# US 11,077,082 B2 · Composition and method for dual targeting in treatment of neuroendocrine tumors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,077,082 B2 - Document ID: US11077082B2 - Status: Granted - Kind: B2 - Application number: 16/398,342 - Filed: 2019-04-30 - Published: 2019-10-17 - Granted: 2021-08-03 - Earliest claimed: 2018-04-11 - Assignees: Nanopharmaceuticals LLC - Applicants: Nanopharmaceuticals LLC - Inventors: Shaker Mousa; Mehdi Rajabi; Ozlem O. Karakus - Web page: https://patentgrep.com/patent/US11077082B2 ## CPC - A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) - A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones - A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug - A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol - A61P 35/00: Antineoplastic agents - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - A61K 31/191: having two or more hydroxy groups, e.g. gluconic acid - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61K 47/16: containing nitrogen, {e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Chemical compositions and methods of synthesis thereof. The compositions disclosed and described herein are directed toward thyroid hormone αvβ3 integrin receptor antagonists conjugated to targets of the norepinephrine transporter (NET) or the catecholamine transporter. The compositions have a dual targeting effect and increased targeting efficiency in the treatment and diagnostic imaging of neuroendocrine tumors. ## Claims ### Claim 1 A composition comprising: a compound of a general formula: or a salt thereof; wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, iodine, fluorine, bromine, a methoxy group, a nitro group, an amine group, and a nitrile group; wherein R5, R6, R7, and R8 are each independently selected from the group consisting of hydrogen, iodine, and an alkane group; and n1≥0; n2≥1; and ### Claim 2 (depends on 1) The composition of claim 1, wherein at least one of R5, R6, R7, and R8 are selected from the group consisting of an isopropyl group and a tert-butyl group. ### Claim 3 (depends on 1) The composition of claim 1, wherein the compound has a chemical formula selected from the group consisting of: ### Claim 4 (depends on 1) The composition of claim 1, wherein the compound having a: N-benzyl guanidine; and a thyrointegrin αvβ3 receptor antagonist moieties. ### Claim 5 (depends on 1) The composition of claim 1, wherein the compound having a polymer. ### Claim 6 (depends on 5) The composition of claim 5, wherein the polymer is polyethylene glycol (PEG). ### Claim 7 (depends on 6) The composition of claim 6, wherein the polyethylene glycol (PEG) has a molecular weight between 200 and 4,000 grams per mole. ### Claim 8 (depends on 1) The composition of claim 1, wherein the thyrointegrin αvβ3 receptor antagonist is selected from the group consisting of triiodothyroacetic acid, triiodothyroacetic acid derivatives, tetraiodothyroacetic acid, and tetraiodothyroacetic acid derivatives. ### Claim 9 (depends on 1) The composition of claim 1, wherein the composition has a utility for the treatment of a neuroendocrine tumor. ### Claim 10 (depends on 9) The composition of claim 9, wherein the neuroendocrine tumor is one of a neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumor, and carcinoid tumor. ### Claim 11 (depends on 9) The composition of claim 9, wherein the utility for the treatment of the neuroendocrine tumor is maximally provided by both the N-benzyl guanidine and the thyrointegrin αvβ3 receptor antagonist. ### Claim 12 (depends on 11) The composition of claim 11, wherein the composition targets neuroendocrine tumor cells via a norepinephrine transporter. ### Claim 13 (depends on 11) The composition of claim 11, wherein the composition targets neuroendocrine tumor cells via binding with an integrin αvβ3 receptor. ### Claim 14 (depends on 11) The composition of claim 11, wherein the composition targets neuroendocrine tumor cells via both a) a norepinephrine transporter and b) binding with an integrin αvβ3 receptor. ### Claim 15 (depends on 14) The composition of claim 14, wherein targeting via the norepinephrine transporter is provided by the N-benzyl guanidine and binding with the integrin αvβ3 receptor is provided by the thyrointegrin αvβ3 receptor antagonist. ### Claim 16 (depends on 1) The composition of claim 1, wherein at least one of R1, R2, R3, and R4 is selected from the group consisting of I(123), I(131), and F(18). ### Claim 17 (depends on 16) The composition of claim 16, wherein the composition is used for imaging a neuroendocrine tumor. ### Claim 18 (depends on 16) The composition of claim 16, wherein the composition is used for the treatment of a neuroendocrine tumor by administration in a therapeutic dose. ### Claim 19 (depends on 16) The composition of claim 16, wherein the composition is used for simultaneous imaging and treatment of a neuroendocrine tumor. ### Claim 20 A method for dual targeting of tumor cells, comprising: administering a composition comprising: a compound of a general formula: or a salt thereof; wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, iodine, fluorine, bromine, a methoxy group, a nitro group, an amine group, and a nitrile group; wherein R5, R6, R7, and R8 are each independently selected from the group consisting of hydrogen, iodine, and an alkane group; and n1≥0; n2≥1; and ### Claim 21 (depends on 20) The method of claim 20, wherein the compound having one of N-benzyl guanidine and an N-benzyl guanidine derivative. ### Claim 22 (depends on 20) The method of claim 20, wherein the composition comprises a thyrointegrin αvβ3 receptor antagonist selected from the group consisting of triiodothyroacetic acid, triiodothyroacetic acid derivatives, tetraiodothyroacetic acid, and tetraiodothyroacetic acid derivatives.