Nucleotide-based prodrugs
First Claim
1. A nucleotide-based prodrug comprising a nucleotide component covalently bonded via a physiologically hydrolyzable junctional ester bond to a drug component;
- wherein said nucleotide-based prodrug is selected from a compound having the following formula;
wherein X is independently selected from the group consisting of a drug with a hydroxyl group, a drug with a carboxyl group and H;
R is independently selected from the group consisting of H, OH, F, OCH3 and NH2;
N is independently selected from the group consisting of any base or modification or analog thereof, or non-nucleoside drug selected from the group consisting of ceramide or analogs thereof, vitamin D or analogs thereof and retinoids;
Z is selected from a lipid bilayer vesicle or a macromolecular support; and
n=1-150.
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Accused Products
Abstract
This invention relates to nucleotide-based prodrugs and their drug-delivery applications. The nucleotide-based prodrugs of the present invention comprise a drug component covalently attached via junctional ester bond(s) to one or more nucleotide components. Release and activation of the drug component of a nucleotide-based prodrug arises from hydrolysis of the junctional ester bond joining the nucleotide component to the drug component. The active drug component may be a nucleoside analog, a nucleic acid ligand, or a non-nucleoside drug. The nucleotide component provides a means of targeting and/or anchoring the nucleotide-based prodrug to the desired tissue compartment and/or a mechanism of sustained release of the active drug, thereby providing for a more effective drug delivery system with reduced toxicity. The targeting and/or anchoring of the nucleotide-based prodrugs to the desired tissue can be achieved through several methods, including employing a nucleic acid ligand as the nucleotide component, and/or by incorporating photocrosslinkable bases into the nucleotide component, and/or by covalently bonding the nucleotide component to a macromolecular support. The invention further includes lipid constructs comprising a nucleotide-based prodrug.
41 Citations
38 Claims
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1. A nucleotide-based prodrug comprising a nucleotide component covalently bonded via a physiologically hydrolyzable junctional ester bond to a drug component;
- wherein said nucleotide-based prodrug is selected from a compound having the following formula;
wherein X is independently selected from the group consisting of a drug with a hydroxyl group, a drug with a carboxyl group and H;
R is independently selected from the group consisting of H, OH, F, OCH3 and NH2;
N is independently selected from the group consisting of any base or modification or analog thereof, or non-nucleoside drug selected from the group consisting of ceramide or analogs thereof, vitamin D or analogs thereof and retinoids;
Z is selected from a lipid bilayer vesicle or a macromolecular support; and
n=1-150. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 38)
a) preparing a candidate mixture of nucleic acids;
b) contacting the candidate mixture with a target, wherein nucleic acids having an increased affinity to the target relative to the total candidate mixture may be partitioned from the remainder of the candidate mixture;
c) partitioning the increased affinity nucleic acids from the remainder of the nucleic acids in the candidate mixture; and
d) amplifying the increased affinity nucleic acids to yield a mixture of nucleic acids enriched for sequences with increased affinity for the target, whereby a nucleic acid ligand may be identified.
- wherein said nucleotide-based prodrug is selected from a compound having the following formula;
-
5. The nucleotide-based prodrug of claim 4 wherein said target is a tissue target.
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6. The nucleotide-based prodrug of claim 5 wherein said tissue target is diseased.
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7. The nucleotide-based prodrug of claim 1 wherein said drug component comprises one or more nucleoside analogs.
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8. The nucleotide-based prodrug of claim 7 wherein said nucleoside analog is covalently bonded to said nucleotide component via a junctional phosphodiester bond.
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9. The nucleotide-based prodrug of claim 1 wherein said non-nucleoside drug is covalently bonded to said nucleotide component via a junctional carbonyl ester bond.
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10. The nucleotide-based prodrug of claim 1 wherein said non-nucleoside drug is covalently bonded to said nucleotide component via a junctional phosphodiester bond.
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11. The nucleotide-based prodrug of claim 1 wherein said drug component is a lipophilic compound.
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12. The nucleotide-based prodrug of claim 1 wherein said lipid bilayer vesicle is a liposome.
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13. The nucleotide-based prodrug of claim 1 wherein said drug component is covalently bonded to the 5′
- -end of the nucleotide component.
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14. The nucleotide-based prodrug of claim 1 wherein said drug component is covalently bonded to the 3′
- -end of the nucleotide component.
-
16. The nucleotide-based prodrug of claim 1 wherein said nucleotide component is comprised of 2′
- -ribose modifications.
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17. The nucleotide-based prodrug of claim 1 wherein said macromolecular support is a biocomparible polymer.
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18. The nucleotide-based prodrug of claim 1 wherein said macromolecular support is selected from the group consisting of polylactic acid, polyglycolic acid, poly(ε
- -caprolactone), poly(β
-hydroxybutyrate), poly(β
-hydroxyvalerate), polydioxanone, poly(ethylene terephthalate), poly(malic acid), poly(tartronic acid), poly(ortho esters), polyanhydrides, polycyanoacrylates, poly(phosphoesters), polyphosphazenes, hyaluronidate, polysulfones, polyacrylamides, polymethacrylate, CarboPol, hydroxyapaptite, chimeric recombinant elastin-silk protein and collagen.
- -caprolactone), poly(β
-
38. The nucleotide-based prodrug of claim 1, wherein N is independly selected from the group of compounds having the following structural formulas:
-
wherein Y is independently selected from the group consisting of Br, I, F, N3, CH2CHBr, CH2CHI, 4-thiouridine and cytosine arabinoside.
-
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15. A nucleotide-based prodrug comprising a nucleotide component covalently bonded via a physiologically hydrolyzable junctional ester bond to a drug component;
- wherein said nucleotide-based prodrug is selected from a compound having the following formula;
wherein X is independently selected from the group consisting of a drug with a hydroxyl group, a drug with a carboxyl group and H;
R is independently selected from the group consisting of H, OH, F, OCH3 and NH2;
N is a photocrosslinkable base; and
n=1-150.
- wherein said nucleotide-based prodrug is selected from a compound having the following formula;
-
19. A method of preparing a nucleotide-based prodrug;
- wherein said nucleotide-based prodrug is selected from a compound having the following formula;
wherein X is independently selected from the group consisting of a drug with a hydroxyl group, a drug with a carboxyl group and H;
R is independently selected from the group consisting of H, OH, F, OCH3 and NH2;
N is independently selected from the group consisting of any base of modification or analog thereof, or non-nucleoside drug selected from the group consisting of ceramide and analogs thereof, vitamin D and analogs thereof and retinoids;
Z is selected from a lipid bilayer vesicle or a macromolecular support; and
n=1-150, said method comprising covalently bonding a nucleotide component to a drug component via a physiologically hydrolyzable junctional ester bond. - View Dependent Claims (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 36, 37)
a) preparing a candidate mixture of nucleic acids;
b) contacting the candidate mixture with a target, wherein nucleic acids having an increased affinity to the target relative to the total candidate mixture may be partitioned from the remainder of the candidate mixture;
c) partitioning the increased affinity nucleic acids from the remainder of the nucleic acids in the candidate mixture; and
d) amplifying the increased affinity nucleic acids to yield a mixture of nucleic acids enriched for sequences with increased affinity for the target, whereby a nucleic acid ligand may be identified.
- wherein said nucleotide-based prodrug is selected from a compound having the following formula;
-
23. The method of claim 22 wherein said target is a tissue target.
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24. The method of claim 23 wherein said tissue target is diseased.
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25. The method of claim 19 wherein said drug component comprises one or more nucleoside analogs.
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26. The method of claim 25 wherein said nucleoside analog is covalently bonded to said nucleotide component via a junctional phosphodiester bond.
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27. The method of claim 19 wherein said drug component comprises a non-nucleoside drug.
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28. The method of claim 19 wherein said non-nucleoside drug is covalently bonded to said nucleotide component via a junctional carbonyl ester bond.
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29. The method of claim 19 wherein said non-nucleoside drug is covalently bonded to said nucleotide component via a junctional phosphodiester bond.
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30. The method of claim 19 wherein said drug component is a lipophilic compound.
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31. The method of claim 19 wherein said lipid bilayer vesicle is a liposome.
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32. The method of claim 19 wherein said drug component is covalently bonded to the 5′
- -end of the nucleotide component.
-
33. The method of claim 19 wherein said drug component is covalently bonded to the 3′
- -end of the nucleotide component.
-
35. The method of claim 19 wherein said nucleotide component is comprised of 2′
- -ribose modifications.
-
36. The method of claim 19 wherein said macromolecular support is a biocompatible polymer.
-
37. The method of claim 19 wherein said macromolecular support is selected from the group consisting of polylactic acid, polyglycolic acid, poly(ε
- -caprolactone), poly(β
-hydroxybutyrate), poly(β
-hydroxyvalerate), polydioxanone, poly(ethylene terephthalate), poly(malic acid), poly(tartronic acid), poly(ortho esters), polyanhydrides, polycyanoacrylates, poly(phosphoesters), polyphosphazenes, hyaluronidate, polysulfones, polyacrylamides, polymethacrylate, CarboPol, hydroxyapaptite, chimeric recombinant elastin-silk protein and collagen.
- -caprolactone), poly(β
-
34. A method of preparing a nucleotide-based prodrug;
- wherein said nucleotide-based prodrug is selected from a compound having the following formula;
wherein X is independently selected from the group consisting of a drug with a hydroxyl group, a drug with a carboxyl group and H;
R is independently selected from the group consisting of H, OH, F, OCH3 and NH2;
N is a photocrosslinkable base; and
n=1-150.
- wherein said nucleotide-based prodrug is selected from a compound having the following formula;
Specification