Formulations for improving the efficacy of hydrophobic drugs
Novel amphiphilic peptide, peptide amphiphile lipid micelles, processes for making peptide amphiphile lipid micelles comprising an amphiphilic peptide and phospholipid and optionally comprising a cargo molecule, and methods of use.
1. A peptide comprising the amino acid sequence: X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 , wherein: X 1 is the amino acid D; X 2 and X 20 are each the amino acid V; X 3 , X 6 , X 10 and X 13 are each an amino acid independently selected from the group consisting of L and F; X 4 , X 12 and X 19 are each the amino acid Q; X 5 is the amino acid A or Aib; X 7 , X 16 and X 18 are each the amino acid K; X 8 and X 15 are each the amino acid E; X 9 and X 14 are each an amino acid independently selected from the group consisting of A, L, F and Aib; X 11 is an amino acid selected from the group consisting of A, Aib and N; and X 17 is an amino acid selected from the group consisting of W, F and L, wherein the peptide is optionally acylated at the N-terminus, amidated at the C-terminus, or both acylated at the N-terminus and amidated at the C-terminus, and the peptide is from 20 to 24 amino acids in length, and wherein the peptide is not DVFQALKELFAQLLEKWKQV (SEQ ID NO: 2); or X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 , wherein: X 1 is an amino acid selected from the group consisting of D and E; X 2 and X 20 are each an amino acid independently selected from the group consisting of V, I, and L; X 3 , X 6 , X 10 and X 13 are each an amino acid independently selected from the group consisting of L, I, V, W, Y, Aib, Amv and F; X 4 , X 12 and X 19 are each an amino acid independently selected from the group consisting of Q and N; X 5 , X 16 and X 18 are each an amino acid independently selected from the group consisting of K, R, H and Orn; X 7 is an amino acid selected from the group consisting of A, G, S, V, Aib and Amv; X 8 and X 15 are each an amino acid independently selected from the group consisting of E and D; X 9 and X 14 are each an amino acid independently selected from the group consisting of A, G, S L, F, V, Amv, and Aib; X 11 is an amino acid selected from the group consisting of A, G, S, Aib, Amv, V and N; and X 17 is an amino acid selected from the group consisting of W, F, Y, I, V, and L, wherein the peptide is optionally acylated at the N-terminus, amidated at the C-terminus, or both acylated at the N-terminus and amidated at the C-terminus, and the peptide is from 20 to 24 amino acids in length.
2. The peptide of claim 1 , comprising an amino acid sequence selected from the group consisting of SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; SEQ ID NO:6; SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; wherein the peptide is optionally acylated at the N-terminus, amidated at the C-terminus, or both acylated at the N-terminus and amidated at the C-terminus, and the peptide is from 20 to 24 amino acids in length.
3. A peptide amphiphile lipid micelle (PALM) comprising a peptide of claim 1 , and a lipid component comprising sphingomyelin and one or more additional phospholipid.
4. The PALM of claim 3 , wherein the one or more additional phospholipid is selected from the group consisting of phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine (PEG-PE), phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, cardiolipin, or any combination thereof.
5. A PALM-cargo composition comprising the PALM of claim 3 , and at least one cargo molecule.
6. The PALM-cargo composition of claim 5 , wherein the at least one cargo molecule is an imaging agent or a drug.
7. The PALM-cargo composition of claim 6 , wherein the drug is miriplatin or fenretinide.
8. The PALM-cargo composition of claim 5 , wherein the at least one cargo molecule is a conjugate having the formula (I):
A-R-L-X (formula I),
wherein A is an agent having a hydroxyl or an amine group R; L is a linker; and X is an anchor moiety selected from the group consisting of cholesterol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol.
9. The PALM-cargo composition of claim 8 , wherein R is a hydroxyl group and the anchor moiety is covalently bonded to the agent by a carbonate ester bond.
10. The PALM-cargo composition of claim 8 , wherein R is an amine group and the anchor moiety is covalently bonded to the agent by a carbamate ester bond.
11. The PALM-cargo composition of claim 8 , wherein the agent is a drug.
12. The PALM-cargo composition of claim 11 , wherein the drug is an anti-cancer drug.
13. The PALM-cargo composition of claim 12 , wherein the anti-cancer drug is a hydroxy camptothecin; daunorubicin; paclitaxel; or docetaxel.
14. The PALM-cargo composition of claim 13 , wherein X is β-tocotrienol.
15. The PALM-cargo composition of claim 14 , wherein the anti-cancer drug is paclitaxel.
16. The PALM-cargo composition of claim 14 , wherein the anti-cancer drug is docetaxel.
17. The PALM-cargo composition of claim 13 , wherein X is δ-tocotrienol.
18. The PALM-cargo composition of claim 8 , wherein the PALM-cargo composition further comprises an imaging agent.
19. The PALM-cargo composition of claim 8 , wherein X is β-tocotrienol.
20. A method for treating a disorder comprising administering to a subject in need thereof, an effective amount of a PALM-cargo composition of claim 11 .
21. The method of claim 20 , wherein the peptide is selected from the group consisting of SEQ ID NO: 25, SEQ ID NO: 28, SEQ ID NO: 34 and SEQ ID NO: 35.