Embolization using degradable crosslinked hydrogels
One aspect of the present invention relates to a method of temporarily embolizing a blood vessel using a hydrolytically degradable crosslinked hydrogel as an embolus. In certain embodiments, the hydrolytically degradable crosslinked hydrogel substantially hydrolyzes only at about physiological pH. In certain embodiments of the method, the hydrolytically degradable crosslinked hydrogel is stable at low pH. In certain embodiments of the method, the hydrolytically degradable crosslinked hydrogel comprises a marker molecule, such as a dye, radiopaque, or an MRI-visible compound. It is to be understood that both the foregoing general description and the following detailed description are exemplary, and are intended to provide further explanation of the invention as claimed.
1. A method of embolizing a vascular site in a mammal, comprising the step of:
introducing into the vasculature of a mammal a microparticle comprising a hydrolytically degradable crosslinked hydrogel, thereby embolizing a vascular site of said mammal; wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound selected from the group consisting of a compound of formula 1 and a compound of formula 2; the compound of formula 1 is represented by:
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR 2 ) n C(O)—, 2-alkylacryloylO(CR 2 ) n C(O)—, 3-alkylacryloylO(CR 2 ) n C(O)—, 2,3-dialkylacryloylO(CR 2 ) n C(O)—, 3,3-dialkylacryloylO(CR 2 ) n C(O)—, 2,3,3-trialkylacryloylO(CR 2 ) n C(O)—, (diene)C(O)—, (vinyl)(CR 2 ) n C(O)—, or (vinyl)ArC(O)—;
R represents independently for each occurrence H or alkyl;
Z represents (CR 2 ) n , (CR 2 ) n J(CR 2 ) m , or (CR 2 ) n Ar(CR 2 ) m ;
Ar represents independently for each occurrence aryl or heteroaryl;
J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH 2 CH 2 O) n , or (CH 2 CH 2 N(R)) n ;
n represents independently for each occurrence an integer in the range 1-10; and
m represents independently for each occurrence an integer in the range 0-10; and
the compound of formula 2 is represented by:
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR 2 ) n C(O)—, 2-alkylacryloylO(CR 2 ) n C(O)—, 3-alkylacryloylO(CR 2 ) n C(O)—, 2,3-dialkylacryloylO(CR 2 ) n C(O)—, 3,3-dialkylacryloylO(CR 2 ) n C(O)—, 2,3,3-trialkylacryloylO(CR 2 ) n C(O)—, (diene)C(O)—, (vinyl)(CR 2 ) n C(O)—, or (vinyl)ArC(O)—;
R represents independently for each occurrence H or alkyl;
Z represents (CR 2 ) n , (CR 2 ) n J(CR 2 ) m , or (CR 2 ) n Ar(CR 2 ) m ;
Ar represents independently for each occurrence aryl or heteroaryl;
J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH 2 CH 2 O) n , or (CH 2 CH 2 N(R)) n ;
G represents (CR (4-t) ), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the range 1-10; and
t represents 3 or 4.
2. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink that substantially hydrolyzes only at about physiological pH.
3. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink that does not substantially hydrolyze at a pH below about 5.
4. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises an acrylic acid, acrylate, or acrylamide.
5. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises acrylic acid, 2-hydroxyethyl acrylate, oligo(ethylene glycol) 2-methacrylate, acrylamide, N,N-dimethylacrylamide, or N-(tris(hydroxymethyl)methyl)acrylamide.
6. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a first acrylamide and a second acrylamide.
7. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a first acrylamide and a second acrylamide, wherein said first acrylamide is acrylamide or N,N-dimethylacrylamide.
8. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a first acrylamide and a second acrylamide, wherein said second acrylamide is N-(tris(hydroxymethyl)methyl)acrylamide.
9. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a first acrylamide and a second acrylamide, wherein said first acrylamide is acrylamide or N,N-dimethylacrylamide; and said second acrylamide is N-(tris(hydroxymethyl)methyl)acrylamide.
10. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises an acrylamide and an acrylate.
11. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises an acrylamide and an acrylate, wherein said acrylamide is acrylamide or N,N-dimethylacrylamide.
12. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises an acrylamide and an acrylate, wherein said acrylate is acrylic acid, 2-hydroxyethyl acrylate, or oligo(ethylene glycol) 2-methacrylate.
13. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises an acrylamide and an acrylate, wherein said acrylamide is acrylamide or N,N-dimethylacrylamide; and said acrylate is acrylic acid, 2-hydroxyethyl acrylate, or oligo(ethylene glycol) 2-methacrylate.
14. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a first acrylate and a second acrylate.
15. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a first acrylate and a second acrylate, wherein said first acrylate is acrylic acid, 2-hydroxyethyl acrylate, or oligo(ethylene glycol) 2-methacrylate.
16. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a first acrylate and a second acrylate, wherein said first acrylate is acrylic acid, 2-hydroxyethyl acrylate, or oligo(ethylene glycol) 2-methacrylate; and said second acrylate is acrylic acid, 2-hydroxyethyl acrylate, or oligo(ethylene glycol) 2-methacrylate.
17. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; and X represents O.
18. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; and L represents —NH—O-Q.
19. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; and Q represents acryloyl, or 2-methacryloyl.
20. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; and R represents H.
21. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; and Z represents (CR 2 ) n .
22. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; X represents O; and L represents —NH—O-Q.
23. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; X represents O; L represents —NH—O-Q; and Q represents acryloyl, or 2-methacryloyl.
24. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; X represents O; L represents —NH—O-Q; Q represents acryloyl, or 2-methacryloyl; and R represents H.
25. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; X represents O; L represents —NH—O-Q; Q represents acryloyl, or 2-methacryloyl; R represents H; and Z represents (CR 2 ) n .
26. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; and X represents O.
27. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; and M represents —NH—O-Q.
28. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; and Q represents acryloyl, or 2-methacryloyl.
29. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; and R represents H.
30. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; X represents O; and M represents —NH—O-Q.
31. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; X represents O; M represents —NH—O-Q; and Q represents acryloyl, or 2-methacryloyl.
32. The method of claim 1 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; X represents O; M represents —NH—O-Q; Q represents acryloyl, or 2-methacryloyl; and R represents H.
33. A method of embolizing a vascular site in a mammal, comprising the step of:
introducing into the vasculature of a mammal a microparticle comprising a hydrolytically degradable crosslinked hydrogel, thereby embolizing a vascular site of said mammal; wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound selected from the group consisting of a compound of formula 1 and a compound of formula 2; the compound of formula 1 is represented by:
wherein
X represents independently for each occurrence O or S;
L represents independently for each occurrence —O—NH-Q;
Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR 2 ) n C(O)—, 2-alkylacryloylO(CR 2 ) n C(O)—, 3-alkylacryloylO(CR 2 ) n C(O)—, 2,3-dialkylacryloylO(CR 2 ) n C(O)—, 3,3-dialkylacryloylO(CR 2 ) n C(O)—, 2,3,3-trialkylacryloylO(CR 2 ) n C(O)—, (diene)C(O)—, (vinyl)(CR 2 ) n C(O)—, or (vinyl)ArC(O)—;
R represents independently for each occurrence H or alkyl;
Z represents —NH(CR 2 ) n NH—, or —NH(CR 2 ) n J(CR 2 ) m NH—;
Ar represents independently for each occurrence aryl or heteroaryl;
J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH 2 CH 2 O) n , or (CH 2 CH 2 N(R)) n ;
n represents independently for each occurrence an integer in the range 1-10; and
m represents independently for each occurrence an integer in the range 0-10; and the compound of formula 2 is represented by:
wherein
X represents independently for each occurrence O or S;
M represents independently for each occurrence —O—NH-Q;
Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR 2 ) n C(O)—, 2-alkylacryloylO(CR 2 ) n C(O)—, 3-alkylacryloylO(CR 2 ) n C(O)—, 2,3-dialkylacryloylO (CR 2 ) n C(O)—, 3,3-dialkylacryloylO(CR 2 ) n C(O)—, 2,3,3-trialkylacryloylO(CR 2 ) n C(O)—, (diene)C(O)—, (vinyl)(CR 2 ) n C(O)—, or (vinyl)ArC(O)—;
R represents independently for each occurrence H or alkyl;
Z represents —NH(CR 2 ) n NH—, or —NH(CR 2 ) n J(CR 2 ) m NH—;
Ar represents independently for each occurrence aryl or heteroaryl;
J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH 2 CH 2 O) n , or (CH 2 CH 2 N(R)) n ;
G represents (CR (4-t) ), aryl, or heteroaryl;
n represents independently for each occurrence an integer in the range 1-10;
m represents independently for each occurrence an integer in the range 0-10; and
t represents 3 or 4.
34. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; and X represents O.
35. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; and Q represents acryloyl, or 2-methacryloyl.
36. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; and R represents H.
37. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; and Z represents —NH(CR 2 ) n NH—.
38. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; X represents O; L represents —O—NH-Q; and Q represents acryloyl, or 2-methacryloyl.
39. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; X represents O; L represents —O—NH-Q; Q represents acryloyl, or 2-methacryloyl; and R represents H.
40. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 1; X represents O; L represents —O—NH-Q; Q represents acryloyl, or 2-methacryloyl; R represents H; and Z represents —NH(CR 2 ) n NH—.
41. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; and X represents O.
42. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; and Q represents acryloyl, or 2-methacryloyl.
43. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; and R represents H.
44. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; X represents O; M represents —O—NH-Q; and Q represents acryloyl, or 2-methacryloyl.
45. The method of claim 33 , wherein said hydrolytically degradable crosslinked hydrogel comprises a crosslink derived from a compound of formula 2; X represents O; M represents —O—NH-Q; Q represents acryloyl, or 2-methacryloyl; and R represents H.
46. The method of claim 1 or 33 , wherein said vascular site is proximal to a hemorrhage, cancerous tissue, a uterine fibroid, a tumor, or an organ.
47. The method of claim 1 or 33 , wherein said hydrolytically degradable crosslinked hydrogel embolizes said vascular site for less than about three months.
48. The method of claim 1 or 33 , wherein said hydrolytically degradable crosslinked hydrogel embolizes said vascular site for less than about two months.
49. The method of claim 1 or 33 , wherein said hydrolytically degradable crosslinked hydrogel embolizes said vascular site for less than about one month.
50. The method of claim 1 or 33 , wherein said hydrolytically degradable crosslinked hydrogel embolizes said vascular site for less than about fourteen days.
51. The method of claim 1 or 33 , wherein said hydrolytically degradable crosslinked hydrogel embolizes said vascular site for less than about seven days.
52. The method of claim 1 or 33 , wherein said hydrolytically degradable crosslinked hydrogel embolizes said vascular site for less than about three days.
53. The method of claim 1 or 33 , wherein said hydrolytically degradable crosslinked hydrogel embolizes said vascular site for less than about one day.
54. The method of claim 1 or 33 , wherein said microparticle further comprises a contrast-enhancing agent.
55. The method of claim 54 , wherein said contrast-enhancing agent is selected from the group consisting of radiopaque materials, paramagnetic materials, heavy atoms, transition metals, lanthanides, actinides, dyes, and radionuclide-containing materials.
56. The method of claim 1 or 33 , wherein said microparticle further comprises a biologically active agent.
57. The method of claim 1 or 33 , wherein said mammal is a primate, equine, canine or feline.
58. The method of claim 1 or 33 , wherein said mammal is a human.
59. The method of claim 1 or 33 , wherein said microparticle is introduced into the vasculature of said mammal using a catheter.
60. The method of claim 1 or 33 , wherein said microparticle is a sphere, rod, plug, or coil.
61. The method of claim 1 or 33 , wherein said microparticle is a sphere.
62. The method of claim 61 , wherein the spherical microparticle has a diameter in the range of 10-5,000 μm inclusive.
63. The method of claim 61 , wherein the spherical microparticle has a diameter in the range of 40-3,000 μm inclusive.