PSMA ligands and uses thereof
Compounds that are PSMA ligands, pharmaceutical compositions comprising these compounds, methods for treating and detecting cancers in a subject, methods for identifying cancer cells in a sample are described herein. Prostate-specific membrane antigen (PSMA) is a 120 kDa protein expressed in prostate tissues and was originally identified by reactivity with a monoclonal antibody designated 7EII-C5 (Horoszewicz et al., 1987, Anticancer Res. 7:927-935; U.S. Pat. No. 5,162,504). PSMA is characterized as a type II transmembrane protein sharing sequence identity with the transferrin receptor (Israeli et al., 1994, Cancer Res. 54:1807-1811).
1. A compound represented by the general formula (I):
wherein:
n and n 1 are each independently 1, 2, 3, or 4;
L comprises at least one ring selected from the group consisting of an optionally substituted 4 to 7 membered nonaromatic heterocyclic ring and an optionally substituted C4-C7 cycloalkyl ring;
B comprises at least one glutamic acid residue; and
Y is a H of B or includes at least one of a detectable moiety, therapeutic agent, or a theranostic agent that is directly or indirectly linked to B.
2. The compound of claim 1 , wherein Y is selected from the group consisting of an imaging agent, anticancer agent, or combination thereof.
3. The compound of claim 1 , wherein B has the following formula:
wherein m is 1, 2, 3, or 4, X 1 is an amino acid, and Y 1 is a H of X 1 or includes at least one of an amino acid, peptide, detectable moiety, therapeutic agent, or theranostic agent that is directly or indirectly linked to X 1 .
4. The compound of claim 1 , wherein B has the following formula:
wherein m is 1, 2, 3, or 4 and Y 2 is a H or includes at least one of an amino acid, peptide, detectable moiety, therapeutic agent, or theranostic agent.
5. The compound of claim 1 , represented by the general formula:
wherein m, n, and n 1 is 1, 2, 3, or 4; n and n 1 are each independently 1, 2, 3, or 4; and Y 2 is a H or includes at least one of an amino acid, peptide, detectable moiety, therapeutic agent, or theranostic agent.
6. A composition for diagnosing and/or treating cancer, the composition comprising a prostate specific membrane antigen (PSMA) ligand that includes general formula (I):
wherein:
n and n 1 are each independently 1, 2, 3, or 4;
L comprises at least one ring selected from the group consisting of an optionally substituted 4 to 7 membered nonaromatic heterocyclic ring and an optionally substituted C4-C7 cycloalkyl ring;
B comprises at least one glutamic acid residue; and
Y is a H of B or includes at least one of a detectable moiety, therapeutic agent, or a theranostic agent that is directly or indirectly linked to B.
7. The composition of claim 6 , wherein Y is selected from the group consisting of an imaging agent, anticancer agent, or combination thereof.
8. The composition of claim 6 , wherein B has the following formula:
wherein m is 1, 2, 3, or 4, X 1 is an amino acid, and Y 1 is a H of X 1 or includes at least one of an amino acid, peptide, detectable moiety, therapeutic agent, or theranostic agent that is directly or indirectly linked to X 1 .
9. The composition of claim 6 , wherein B has the following formula:
wherein m is 1, 2, 3, or 4 and Y 2 is a H or includes at least one of an amino acid, peptide, detectable moiety, therapeutic agent, or theranostic agent.
10. The composition of claim 6 , comprising the general formula:
wherein m, n, and n 1 is 1, 2, 3, or 4; n and n 1 are each independently 1, 2, 3, or 4; and Y 2 is a H or includes at least one of an amino acid, peptide, detectable moiety, therapeutic agent, or theranostic agent.
11. A composition for treating prostate cancer in a subject, the composition comprising:
a polyethylene glycolylated (PEGylated) nanoparticle;
at least one anti-cancer agent coupled to the surface of the nanoparticle; and
at least one prostate specific membrane antigen (PSMA) ligand coupled to polyethylene glycol of the nanoparticle for targeting the composition to a prostate cancer cell, wherein the PSMA ligand includes general formula (I):
wherein:
n and n 1 are each independently 1, 2, 3, or 4;
L is an optionally substituted aliphatic or heteroaliphatic linking group;
B comprises at least one negatively charged amino acid; and
Y is the (PEGylated) nanoparticle that is directly or indirectly linked to B.
12. The composition of claim 11 , the anti-cancer agent comprising Phthalocyanine 4.
13. The composition of claim 11 , the polyethylene glycolylated (PEGylated) nanoparticle comprising a polyethylene glycolylated (PEGylated) gold nanoparticle.
14. The composition of claim 11 , wherein B has the following formula:
wherein m is 1, 2, 3, or 4, X 1 is an amino acid, and Y 1 is the (PEGylated) nanoparticle.
15. The composition of claim 11 , wherein B has the following formula:
wherein m is 1, 2, 3, or 4 and Y 2 is the (PEGylated) nanoparticle.
16. The composition of claim 11 , wherein L includes at least one ring selected from the group consisting of an optionally substituted 4 to 7 membered nonaromatic heterocyclic ring and an optionally substituted C4-C7 cycloalkyl ring.
17. The composition of claim 11 , comprising the general formula:
wherein m, n, and n 1 is 1, 2, 3, or 4; n and n 1 are each independently 1, 2, 3, or 4; and Y 2 is the (PEGylated) nanoparticle.
18. A method for treating prostate cancer comprising:
(a) administering systemically to a subject with prostate cancer a therapeutically effective amount of a composition comprising:
PEGylated gold nanoparticle;
Phthalocyanine 4 conjugated to the PEGylated gold nanoparticle; and
at least one prostate specific membrane antigen (PSMA) ligand coupled to polyethylene glycol of the nanoparticle for targeting the composition to a prostate cancer cell, wherein the PSMA ligand includes general formula (I):
wherein:
n and n 1 are each independently 1, 2, 3, or 4;
L is an optionally substituted aliphatic or heteroaliphatic linking group;
B comprises at least one negatively charged amino acid; and
Y is the (PEGylated) nanoparticle that is directly or indirectly linked to B; and
(b) exposing the cancer cell to light, thereby inducing the cytotoxic effects of Phthalocyanine 4.
19. The method of claim 18 , wherein the composition is administered by intravenous injection.
20. The method of claim 18 , wherein B has the following formula:
wherein m is 1, 2, 3, or 4, X 1 is an amino acid, and Y 1 is the (PEGylated) nanoparticle.
21. The composition of claim 18 , wherein B has the following formula:
wherein m is 1, 2, 3, or 4 and Y 2 is the (PEGylated) nanoparticle.
22. The method of claim 18 , wherein L includes at least one ring selected from the group consisting of an optionally substituted 4 to 7 membered nonaromatic heterocyclic ring and an optionally substituted C4-C7 cycloalkyl ring.
23. The method of claim 18 , wherein the PSMA ligand comprises the general formula:
wherein m, n, and n 1 is 1, 2, 3, or 4; n and n 1 are each independently 1, 2, 3, or 4; and Y 2 is the (PEGylated) nanoparticle.