Enrichment-triggered chemical delivery system

Patent metadata

Field	Value
Publication number	US-11607458-B2
Application number	US-201816758833-A
Country	US
Kind code	B2
Filing date	Oct 25, 2018
Priority date	Oct 25, 2017
Publication date	Mar 21, 2023
Grant date	Mar 21, 2023

Abstract

Disclosed herein is a chemical delivery system having: i) a cargo compound comprising a first reactive moiety covalently bonded to a first enrichment moiety and a tethered cargo moiety, wherein the first reactive moiety is bonded to the tethered cargo moiety via a cleavable linker; and ii) a trigger compound comprising a second reactive moiety covalently bonded to a second enrichment moiety and a cargo-releasing moiety. The first enrichment moiety and the second enrichment moiety cause an increase in concentration of the cargo compound and the concentration of the trigger compound at a target site, causing a bimolecular reaction between the first reactive moiety and the second reactive moiety to form a cyclization precursor compound. The cargo moiety is then released from the cyclization precursor compound in a unimolecular cyclization reaction. Methods for treating conditions such as cancer, inflammatory conditions, and infections with the chemical delivery systems are also described.

First claim

What is claimed is:

1. A chemical delivery system having:
i) a cargo compound according to Formula I:

 wherein:
R 1 is a first enrichment moiety,
R 2 is a cleavable linker, and
R 3 is a tethered cargo moiety

ii) a trigger compound according to Formula II:

 wherein:
R 4 is a second enrichment moiety, and
R 5 is a cargo-releasing moiety selected from the group consisting of —OH, —SH, and —NH 2 ;

wherein:
the first enrichment moiety and the second enrichment moiety are independently selected from the group consisting of a positively charged phosphine, a folic acid moiety, a biotin moiety, an RGD peptide, a glucose moiety, an antibody, an aptamer, a prostate specific membrane antigen moiety, and a boronic acid moiety;
the tethered cargo moiety is selected from the group consisting of an amine-containing or alcohol-containing antibiotic, an amine-containing or alcohol-containing anti-inflammatory agent, and an amine-containing or alcohol-containing antiproliferative drug;
an increase in concentration of the cargo compound and an increase in concentration of the trigger compound at a target site cause a bimolecular reaction between the cargo compound and the trigger compound to form a cyclization precursor compound; and
the cargo moiety is released from the cyclization precursor compound in a unimolecular cyclization reaction resulting in the formation of a lactone, a thiolactone, or a lactam.

2. The chemical delivery system of claim 1 , wherein the rate of the bimolecular reaction after the increase in concentration of the cargo compound and the concentration of the trigger compound at the target site is at least 2-500 times the rate of the bimolecular reaction without the increase in concentration.

3. The chemical delivery system of claim 1 , wherein the second order rate constant for the bimolecular reaction ranges from about 10 −5 M −1 s −1 to about 120 M −1 s −1 .

4. The chemical delivery system of claim 1 , wherein the first enrichment moiety and the second enrichment moiety are positively charged phosphines.

5. The chemical delivery system of claim 1 , wherein the first enrichment moiety and the second enrichment moiety are selected from the group consisting of a folic acid moiety, a biotin moiety, an RGD peptide, a glucose moiety, an antibody, an aptamer, a prostate specific membrane antigen moiety, and a boronic acid moiety.

6. The chemical delivery system of claim 1 , wherein the cargo compound is:

7. The chemical delivery system of claim 1 , wherein the trigger compound has a structure according to Formula IIa:

8. The chemical delivery system of claim 7 , wherein the trigger compound has a structure according to Formula IIb:

9. The chemical delivery system of claim 7 , wherein the trigger compound is:

10. A pharmaceutical composition comprising the chemical delivery system of claim 1 and a pharmaceutically acceptable excipient.

11. A method for treating a disease or condition, the method comprising administering to a subject in need thereof an effective amount of a chemical delivery system according to claim 1 , wherein the disease or condition is selected from the group consisting of cancer, inflammation, and bacterial infection.

Assignees

• Univ Georgia State Res Found

Inventors

• Wang Binghe
• Zheng Yueqin
• Ji Xingyue
• Aghoghovbia Robert Emuobonuvie

Classifications

• C07F9/5407

  Acyclic saturated phosphonium compounds · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title

• C07D257/08

  Six-membered rings · CPC title

• A61K47/55 Primary

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title