Stimulus-responsive micellar carrier

Patent metadata

Field	Value
Publication number	US-11890342-B2
Application number	US-202017130415-A
Country	US
Kind code	B2
Filing date	Dec 22, 2020
Priority date	Apr 4, 2017
Publication date	Feb 6, 2024
Grant date	Feb 6, 2024

Abstract

A stimulus-responsive micellar carrier, methods that may be associated with making a stimulus-responsive micellar carrier, and methods that may be associated with using a stimulus-responsive micellar carrier are disclosed. The stimulus-responsive micellar carrier comprises a cargo molecule, and a linear block copolymer having a hydrophilic block connected to a hydrophobic block by a stimulus-responsive junction moiety. The micellar carrier can be supplied to a patient body for therapeutic purposes, such as the treatment of cancerous tissue. A method of preparing or obtaining a stimulus-responsive micellar carrier may include preparing a polyethylene glycol material having an acetal end group and then preparing a block copolymer by forming a reaction mixture including the polyethylene glycol material, a cyclic carbonate monomer, and a base.

First claim

What is claimed is:

1. A method for producing a linear block copolymer, comprising:
preparing an alcohol terminated polyethylene glycol (PEG) material having an acetal group, the preparation comprising:
reacting an alcohol terminated PEG with 2-(vinyloxy)ethyl acetate to form an acetate terminated PEG having the acetal group, and
hydrolyzing the acetate terminated PEG having the acetal group to form the alcohol terminated PEG material having the acetal group;

introducing the alcohol terminated PEG having the acetal group with a cyclic carbonate monomer; and
mixing the alcohol terminated PEG having the acetal group, the cyclic carbonate monomer, and a base to form a linear block copolymer, wherein the linear block copolymer consists of a hydrophilic block comprising a polyethylene glycol, a hydrophobic block having a structure comprising a carbonate group, and a stimulus-responsive junction moiety having the structure

wherein one wavy bond represents a bond to the polyethylene glycol of the hydrophilic block and the other wavy bond represents a bond to the carbonate group of the hydrophobic block.

2. The method of claim 1 , wherein the base is 1,8-diazabicycloundec-7-ene.

3. The method of claim 1 , wherein the cyclic carbonate monomer has the following structure:

wherein R includes at least one carbon atom.

4. The method of claim 1 , further comprising:
mixing the linear block copolymer with a cargo molecule to form a micellar carrier.

5. The method claim 4 , further comprising:
supplying the micellar carrier to a patient body.

6. The method of claim 5 , wherein supplying the micellar carrier is performed via intravenous injection.

7. A micellar carrier, comprising:
a linear block copolymer having a hydrophilic block comprising a polyethylene glycol and connected to a hydrophobic block by a stimulus-responsive junction moiety having the structure

the linear block copolymer produced by the method of claim 1 , and
a hydrophobic cargo molecule,
the hydrophobic block represented by:

wherein;
m is a numerical value greater than 1, and
R is selected from the group consisting of a benzyl group, an alkyl group, a boronic acid, a urea, and a hydrogen atom.

8. The micellar carrier of claim 7 , wherein
the cargo molecule is a therapeutic agent, and
the linear block copolymer is represented by the following:

wherein n and m are independently a positive integer.

9. A micellar carrier, comprising:
a linear block copolymer comprising a hydrophilic block connected to a hydrophobic block by a stimulus-responsive junction moiety, wherein the hydrophilic block comprises a polyethylene glycol, the hydrophobic block comprises a carbonate group, and the stimulus-responsive junction moiety has the structure

wherein one wavy bond represents a bond to the polyethylene glycol of the hydrophilic block and the other wavy bond represents a bond to the carbonate group of the hydrophobic block; and
a cargo molecule that is hydrophobic.

10. The micellar carrier of claim 9 , wherein the micellar carrier has a diameter between 20 nm and 200 nm.

11. The micellar carrier of claim 9 , wherein the cargo molecule is a therapeutic agent.

12. The micellar carrier of claim 9 , wherein the cargo molecule is an anti-cancer compound.

13. The micellar carrier of claim 9 , wherein a structure of the hydrophobic block further comprises an R group, wherein the R group is one of a methyl group, a benzyl group, a derivate of a benzyl group, a linear alkyl group having 2 to 20 carbon atoms, a branched alkyl group having 2 to 20 carbon atoms, a carbamide group having the chemical formula (R 1 R 2 N)CO(NR 3 R 4 ), or a thiourea group having the chemical formula (R 1 R 2 N)CS(NR 3 R 4 ), wherein each of R 1 , R 2 , R 3 , and R 4 is independently a hydrogen or a group that includes at least one carbon atom.

14. The micellar carrier of claim 9 , wherein a structure of the hydrophobic block further comprises an R group, wherein the R group includes a boronic acid functional group, a carbamide group having the chemical formula (R 1 R 2 N)CO(NR 3 R 4 ), a thiourea group having the chemical formula (R 1 R 2 N)CS(NR 3 R 4 ), one or more unsaturated groups, one or more cyclic groups, or one or more heterocyclic groups, wherein each of R 1 , R 2 , R 3 , and R 4 is independently a hydrogen or a group that includes at least one carbon atom.

15. The micellar carrier of claim 9 , wherein a structure of the hydrophobic block further comprises an R group, wherein the R group is one of a methyl group or a benzyl group.

16. The micellar carrier of claim 9 , wherein the cargo molecule comprises protein.

17. The micellar carrier of claim 9 , wherein the cargo molecule is a DNA fragment or RNA fragment.

18. The method of claim 1 , wherein reacting the alcohol terminated PEG with 2-(vinyloxy)ethyl acetate to form the acetate terminated PEG having the acetal group further comprises using an acid catalyst.

Assignees

• IBM
• Agency For Science Tech And Research Astar

Inventors

• Boday Dylan J
• Garcia Jeannette M
• Hedrick James L
• Park Nathaniel
• Wojtecki Rudy J
• Chuan Yang
• Lee Ashlynn
• Liang zhen chang
• Liu Shaoqiong
• Yang Yi Yan

Classifications

• A61K47/34 Primary

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title

• A61K9/0019

  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 title

• A61K9/107

  Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)} · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title