PSMA ligands and uses thereof

Patent metadata

Field	Value
Publication number	US-9889199-B2
Application number	US-201414767984-A
Country	US
Kind code	B2
Filing date	Feb 18, 2014
Priority date	Feb 15, 2013
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

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).

First claim

Having described the invention, we claim:

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,

Assignees

• Univ Case Western Reserve

Inventors

• Basilion James
• Wang Xinning
• Burda Clemens

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K41/0071

  PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines · CPC title

• A61N5/062

  Photodynamic therapy, i.e. excitation of an agent · CPC title

• A61K47/6929

  the form being a nanoparticle, e.g. an immuno-nanoparticle · CPC title

• A61K49/0423

  Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer · CPC title