Enrichment-triggered chemical delivery system

Patent metadata

Field	Value
Publication number	US-2021000965-A1
Application number	US-201816758833-A
Country	US
Kind code	A1
Filing date	Oct 25, 2018
Priority date	Oct 25, 2017
Publication date	Jan 7, 2021
Grant date	—

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

1 . A chemical delivery system comprising:
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; wherein: 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; the first reactive moiety and the second reactive moiety are substantially unreactive toward one another without the increase in concentration of the cargo compound and the increase in concentration of the trigger compound at the target site; the increase in concentration of the cargo compound and the increase in concentration of the trigger compound at the target site cause a bimolecular reaction between the first reactive moiety and the second reactive moiety to form a cyclization precursor compound; and the cargo moiety is released from the cyclization precursor compound in a unimolecular cyclization reaction.

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 . (canceled)

4 . 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 .

5 - 6 . (canceled)

7 . The chemical delivery system of claim 1 , wherein the first enrichment moiety and the second enrichment moiety are independently selected mitochondrion-targeting moieties.

8 . The chemical delivery system of claim 7 , wherein the mitochondrion-targeting moiety is a positively charged phosphine.

9 . The chemical delivery system of claim 1 , wherein the first enrichment moiety and the second enrichment moiety are independently 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.

10 . (canceled)

11 . The chemical delivery system of claim 1 , wherein the first reactive moiety is selected from the group consisting of a tetrazine, a thiophene 1,1-dioxide, and a cyclopentadienone, and wherein the second reactive moiety is selected from the group consisting of a cyclooctyne and a cyclooctene.

12 . (canceled)

13 . The chemical delivery system of claim 1 , wherein the cargo compound has a structure according to Formula I:

wherein R 1 is the first targeting moiety, R 2 is the cleavable linker, and R 3 is the tethered cargo moiety.

14 . The chemical delivery system of claim 13 , wherein the cargo compound has a structure according to Formula Ia:

wherein R 1a is a linking diradical, R 1b is a targeting radical, and R 3a is a cargo radical.

15 . (canceled)

16 . The chemical delivery system of claim 14 , wherein the cargo compound is:

17 . The chemical delivery system claim 13 , wherein the unimolecular cyclization reaction results in the formation of a lactone, a thiolactone, or a lactam.

18 . (canceled)

19 . The chemical delivery system of claim 13 , wherein the trigger compound has a structure according to Formula II:

wherein R 4 is the second targeting moiety and R 5 is the cargo-releasing moiety.

20 . The chemical delivery system of claim 19 , wherein R 5 is selected from the group consisting of —OH, —SH, and —NH 2 .

21 . The chemical delivery system of claim 19 , wherein the trigger compound has a structure according to Formula IIa:

22 . The chemical delivery system of claim 21 , wherein the trigger compound has a structure according to Formula IIb:

23 . The chemical delivery system of claim 21 , wherein the trigger compound is:

24 . The chemical delivery system of claim 1 , wherein the cargo moiety is a drug moiety.

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

26 . 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 .

27 . The method of claim 26 , 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

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• A61K31/675

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

• A61K31/66

  Phosphorus compounds · CPC title

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · CPC title

• C07D257/08

  Six-membered rings · CPC title