Radiopharmaceuticals and methods of use thereof
View Patent ↗Targeted pharmaceuticals, particularly targeted radiopharmaceuticals, are provided which possess extended tumor retention time.
1 . A compound consisting of
a) a targeting moiety, wherein said targeting moiety binds a receptor expressed on a cancer cell and is an agonist of said receptor, and wherein said targeting moiety is a peptide of less than 20 amino acids in length;
b) a cysteine cathepsin trapping agent (CCTA), wherein said CCTA is an epoxide CCTA, and
c) a cytotoxic or radioactive moiety,
wherein said cysteine cathepsin trapping agent is linked either directly or via a linker to said cytotoxic or radioactive moiety, and wherein said cytotoxic or radioactive moiety is linked to the N-terminus of said targeting moiety either directly or via a linker, and
wherein the log D 7.4 of the compound is −2.5 to −4.0.
2 . The compound of claim 1 , wherein said receptor is selected from the group consisting of neurotensin receptors, gastrin-releasing peptide receptors, folate receptors, somatostatin receptors, prostate specific membrane antigen, vasoactive intestinal peptide receptors, cholecystokinin receptors, calcitonin receptors, vitronectin receptors, integrin receptors, asialoglycoprotein receptors, vascular endothelia growth factor receptors, transferrin receptors, luteinizing hormone-releasing hormone receptor, melanocortin receptors, glucagon-like peptide receptors, neurokinin receptors, sigma receptors, tropomyosin receptor kinase, aminopeptidase n receptor, and epidermal growth factor receptor.
3 . The compound of claim 2 , wherein said receptor is selected from the group consisting of neurotensin receptors, gastrin-releasing peptide receptors, folate receptors, and somatostatin receptor.
4 . The compound of claim 3 , wherein said receptor is neurotensin receptor 1 .
5 . The compound of claim 1 , wherein said CCTA is an epoxysuccinyl peptide.
6 . The compound of claim 1 , wherein said cytotoxic or radioactive moiety is a radionuclide.
7 . The compound of claim 6 , wherein said radionuclide is contained within 1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane (TCMC) or 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).
8 . The compound of claim 6 , wherein said radionuclide is 177 Lu.
9 . The compound of claim 1 , wherein at least one of said linkers comprises a peptide linker.
10 . The compound of claim 1 , wherein at least one of said linkers comprises poly(ethylene glycol).
11 . The compound of claim 1 , wherein the log D 7.4 of the compound is −3.0 to −4.0.
12 . The compound of claim 1 , wherein the compound has a structure selected from the group consisting of:
13 . A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
14 . The composition of claim 13 , further comprising a chemotherapeutic agent.
15 . A method of treating a disease or disorder in a subject in need thereof, said method comprising administering a compound of claim 1 to said subject.
16 . The method of claim 15 , wherein said compound is administered as a composition further comprising a pharmaceutically acceptable carrier.
17 . The method of claim 15 , wherein said disease or disorder is cancer.
18 . The method of claim 17 , wherein said compound or composition is administered intravenously or to the tumor site.
19 . The compound of claim 1 , wherein said CCTA forms a thioether linkage with cysteine cathepsin.
20 . The compound of claim 1 ,
wherein said targeting moiety is linked to said cytotoxic or radioactive moiety by a peptide linker of 1-5 amino acids, and
wherein said CCTA is linked to said cytotoxic or radioactive moiety by a peptide linker of 1-5 amino acids.
21 . The compound of claim 20 , wherein both peptide linkers comprise at least one D-amino acid.
22 . The compound of claim 20 , wherein both peptide linkers comprise three serine residues.
23 . The compound of claim 20 , wherein said receptor is selected from the group consisting of neurotensin receptors, gastrin-releasing peptide receptors, folate receptors, and somatostatin receptor.
24 . The compound of claim 12 , wherein the compound has the structure:
25 . The compound of claim 12 , wherein the compound has the structure:
26 . The compound of claim 12 , wherein the compound has the structure