Composition and method for dual targeting in treatment of neuroendocrine tumors

• US 10,328,043 B1
• Filed: 04/11/2018
• Issued: 06/25/2019
• Est. Priority Date: 04/11/2018
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Mousa, Shaker, Rajabi, Mehdi, Karakus, Ozlem O.
• Primary Examiner(s): Chu, Yong L
• Application Number:
  US15/950,870
• Time in Patent Office: 440 Days
• Field of Search: 514634
• CPC Class Codes: A61K 31/191 having two or more hydroxy groups, e.g. gluconic acid
• CPC Class Codes: 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
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/16 containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: 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
• CPC Class Codes: A61P 35/00 Antineoplastic agents

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

1. A composition comprising:

a compound of

a general formula;

2. The composition of claim 1, wherein the compound has a general formula of

3. The composition of claim 1, wherein the composition is used for the treatment of a neuroendocrine tumor by administration in a therapeutic dose.

4. The composition of claim 1, wherein the composition has a utility for the treatment of a neuroendocrine tumor.

5. The composition of claim 4, wherein the neuroendocrine tumor is one of a neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumor, and carcinoid tumor.

6. The composition of claim 1, wherein the composition targets neuroendocrine tumor cells via a norepinephrine transporter.

7. The composition of claim 1, wherein the composition targets neuroendocrine tumor cells via binding with an integrin α

vβ

3 receptor.

8. The composition of claim 1, wherein the composition targets neuroendocrine tumor cells via both a) the norepinephrine transporter and b) reaction with the integrin α

vβ

3 receptor.

9. A method of treating a neuroendocrine tumor, comprising:

administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound having a chemical formula;

10. The method of claim 9, wherein the compound has a chemical formula of

11. The method of claim 9, wherein the neuroendocrine tumor is one of a neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumor, and carcinoid tumor.

12. The method of claim 9, wherein the composition targets neuroendocrine tumor cells via a norepinephrine transporter.

13. The method of claim 9, wherein the composition targets neuroendocrine tumor cells via binding with an integrin α

vβ

3 receptor.

14. The method of claim 9, wherein the composition targets neuroendocrine tumor cells via both a) the norepinephrine transporter and b) reaction with the integrin α

vβ

3 receptor.

15. A composition comprising:

N-benzyl guanidine; and

triazole tetrac;

wherein the N-benzyl guanidine and the triazole tetrac are conjugated by polyethylene glycol.

16. The composition of claim 15, wherein the composition is used for the treatment of a neuroendocrine tumor by administration in a therapeutic dose.

17. The composition of claim 15, wherein the composition has a utility for the treatment of a neuroendocrine tumor.

18. The composition of claim 17, wherein the neuroendocrine tumor is one of a neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumor, and carcinoid tumor.

19. The composition of claim 15, wherein the composition targets neuroendocrine tumor cells via a norepinephrine transporter.

20. The composition of claim 15, wherein the composition targets neuroendocrine tumor cells via binding with an integrin α

vβ

3 receptor.

21. The composition of claim 15, wherein the composition targets neuroendocrine tumor cells via both a) the norepinephrine transporter and b) reaction with the integrin α

vβ

3 receptor.