In situ solidifying solutions and methods of making and using thereof
Described herein are fluid complex coacervates that produce solid adhesives in situ. Oppositely charged polyelectrolytes were designed to form fluid adhesive complex coacervates at ionic strengths higher than the ionic strength of the application site, but an insoluble adhesive solid or gel at the application site. When the fluid, high ionic strength adhesive complex coacervates are introduced into the lower ionic strength application site, the fluid complex coacervate is converted to a an adhesive solid or gel as the salt concentration in the complex coacervate equilibrates to the application site salt concentration. In one embodiment, the fluid complex coacervates are designed to solidify in situ at physiological ionic strength and have numerous medical applications. In other aspects, the fluid complex coacervates can be used in aqueous environment for non-medical applications.
1. An injectable solution comprising water, at least one polycation, at least one polyanion, and a concentration of monovalent ions in water sufficient to prevent association of the polycation and polyanion, wherein the concentration of the monovalent ions in the injectable solution is greater than the concentration of the monovalent ions at an application site, whereupon introduction of the injectable solution at the application site a solid or gel is produced in situ,
wherein the total positive/negative charge ratio of the polycation to the polyanion is from 4 to 0.25 and the concentration of each monovalent ion in the injectable solution is from 0.5 M to 2.0 M.
2. The injectable solution of claim 1 , wherein the concentration of the monovalent ions in the injectable solution is 1.5 to 10 times greater than the concentration of the monovalent ions at the application site.
3. The injectable solution of claim 1 , wherein the monovalent ions in the solution are sodium ions and chloride ions.
4. The injectable solution of claim 1 , wherein the polycation comprises a biodegradable polyamine comprising a polysaccharide, a protein, a recombinant protein, a synthetic polyamine, a protamine, a branched polyamine, or an amine-modified natural polymer.
5. The injectable solution of claim 4 , wherein the branched polyamine comprises a dendrimer having 3 to 20 arms, wherein each arm comprises a terminal amino group.
6. The injectable solution of claim 1 , wherein the polycation comprises a polyacrylate comprising two or more pendant amino groups, wherein the amino group comprises a primary amino group, a secondary amino group, tertiary amino group, a quaternary amine, an alkylamino group, a heteroaryl group, a guanidinyl group, an imidazole, or an aromatic group substituted with one or more amino groups.
7. The injectable solution of claim 1 , wherein the polycation comprises a polycationic micelle or a polycationic liposome.
8. The injectable solution of claim 1 , wherein the polycation is synthetic polyguanidinyl copolymer comprising an acrylate, methacrylate, acrylamide, or methacrylamide backbone and two or more guanidinyl groups pendant to the backbone.
9. The injectable solution of claim 1 , wherein the polyanion comprises a synthetic polymer or a naturally-occurring polymer comprising two or more carboxylate, sulfate, sulfonate, borate, boronate, phosphonate, or phosphate groups.
10. The injectable solution of claim 1 , wherein the polyanion comprises a glycosaminoglycan or an acidic protein.
11. The injectable solution of claim 10 , wherein the glycosaminoglycan comprises chondroitin sulfate, heparin, heparin sulfate, dermatan sulfate, keratin sulfate, or hyaluronic acid.
12. The injectable solution of claim 1 , wherein the polyanion comprises a polymer comprising anionic groups pendant to the backbone of the polymer, incorporated in the backbone of the polymer backbone, or a combination thereof.
13. The injectable solution of claim 1 , wherein the polyanion is a copolymer comprising two or more fragments having the formula XI
wherein R 4 is hydrogen or an alkyl group;
n is from 1 to 10;
Y is oxygen, sulfur, or NR 30 , wherein R 30 is hydrogen, an alkyl group, or an aryl group;
Z′ is carboxylate, sulfate, sulfonate, borate, boronate, a substituted or unsubstituted phosphate or phosphonate.
14. The injectable solution of claim 1 , wherein the polyanion comprises a polyphosphate, wherein the polyphosphate comprises a natural polymer or a synthetic polymer.
15. The injectable solution of claim 14 , wherein the polyphosphate is the copolymerization product between a phosphate acrylate and/or phosphate methacrylate with one or more additional polymerizable monomers.
16. The injectable solution of claim 1 , wherein the polyanion has from 3-10 phosphate groups.
17. The injectable solution of claim 1 , wherein the polyanion is an inorganic polyphosphate, a phosphorylated sugar, or a polyphosphoserine.
18. The injectable solution of claim 1 , wherein the polyanion is inositol hexaphosphate.
19. The injectable solution of claim 1 , wherein the polyanion comprises a hexametaphosphate salt.
20. The injectable solution of claim 1 , wherein the polyanion is the copolymerization product between a phosphate or phosphonate acrylate or phosphate or phosphonate methacrylate with one or more additional polymerizable monomers.
21. The injectable solution of claim 1 , wherein the injectable solution further comprises a contrast agent or a visualization agent.
22. The injectable solution of claim 21 , wherein the contrast agent comprises tantalum particles, gold particles, or an iodine complex.
23. The injectable solution of claim 21 , wherein the contrast agent comprises tantalum particles having a particle size of from 0.5 μm to 50 μm and is from 10 wt % to 60 wt % of the solution.
24. The solution of claim 1 , wherein the injectable solution further comprises a reinforcing component, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, a nanoparticle, or a microparticle.
25. The injectable solution of claim 1 , wherein the injectable solution further comprises one or more bioactive agents, wherein the bioactive agent comprises an antibiotic, a pain reliever, an immune modulator, a growth factor, an enzyme inhibitor, a hormone, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapy agent, a receptor antagonist, a nucleic acid, or any combination thereof.
26. A method for producing a solid or gel in a subject in situ comprising introducing into the subject the injectable solution of claim 1 , wherein the concentration of the monovalent ions in the solution is greater than the concentration of the monovalent ions in the subject, wherein upon introduction of the injectable solution into the subject the solution is converted to a solid or gel in situ.
27. A method for producing a bioactive eluting depot in the subject comprising injecting into the subject the injectable solution of claim 26 .
28. A method for reducing or inhibiting blood flow in a blood vessel of a subject comprising introducing into the vessel the injectable solution of claim 1 , wherein the concentration of the monovalent ions in the solution is greater than the concentration of the monovalent ions in the blood vessel of the subject, whereupon introduction of the injectable solution into the vessel the injectable solution is converted to a solid in situ within the vessel.
29. The method of claim 28 , wherein the method reduces or inhibits blood flow to a tumor, an aneurysm, a varicose vein, a vascular malformation, or a bleeding wound.
30. The method of claim 28 , wherein the method reinforces the inner wall of a blood vessel in the subject.