19. The method of claim 18, wherein said nucleic acid comprises plasmid DNA.

20. A method for eliciting an immune response, comprising administering to a subject the cryogel composition of claim 8.

21. The method of claim 20, wherein said cryogel composition is administered prophylactically or therapeutically.

22. The cryogel composition of claim 1, wherein the highly crosslinked cryogel composition comprises a crosslinking density of at least 50% polymer crosslinking.

23. The cryogel composition of claim 1, wherein the highly crosslinked cryogel composition comprises a crosslinking density of at least 50-100% polymer crosslinking.

24. The cryogel composition of claim 8, wherein said live attenuated cancer cell is a live attenuated melanoma cancer cell.

25. The cryogel composition of claim 4, which returns to its original undeformed three-dimensional shape after it is compressed by up to 90% of its volume.

26. The cryogel composition of claim 1, further comprising a tumor antigen.

27. A syringe comprising (i) a needle, (ii) a reservoir that comprises the cryogel composition of claim 1, and (iii) a plunger.

28. The syringe of claim 27, comprising a 16-gauge, an 18-gauge, a 22-gauge, a 24-gauge, a 26-gauge, a 28-gauge, a 30-gauge, a 32-gauge, or a 34-gauge needle.

29. The syringe of claim 27, comprising an 18 to 30-gauge needle.

30. The syringe of claim 28, wherein the device is between 1 mm³ to 50 mm³ in size.

31. The syringe of claim 28, therein the cryogel composition further comprises live attenuated cancer cells, wherein 90% or more of the cancer cells survive passage of the cryogel composition through the bore of the needle.

32. The syringe of claim 27, wherein the cryogel composition is filled with a physiologically-compatible solution, wherein said cryogel composition is characterized by shape memory following deformation by compression from the reservoir through the needle, such that said cryogel composition returns to its original undeformed three-dimensional shape less than one second after compression from the reservoir through the needle.

33. The cryogel composition of claim 1, wherein said cryogel composition comprises macropores having a diameter of 10 μ

m to 600 μ

m.

34. The syringe of claim 27, wherein said cryogel composition comprises macropores having a diameter of 10 μ

m to 600 μ

m.

35. The cryogel composition of claim 9, wherein said biomolecule comprises a pathogen-associated molecular pattern (PAMP).

36. The cryogel composition of claim 1, wherein said cryogel composition is characterized by shape memory following deformation by compression from a reservoir of a syringe, in which the cryogel composition is filled with a physiologically-compatible solution, through a needle of the syringe, such that said cryogel composition returns to its original undeformed three-dimensional shape less than one second after compression from the reservoir through the needle.

37. The cryogel composition of claim 1, wherein said cryogel composition comprises a Young'"'"'s modulus of 4±

2 kPa.

38. The syringe of claim 27, wherein the reservoir holds a liquid.

39. The syringe of claim 38, wherein the liquid is a physiologically-compatible solution.