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Details for Patent: 5,639,473

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Details for Patent: 5,639,473

Title: Methods for the preparation of nucleic acids for in vivo delivery
Abstract:In accordance with the present invention, there are provided compositions useful for the in vivo delivery of a biologic, wherein the biologic is associated with a polymeric shell formulated from a biocompatible material. The biologic can be associated with the polymeric shell itself, and/or the biologic, optionally suspended/dispersed in a biocompatible dispersing agent, can be encased by the polymeric shell. In another aspect, the biologic associated with polymeric shell is administered to a subject, optionally dispersed in a suitable biocompatible liquid.
Inventor(s): Grinstaff; Mark W. (Pasadena, CA), Soon-Shiong; Patrick (Los Angeles, CA), Wong; Michael (Champaign, IL), Sandford; Paul A. (Los Angeles, CA), Suslick; Kenneth S. (Champaign, IL), Desai; Neil P. (Los Angeles, CA)
Assignee: Vivorx Pharmaceuticals, Inc. (Santa Monica, CA)
Filing Date:Jun 07, 1995
Application Number:08/483,295
Claims:1. A method for the preparation of articles for in vivo delivery of nucleic acid constructs, said method comprising subjecting aqueous medium containing biocompatible material capable of being crosslinked by disulfide bonds and nucleic acid construct to high intensity ultrasound conditions for a time sufficient to promote crosslinking of said biocompatible material by disulfide bonds;

wherein said nucleic acid construct is substantially completely contained within a polymeric shell, and

wherein the largest cross-sectional dimension of said shell is no greater than about 10 microns.

2. The method according to claim 1, wherein said biocompatible material is a naturally occurring polymer, a synthetic polymer, or a combination thereof,

wherein said polymer, prior to crosslinking, has covalently attached thereto sulfhydryl groups or disulfide linkages.

3. The method according to claim 2, wherein said naturally occurring polymer is selected from proteins containing sulfhydryl groups and/or disulfide groups, polypeptides containing sulfhydryl groups and/or disulfide groups, lipids containing sulfhydryl groups and/or disulfide groups, polynucleic acids containing sulfhydryl groups and/or disulfide groups, or polysaccharides containing sulfhydryl groups and/or disulfide groups.

4. The method according to claim 3, wherein said protein is selected from hemoglobin, myoglobin, albumin, insulin, lysozyme, immunoglobulins, .alpha.-2-macroglobulin, fibronectin, vitronectin, fibrinogen, or combinations of any two or more thereof.

5. The method according to claim 4, wherein said protein is albumin.

6. The method according to claim 4, wherein said protein is hemoglobin.

7. The method according to claim 4, wherein said protein is a combination of albumin and hemoglobin.

8. The method according to claim 3, wherein said polysaccharides are selected from alginate, high M-content alginates, polymannuronic acid, polymannuronates, hyaluronic acid, hyaluronate, heparin, dextran, chitosan, chitin, cellulose, starch, glycogen, guar gum, locust bean gum, dextran, levan, inulin, cyclodextrin, agarose, xanthan gum, carrageenan, heparin, pectin, gellan gum, scleroglucan, or combinations of any two or more thereof.

9. The method according to claim 2, wherein said synthetic polymer is selected from synthetic polyamino acids containing cysteine residues and/or disulfide groups, synthetic polypeptides containing sulfhydryl groups and/or disulfide groups, polyvinyl alcohol modified to contain free sulfhydryl groups and/or disulfide groups, polyhydroxyethyl methacrylate modified to contain free sulfhydryl groups and/or disulfide groups, polyacrylic acid modified to contain free sulfhydryl groups and/or disulfide groups, polyethyloxazoline modified to contain free sulfhydryl groups and/or disulfide groups, polyacrylamide modified to contain free sulfhydryl groups and/or disulfide groups, polyvinyl pyrrolidinone modified to contain free sulfhydryl groups and/or disulfide groups, polyalkylene glycols modified to contain free sulfhydryl groups and/or disulfide groups, as well as mixtures of any two or more thereof.

10. The method according to claim 1, wherein said polymeric shell is modified by a suitable agent, wherein said suitable agent is selected from a synthetic polymer, phospholipid, a protein, a polysaccharide, a surface active agent, a chemical modifying agent, or combination thereof, wherein said agent is associated with said polymeric shell through an optional covalent linkage.

11. The method according to claim 10, wherein said synthetic polymer is selected from polyalkylene glycols, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylic acid, polyethyloxazoline, polyacrylamide, or polyvinyl pyrrolidinone.

12. The method according to claim 10, wherein said phospholipid is selected from phosphatidyl choline (PC), phosphatidyl ethanolamine (PE), phosphatidyl inositol (PI), or sphingomyelin.

13. The method according to claim 10, wherein said protein is selected from an enzyme or antibody.

14. The method according to claim 10, wherein said polysaccharide is selected from starch, cellulose, dextrans, alginates, chitosan, pectin, or hyaluronic acid.

15. The method according to claim 10, wherein said chemical modifying agent is selected from pyridoxal 5'-phosphate, derivatives of pyridoxal, dialdehydes, or diaspirin esters.

16. The method according to claim 1, wherein said nucleic acid constructs are selected from IGF-1 encoding sequence, Factor VIII encoding sequence, Factor IX encoding sequence, or antisense nucleotide sequences.

17. The method according to claim 16, wherein said nucleic acid construct is an IGF-1 encoding sequence.

18. The method according to claim 16, wherein said nucleic acid construct is a Factor VIII encoding sequence.

19. The method according to claim 16, wherein said nucleic acid construct is a Factor IX encoding sequence.

20. The method according to claim 16, wherein said nucleic acid construct is an antisense nucleotide sequence.

21. The method according to claim 1, wherein said nucleic acid construct within said shell is dissolved or suspended in a biocompatible dispersing agent.

22. The method according to claim 21, wherein said biocompatible dispersing agent is selected from soybean oil, coconut oil, olive oil, safflower oil, cotton seed oil, aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms, aliphatic or aromatic alcohols having 2-30 carbon atoms, aliphatic or aromatic esters having 2-30 carbon atoms, alkyl, aryl, or cyclic ethers having 2-30 carbon atoms, alkyl or aryl halides having 1-30 carbon atoms, optionally having more than one halogen substituent, ketones having 3-30 carbon atoms, polyalkylene glycol, or combinations of any two or more thereof.

23. The method according to claim 21, wherein said dispersing agent comprises a volatile dispersing agent.

24. The method according to claim 23, wherein said volatile dispersing agent is selected from benzene, toluene, hexane, ethyl ether, dichloromethane, ethyl acetate, or combinations of any two or more thereof.

25. The method according to claim 1, wherein said polymeric shell containing said nucleic acid construct is suspended in a biocompatible medium, and wherein said biocompatible medium is selected from water, buffered aqueous media, saline, buffered saline, solutions of amino acids, solutions of proteins, solutions of sugars, solutions of vitamins, solutions of carbohydrates, solutions of synthetic polymers, lipid-containing emulsions, or combinations of any two or more thereof.

26. A method for the delivery of a nucleic acid construct to a subject in need thereof, said method comprising administering to said subject an article prepared by the method of claim 1 by oral, intravenous, subcutaneous, intraperitoneal, intraperitoneal, intrathecal, intramuscular, intracranial, inhalational, topical, transdermal, suppository (rectal), or pessary (vaginal) routes of administration.
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