Nanoparticle-peptide compositions
View Patent ↗The present invention provides nanoparticles and compositions comprising such nanoparticles, as well as methods for intracellular delivery of peptides, and methods of producing nanoparticles and related products. The nanoparticles comprise a core comprising a metal and/or a semiconductor atom; and a corona comprising a plurality of ligands covalently linked to the core, wherein at least a first ligand of said plurality comprises a carbohydrate moiety that is covalently linked to the core via a first linker, and wherein at least a second ligand of said plurality comprises a peptide of choice that is covalently linked to the core via a second linker. The second linker comprises a peptide portion and a non-peptide portion, wherein said peptide portion of said second linker comprises the sequence X 1 X 2 Z 1 , wherein: X 1 is an amino acid selected from A and G; X 2 is an amino acid selected from A and G; and Z 1 is an amino acid selected from Y and F.
1. A nanoparticle comprising:
(i) a core comprising a metal and/or a semiconductor atom;
(ii) a corona comprising a plurality of ligands covalently linked to the core, wherein at least a first ligand of said plurality comprises a carbohydrate moiety that is covalently linked to the core via a first linker or comprises glutathione, and wherein at least a second ligand of said plurality comprises a peptide of choice that is covalently linked to the core via a second linker, said second linker comprising:
a peptide portion and a non-peptide portion, wherein said peptide portion of said second linker comprises the sequence FLAAY (SEQ ID NO: 1).
2. The nanoparticle of claim 1 , wherein said peptide of choice consists of a sequence of 8 to 12 amino acid residues and is an epitopic peptide that binds to a class I Major Histocompatibility Complex (MHC) molecule.
3. The nanoparticle according to claim 1 , wherein said non-peptide portion of the second linker comprises C2-C15 alkyl and/or C2-C15 glycol.
4. The nanoparticle according to claim 1 , wherein said first ligand and/or said second ligand are covalently linked to the core via a sulphur-containing group, an amino-containing group, a phosphate-containing group or an oxygen-containing group.
5. The nanoparticle according to claim 1 , wherein the peptide of choice is an epitopic peptide that is presented by a class I MHC molecule so as to stimulate a Cytotoxic T Lymphocyte (CTL) response.
6. The nanoparticle according to claim 1 , wherein the peptide of choice forms at least a portion of or is derived from a Tumour-Associated Antigen (TAA) or a viral-, bacterial-, or parasite-associated antigen.
7. The nanoparticle according to claim 6 , wherein the TAA is a lung cancer antigen.
8. The nanoparticle according to claim 1 wherein:
(i) the carbohydrate moiety of said first ligand comprises a monosaccharide and/or a disaccharide; and/or
(ii) said plurality of ligands comprises at least one glutathione ligand covalently linked to the core of the nanoparticle via the glutathione sulphur atom; and/or
(iii) said plurality of ligands comprises:
(a) glucose;
(b) N-acetylglucosamine;
(c) glutathione;
(d) glucose and N-acetylglucosamine;
(e) glucose and glutathione;
(f) N-acetylglucosamine and glutathionie; or
(g) glucose, N-acetylglucosamine and glutathione.
9. The nanoparticle according to claim 1 , wherein said first linker comprises C2-C15 alkyl and/or C2-C15 glycol.
10. The nanoparticle according to claim 1 , wherein said first ligand comprises 2′-thioethyl-β-D-glucopyranoside or 2′-thioethyl-α-D-glucopyranoside covalently attached to the core via the thiol sulphur atom.
11. The nanoparticle according to claim 1 , wherein the plurality of ligands are in a molar ratio of carbohydrate-containing ligands and/or glutathione ligands to peptide of choice containing ligands in the range of 5:1 to 100:1.
12. The nanoparticle according to claim 1 , wherein the diameter of the core of the nanoparticle is in the range 1 nm to 5 nm.
13. The nanoparticle according to claim 1 , wherein the core comprises a metal selected from the group consisting of: Au, Ag, Cu, Pt, Pd, Fe, Co, Gd, Zn and any combination of said metals.
14. A composition comprising a plurality of nanoparticles as defined in claim 1 , and at least one pharmaceutically acceptable carrier, salt and/or diluents.
15. The composition according to claim 14 , wherein the composition comprises a first species of nanoparticle having a first peptide of choice-containing ligand and a second species of nanoparticle having a second peptide of choice-containing ligand, wherein the peptides of choice of said first and second species differ.
16. The composition according to claim 14 , further comprising at least one adjuvant covalently attached to the core of at least one nanoparticle.
17. The composition according to claim 16 , wherein the adjuvant comprises (S)-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys 4 -OH (Pam 3 Cys).
18. A vaccine comprising a composition as defined in claim 14 .