Targeting lipids
The present invention provides targeting lipids of structure L 100 -linker-L 101 (CI), where L 100 is a lipid, lipophile, alkyl, alkenyl or alkynyl, L 101 is a ligand or —CH 2 CH 2 (OCH 2 CH 2 ) p O(CH 2 ) q CH 2 -ligand, p is 1-1000, and q is 1-20. In addition, the invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo.
1. A pharmaceutical formulation, comprising:
(i) a targeting lipid having a structure shown in formula (I)
L A [-P-Q-R-] q T-L B Formula (I)
wherein:
L A has the structure shown in formula V:
q 5A , q 5B and q 5c represent independently for each occurrence 0-20; P 5A , P 5B , P 5C , T 5A , T 5B and T 5C are each independently for each occurrence absent, NR′, O, C(O), NHC(O), or C(O)NH
Q 5A , Q 5B and Q 5C are independently for each occurrence —(CH 2 ) n —
R 5A , R 5B and R 5C are each independently for each occurrence absent, CO, NH, O, NHC(O), or C(O)NH;
L 5A , L 5B and L 5C are each N-acetyl-galactosamine,
q represents 0-20;
P is each independently for each occurrence absent, NR′, O, C(O), NHC(O), or C(O)NH
Q is independently for each occurrence, —(CH 2 ) n —, or —(CH 2 CH 2 O) P CH 2 CH 2 —;
R is each independently for each occurrence absent, CO, NH, O, NHC(O), or C(O)NH;
T is NHC(O);
L B has the structure of formula (VI):
R 6 , R 6A and R 6B are O,
R′ is H;
L 6A and L 6B are each independently C 6 -C 28 alkyl:
n represent independently for each occurrence 1-20; and
p represent independently for each occurrence 0-50;
(ii) a cationic lipid;
(iii) a neutral lipid selected from DSPC, POPC, DOPE, and SM;
(iv) cholesterol; and
(v) PEG-DMG, or PEG-DMA, wherein the components are in a molar ratio of about 0.5-50% targeting lipid:20-60% cationic lipid:5-25% neutral lipid:25-55% Chol:0.5-15% PEG-DMG or PEG-DMA.
2. The pharmaceutical formulation of claim 1 , wherein L A is
L B is
3. A pharmaceutical formulation, comprising:
(i) a targeting lipid having a structure shown in formula 214 or 216
(ii) a cationic lipid;
(iii) a neutral lipid selected from DSPC, POPC, DOPE, and SM;
(iv) cholesterol; and
(v) PEG-DMG, or PEG-DMA, wherein the components are in a molar ratio of about 0.5-50% targeting lipid:20-60% cationic lipid:5-25% neutral lipid:25-55% cholesterol:0.5-15% PEG-DMG or PEG-DMA.
4. The pharmaceutical formulation of claim 1 , further comprising an oligonucleotide.
5. The pharmaceutical formulation of claim 4 , wherein said oligonucleotide is single stranded.
6. The pharmaceutical formulation of claim 4 , wherein said oligonucleotide is double stranded.
7. The pharmaceutical formulation of claim 4 , wherein said oligonucleotide is a iRNA agent.
8. The pharmaceutical formulation of claim 4 , wherein said oligonucleotide is an siRNA agent.
9. The pharmaceutical formulation of claim 4 , wherein said oligonucleotide is modified to resist degradation.
10. The pharmaceutical formulation of claim 4 , wherein said oligonucleotide comprises a conjugated ligand.
11. A compound having a structure shown in formula 214 or 216