High affinity CXCR4 selective binding conjugate and method for using the same

1. A high affinity CXCR4 selective binding ligand peptide conjugate (PC) of the Formula:

P L-A) n    I

or a pharmaceutically acceptable salt thereof, wherein

n is an integer from 1 to about 5 or the sum of (the total number of side-chain functional groups within P)

A is one or more diagnostic agents, therapeutic agents, or imaging agents;

L is a bifunctional linker or absent; and

P is a high affinity CXCR4 selective binding peptidyl ligand of the formula:

wherein:

a is 0 or 1;

AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine;

AA 2 along with the sulfur atom that is attached thereto is cysteine or homocysteine;

Ar 1 is an optionally substituted aryl;

X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);

X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-Dab, D-Orn, D-Lys, D-Dap(iPr), D-Dab(iPr), D-Orn(iPr), D-Lys(iPr), or absent;

X 3 is Lys, Gly or absent;

X 4 is Lys, Phe, 2Nal, 1Nal, the D-isomer thereof, Gly, or absent;

X 5 is Lys, Gly or absent; and

R 2 is —OR 4 or —NHR 5 , wherein R 4 and R 5 are H, alkyl, optionally substituted aryl or optionally substituted aralkyl.

2. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 , wherein A is attached to the N-terminal end or the C-terminal end of said peptide, or to a function group that is present on the side-chain of the amino acid residue of said peptide, or a combination of any one of the positions thereof.

3. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 , wherein said high affinity CXCR4 selective binding ligand peptide conjugate comprises a plurality of A.

4. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 , wherein A is an imaging agent.

5. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 , wherein A is a diagnostic agent.

6. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 , wherein said diagnostic agent is an imaging agent, an isotopic agent, or a radioactive agent.

7. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 , wherein said linker comprises a functional group that is capable of releasing A in vivo.

8. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 , wherein A is a therapeutic agent.

9. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 8 , wherein said therapeutic agent is selected from the group consisting of bleomycin, calicheamicin, daunorubicin, docetaxel, doxorubicin, irinotecan, mertansine, monomethyl auristatin E, paclitaxel, SN-38, tesirine, topotecan, tubulysin, vinca alkaloids, and an analog or derivative thereof, and a combination thereof.

10. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 , wherein said high affinity CXCR4 selective binding ligand peptide conjugate is:

cyclo[Phe-Tyr-Lys(iPr)-(D-Arg)-2Nal-Gly-(D-Glu)]-Lys(iPr)-(mini-PEG6)-Cys(S-paclitaxel)-Gly-NH 2 (SEQ ID NO:3), wherein the cyclic structure is formed between the α-amino of Phe connected to the side chain of D-Glu; or

R a -cyclo[Cys-Tyr-Lys(iPr)-(D-Arg)-2Nal-Gly-Cys]-Lys(iPr)-R b (SEQ ID NO:4);

R a -cyclo[hCys-Tyr-Lys(iPr)-(D-Arg)-2Nal-Gly-Cys]-Lys(iPr)-R b (SEQ ID NO:5);

R a -cyclo[Cys-Tyr-Lys(iPr)-(D-Arg)-2Nal-Gly-hCys]-Lys(iPr)-R b (SEQ ID NO:6); and

wherein

R a is acetyl-, acetyl-Cys(S-paclitaxel)-, or acetyl-Cys(S-paclitaxel)-(mini-PEG6)-; and

R b is glycyl-amide, glycyl-Cys(S-paclitaxel)-amide, or (mini-PEG6)-Cys(S-paclitaxel)-amide,

provided at least one of R a or R b comprises 5-paclitaxel.

11. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 of the Formula:

or a pharmaceutically acceptable salt thereof, wherein:

a is 0 or 1;

AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine, wherein A is optionally attached to α-amino group of said cysteine or homocysteine;

AA 2 along with the sulfur atom that is attached thereto is cysteine or homocysteine;

Ar 1 is an optionally substituted aryl;

X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);

X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-Dab, D-Orn, D-Lys, D-Dap(iPr), D-Dab(iPr), D-Orn(iPr), D-Lys(iPr), or absent;

L is an optional linker; and

A is as defined in claim 1 .

12. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 , wherein A is selected from the group consisting of HIV protease inhibitors, HIV fusion inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV entry inhibitors, and a combination thereof.

13. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 12 , wherein A is HIV fusion inhibitor enfuvirtide.

14. A composition comprising a high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 and a pharmaceutically acceptable carrier, diluent, excipient or a combination thereof.

15. A diagnostic or an imaging kit comprising a high affinity CXCR4 selective binding ligand peptide conjugate (PC) of claim 1 , wherein A of Formula I is a diagnostic agent or an imaging agent.

16. A method for imaging cancer cells in a patient comprising:

administering to a patient an imaging effective amount of a high affinity CXCR4 selective binding ligand peptide conjugate of claim 4 ; and

imaging cancer cells in said patient using an imaging apparatus.

17. A method for treating cancer in a patient, said method comprising administering a therapeutically effective amount of a compound of claim 11 to a cancer patient, wherein A is a cancer drug.

18. A method for treating a patient suffering from rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer, said method comprising administering a therapeutically effective amount of a compound of claim 11 to a patient in need of treatment thereof, wherein said cancer is selected from the group consisting of breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.

19. A high affinity CXCR4 selective binding ligand peptide conjugate (PC) of the Formula:

P L-A) n    I

or a pharmaceutically acceptable salt thereof, wherein

n is an integer from 2 to about 5 or the sum of (the total number of side-chain functional groups within P)

A is atherapeutic agent;

L is a bifunctional linker or absent; and

P is a high affinity CXCR4 selective binding peptidyl ligand of the formula:

wherein:

a is 0 or 1;

AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine;

AA 2 along with the sulfur atom that is attached thereto is cysteine or homocysteine;

Ar 1 is an optionally substituted aryl;

X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);

X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-Dab, D-Orn, D-Lys, D-Dap(iPr), D-Dab(iPr), D-Orn(iPr), D-Lys(iPr), or absent;

X 3 is Lys, Gly or absent;

X 4 is Lys, Phe, 2Nal, 1Nal, the D-isomer thereof, Gly, or absent;

X 5 is Lys, Gly or absent; and

R 2 is —OR 4 or —NHR 5 , wherein R 4 and R 5 are H, alkyl, optionally substituted aryl or optionally substituted aralkyl.

20. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 19 , wherein each of said therapeutic agent is independently selected from the group consisting of bleomycin, calicheamicin, daunorubicin, docetaxel, doxorubicin, irinotecan, mertansine, monomethyl auristatin E, paclitaxel, SN-38, tesirine, topotecan, tubulysin, vinca alkaloids, and an analog or derivative thereof, and a combination thereof.