Amphiphilic macromolecules for nucleic acid delivery
The invention provides amphiphilic macromolecules that are useful for delivering nucleic acids to cells and that are useful as delivery agents for gene therapy.
1. A compound of formula I:
wherein:
B is the group —NH(-A-NH—) n —(CH 2 ) 2 —NH—C(═O)-D-;
each A is independently an ethylene group that is optionally substituted with one or more (C 1 -C 3 )alkyl groups;
D is (C 1 -C 6 )alkyl
m is an integer from 0 to 100;
n is an integer from 0 to 100;
p is an integer from 1 to 200; and
each r is independently an integer from 0 to 20;
or a salt thereof; and
wherein the compound of formula I is not a compound of formula:
or a salt thereof.
2. The compound of claim 1 wherein B is —NH(-A-NH—) n —(CH 2 ) 2 —NH—C(═O)—CH 2 CH 2 —.
3. The compound of claim 1 wherein the compound of formula I is a compound formula I′:
wherein:
each A is independently an ethylene group that is optionally substituted with one or more (C 1 -C 3 )alkyl groups;
m is an integer from 0 to 100;
n is an integer from 0 to 100;
p is an integer from 1 to 200; and
each r is independently an integer from 0 to 20;
or a salt thereof.
4. The compound of claim 1 wherein the compound of formula I is a compound formula I′:
wherein:
each A is independently an ethylene group that is optionally substituted with one or more (C 1 -C 3 )alkyl groups;
m is an integer from 1 to 100;
n is an integer from 1 to 100;
p is an integer from 20 to 200; and
each r is independently an integer from 0 to 20;
or a salt thereof.
5. The compound of claim 1 wherein the compound of formula I is a compound of formula Ia:
wherein:
m is an integer from 0 to 100;
n is an integer from 0 to 100;
p is an integer from 1 to 200; and
each r is independently an integer from 0 to 20;
or a salt thereof.
6. The compound of claim 1 wherein the compound of formula I is a compound of formula Ia:
wherein:
m is an integer from 1 to 100;
n is an integer from 1 to 100;
p is an integer from 20 to 200; and
each r is independently an integer from 0 to 20;
or a salt thereof.
7. The compound of claim 1 , wherein m is 0, 1, 2 or 3.
8. A compound of formula I:
wherein:
B is absent or the group —NH(-A-NH—) n —(CH 2 ) 2 —NH—C(═O)-D-;
each A is independently an ethylene group that is optionally substituted with one or more (C 1 -C 3 )alkyl groups;
D is (C 1 -C 6 )alkyl
m is an integer from 0 to 100, other than 1;
n is an integer from 0 to 100;
p is an integer from 1 to 200; and
each r is independently an integer from 0 to 20;
or a salt thereof; and
wherein the compound of formula I is not a compound of formula:
or a salt thereof.
9. The compound of claim 1 wherein m is an integer from 2 to 20 and n is an integer from 1 to 20.
10. The compound of claim 1 wherein m is 2, 3, or 4.
11. The compound of claim 1 wherein n is 1, 2, 3, or 4.
12. The compound of claim 1 wherein p is an integer from 20 to 200.
13. The compound of claim 1 wherein p is about 109.
14. The compound of claim 1 wherein each r is independently an integer from 0 to 20.
15. The compound of claim 1 wherein each r is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
16. The compound of claim 1 wherein: m is 2, 3, 4, or 5; n is 2, 3, 4, or 5; p is an integer from about 95 to about 125; and each r is independently 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
17. The compound of claim 1 wherein the compound of formula I is a compound of formula Ib:
or a salt thereof.
18. A compound of claim 1 which is:
or a salt thereof.
19. A composition comprising a compound of formula I or a salt thereof as described in claim 1 and a nucleic acid.
20. The composition of claim 19 further comprising one or more lipids.
21. A method for delivering a nucleic acid into a cell comprising contacting the cell with a composition comprising a compound of formula I or a salt thereof as described in claim 1 and the nucleic acid under conditions such that the nucleic acid is delivered into the cell.
22. The method of claim 21 wherein the composition further comprises one or more lipids.
23. A compound of formula I:
wherein:
B is absent or the group —NH(-A-NH—) n —(CH 2 ) 2 —NH—C(═O)-D-;
each A is independently an ethylene group that is optionally substituted with one or more (C 1 -C 3 )alkyl groups;
D is (C 1 -C 6 )alkyl
m is an integer from 0 to 100;
n is an integer from 0 to 100;
p is an integer from 1 to 200; and
each r is independently an integer from 0 to 20, other than 10;
or a salt thereof.
24. A compound of formula I:
wherein:
B is absent;
each A is independently an ethylene group that is optionally substituted with one or more (C 1 -C 3 )alkyl groups;
D is (C 1 -C 6 )alkyl
m is 2 or 3;
n is an integer from 0 to 100;
p is an integer from 1 to 200; and
each r is independently an integer from 0 to 20;
or a salt thereof.