Biodegradable poly(β-amino esters) and uses thereof
Poly(β-amino esters) prepared from the conjugate addition of bis(secondary amines) or primary amines to a bis(acrylate ester) are described. Methods of preparing these polymers from commercially available starting materials are also provided. These tertiary amine-containing polymers are preferably biodegradable and biocompatible and may be used in a variety of drug delivery systems. Given the poly(amine) nature of these polymers, they are particularly suited for the delivery of polynucleotides. Nanoparticles containing polymer/polynucleotide complexes have been prepared. The inventive polymers may also be used to encapsulate other agents to be delivered. They are particularly useful in delivering labile agents given their ability to buffer the pH of their surroundings. A system for preparing and screening polymers in parallel using semi-automated robotic fluid delivery systems is also provided.
1. A polymer of the formula:
wherein X is methyl, OR or NR2 NR 2 ;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyclic, heterocyclic, aryl, and heteroaryl;
each R′ is independently selected from the group consisting of hydrogen, C1-C6 C 1 -C 6 lower alkyl, C1-C6 C 1 -C 6 lower alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano, thiol, heteroaryl, aryl, phenyl, heterocyclic, carbocyclic, and halogen;
n is an integer between 3 and 10,000;
x is an integer between 1 5 and 10;
y is an integer between 1 and 10; and salts thereof.
2. The polymer of claim 1 , wherein the polymer is amine-terminated.
3. The polymer of claim 1 , wherein the polymer is acrylate-terminated.
4. The polymer of claim 1 , wherein x is an integer between 2 5 and 7.
5. The polymer of claim 1 , wherein x is 4 5.
6. The polymer of claim 1 , wherein x is 5 6.
7. The polymer of claim 1 , wherein x is 6 7.
8. The polymer of claim 1 , wherein y is an integer between 2 and 7.
9. The polymer of claim 1 , wherein y is 4.
10. The polymer of claim 1 , wherein y is 5.
11. The polymer of claim 1 , wherein y is 6.
12. The polymer of claim 1 , wherein R is hydrogen.
13. The polymer of claim 1 , wherein R is methyl, ethyl, propyl, butyl, pentyl, and hexyl.
14. The polymer of claim 1 , wherein the structure of the compound is
wherein R is hydrogen, x is 4, and y is 4.
15. The polymer of claim 1 , wherein the structure of the compound polymer is
wherein R is hydrogen, x is 6, and y is 4.
16. The polymer of claim 1 37, wherein the structure of the compound polymer is
wherein R is hydrogen, x is 4, and y is 5.
17. The polymer of claim 1 , wherein the structure of the compound polymer is
wherein R is hydrogen, x is 5, and y is 4.
18. The polymer of claim 1 , wherein the structure of the compound polymer is
wherein R is hydrogen, x is 5, and y is 5.
19. The polymer of claim 1 , wherein the structure of the compound polymer is
wherein R is hydrogen, x is 5, and y is 6.
20. A The polymer of claim 37 the formula:
wherein n is an integer between 3 and 10,000; and salts thereof.
21. The polymer of claim 1 , wherein the polymer has a molecular weight between 1,000 and 100,000 g/mol.
22. The polymer of claim 1 , wherein the polymer has a molecular weight between 2,000 and 40,000 g/mol.
23. A pharmaceutical composition comprising a polynucleotide and a polymer of claim 1 the formula:
wherein X is OR or NR 2 ;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyclic, heterocyclic, aryl, and heteroaryl;
each R′ is independently selected from the group consisting of hydrogen, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano, thiol, heteroaryl, aryl, phenyl, heterocyclic, carbocyclic, and halogen;
n is an integer between 3 and 10,000;
x is an integer between 1 and 10;
y is an integer between 1 and 10; and salts thereof.
24. A pharmaceutical composition comprising nanoparticles containing a polynucleotide and a polymer of claim 1 the formula:
wherein X is OR or NR 2 ;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyclic, heterocyclic, aryl, and heteroaryl;
each R′ is independently selected from the group consisting of hydrogen, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano, thiol, heteroaryl, aryl, phenyl, heterocyclic, carbocyclic, and halogen;
n is an integer between 3 and 10,000;
x is an integer between 1 and 10;
y is an integer between 1 and 10; and salts thereof.
25. A pharmaceutical composition comprising nanoparticles containing a pharmaceutical agent and a polymer of claim 1 the formula:
wherein X is OR or NR 2 ;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyclic, heterocyclic, aryl, and heteroaryl;
each R′ is independently selected from the group consisting of hydrogen, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano, thiol, heteroaryl, aryl, phenyl, heterocyclic, carbocyclic, and halogen;
n is an integer between 3 and 10,000;
x is an integer between 1 and 10;
y is an integer between 1 and 10; and salts thereof.
26. A pharmaceutical composition comprising microparticles containing pharmaceutical agent encapsulated in a matrix of a polymer of claim 1 the formula:
wherein X is OR or NR 2 ;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyclic, heterocyclic, aryl, and heteroaryl;
each R′ is independently selected from the group consisting of hydrogen, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano, thiol, heteroaryl, aryl, phenyl, heterocyclic, carbocyclic, and halogen;
n is an integer between 3 and 10,000;
x is an integer between 1 and 10;
y is an integer between 1 and 10; and salts thereof.
27. The pharmaceutical composition of claim 26 wherein the microparticles have a mean diameter of 1-10 micrometers.
28. The pharmaceutical composition of claim 26 wherein the microparticles have a mean diameter of less than 5 micrometers.
29. The pharmaceutical composition of claim 26 wherein the microparticles have a mean diameter of less than 1 micrometer.
30. The pharmaceutical composition of claim 26 wherein the pharmaceutical agent is a polynucleotide.
31. The pharmaceutical composition of claim 30 wherein the polynucleotide is DNA.
32. The pharmaceutical composition of claim 30 wherein the polynucleotide is RNA.
33. The pharmaceutical composition of claim 30 wherein the polynucleotide is an siRNA.
34. The pharmaceutical composition of claim 26 wherein the pharmaceutical agent is a small molecule.
35. The pharmaceutical composition of claim 26 wherein the pharmaceutical agent is a peptide.
36. The pharmaceutical composition of claim 26 wherein the pharmaceutical agent is a protein.
37. A polymer of the formula:
wherein X is methyl, OR, or NR 2 ;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyclic, heterocyclic, aryl, and heteroaryl;
each R′ is independently selected from the group consisting of hydrogen, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano, thiol, heteroaryl, aryl, phenyl, heterocyclic, carbocyclic, and halogen;
n is an integer between 3 and 10,000;
x is an integer between 1 and 10;
y is an integer between 6 and 10; and salts thereof.
38. The polymer of claim 37, wherein the polymer is amine-terminated.
39. The polymer of claim 37, wherein the polymer is acrylate-terminated.
40. The polymer of claim 37, wherein x is an integer between 2 and 7.
41. The polymer of claim 37, wherein x is 4.
42. The polymer of claim 37, wherein x is 5.
43. The polymer of claim 37, wherein x is 6.
44. The polymer of claim 37, wherein y is 6.
45. The polymer of claim 37, wherein y is 7.
46. The polymer of claim 37, wherein R is hydrogen.
47. The polymer of claim 37, wherein R is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
48. A polymer of the formula:
wherein X is methyl, OR, or NR 2 ;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyclic, heterocyclic, aryl, and heteroaryl;
each R′ is independently selected from the group consisting of hydrogen, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano, thiol, heteroaryl, aryl, phenyl, heterocyclic, carbocyclic, and halogen; wherein at least one R′ is independently selected from the group consisting of C 1 -C 6 lower alkoxy, hydroxy, amino, alkylamino, dialkylamino, cyano, thiol, heteroaryl, aryl, phenyl, heterocyclic, carbocyclic, and halogen;
n is an integer between 3 and 10,000;
x is an integer between 1 and 10;
y is an integer between 1 and 10; and salts thereof.
49. The polymer of claim 48, wherein the polymer is amine-terminated.
50. The polymer of claim 48, wherein the polymer is acrylate-terminated.
51. The polymer of claim 48, wherein x is an integer between 2 and 7.
52. The polymer of claim 48, wherein x is 4.
53. The polymer of claim 48, wherein x is 5.
54. The polymer of claim 48, wherein x is 6.
55. The polymer of claim 48, wherein y is an integer between 2 and 7.
56. The polymer of claim 48, wherein y is 4.
57. The polymer of claim 48, wherein y is 5.
58. The polymer of claim 48, wherein y is 6.
59. The polymer of claim 48, wherein R is hydrogen.
60. The polymer of claim 48, wherein R is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
61. The polymer of claim 1, wherein X is methyl.
62. The polymer of claim 1, wherein X is OR.
63. The polymer of claim 1, wherein X is NR 2 .
64. The polymer of claim 37, wherein X is methyl.
65. The polymer of claim 37, wherein X is OR.
66. The polymer of claim 37, wherein X is NR 2 .
67. The polymer of claim 48, wherein X is methyl.
68. The polymer of claim 48, wherein X is OR.
69. The polymer of claim 48, wherein X is NR 2 .