Prostate specific membrane antigen (PSMA) targeted nanoparticles for therapy of prostate cancer

Patent metadata

Field	Value
Publication number	US-9422234-B2
Application number	US-74498208-A
Country	US
Kind code	B2
Filing date	Nov 26, 2008
Priority date	Nov 30, 2007
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

The invention provides a nanoparticle composition that is decorated with a urea-based small-molecule peptidomimetic inhibitor of prostate specific membrane antigen (PSMA), which is expressed by almost all solid tumors. This strategy takes advantage of both the avidity of the functionalized nanoparticle for binding to PSMA and the ability of the nanoparticle to be retained for longer periods of time in the tumor due to enhanced leakage via EPR into the tumor interstitium and poor clearance due to underdeveloped or non-existent lymphatics within the tumor.

First claim

What is claimed is:

1. A nanoparticle composition comprising formula I:
(X) m —(Y) n —Z  (I);

wherein,
X is a prostate specific membrane antigen (PSMA) inhibitor that is a compound of formula II,

wherein,
R 1 is (CH 2 ) p —NR 3 —Y, wherein p is 1-6;
R 2 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted alkylcarboxy, and optionally substituted carbocyclic;
R′ and R″ are each independently selected from the group consisting of —OR 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , —N(R 3 )S(O) 2 —R 4 , —N(R 3 )(SO 2 )NR 3 R 4 , —NR 3 R 4 , —C(O)—O—R 4 , —C(O)R 4 , —C(O)NR 3 R 4 , and —N(R 3 )C(O)R 4 ;
R 3 and R 4 are each independently selected at each occurrence from the group consisting of: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; and optionally substituted carbocyclic;
a pharmaceutically acceptable salt thereof;

Y is

wherein
A is selected from the group consisting of O, S, NH, N(alkyl) and N(aryl); and
R A is (CH 2 ) r -Q-Z;
Q is CO, C(O)O, C(O)NH, C(O)NR B , OCO, OC(O)O, OC(O)NH, OC(O)NR B , NHCO, NHC(O)O, NHC(O)NH, NHC(O)NR B , NR B CO, NR B C(O)O, NR B C(O)NH, NR B C(O)NR B , CS, C(S)O, C(S)NH, C(S)NR B , OCS, OC(S)O, OC(S)NH, OC(S)NR B , NHCS, NHC(S)O, NHC(S)NH, NHC(S)NR B , NR B CS, NR B C(S)O, NR B C(S)NH, NR B C(S)NR B ;
each R B is independently optionally substituted alkyl or optionally substituted aryl; and
r is 3-20;
Z is a nanoparticle
m is 1-1000, and
n is 1-1000, and
a biologically active agent.

2. The composition of claim 1 , wherein the biologically active agent is encapsulated in the nanoparticle.

3. A kit comprising a nanoparticle composition of claim 1 , and instructions for use in treating cancer.

4. A pharmaceutical composition comprising a nanoparticle composition of claim 1 , and a pharmaceutically suitable excipient.

5. The nanoparticle composition of claim 1 , wherein the biologically active agent is docetaxel.

6. The nanoparticle composition of claim 1 , wherein the nanoparticles are capable of binding PSMA.

7. A nanoparticle composition of formula I:
(X) m —(Y) n —Z  (I);

wherein
X is an organic small molecule PSMA inhibitor inhibitor that is a compound of formula II,

wherein,
R 1 is (CH 2 ) p —NR 3 —Y, wherein p is 1-6;
R 2 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted alkylcarboxy, or optionally substituted carbocyclic;
R′ and R″ are each independently —OR 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , —N(R 3 )S(O) 2 —R 4 , —N(R 3 )(SO 2 )NR 3 R 4 , —NR 3 R 4 , —C(O)—O—R 4 , —C(O)R 4 , —C(O)NR 3 R 4 , or —N(R 3 )C(O)R 4 ;
R 3 and R 4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic;
or a pharmaceutically acceptable salt thereof;

Y is

wherein
A is O, S, NH, N(alkyl) or N(aryl); and
R A is (CH 2 ) r -Q-Z;
Q is CO, C(O)O, C(O)NH, C(O)NR B , OCO, OC(O)O, OC(O)NH, OC(O)NR B , NHCO, NHC(O)O, NHC(O)NH, NHC(O)NR B , NR B CO NR B C(O)O, NR B C(O)NH, NR B C(O)NR B , CS, C(S)O, C(S)NH, C(S)NR B , OCS, OC(S)O, OC(S)NH, OC(S)NR B , NHCS, NHC(S)O, NHC(S)NH, NHC(S)NR B NR B CS NR B C(S)O, NR B C(S)NH, NR B C(S)NR B ;
each R B is independently optionally substituted alkyl or optionally substituted aryl; and
r is 3-20;
Z is a nanoparticle comprising a biologically active agent;
m is 1-1000 and
n is 1-1000.

8. The composition of claim 7 , wherein the nanoparticle has a diameter ranging from about 1 nm to about 500 nm.

9. The composition of claim 7 , wherein the biologically active agent is selected from the group consisting of a nucleic acid, a polynucleotide, an amino acid, a peptide a protein, a polypeptide, a carbohydrate, a lipid, a glycoprotein, a glycan, a lipoprotein, and a small molecule.

10. The composition of claim 7 , wherein the biologically active agent is selected from the group consisting of an anti-AIDS agent, anti-cancer agent, antibiotic, antioxidants, immunosuppressant, anti-viral agent, enzyme inhibitor, protease inhibitor, reverse transcriptase inhibitor, fusion inhibitor, neurotoxin, opiod, hypnotic, anti-histamine, lubricant, tranquilizer, anti-convulsant, muscle relaxant, anti-Parkinson agent, anti-spasmodic, muscle contractant, channel blocker, miotic, anti-cholinergic, anti-glaucoma agent, anti-parasite, anti-protozoal, modulator of cell-extracellular matrix interaction, cell growth inhibitor, anti-adhesion agent, vasodilating agent, inhibitor of DNA, inhibitor of RNA, inhibitor of protein synthesis, inhibitors of apoptotic genes, modulators of transcription factors, anti-hypertensive, analgesic, anti-pyretic, steroidal anti-inflammatory agent, non steroidal anti-inflammatory agent, anti-angiogenic, anti-secretory, anticoagulant, antithrombotic agent, local anesthetic, ophthalmic, prostaglandin, anti-depressant, anti-psychotic, anti-emetic, antiproliferative, antimigration, antiangiogenic, antithrombotic, anti-inflammatory, antiphlogistic, cytostatic, cytotoxic, anticoagulative, antibacterial, antiviral and/or antimycotic agent and an imaging agent.

11. The nanoparticle composition of claim 7 , wherein the nanoparticles are capable of inhibiting the growth of prostate cancer cells.

12. The nanoparticle composition of claim 7 , wherein the nanoparticles are capable of inhibiting the growth of prostate cancer cells.

13. A nanoparticle composition of formula I:
(X) m —(Y) n —Z  (I);

wherein
X is an organic small molecule PSMA inhibitor
of formula III:

wherein,
R 1 is (CH 2 ) p —NR 3 —Y, wherein p is 1-6;
R 2 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, opti

Assignees

• Chandran Sachin S
• Ray Sangeeta
• Pomper Martin G
• Denmeade Samuel R
• Mease Ronnie C
• Univ Johns Hopkins

Inventors

• Chandran Sachin S
• Ray Sangeeta
• Pomper Martin G
• Denmeade Samuel R
• Mease Ronnie C

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title