Compositions and methods for delivery of kinase inhibiting peptides
The invention relates to compositions and methods for the treatment of inflammatory disease states. In particular, the invention relates to the use of a nanoparticle incorporated kinase inhibiting peptide to treat inflammatory disease states.
1. A composition comprising:
(i) at least one kinase inhibiting peptide incorporated with a nanoparticle, wherein the kinase inhibiting peptide is of Formula I:
Z1-X1-X2-X3-X4 X5-X6-X7-X8-X9-X10-Z2
wherein Z1 and Z2 are independently absent or are transduction domains;
X1 is KA;
X2 is L;
X3 is selected from the group consisting of V, L, I, A, G, Q, N, S, T, and C;
X4 is R;
X5 is Q;
X6 is L;
X7 is selected from the group consisting of S, A, C, T, and G;
X8 is V;
X9 is A; and
X10 is A or is absent,
wherein the nanoparticle comprises at least one copolymerized monomer having an anionic side chain and at least one additional copolymerized monomer, wherein the at least one copolymerized anionic monomer is 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS), wherein the AMPS is effective to increase drug loading and control drug release;
(ii) a crosslinker, wherein the crosslinker is selected from the group consisting of N,O dimethacryloylhydroxylamine, divinyl adipate, N,N-Bis(acryloyl)cystamine and N,N′-methylenebisacrylamide; and
(iii) a stabilizer that is coupled to the nanoparticle, wherein the stabilizer is effective to reduce aggregation of the nanoparticles to maintain the stability of the nanoparticles.
2. The composition of claim 1 wherein the kinase inhibiting peptide is an MK2 inhibitor peptide.
3. The composition of claim 1 wherein the amino acid sequence of the kinase inhibiting peptide has at least 90% sequence identity to a peptide selected from the group consisting of YARAAARQARAKALARQLGVAA (SEQ ID NO: 1), YARAAARQARAKALNRQLGVA (SEQ ID NO: 2), FAKLAAR LYRKALARQLGVAA (SEQ ID NO: 3), KAFAKLAARLYRKALARQLGVAA (SEQ ID NO: 4), HRRIKAWLKKIKALARQLGVAA (SEQ ID NO: 5), YARAAARQARAKALNRQLAVAA (SEQ ID NO: 6) and YARAAARQARAKALNRQLAVA (SEQ ID NO: 7).
4. The composition of claim 1 wherein the at least one additional copolymerized monomer is N-isopropylacrylamide.
5. A dose of the composition of claim 1 effective to treat inflammation for administration to a patient in need thereof, wherein the effective dose ranges from about 1 pg to about 10 ng per kilogram of body weight.
6. The composition of claim 1 wherein the at least one copolymerized anionic monomer is 2-acrylamido-2-methyl-1-propanesulfonic acid, and wherein the at least one additional copolymerized monomer is N-isopropylacrylamide.
7. The composition of claim 1 wherein the at least one additional copolymerized monomer and the copolymerized anionic monomer are present in the composition at a ratio of about 10:1.
8. A method for treating osteoarthritis, the method comprising the step of administering a composition comprising:
(i) at least one kinase inhibiting peptide incorporated with a nanoparticle,
wherein the kinase inhibiting peptide is of Formula I:
Z1-X1-X2-X3-X4X5-X6-X7-X8-X9-X10-Z2
wherein Z1 and Z2 are independently absent or are transduction domains;
X1 is KA;
X2 is L;
X3 is selected from the group consisting of V, L, I, A, G, Q, N, S, T, and C;
X4 is R;
X5 is Q;
X6 is L;
X7 is selected from the group consisting of S, A, C, T, and G;
X8 is V;
X9 is A; and
X10 is A or is absent,
wherein the nanoparticle comprises at least one copolymerized anionic monomer and at least one additional copolymerized monomer, wherein the at least one copolymerized anionic monomer is 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS), wherein the AMPS is effective to increase drug loading and control drug release;
(ii) a crosslinker, wherein the crosslinker is selected from the group consisting of N,O dimethacryloylhydroxylamine, divinyl adipate, N,N-Bis(acryloyl)cystamine, and N,N′-methylenebisacrylamide; and
(iii) a stabilizer that is coupled to the nanoparticle, wherein the stabilizer is effective to reduce aggregation of the nanoparticles to maintain the stability of the nanoparticles.
9. The method of claim 8 wherein the kinase inhibiting peptide is an MK2 inhibitor peptide.
10. The method of claim 8 wherein the amino acid sequence of the kinase inhibiting peptide has at least 90% sequence identity to a peptide selected from the group consisting of YARAAARQARAKALARQLGVAA (SEQ ID NO: 1), YARAAARQARAKALNRQLGVA (SEQ ID NO: 2), FAKLAAR LYRKALARQLGVAA (SEQ ID NO: 3), KAFAKLAARLYRKALARQLGVAA (SEQ ID NO: 4), HRRIKAWLKKIKALARQLGVAA (SEQ ID NO: 5), YARAAARQARAKALNRQLAVAA (SEQ ID NO: 6), and YARAAARQARAKALNRQLAVA (SEQ ID NO: 7).
11. The method of claim 8 wherein the at least one copolymerized anionic monomer is 2-acrylamido-2-methyl-1-propanesulfonic acid.
12. The method of claim 8 wherein the at least one additional copolymerized monomer is N-isopropylacrylamide.
13. The method of claim 8 wherein the nanoparticle further comprising a crosslinker.
14. The method of claim 13 wherein the crosslinker is selected from the group consisting of N,O-dimethacryloylhydroxylamine, divinyl adipate, N,N-Bis(acryloyl)cystamine, and N,N′-methylenebisacrylamide.
15. The method of claim 8 wherein the at least one additional copolymerized monomer and the copolymerized anionic monomer are present in the composition at a ratio of about 10:1.
16. The composition of claim 1 wherein the anionic monomer is a sulfonic monomer.
17. The method of claim 8 wherein the anionic monomer is a sulfonic monomer.