Cyclic peptide and conjugate thereof for binding to keratinocytes
A cyclic peptide capable of binding specifically to the α2 I domain of a collagen binding integrin receptor may be conjugated to a drug containing particle via a linker moiety. The conjugate may be used to target a therapeutic drug to a cell expressing a collagen binding integrin receptor on its surface.
1. A pharmaceutical composition for topical application comprising a conjugate of a drug-containing carrier particle and a cyclic peptide capable of binding specifically to the α2 I domain of the integrin α2β1 receptor of the subgroup of collagen binding integrin receptors, said peptide having the amino acid sequence
(SEQ ID NO: 2)
Ser-Thr-Arg-Lys-Lys-His-Asp-Asn-Ala-Gln-Ser-Lys-L
wherein
L is a linker moiety comprising a thiol group that is suitable for conjugating the drug-containing carrier particle; and
a pharmaceutically acceptable carrier or excipient.
2. A composition according to claim 1 , wherein L is synthesized from S-succinimidyl-S-thioacetate (SATA), N-hydroxysuccinimidyl 3-(2-pyridyldithio) propionate (SPDP), SATP, or SAT-PEO4-Ac.
3. A composition according to claim 1 wherein the cyclic peptide is capable of binding specifically to the α2 I domain of the integrin α2β1 receptor.
4. A composition according to claim 1 , wherein the drug-containing carrier particle is a liposome, a niosome, a transfersome, a polymeric nanoparticle or a lipid nanoparticle.
5. A composition according to claim 4 , wherein the liposome comprises one or more of the lipids dipalmitoylphosphatidylcholine, disteraroylphosphatidylethanolamine, distearoylphosphatidylcholine, disteraroylphosphatidylglycerol, dioleoylphosphatidylethanolamine, dimyristoylphosphatidylcholine, dimyristoylphosphatidylglycerol, sphingomyelin, soy phosphatidylcholine, egg phosphatidylcholine, cholesterol or cholate.
6. A composition according to claim 5 , wherein at least one lipid included in the liposomes comprises PEG groups attached thereto.
7. A composition according to claim 4 , wherein the polymeric nanoparticle comprises one or more of polylactic acid, polyglycolic acid, poly(lactide-co-glycolide), poly(ε-caprolactone), polyvinylalcohol, poly(methyl methacrylate), polydimethylsiloxane or chitosan.
8. A composition according to claim 4 , wherein the drug included in the carrier particle is a vitamin D analogue, a corticosteroid, a calcineurin inhibitor, a PDE4 inhibitor, a p38 MAP kinase inhibitor, a JAK inhibitor, a histamine receptor antagonist, ingenol-3-angelate, or a naturally occurring or synthetic nucleotide such as siRNA, miRNA, LNA or PNA.
9. A composition according to claim 8 , wherein the vitamin D analogue is calcipotriol.
10. A composition according to claim 1 for targeting a therapeutic drug to a keratinocyte expressing on its surface the integrin α2β1 receptor of the subgroup of collagen binding integrin receptors.
11. A method of treating a dermal inflammatory disease or condition, the method comprising administering to a patient in need thereof an effective dose of a composition according to claim 8 .
12. The method of claim 11 , wherein the dermal inflammatory disease or condition is selected from the group consisting of psoriasis, atopic dermatitis, eczema, urticaria, acne, allergic contact dermatitis and irritant dermatitis.