Layer-by-layer nanoparticles for cytokine therapy in cancer treatment
Disclosed are particles for delivering cytokinese, such as IL-12, for the treatment of cancer. The particles comprise cytokines non-covalently bound to liposomes, where the liposomes are coated with polyelectrolytes.
1. A particle comprising:
a liposome, wherein the liposome comprises a first lipid covalently bonded to an affinity ligand; and the first lipid forms an outer surface of the liposome;
a cytokine covalently bonded to a tag, wherein the tag is associated with the affinity ligand, and wherein the cytokine binds a receptor on the surface of a cancer cell when the particle contacts the cancer cell; and
a polymer coating, wherein the polymer coating comprises:
at least one layer including a polycation, wherein the polycation is non-covalently associated with the outer surface of the liposome; and
at least one layer including polyglutamic acid, wherein the polyglutamic acid is non-covalently associated with the at least one polycation layer.
2. The particle of claim 1 , further comprising a metal ion,
wherein:
the affinity ligand is a metal-affinity ligand;
the tag is a peptide tag;
the metal ion is coordinated with the metal-affinity ligand, thereby forming a metal-coordinated ligand;
the peptide tag is associated with the metal-coordinated ligand.
3. The particle of claim 2 , wherein the metal-coordinated ligand is non-covalently associated with the peptide tag.
4. The particle of claim 3 , wherein the metal-affinity ligand is iminodiacetic acid or iminodipropionic acid.
5. The particle of claim 3 , wherein the metal ion is selected from the group consisting of Fe(III), Co(II), Ni(II), Cu(II), and Zn(II).
6. The particle of claim 3 , wherein the peptide tag is at least two amino acid monomers in length.
7. The particle of claim 3 , wherein the peptide tag comprises a histidine monomer.
8. The particle of claim 1 , wherein the first lipid is 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid)succinyl].
9. The particle of claim 1 , wherein the liposome further comprises a second lipid; and the second lipid is a phosphatidylcholine.
10. The particle of claim 1 , wherein the liposome further comprises a third lipid.
11. The particle of claim 1 , wherein the liposome further comprises a fourth lipid; and the fourth lipid is cholesterol.
12. The particle of claim 1 , wherein the tag is non-covalently associated with the affinity ligand on the outer surface of the liposome.
13. The particle of claim 1 , wherein the tag is covalently associated with the affinity ligand on the outer surface of the liposome.
14. The particle of claim 1 , wherein the cytokine is a single-chain variant of IL-12.
15. The particle of claim 1 , wherein the polycation is selected from the group consisting of polyarginine and polylysine.
16. The particle of claim 1 , wherein the particle further comprises a second polycation coating non-covalently associated with the outer surface of the polyglutamic acid coating; and a second polyglutamic acid coating non-covalently associated with the outer surface of the second polycation coating.
17. A pharmaceutical formulation comprising a plurality of particles of claim 1 , and a pharmaceutically acceptable carrier.
18. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a particle of claim 1 .
19. The particle of claim 1 , wherein
the first lipid covalently bonded to the affinity ligand is 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid)succinyl];
the particle further comprises a metal ion selected from the group consisting of Fe(III), Co(II), Ni(II), Cu(II), and Zn(II);
the metal ion is coordinated with the affinity ligand, thereby forming a metal-coordinated ligand;
the metal-coordinated ligand is non-covalently associated with the tag;
the tag is a peptide tag;
the peptide tag is at least two amino acid monomers in length;
the peptide tag comprises a histidine monomer;
the cytokine is a single-chain variant of IL-12; and
the polycation is selected from the group consisting of polyarginine and polylysine.
20. The method of claim 18 , wherein the cancer is colon cancer or ovarian cancer.