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 a first copolymerized monomer and a second copolymerized monomer, wherein the first copolymerized 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
wherein a ratio of the first copolymerized monomer to the second copolymerized monomer is from 5:1 to 15:1.
2. The composition of claim 1 , wherein the ratio of the first copolymerized monomer to the second copolymerized monomer is 5:1.
3. The composition of claim 1 , wherein the ratio of the first copolymerized monomer to the second copolymerized monomer is 8:1.
4. The composition of claim 1 , wherein the ratio of the first copolymerized monomer to the second copolymerized monomer is 9:1.
5. The composition of claim 1 , wherein the ratio of the first copolymerized monomer to the second copolymerized monomer is 10:1.
6. The composition of claim 1 , wherein the ratio of the first copolymerized monomer to the second copolymerized monomer is 11:1.
7. The composition of claim 1 , wherein the ratio of the first copolymerized monomer to the second copolymerized monomer is 12:1.
8. The composition of claim 1 , wherein the ratio of the first copolymerized monomer to the second copolymerized monomer is 15:1.
9. The composition of claim 1 , wherein the crosslinker comprises from 0.5 mole % to 5 mole % of the nanoparticle.
10. The composition of claim 1 , wherein the crosslinker comprises at least 1 mole % of the nanoparticle.
11. The composition of claim 1 , wherein the crosslinker comprises at least 2 mole % of the nanoparticle.
12. The composition of claim 1 , wherein the crosslinker comprises at least 4 mole % of the nanoparticle.
13. The composition of claim 1 , wherein the nanoparticle comprises a core comprising a first material and a shell comprising a second material.
14. The composition of claim 13 , wherein the nanoparticle comprises a core comprising pNIPAM and a shell comprising AMPS.
15. The composition of claim 1 , wherein the first copolymerized monomer comprises from 0.5% to 15′ of the nanoparticle.
16. 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 a first copolymerized monomer and a second copolymerized monomer, wherein the first copolymerized 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
wherein the nanoparticle has at least one dimension of between 1 nm to 700 nm.
17. The composition of claim 1 , wherein the nanoparticle has at least one dimension of from 30 nm to 700 nm.
18. The composition of claim 1 , wherein the nanoparticle has at least one dimension of from 50 nm to 700 nm.
19. The composition of claim 1 , wherein the nanoparticle has at least one dimension of from 60 nm to 700 nm.
20. The composition of claim 1 , wherein the nanoparticle has at least one dimension of from 80 nm to 700 nm.