Zwitterionic lipids
In various embodiments, the present invention provides zwitterionic lipids, encapsulants incorporating these zwitterionic lipids and such encapsulants encapsulating one or more bioactive agent. An exemplary bioactive agent is a nucleic acid. Also provided are pharmaceutical formulations of the encapsulants and methods of using such formulations to deliver a bioactive agent to a subject in treating or diagnosing disease in that subject.
1. A zwitterionic lipid having the formula:
wherein
X − is a member selected from:
wherein R x is selected from H and substituted or unsubstituted alkyl;
a is selected from the integers from 1 to 6;
b is selected from the integers from 0 to 18;
R l is a member selected from substituted alkyl, substituted or unsubstituted heteroalkyl, substituted aryl, and substituted heteroaryl, wherein R l includes the moiety;
in which
R l and R m are independently selected from H and alkyl;
Z + is:
wherein
R 4 and R 5 are members independently selected from H, substituted or unsubstituted alkyl; and
R 2 and R 3 are members independently selected from H, and substituted or unsubstituted alkyl,
with the proviso that at least one of R 2 and R 3 is other than H.
2. The zwitterionic lipid according to claim 1 , wherein a member selected from R 2 and R 3 is unbranched and the other member is branched.
3. The zwitterionic lipid according to claim 2 , wherein said unbranched chain comprises a subunit which is terminated with a functional group, said subunit being a member selected from a C 6 -C 12 fluorocarbyl and a C 6 -C 18 hydrocarbyl moiety.
4. The zwitterionic lipid according to claim 3 , wherein said functional group is a member selected from hydroxyl, amine, carboxylic acid, aldehyde, carboxylic acid ester, and thiol.
5. The zwitterionic lipid according to claim 1 , wherein a member selected from R 2 , R 3 and a combination thereof comprises a guanadinyl moiety.
6. The zwitterionic lipid according to claim 1 , wherein a member selected from R 2 , R 3 and a combination thereof comprises a thioether moiety.
7. The zwitterionic lipid according to claim 1 , having the formula:
wherein
c and e are independently selected from the integers from 1 to 18;
d is selected from the integers 0 and 1;
R 6 is a member selected from selected from substituted or unsubstituted alkyl.
8. The zwitterionic lipid according to claim 1 , wherein
a member selected from R 4 , R 5 and a combination thereof is H.
9. The zwitterionic lipid according to claim 1 , said lipid having a pKa of greater than 5.
10. The zwitterionic lipid according to claim 1 , said lipid having a pKa of from about 6 to about 7.
11. A pharmaceutical formulation comprising a zwitterionic lipid according to claim 1 and a pharmaceutically acceptable carrier.
12. The pharmaceutical formulation according to claim 11 , further comprising a bioactive compound.
13. An encapsulator particle selected from the group consisting of liposomes, emulsions, micelles and lipidic bodies, wherein the encapsulator particle comprises the zwitterionic lipid according to claim 1 .
14. The encapsulator particle of claim 13 further comprising a bioactive agent encapsulated in said particle.
15. A zwitterionic lipid having the formula:
in which
R a is an alkylene linker moiety;
R l , R m , R n and R o are independently selected from H and alkyl;
each R b is independently selected from substituted or unsubstituted alkyl an substituted or unsubstituted heteroalkyl; and
n is 2.
16. The zwitterionic lipid of claim 15 , wherein each R b is a linoleoyl.
17. The zwitterionic lipid of claim 15 , wherein each of R l , R m , R n and R o is methyl.