Biodegradable cationic polymers
Polymers comprising a polyethylenimine having a molecular weight less than 600 Daltons, a biodegradable group, and a relatively hydrophobic group that are useful for the delivery of bioactive agents to cells.
1. A polymer comprising a recurring unit selected from the group consisting of formula (I):
wherein:
PEI is a polyethyleneimine recurring unit having a molecular weight less than 600 Daltons;
R is selected from the group consisting of an electron pair, hydrogen, C 2 -C 10 alkyl, C 2 -C 10 heteroalkyl, C 5 -C 30 aryl, and C 2 -C 30 heteroaryl;
L is selected from the group consisting of C 2 -C 50 alkyl, C 2 -C 50 heteroalkyl, C 2 -C 50 alkenyl, C 2 -C 50 heteroalkenyl, C 5 -C 50 aryl, C 2 -C 50 heteroaryl, C 2 -C 50 alkynyl, C 2 -C 50 heteroalkynyl, C 2 -C 50 carboxyalkenyl and C 2 -C 50 carboxyheteroalkenyl; and
m is an integer in the range of about 1 to about 30.
2. The polymer of claim 1 in which the PEI comprises at least one recurring unit selected from the group consisting of formula (IIa) and formula (IIb):
wherein x is an integer in the range of about 1 to about 12, y is an integer in the range of about 1 to about 6, and z is an integer in the range of about 1 to about 13.
3. The polymer of claim 1 that is biodegradable.
4. The polymer of claim 1 that is degradable by a mechanism selected from the group consisting of hydrolysis, enzyme cleavage, reduction, photo-cleavage, and sonication.
5. The polymer of claim 1 in which L is selected from the group consisting of C 2 -C 50 alkyl, C 2 -C 50 heteroalkyl, C 2 -C 50 alkenyl, C 2 -C 50 heteroalkenyl, C 2 -C 50 alkynyl and C 2 -C 50 heteroalkynyl.
6. The polymer of claim 1 in which L is selected from the group consisting of C 12 to C 18 fatty acid, cholesterol, C 12 to C 18 fatty acid derivative, and cholesterol derivative.
7. The polymer of claim 1 having a weight average molecular weight in the range of about 500 Daltons to about 1,000,000 Daltons.
8. The polymer of claim 1 having a weight average molecular weight in the range of about 1,000 Daltons to about 200,000 Daltons.
9. The polymer of claim 1 which is crosslinked.
10. A composition comprising an oligonucleotide that is complexed to the polymer of claim 1 .
11. The composition of claim 10 in which the oligonucleotide is selected from the group consisting of a RNA-oligomer and a DNA-oligomer.
12. The composition of claim 10 in which the oligonucleotide is siRNA or antisense.
13. The composition of claim 10 further comprising a delivery enhancing agent capable of entering a eukaryotic cell.
14. The composition of claim 13 further comprising a diagnostic imaging compound that is complexed to the polymer.
15. The composition of claim 13 in which the delivery enhancing agent facilitates one or more functions in the eukaryotic cell selected from the group consisting of receptor recognition, internalization, escape of the oligonucleotide from cell endosome, nucleus localization, and oligonucleotide release.
16. The composition of claim 15 in which the oligonucleotide is selected from the group consisting of siRNA and antisense.
17. The composition of claim 13 in which the delivery enhancing agent is coupled to the polymer.
18. A polymer comprising a recurring unit selected from the group consisting of formula (I):
wherein:
PEI is a polyethyleneimine recurring unit comprising at least one recurring unit of the formula (IIb):
wherein z is an integer in the range of about 1 to about 13;
R is selected from the group consisting of an electron pair, hydrogen, C 2 -C 10 alkyl, C 2 -C 10 heteroalkyl, C 5 -C 30 aryl, and C 2 -C 30 heteroaryl;
L is selected from the group consisting of C 2 -C 50 alkyl, C 2 -C 50 heteroalkyl, C 2 -C 50 alkenyl, C 2 -C 50 heteroalkenyl, C 5 -C 50 aryl, C 2 -C 50 heteroaryl, C 2 -C 50 alkynyl, C 2 -C 50 heteroalkynyl, C 2 -C 50 carboxyalkenyl and C 2 -C 50 carboxyheteroalkenyl; and
m is an integer in the range of about 1 to about 30.
19. The polymer of claim 18 , wherein the PEI has a molecular weight of less than 600 Daltons.
20. The polymer of claim 18 , wherein the PEI further comprises a recurring unit of the formula IIa:
wherein x is an integer in the range of about 1 to about 12 and y is an integer in the range of about 1 to about 6.
21. The polymer of claim 20 , wherein the PEI has a molecular weight of less than 600 Daltons.
22. A method of transfecting a eukaryotic cell, comprising contacting the cell with the composition of claim 11 to thereby deliver the oligonucleotide to the cell.
23. A polymer library comprising a plurality of polymers of claim 1 , wherein at least one parameter selected from the group consisting of R, L, PEI and m is different for at least two of the polymers.