Sustained-release nucleic acid matrix compositions
There are provided compositions for extended release of a nucleic acid agent, comprising a lipid-saturated matrix formed with a biodegradable polymer. Also provided are methods of producing the matrix compositions and methods for using the matrix compositions to provide controlled release of the nucleic acid agent.
1. A substrate at least a portion of the surface of which is coated by a matrix composition comprising:
a. a biocompatible polymer comprising a polyester;
b. a first lipid component comprising at least one lipid having a polar group;
c. a second lipid component comprising at least one phospholipid having fatty acid moieties of at least 14 carbons;
d. at least one nucleic acid based agent; and
e. polyethylene glycol (PEG);
wherein when maintained in an aqueous environment the matrix composition provides sustained and/or controlled release of the nucleic acid based agent.
2. The coated substrate of claim 1 , wherein the substrate to be coated includes at least one material selected from the group consisting of carbon fibers, stainless steel, cobalt-chromium, titanium alloy, tantalum, ceramic, collagen, gelatin and tri-calcium phosphate.
3. The coated substrate of claim 1 , wherein the PEG is a linear PEG having a molecular weight in the range of 1,000-10,000.
4. The coated substrate of claim 1 , wherein the lipid having a polar group is selected from the group consisting of a sterol, a tocopherol a phosphatidylethanolamine and derivatives thereof.
5. The coated substrate of claim 3 , wherein the sterol is cholesterol.
6. The coated substrate of claim 4 , wherein the cholesterol is present in an amount of 5-50mole percent of the total lipid content of said matrix composition.
7. The coated substrate of claim 1 , wherein the second lipid component comprises a phospholipid selected from the group consisting of phosphatidylcholine or a derivative thereof; a mixture of phosphatidylcholines or derivatives thereof; a phosphatidylethanolamine or a derivative thereof; and any combination thereof.
8. The coated substrate of claim 1 , further comprising a cationic lipid selected from the group consisting of DC-Cholesterol, 1,2-dioleoy-3-trimethylammonium-propane (DOTAP), Dimethyldioctadecylammonium (DDAB), 1,2-dilauroyl-sn-glycero-3-ethylphosphocholine (Ethyl PC), 1,2-di-O-octadecenyl -3-trimethylammonium propane (DOTMA) and any combination thereof.
9. The coated substarte of claim 1 , wherein the biocompatible polymer further comprises a non-biodegradable polymer.
10. The coated substrate of claim l, wherein the polyester is selected from the group consisting of PLA (polylactic acid), PGA (poly glycolic acid) PLGA (Poly (lactic co glycolic acid) and combinations thereof.
11. The coated substrate of claim 9 , wherein the non-biodegradable polymer is selected from the group consisting of polyethylene glycol (PEG), PEG acrylate, PEG methacrylate, methylmethacrylate, ethylmethacrylate, butylmethacrylate, 2-ethylhexylmethacrylate, laurylmethacrylate, hydroxylethyl methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC), polystyrene, derivatized polystyrene, polylysine, poly N-ethyl-4-vinyl-pyridinium bromide, poly-methylacrylate, silicone, polyoxymethylene, polyurethane, polyamides, polypropylene, polyvinyl chloride, polymethacrylic acid and combination thereof.
12. The coated substrate of claim 11 , wherein the biocompatible polymer comprises co-block of a biodegradable polyester and a non-biodegradable polymer.
13. The coated substrate of claim 1 , wherein the weight ratio of total lipids to the biodegradable polymer is between 1:1 and 9:1 inclusive.
14. The coated substrate of claim 1 , wherein said matrix composition is homogeneous.
15. The coated substrate of claim 1 , further comprising at least one compound selected from the group consisting of a sphingolipid, tocopherol, a free fatty acid having 14 or more carbon atoms, a pegylated lipid and an additional phospholipid selected from the group consisting of a phosphatidylserine, a phosphatidylglycerol, and a phosphatidylinositol.
16. The coated substrate of claim 1 wherein the nucleic acid based agent is selected from the group consisting of: plasmid DNA, linear DNA selected from poly and oligo-nucleotides, chromosomal DNA, messenger RNA (mRNA), antisense DNA/RNA, RNAi, siRNA, microRNA (miRNA), ribosomal RNA, oligonucleotide DNA (ODN) single and double strand, siRNA, imunostimulating sequence (ISS), locked nucleic acid (LNA) and ribozyme.
17. A method of administering a nucleic acid based agent to a subject in need thereof, said method comprising the step of administering to said subject a coated substrate according to claim 1 .
18. A method of producing the coated substrate of claim 1 comprising the steps of:
a. mixing into a first volatile organic solvent (i) a biocompatible polymer and (ii) a first lipid component comprising at least one lipid having a polar group;
b. mixing polyethylene glycol into a water-based solution of the nucleic acid agent;
c. mixing the solution obtained in step (b) with a second volatile organic solvent and a second lipid component comprising at least one phospholipid having fatty acid moieties of at least 14 carbons;
d. mixing the solutions obtained in steps (a) and (c) to form a homogeneous mixture;
e. mixing the homogeneous mixture obtained in step (d) with a substrate; and
f. removing the volatile solvents and water.
19. The method of claim 18 , wherein step (c) further comprises (i) removing the solvents by evaporation, freeze drying or centrifugation to form a sediment; and (ii) suspending the resulted sediment in the second volatile organic solvent.
20. The coated substrate of claim 1 , wherein at least 30% of said nucleic acid based agent is released from the composition at zero order kinetics.