MMP-targeted therapeutic and/or diagnostic nanocarriers
View Patent ↗The present invention provides targeted delivery compositions and methods of using the compositions for treating and diagnosing a disease state in a subject.
1. A targeted delivery composition, comprising:
(a) a nanocarrier including a therapeutic or diagnostic agent or a combination thereof; and
(b) a conjugate having the formula:
A-(LPEG)-MMP i ;
wherein,
A is an attachment component for attaching said conjugate to said nanocarrier;
(LPEG) is selected from:
(i) a linking group having a linear assembly of from 1 to 3 polyethylene glycol components,
(ii) a linking group having the formula [(EG)(P)] m wherein each EG is an ethylene glycol group independently selected from the group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol and octaethylene glycol, P is a phosphoryl or thiophosphoryl group, and m is an integer of from 1 to 20; or
(iii) a linking group having the formula —Z 1 —Z 2 —Z 3 —, wherein
Z 1 and Z 3 are independently selected from the group consisting of a PEG component having a defined length and W n , wherein W is an amino acid and the subscript n is an integer from 0 to 3; and
Z 2 is selected from the group consisting of a PEG component having a defined length and a coupling group selected from an amide, thioamide, ester, carbamate or urea for connecting Z 1 and Z 3 ; and
MMP i is a MMP enzyme inhibitor having the formula:
wherein
X is a member selected from the group consisting of O and S;
Y is a member selected from the group consisting of pyridyl and phenyl, wherein said phenyl is optionally substituted with OH, OCH 3 , OCF 3 and CH 3 ; and
the wavy line indicates the point of attachment to (LPEG).
2. The targeted delivery composition of claim 1 , wherein (LPEG) is —Z 1 —Z 2 —Z 3 —.
3. The targeted delivery composition of claim 2 , wherein Z 1 is W n ; Z 2 is selected from an amide, thioamide, ester, carbamate or urea; and Z 3 is a PEG component having a defined length.
4. The targeted delivery composition of claim 3 , wherein the subscript n is 3.
5. The targeted delivery composition of claim 3 , wherein the subscript n is 2.
6. The targeted delivery composition of claim 3 , wherein the subscript n is 1.
7. The targeted delivery composition of claim 1 , wherein the subscript n is 0.
8. The targeted delivery composition of claim 1 , wherein the amino acid is an α-amino acid.
9. The targeted delivery composition of claim 8 , wherein the α-amino acid is selected from the group consisting of aspartic acid, glutamic acid, lysine, arginine, and glycine.
10. The targeted delivery composition of claim 9 , wherein the α-amino acid is selected from the group consisting of glutamic acid and lysine.
11. The targeted delivery composition of claim 1 , wherein said nanocarrier is selected from the group consisting of a liposome, a micelle, a lipid-coated bubble, and a block copolymer micelle.
12. The targeted delivery composition of claim 1 , wherein said nanocarrier further comprises a stealth agent.
13. The targeted delivery composition of claim 1 , wherein said nanocarrier comprises a therapeutic agent selected from the group consisting of doxorubicin, cisplatin, oxaliplatin, carboplatin, 5-fluorouracil, gemcitibine and a taxane.
14. The targeted delivery composition of claim 1 , wherein said attachment component is a lipid.
15. The targeted delivery composition of claim 1 , wherein (LPEG) has the formula:
—Z 1 —Z 2 —Z 3 —
wherein each of Z 1 and Z 3 are a PEG component having a defined length, and Z 2 is a coupling group selected from an amide, thioamide, ester, carbamate or urea for connecting the two PEG components.
16. The targeted delivery composition of claim 1 , wherein MMP i is selected from the group consisting of
17. The targeted delivery composition of claim 1 , wherein MMP i is selected from the group consisting of
18. A targeted delivery composition, comprising:
(a) a nanocarrier including a therapeutic or diagnostic agent or a combination thereof; and
(b) a conjugate having the formula:
A-(LPEG)-MMP i ;
wherein,
A is an attachment component for attaching said conjugate to said nanocarrier;
(LPEG) is a linking group having a linear assembly of from 1 to 3 polyethylene glycol components, or a linking group having the formula [(EG)(P)] m wherein each EG is an ethylene glycol group independently selected from the group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol and octaethylene glycol, P is a phosphoryl or thiophosphoryl group, and m is an integer of from 1 to 20; and
MMP i is a MMP enzyme inhibitor.
19. The targeted delivery composition of claim 18 , wherein said MMP inhibitor has the formula:
wherein
X is a member selected from the group consisting of O and S;
Y is a member selected from the group consisting of pyridyl and phenyl, wherein said phenyl is optionally substituted with OH, OCH 3 , OCF 3 and CH 3 ; and
the wavy line indicates the point of attachment to (LPEG).
20. The targeted delivery composition of claim 18 , wherein said nanocarrier is selected from the group consisting of a liposome, a micelle, a lipid-coated bubble, and a block copolymer micelle.
21. The targeted delivery composition of claim 18 , wherein said nanocarrier further comprises a stealth agent.
22. The targeted delivery composition of claim 21 , wherein said stealth agent is poly(ethylene glycol).
23. The targeted delivery composition of claim 18 , wherein said therapeutic or diagnostic agent is embedded in, encapsulated in, or tethered to said nanocarrier.
24. The targeted delivery composition of claim 23 , wherein said nanocarrier is a liposome.
25. The targeted delivery composition of claim 18 , wherein said nanocarrier is a liposome selected from the group consisting of SUVs, LUVs and MLVs.
26. The targeted delivery composition of claim 18 , wherein said nanocarrier comprises a therapeutic agent selected from the group consisting of doxorubicin, cisplatin, oxaliplatin, carboplatin, 5-fluorouracil, gemcitibine and a taxane.
27. The targeted delivery composition of claim 18 , wherein said diagnostic agent is a radioactive agent, a fluorescent agent, or a contrast agent.
28. The targeted delivery composition of claim 18 , wherein said diagnostic agent is a radioactive agent selected from the group consisting of 111 In-DTPA, 99m Tc(CO) 3 -DTPA, and 99m Tc(CO) 3 -ENPy2.
29. The targeted delivery composition of claim 18 , wherein said diagnostic agent is a fluorescent agent.
30. The targeted delivery composition of claim 18 , wherein said diagnostic agent is a MR agent or a X-ray contrast agent.
31. The targeted delivery composition of claim 18 , wherein said attachment component comprises a functional group for covalent attachment to said nanocarrier.
32. The targeted delivery composition of claim 18 , wherein said attachment component is a lipid.
33. The targeted delivery composition of claim 32 , wherein said lipid is a phospholipid, glycolipid, sphingolipid, or cholesterol.
34. The targeted delivery composition of claim 18 , wherein the A portion of said conjugate is present in a lipid bilayer portion of said nanocarrier.
35. The targeted delivery composition of claim 34 , wherein said nanocarrier is a liposome.