KR102478594B1 - A copolymer, a method of the copolymer, and a redox responsive hydrogel comprising the copolymer - Google Patents

Abstract

[화학식 2]
* ---[O-(C_nH_2n)-]---*
상기 화학식 1 및 2에서, X, Y, m, n, 및 *의 정의는 명세서에 기재한 바와 같다.A copolymer comprising two or more moieties represented by Formula 1 below, and a linking group present between the two or more moieties, wherein the linking group includes a structural unit represented by Formula 2 below, and a method for preparing the copolymer , And it provides a redox-sensitive hydrogel comprising the copolymer.
[Formula 1]

[Formula 2]
* ---[O-(C _n H _2n )-]---*
In Formulas 1 and 2, the definitions of X, Y, m, n, and * are as described in the specification.

Description

Copolymer, method for preparing the copolymer, and redox-sensitive hydrogel containing the copolymer

It relates to a copolymer, a method for preparing the copolymer, and a redox-sensitive hydrogel comprising the copolymer.

A hydrogel is a water-soluble polymer and has a network structure by forming three-dimensional crosslinks through physical and/or chemical bonding. For example, the physical bond may be a hydrogen bond, van der Waals force, hydrophobic interaction, and the like, and the chemical bond may be a covalent bond.

Hydrogel has high hydrophilicity but is insoluble in water, and can form a gel form by inducing physical and/or chemical bonding between polymers, so it is used in various biomaterial fields such as biomedicine, pharmacology, tissue engineering, and beauty. It is attracting attention as a material that can be applied.

However, in order to be applied as a material in the fields of biomedicine, pharmacology, tissue engineering, beauty, etc., it is necessary to develop a hydrogel that can respond to external stimuli while having biocompatibility, and/or a method for producing the hydrogel. .

In one embodiment, it is intended to provide a copolymer that can be applied to various biomaterial fields such as biomedicine, pharmacology, tissue engineering, and beauty because it has redox sensitivity, self-healing property, injectability, and biocompatibility.

Another embodiment is to provide a method for preparing the copolymer.

Another embodiment is to provide a redox-sensitive hydrogel containing the copolymer.

One embodiment of the present invention includes two or more moieties represented by Formula 1 below, and a linking group present between the two or more moieties, wherein the linking group includes a structural unit represented by Formula 2 below. provide synthesis.

[Formula 1]

In Formula 1,

X is a single bond or a substituted or unsubstituted, saturated or unsaturated C1 to C6 aliphatic hydrocarbon group,

Y is a substituted or unsubstituted C1 to C18 alkylene group,

m is an integer greater than or equal to 1;

* is the connection point:

[Formula 2]

* ---[O-(C _n H _2n )-]---*

In Formula 2,

n is an integer of 2 or more and 4 or less;

* is a connection point.

X in Formula 1 may be a substituted or unsubstituted C1 to C4 alkylene group, a substituted or unsubstituted C2 to C4 alkenylene group, or a combination thereof.

X in Formula 1 may be a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, or a combination thereof.

Y in Formula 1 may be a substituted or unsubstituted C2 to C8 alkylene group.

Y in Formula 1 is a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, a substituted or unsubstituted pentylene group, a substituted or unsubstituted hexylene group, or a combination thereof can be

In Formula 1, m may be an integer of 5 to 50.

The number average molecular weight of the linking group may be 250 to 100,000 g/mol.

The copolymer may have a number average molecular weight of 500 to 200,000 g/mol.

Polydispersity of the copolymer may be 1 to 2.

In another embodiment of the present invention, reacting a substituted or unsubstituted polyalkylene glycol with a compound represented by Formula 3, and

Dithiothreitol (DTT), Glutathione (GSH), Tris(2-carboxyethyl)phosphine (TCEP), Beta-Mercaptoethanol (BME) , or a method for preparing a copolymer comprising the step of treating a reducing agent containing a combination thereof.

[Formula 3]

In Formula 3,

X is a single bond or a substituted or unsubstituted, saturated or unsaturated C1 to C6 aliphatic hydrocarbon group,

Z ¹ is a substituted or unsubstituted, saturated or unsaturated C1 to C18 aliphatic hydrocarbon group, a substituted or unsubstituted, saturated or unsaturated C1 to C18 heteroaliphatic hydrocarbon group, or a combination thereof;

Z ² is hydrogen or a monovalent organic group;

a and b are each independently 0 or 1.

The substituted or unsubstituted polyalkylene glycol is polyethylene glycol, polypropylene glycol, methoxy polyethylene glycol, ethoxy polyethylene glycol, propoxy polyethylene glycol, methoxy polypropylene glycol, ethoxy polypropylene glycol, propoxy polypropylene glycol , or a combination thereof.

Z ¹ in Formula 3 is a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, a substituted or unsubstituted pentylene group, a substituted or unsubstituted hexylene group, or any of these can be a combination.

Z ² in Formula 3 may be a substituted or unsubstituted C2 to C18 alkenyl group or a C2 to C13 monovalent organic group including at least one carbonyl group.

When b in Formula 3 is 1, a may be 1.

In the method for preparing the copolymer, when b in Formula 3 is 0, after reacting the substituted or unsubstituted polyalkylene glycol with a compound represented by Formula 3,

A step of treating the substituted or unsubstituted thioester compound may be further included.

The thioester compound may be represented by Formula 4 below.

[Formula 4]

In Formula 4,

R ¹ and R ² are each independently hydrogen or a substituted or unsubstituted C1 to C12 alkyl group.

R ¹ in Formula 4 may be a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted propyl group, a substituted or unsubstituted butyl group, or a combination thereof, and R ² may be hydrogen. there is.

Another embodiment of the present invention provides a redox-sensitive hydrogel comprising the copolymer.

The copolymer according to the embodiment provides a redox-sensitive hydrogel that can be applied to various biomaterial fields such as biomedicine, pharmacology, tissue engineering, and beauty because it has redox-sensitive, self-healing, injectable, and biocompatibility. can do.

Figure 1 (a) is a schematic diagram schematically showing how the copolymer 100 according to the embodiment of the present application has a sol form, Figure 1 (b) is at least one of the copolymer 100 according to the embodiment of the present application It is a schematic diagram of forming a gel by oxidizing the thiol group of and forming a disulfide bond between copolymers,
2 is a diagram of Examples 1-1, 1-2, 1-4, 1-6, 2-1, 2-2, 2-4, 2-6, 2-9, 3-9, and 4-4 This is a picture observed from the front 4 days after mixing the vials containing each hydrogel with a vortex mixer,
Figure 3 is a graph showing the change in G 'and G'' values of the hydrogel of Example 1-2 according to temperature,
Figure 4 is a graph showing the change in G' and G'' values of the hydrogels of Examples 1-2, 1-5, 1-7, and 1-8 according to frequency;
Figure 5 is a photograph of the red-colored hydrogel of Example 1-3 and the transparent hydrogel of Example 1-3 attached side by side by pulling them from both sides after 24 hours,
Figure 6 shows the hydrogel of Example 1-3 and the transparent hydrogel of Example 1-3, which are red-colored and attached side by side by treating hydrogen peroxide (H ₂ O ₂ ) on the interface, pulled from both sides after 24 hours and observed is a picture,
7 is a graph showing changes in G' and G″ values of the hydrogel of Example 1-2 according to a change in pressure (strain);
Figure 8a is a picture immediately after injecting the red hydrogel of Example 1-2 into water, Figure 8b is a picture after 24 hours,
9 is a graph showing the change in G' and G'' values of the hydrogels of Examples 1-8 according to the amount of hydrogen peroxide treated according to frequency;
10 is a graph showing the relaxation time of the hydrogels of Examples 1-8 according to the amount of DTT added and the amount of hydrogen peroxide treated,
11 shows that the hydrogel of Example 1-3 was added to human dermal fibroblasts and green fluorescent protein-labeled human umbilical vein endothelial cells, respectively, and the number of cells was measured 5 times, respectively, 1 day and 3 days later, and the average values were obtained. It is a graph showing the standard deviation as an error range.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present invention. However, the present invention may be embodied in many different forms and is not limited to the embodiments set forth herein.

Terminology used herein is for describing the embodiments and is not intended to limit the present invention. In this specification, singular forms also include plural forms unless specifically stated otherwise in a phrase. As used herein, 'comprises' and/or 'comprising' does not preclude the presence or addition of one or more other elements or steps to a stated element or step.

Unless otherwise specified herein, 'substituted' means that a hydrogen atom in a compound is deuterium, a halogen atom (F, Br, Cl, or I), a hydroxyl group, a nitro group, a cyano group, an amino group, an azido group, or an amidino group. , Hydrazino group, hydrazono group, carbonyl group, carbamyl group, thiol group, ester group, carboxyl group or its salt thereof, sulfonic acid group or its salt thereof, phosphoric acid group or its salt thereof, C1 to C30 Alkyl group, C2 to C30 Alkenyl group, C2 to C30 Alkynyl group, C6 to C30 aryl group, C7 to C30 arylalkyl group, C1 to C30 alkoxy group, C1 to C20 heteroalkyl group, C3 to C20 heteroarylalkyl group, C3 to C30 cycloalkyl group, C3 to C15 cycloalkenyl group, C6 to C20 It means that it is substituted with a substituent selected from a C15 cycloalkynyl group, a C2 to C30 heterocyclic group, and combinations thereof.

In addition, the substituted halogen atom (F, Br, Cl, or I), hydroxy group, nitro group, cyano group, amino group, azido group, amidino group, hydrazino group, hydrazono group, carbonyl group, carbamyl group, thiol group , ester group, carboxyl group or its salt, sulfonic acid group or its salt, phosphoric acid or its salt, C1 to C30 alkyl group, C2 to C30 alkenyl group, C2 to C30 alkynyl group, C6 to C30 aryl group, C7 to C30 arylalkyl group, C1 to C30 Two adjacent substituents of a C30 alkoxy group, a C1 to C20 heteroalkyl group, a C3 to C20 heteroarylalkyl group, a C3 to C30 cycloalkyl group, a C3 to C15 cycloalkenyl group, a C6 to C15 cycloalkynyl group, or a C2 to C30 heterocyclic group They can also fuse to form rings. For example, the substituted C6 to C30 aryl group may be fused with another adjacent substituted C6 to C30 aryl group to form a substituted or unsubstituted fluorene ring.

In addition, unless otherwise defined herein, 'hetero' means containing 1 to 3 heteroatoms selected from N, O, S, Se and P.

In the present specification, an "alkylene group" is a straight-chain or branched-chain saturated aliphatic hydrocarbon group having two or more valences optionally including one or more substituents.

In addition, "aliphatic hydrocarbon group" means a C1 to C30 straight chain or branched chain alkyl group, "aromatic hydrocarbon group" means a C6 to C30 aryl group or C2 to C30 heteroaryl group, "alicyclic hydrocarbon group" A C3 to C30 cycloalkyl group, a C3 to C30 cycloalkenyl group, and a C3 to C30 cycloalkynyl group.

In the present specification, the term "saturated aliphatic hydrocarbon group" means a hydrocarbon group in which the bond between carbon atoms in the molecule is a single bond, unless otherwise defined. The saturated aliphatic hydrocarbon group may be a C1 to C20 saturated aliphatic hydrocarbon group. For example, the saturated aliphatic hydrocarbon group may be a C1 to C10 saturated aliphatic hydrocarbon group, a C1 to C8 saturated aliphatic hydrocarbon group, a C1 to C6 saturated aliphatic hydrocarbon group, a C1 to C4 saturated aliphatic hydrocarbon group, or a C1 to C2 saturated aliphatic hydrocarbon group. . For example, the C1 to C6 saturated aliphatic hydrocarbon group may be a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a 2,2-dimethylpropyl group, or a tert-butyl group. .

In this specification, "unsaturated aliphatic hydrocarbon group" means an aliphatic hydrocarbon group containing at least one double bond or triple bond, unless otherwise defined. The unsaturated aliphatic hydrocarbon group may be a C2 to C20 unsaturated aliphatic hydrocarbon group. For example, the unsaturated aliphatic hydrocarbon group may be a C2 to C10 unsaturated aliphatic hydrocarbon group, a C2 to C8 unsaturated aliphatic hydrocarbon group, a C2 to C6 unsaturated aliphatic hydrocarbon group, a C2 to C4 unsaturated aliphatic hydrocarbon group, or a C2 or C3 unsaturated aliphatic hydrocarbon group. . For example, the unsaturated aliphatic hydrocarbon group may be an alkenyl group or an alkynyl group, and for example, the C2 to C6 unsaturated aliphatic hydrocarbon group is an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, an ethynyl group, and a propynyl group. , a butynyl group, a pentynyl group, or a hexynyl group.

In this specification, "alkyl (alkyl) group" means a linear or branched aliphatic hydrocarbon group unless otherwise defined. An alkyl group may be a "saturated alkyl group" that does not contain any double or triple bonds. The alkyl group may be a C1 to C20 alkyl group. For example, the alkyl group may be a C1 to C10 alkyl group, a C1 to C8 alkyl group, a C1 to C6 alkyl group, or a C1 to C4 alkyl group. For example, the C1 to C4 alkyl group may be a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl group.

In this specification, "alkenyl group" means a linear or branched unsaturated aliphatic hydrocarbon group containing at least one double bond, unless otherwise defined. The alkenyl group may be a C2 to C20 alkynyl group. For example, the alkenyl group may be a C2 to C10 alkenyl group, a C2 to C8 alkenyl group, a C2 to C6 alkenyl group, or a C2 to C4 alkenyl group. For example, the C2 to C6 alkenyl group may be an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, or a hexenyl group.

In this specification, "alkynyl group" means a linear or branched unsaturated aliphatic hydrocarbon group containing at least one triple bond, unless otherwise defined. The alkynyl group may be a C2 to C20 alkynyl group. For example, the alkynyl group may be a C2 to C10 alkynyl group, a C2 to C8 alkynyl group, a C2 to C6 alkynyl group, or a C2 to C4 alkynyl group. For example, the C2 to C6 alkynyl group may be an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, or a hexynyl group.

In this specification, a polymer means something including an oligomer and a polymer.

Unless otherwise defined herein, copolymers are alternating copolymers, block copolymers, random copolymers, graft copolymers, and crosslinked copolymers. copolymer), or including both of them.

In order to manufacture a hydrogel, a copolymer capable of forming a three-dimensional network structure is required, and in order to apply the hydrogel as a material in the fields of biomedicine, pharmacology, tissue engineering, and beauty, the copolymer is biocompatible and While having self-healing properties, it should be able to respond to external stimuli. However, the copolymers used in conventional hydrogel production have a main chain based on polyalkylene, polyester, etc., and thus generally have biotoxicity. Therefore, a copolymer whose physical properties can be controlled is required.

Hereinafter, a copolymer according to an embodiment will be described.

The copolymer may be a copolymer having hydrophilicity, and may be, for example, a block copolymer including three or more blocks. At least one of the three or more blocks may include repeating units including a substituted or unsubstituted alkylene glycol as a main chain and a monovalent organic group including a thiol group at a terminal as a side chain.

For example, all three or more blocks may include a substituted or unsubstituted alkylene glycol as a main chain, and at least one of the three or more blocks may include repeating units represented by a specific chemical formula, for example, At least one of the three or more blocks may be represented by Chemical Formula 1 described below. Accordingly, while the copolymer has hydrophilicity, it is possible to provide a hydrogel that forms a three-dimensional network structure by chemical bonding (eg, covalent bonding) between the copolymers, and can impart strong physical properties.

The linking group may be a polymer having hydrophilicity. For example, the linking group may be a polymer containing a substituted or unsubstituted C1 to C20 heteroaliphatic hydrocarbon, and for example, a substituted or unsubstituted C1 to C20 heteroaliphatic hydrocarbon containing at least one oxygen atom. It may be a polymer containing, for example, it may include a structural unit represented by the following formula (2). Accordingly, since the copolymer has excellent biocompatibility, it can be applied as a material in fields such as biomedicine, pharmacology, tissue engineering, and beauty.

For example, the copolymer may include two or more moieties represented by Formula 1 below, and a linking group present between the two or more moieties, and the linking group may include a structural unit represented by Formula 2 below. can Accordingly, since the copolymer has a main chain based on polyalkylene glycol, it may have excellent biocompatibility. In addition, a disulfide bond between the copolymers may be formed by a thiol group of the moiety represented by Formula 1, the copolymer may react with an oxidizing agent and/or a reducing agent, and the copolymer may have redox sensitivity It is possible to provide a hydrogel having.

[Formula 1]

In Formula 1,

X is a single bond or a substituted or unsubstituted, saturated or unsaturated C1 to C6 aliphatic hydrocarbon group,

Y is a substituted or unsubstituted C1 to C18 alkylene group,

m is an integer greater than or equal to 1;

* is the connection point:

[Formula 2]

* ---[O-(C _n H _2n )-]---*

In Formula 2,

n is an integer of 2 or more and 4 or less;

* is a connection point.

For example, X in Formula 1 may be a single bond or a substituted or unsubstituted, saturated or unsaturated C1 to C4 aliphatic hydrocarbon group, and for example, X in Formula 1 may be a single bond or a substituted or unsubstituted, saturated or It may be an unsaturated C1 to C3 aliphatic hydrocarbon group, and for example, X in Formula 1 may be a single bond or a substituted or unsubstituted, saturated or unsaturated C1 or C2 aliphatic hydrocarbon group.

For example, X in Formula 1 may be a substituted or unsubstituted C1 to C4 alkylene group, a substituted or unsubstituted C2 to C4 alkenylene group, or a combination thereof.

For example, X in Formula 1 may be a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, or a combination thereof, but is limited thereto It doesn't work.

For example, Y in Formula 1 may be a substituted or unsubstituted C2 to C16 alkylene group, for example, a substituted or unsubstituted C2 to C12 alkylene group, and for example, a substituted or unsubstituted C2 to C12 alkylene group. to C10 alkylene group, for example, it may be a substituted or unsubstituted C2 to C8 alkylene group, for example, it may be a substituted or unsubstituted C2 to C6 alkylene group, for example, a substituted or unsubstituted C2 to C8 alkylene group. It may be an unsubstituted C2 to C4 alkylene group, for example, a substituted or unsubstituted C2 or C3 alkylene group.

For example, Y in Formula 1 is a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, a substituted or unsubstituted pentylene group, a substituted or unsubstituted hexylene group, or It may be a combination of these, but is not limited thereto.

For example, the sum of carbon atoms of X and Y in Formula 1 may be 20 or less, for example, 16 or less, for example, 12 or less, for example, 10 or less, for example, It may be 8 or less, for example, 6 or less. In addition, the sum of carbon atoms of X and Y in Formula 1 may be 1 or more, for example, 2 or more, for example, 3 or more. When the copolymer has the sum of carbon atoms of X and Y in Chemical Formula 1 satisfying the above-mentioned range, it can have more excellent hydrophilicity without being dissolved in water.

For example, the number of carbon atoms of X and Y in Formula 1 may be the same or different. For example, there may be more carbon atoms in Y than in X. Specifically, X is a substituted or unsubstituted methylene group, and Y may be a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, or a substituted or unsubstituted butylene group, but is not limited thereto.

For example, m in Formula 1 may be an integer of 2 or more, for example, an integer of 2 to 100, for example, an integer of 3 to 80, for example, an integer of 4 to 60, , For example, it may be an integer of 5 to 50, for example, it may be an integer of 5 to 44, for example, it may be an integer of 5 to 30, for example, it may be an integer of 5 to 20, for example For example, it may be an integer of 5 to 14, for example, it may be an integer of 8 to 12. Accordingly, the copolymer may exhibit better redox sensitivity, may undergo a reversible reaction by an oxidizing agent or a reducing agent, and may have self-healing properties.

For example, in Chemical Formula 2, n may be 2 or 3, but preferably n may be 2.

Specifically, the linking group is polyethylene glycol, polypropylene glycol, methoxy polyethylene glycol, ethoxy polyethylene glycol, propoxy polyethylene glycol, methoxy polypropylene glycol, ethoxy polypropylene glycol, propoxy polypropylene glycol, or combinations thereof can include

For example, the linking group may include 2 to 2,500 structural units represented by Formula 2, for example, 2 to 2,300 structural units, for example, 2 to 1,000 structural units, For example, it may include 2 to 500 pieces, for example, it may include 2 to 100 pieces, for example, it may include 2 to 50 pieces, for example, it may include 2 to 35 pieces. And, for example, it may include 2 to 34, but is not limited thereto.

The number average molecular weight of the linking group may be 250 to 100,000 g/mol, for example 300 to 80,000 g/mol, for example 350 to 70,000 g/mol, for example 400 g/mol to 66,000 g/mol, for example 440 to 50,000 g/mol, for example 440 to 25,000 g/mol, for example 440 to 20,000 g/mol , for example 440 to 15,000 g/mol, for example 440 to 10,000 g/mol. When the linking group has a number average molecular weight within the above-mentioned range, the copolymer can exhibit properties similar to tissues by having a superior water content without being soluble in water, and can be effectively applied to the field of tissue engineering.

The copolymer according to one embodiment includes two moieties (moiety A) represented by Formula 1 and one linking group (moiety B) connecting the two moieties represented by Formula 1. can do. That is, the copolymer may be an ABA-type triblock copolymer.

1(a) schematically shows a copolymer 100 according to an embodiment of the present application having a sol form, and FIG. 1(b) shows at least one of the copolymer 100 according to an embodiment of the present application. It schematically shows how a gel is formed by oxidizing a thiol group to form a disulfide bond between copolymers.

Referring to FIG. 1 , the moiety (moiety A) represented by Chemical Formula 1 in the ABA-type triblock copolymer may impart redox responsiveness and self-healing properties as described above. Accordingly, the ABA-type triblock copolymer can be applied to the production of a redox-sensitive hydrogel, and a gel form can be formed even with a relatively small amount of the copolymer.

Meanwhile, one linking group (moiety B) linking the two moieties represented by Chemical Formula 1 may be relatively stable against oxidizing agents and reducing agents. In addition, the ABA-type triblock copolymer can be transformed from a gel form to a sol form when pressure (eg, shear stress) is applied, and can return to a gel form when the applied pressure (eg, shear stress) is removed Injectable hydrogels can be prepared by extrusion. Accordingly, the hydrogel can be 3D printed in a desired shape, and can be more effectively applied to the field of tissue engineering.

For example, the copolymer may be represented by Formula 1-1 below.

[Formula 1-1]

In Formula 1-1, X ¹ and X ² are the same as or different from each other, and each independently represents a single bond or a substituted or unsubstituted, saturated or unsaturated C1 to C6 aliphatic hydrocarbon group,

Y ¹ and Y ² are the same as or different from each other, and each independently represents a substituted or unsubstituted C1 to C18 alkylene group;

T ¹ and T ² are the same as or different from each other, and are each independently hydrogen, a hydroxyl group, a substituted or unsubstituted C1 to C20 aliphatic hydrocarbon group, a substituted or unsubstituted C1 to C20 heteroaliphatic hydrocarbon group, a substituted or unsubstituted C3 to C20 aliphatic hydrocarbon group, A C20 alicyclic hydrocarbon group, a substituted or unsubstituted C1 to C20 heteroalicyclic hydrocarbon group, a substituted or unsubstituted C6 to C20 aromatic hydrocarbon group, a substituted or unsubstituted C2 to C20 heteroaromatic hydrocarbon group, or a combination thereof. ,

m ¹ and m ² are the same as or different from each other, and are each independently an integer of 1 or more;

L is a divalent group containing a structural unit represented by the above-mentioned formula (2), wherein the formula (2) is as described above.

For example, in Formula 1-1, X ¹ and X ² may each independently be a single bond or a substituted or unsubstituted, saturated or unsaturated C1 to C4 aliphatic hydrocarbon group. For example, X in Formula 1 is It may be a single bond or a substituted or unsubstituted, saturated or unsaturated C1 to C3 aliphatic hydrocarbon group, for example, X in Formula 1 may be a single bond or a substituted or unsubstituted, saturated or unsaturated C1 or C2 aliphatic hydrocarbon group. can

Specifically, in Formula 1-1, X ¹ and X ² may each independently be a substituted or unsubstituted C1 to C4 alkylene group, a substituted or unsubstituted C2 to C4 alkenylene group, or a combination thereof. More specifically, in Formula 1-1, X ¹ and X ² are each independently a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, or a substituted or unsubstituted butyl group. It may be a rene group, or a combination thereof, but is not limited thereto.

For example, in Formula 1-1, Y ¹ and Y ² may each independently be a substituted or unsubstituted C2 to C16 alkylene group, for example, a substituted or unsubstituted C2 to C12 alkylene group, , For example, it may be a substituted or unsubstituted C2 to C10 alkylene group, for example, it may be a substituted or unsubstituted C2 to C8 alkylene group, for example, a substituted or unsubstituted C2 to C6 alkylene group. It may be a rene group, for example, it may be a substituted or unsubstituted C2 to C4 alkylene group, for example, it may be a substituted or unsubstituted C2 or C3 alkylene group.

Specifically, in Formula 1-1, Y ¹ and Y ² are each independently a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, or a substituted or unsubstituted pentylene group , a substituted or unsubstituted hexylene group, or a combination thereof, but is not limited thereto.

For example, in Formula 1-1, the sum of carbon atoms of X ¹ and Y ¹ may be 20 or less, eg, 16 or less, eg, 12 or less, eg, 10 or less. It may be, for example, 8 or less, for example, 6 or less. In addition, the sum of carbon atoms of X ¹ and Y ¹ in Formula 1-1 may be 1 or more, for example, 2 or more, for example, 3 or more.

For example, in Formula 1-1, the sum of carbon atoms of X ² and Y ² may be 20 or less, eg, 16 or less, eg, 12 or less, eg, 10 or less. It may be, for example, 8 or less, for example, 6 or less. In addition, the sum of carbon atoms of X ² and Y ² in Formula 1-1 may be 1 or more, for example, 2 or more, for example, 3 or more.

For example, in Formula 1-1, the number of carbon atoms of X ¹ and X ² may be greater than that of Y ¹ and Y ² , and for example, X ¹ and X ² are each independently substituted or unsubstituted methylene group, Y ¹ and Y ² may each independently be a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, or a substituted or unsubstituted butylene group, but is not limited thereto.

For example, in Formula 1-1, T ¹ and T ² may each independently be hydrogen, a hydroxyl group, a substituted or unsubstituted C1 to C20 heteroaliphatic hydrocarbon group, or a combination thereof.

For example, in Formula 1-1, at least one of T ¹ and T ² may be hydrogen or a hydroxyl group, and for example, T ¹ and T ² may each independently be hydrogen or a hydroxyl group, For example, T ¹ may be hydrogen and T ² may be a hydroxyl group.

For example, in Formula 1-1, m ¹ and m ² may each independently be an integer of 2 or more, for example, an integer of 2 to 100, for example, an integer of 3 to 80, For example, it may be an integer of 4 to 60, for example, it may be an integer of 5 to 50, for example, it may be an integer of 5 to 44, for example, it may be an integer of 5 to 30, for example For example, it may be an integer of 5 to 20, for example, an integer of 5 to 14, and for example, an integer of 8 to 12.

For example, in Chemical Formula 1-1, X ¹ and X ² may be the same, Y ¹ and Y ² may be the same, and m ¹ and m ² may be the same.

For example, in Formula 1-1, L may include 2 to 2,500 structural units represented by Formula 2, for example, 2 to 2,300, for example, 2 to 1,000 Can include, for example, 2 to 500, for example, 2 to 100, for example, 2 to 50, for example, 2 to 35, for example, may include 2 to 34, but is not limited thereto.

For example, in Formula 1-1, the number average molecular weight of L may be 250 to 100,000 g/mol, for example, 300 to 80,000 g/mol, and for example, 350 to 70,000 g/mol. , for example, 400 to 66,000 g / mol, for example, 440 to 50,000 g / mol, for example, 440 to 25,000 g / mol, for example, 440 to 20,000 g/mol, for example 440 to 15,000 g/mol, for example 440 to 10,000 g/mol.

For example, the number average molecular weight of the copolymer may be 500 to 200,000 g / mol, for example, 1,000 to 100,000 g / mol, for example, 1,000 to 70,000 g / mol, for example For example, it may be 3,000 to 50,000 g/mol, for example, 5,000 to 35,000 g/mol, and for example, 6,000 to 30,000 g/mol.

For example, the polydispersity of the copolymer may be 1 to 2, preferably 1 to 1.5.

Another embodiment of the present invention provides a method for preparing the copolymer.

In the method for preparing the copolymer according to an embodiment, the copolymer may be prepared by preparing a precursor polymer and post-processing, and the post-treatment may include treatment with a reducing agent.

The reducing agent is, for example, dithiothreitol (DTT), glutathione (Glutathione, GSH), tris (2-carboxyethyl) phosphine (Tris (2-carboxyethyl) phosphine, TCEP), beta-mercarboethanol (beta -Mercaptoethanol, BME), or may include a combination thereof, but is not limited thereto.

For example, reacting a substituted or unsubstituted polyalkylene glycol with a compound represented by Formula 3, and

Dithiothreitol (DTT), Glutathione (GSH), Tris(2-carboxyethyl)phosphine (TCEP), Beta-Mercaptoethanol (BME) , or a step of treating a reducing agent including a combination thereof.

Accordingly, side reactions in which monomers and monomers or monomers and copolymers first react with each other while the copolymer is being prepared can be offset. For example, a side reaction in which a thiol group of a monomer reacts with a thiol group of another monomer or a thiol group of a monomer and a thiol group of a copolymer can be offset.

[Formula 3]

In Formula 3, X is the same as defined in Formula 1,

Z ¹ is a substituted or unsubstituted, saturated or unsaturated C1 to C18 aliphatic hydrocarbon group, a substituted or unsubstituted, saturated or unsaturated C1 to C18 heteroaliphatic hydrocarbon group, or a combination thereof;

Z ² is hydrogen or a monovalent organic group;

a and b are each independently 0 or 1.

For example, the substituted or unsubstituted polyalkylene glycol may include a structural unit represented by Formula 2 above.

For example, the substituted or unsubstituted polyalkylene glycol is polyethylene glycol, polypropylene glycol, methoxy polyethylene glycol, ethoxy polyethylene glycol, propoxy polyethylene glycol, methoxy polypropylene glycol, ethoxy polypropylene glycol, Poxy polypropylene glycol, or a combination thereof.

For example, the number average molecular weight of the substituted or unsubstituted polyalkylene glycol may be 250 to 100,000 g/mol, for example, 300 to 80,000 g/mol, for example, 350 to 70,000 g /mol, for example 400 to 66,000 g/mol, for example 440 to 50,000 g/mol, for example 440 to 25,000 g/mol, for example For example, it may be 440 to 20,000 g/mol, for example 440 to 15,000 g/mol, for example 440 to 10,000 g/mol.

For example, Z ¹ in Formula 3 may be a substituted or unsubstituted, saturated or unsaturated C1 to C18 aliphatic hydrocarbon group, for example, a substituted or unsubstituted, saturated or unsaturated C2 to C16 aliphatic hydrocarbon group, , For example, it may be a substituted or unsubstituted, saturated or unsaturated C2 to C12 aliphatic hydrocarbon group, for example, it may be a substituted or unsubstituted, saturated or unsaturated C2 to C10 aliphatic hydrocarbon group, for example , It may be a substituted or unsubstituted, saturated or unsaturated C2 to C8 aliphatic hydrocarbon group, for example, it may be a substituted or unsubstituted, saturated or unsaturated C2 to C6 aliphatic hydrocarbon group, for example, a substituted or unsaturated It may be a cyclic, saturated or unsaturated C2 to C4 aliphatic hydrocarbon group, for example, a substituted or unsubstituted, saturated or unsaturated C2 or C3 aliphatic hydrocarbon group. Here, the substituted or unsubstituted, saturated or unsaturated aliphatic hydrocarbon group means a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, or a combination thereof. can do.

For example, Z ¹ in Formula 3 may be a substituted or unsubstituted C2 to C16 alkylene group, for example, a substituted or unsubstituted C2 to C12 alkylene group, for example, a substituted or unsubstituted C2 to C12 alkylene group. It may be a C2 to C10 alkylene group, for example, it may be a substituted or unsubstituted C2 to C8 alkylene group, for example, it may be a substituted or unsubstituted C2 to C6 alkylene group, for example, a substituted or unsubstituted C2 to C8 alkylene group. Or it may be an unsubstituted C2 to C4 alkylene group, for example, it may be a substituted or unsubstituted C2 or C3 alkylene group.

Specifically, Z ¹ in Formula 3 is a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, a substituted or unsubstituted pentylene group, a substituted or unsubstituted hexylene group, Or it may be a combination thereof, but is not limited thereto.

For example, Z ² in Formula 3 may be a substituted or unsubstituted C2 to C18 alkenyl group or a C2 to C13 monovalent organic group including at least one carbonyl group.

For example, the C2 to C13 monovalent organic group including at least one carbonyl group may be *-C(=O)R ^a , wherein R ^a is a substituted or unsubstituted C1 to C12 alkyl group, a substituted or It may be an unsubstituted C2 to C12 alkenyl group, a substituted or unsubstituted C2 to C12 alkynyl group, or a combination thereof. Specifically, R ^a is a substituted or unsubstituted C1 to C12 alkyl group, such as a substituted or unsubstituted C1 to C11 alkyl group, such as a substituted or unsubstituted C1 to C9 alkyl group, for example, a substituted or unsubstituted C1 to C9 alkyl group, An unsubstituted C1 to C7 alkyl group, such as a substituted or unsubstituted C1 to C5 alkyl group, such as a substituted or unsubstituted C1 to C3 alkyl group, such as a substituted or unsubstituted C1 or C2 alkyl group, or a combination thereof. More specifically, R ^a may be a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted propyl group, a substituted or unsubstituted butyl group, or a combination thereof.

For example, when b is 1, Z ² may be a C2 to C13 monovalent organic group containing at least one carbonyl group, wherein the C2 to C13 monovalent organic group containing at least one carbonyl group is as described above. can be the same

For example, when b is 0, Z ² may be a substituted or unsubstituted C2 to C18 alkenyl group. Specifically, when b is 0, Z ² may be a substituted or unsubstituted C2 to C16 alkenyl group, for example, a substituted or unsubstituted C2 to C12 alkenyl group, for example, a substituted or unsubstituted C2 to C12 alkenyl group. It may be an unsubstituted C2 to C10 alkenyl group, for example, it may be a substituted or unsubstituted C2 to C8 alkenyl group, for example, it may be a substituted or unsubstituted C2 to C6 alkenyl group, for example For example, it may be a substituted or unsubstituted C2 to C4 alkenyl group, and for example, it may be a substituted or unsubstituted C2 or C3 alkenyl group. More specifically, when b is 0, Z ² may be a substituted or unsubstituted ethenyl group, a substituted or unsubstituted propenyl group, a substituted or unsubstituted butenyl group, or a combination thereof, but is not limited thereto. .

For example, a and b in Formula 3 may be the same as or different from each other, but preferably may be the same as each other.

For example, when b in Chemical Formula 3 is 1, a may be 1.

For example, when b in Chemical Formula 3 is 0, a may be 0.

For example, Chemical Formula 3 may be represented by Chemical Formula 3-1 or 3-2.

[Formula 3-1] [Formula 3-2]

In Chemical Formulas 3-1 and 3-2, X, Z ¹ , Z ² , and R ^a are each as described above.

For example, Z ² in Formula 3-1 may be a substituted or unsubstituted C2 to C18 alkenyl group. Specifically, Z ² of Formula 3-1 may be a substituted or unsubstituted C2 to C16 alkenyl group, for example, a substituted or unsubstituted C2 to C12 alkenyl group, for example, a substituted or unsubstituted C2 to C12 alkenyl group. It may be an unsubstituted C2 to C10 alkenyl group, for example, it may be a substituted or unsubstituted C2 to C8 alkenyl group, for example, it may be a substituted or unsubstituted C2 to C6 alkenyl group, for example For example, it may be a substituted or unsubstituted C2 to C4 alkenyl group, and for example, it may be a substituted or unsubstituted C2 or C3 alkenyl group. More specifically, Z ² of Formula 3-1 may be a substituted or unsubstituted ethenyl group, a substituted or unsubstituted propenyl group, a substituted or unsubstituted butenyl group, or a combination thereof, but is not limited thereto. .

For example, in the method for preparing the copolymer, when b in Formula 3 is 0, after reacting the substituted or unsubstituted polyalkylene glycol with a compound represented by Formula 3, a substituted or unsubstituted thioester is obtained. A step of treating the compound may be further included. Accordingly, side reactions in the polymerization process can be further reduced.

Specifically. In the method for preparing the copolymer, when the compound represented by Chemical Formula 3 is represented by the above-mentioned 3-1, after the step of reacting the substituted or unsubstituted polyalkylene glycol with the compound represented by Chemical Formula 3, the substitution Alternatively, a step of treating the unsubstituted thioester compound may be further included.

For example, the thioester compound may be represented by Formula 4 below.

[Formula 4]

In Formula 4,

R ¹ and R ² are each independently hydrogen or a substituted or unsubstituted C1 to C12 alkyl group.

For example, R ¹ and R ² in Formula 4 are each independently hydrogen, a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted propyl group, a substituted or unsubstituted butyl group, or these may be a combination of

For example, at least one of R ¹ and R ² in Formula 4 may be hydrogen.

For example, at least one of R ¹ and R ² in Formula 4 may be a substituted or unsubstituted C1 to C6 alkyl group. Specifically, at least one of R ¹ and R ² in Formula 4 is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted propyl group, a substituted or unsubstituted butyl group, or a combination thereof. can

For example, R ¹ in Formula 4 may be a substituted or unsubstituted C1 to C6 alkyl group, and R ² may be hydrogen.

Specifically, R ¹ in Formula 4 may be a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted propyl group, a substituted or unsubstituted butyl group, or a combination thereof, and R ² is may be hydrogen.

According to another embodiment, a redox-sensitive hydrogel containing the aforementioned copolymer is provided. As described above, the redox-sensitive hydrogel can have biocompatibility by including the above-described copolymer, and can react reversibly with an oxidizing agent and / or a reducing agent to exhibit self-healing properties, Injectable by extrusion. Accordingly, the redox-sensitive hydrogel can be effectively applied as a material in various bio fields such as biomedicine, pharmacology, tissue engineering, and beauty.

For example, the redox-sensitive hydrogel reacts with a reducing agent such as glutathione in the body and can be used as a drug delivery system for insertion into the body that can selectively release drugs, tissue engineering materials through extrusion-based 3D printing, medical patches, and disulfide bonds in hair. It can be applied as a composition for treating hair that can react. For example, the hair treatment composition further includes various additives such as surfactants and dyes depending on the purpose, such as a composition for shaping or modifying the shape of hair, a composition for conditioning hair, a cosmetic composition for hair, and a composition for washing hair. , It can be used as a composition for dyeing hair.

On the other hand, the redox-sensitive hydrogel may further include a solvent, and the solvent is not particularly limited as long as it has sufficient solubility or dispersibility for the above-described copolymer, but, for example, water, phosphate buffered saline (PBS) , physiological saline (NaCl aqueous solution), seawater, blood, or a combination thereof.

The redox-sensitive hydrogel may further include an additive, and physical properties of the redox-sensitive hydrogel may be adjusted by adjusting the type and/or content of the additive.

For example, the additive may be an oxidizing agent, a reducing agent, or a combination thereof. The type of oxidizing agent and reducing agent is not specifically limited, but may preferably include sulfur (S), specifically dithiothreitol (DTT), glutathione (GSH), tris (2-carboxyethyl) phosphine (TCEP), beta-mercaboethanol (BME), or a combination thereof. Accordingly, more excellent self-healing properties and injectability can be imparted to the redox-sensitive hydrogel.

The copolymer is about 0.1 to 50% by weight, for example, 0.2 to 30% by weight, for example, 0.3 to 20% by weight, for example, 0.4 to 20% by weight based on the total weight of the redox-sensitive hydrogel. 10% by weight, for example, 0.5 to 7% by weight, for example, 1 to 5% by weight.

0.1 to 30 equivalents, such as 0.5 to 20 equivalents, such as 1 to 15 equivalents, such as 2 to 10 equivalents, such as 2 equivalents, relative to the thiol moiety included in the copolymer. to 7 equivalents, such as 2 to 5 equivalents, such as 2 to 4 equivalents.

The hydrogel may further include other compounds other than the aforementioned copolymer, solvent, and additives.

Hereinafter, specific embodiments of the present invention are presented. However, the embodiments described below are only intended to specifically illustrate or explain the present invention, and thus the present invention should not be limited.

synthesis of copolymers

Synthesis Example 1

Copolymer 1 is prepared by preparing precursor copolymer 1 by anionic ring-opening polymerization, then reacting precursor copolymer 1 with thioacetic acid and thiol-ene, and removing the thioester group.

(1) First, precursor copolymer 1 is prepared in a 500 ml flask under an inert argon atmosphere, and the reactor is flame-dried under vacuum and refilled with argon three times. α,ω-hydroxy-terminated polyethylene glycol (α,ω-hydroxy-terminated PEO, 20 g, 1.0 mmol) having a number average molecular weight (Mn) of 20,000 Da was added to the flask under nitrogen flow and dried overnight under high vacuum. Here, anhydrous tetrahydrofuran (THF) was added and stirred at 40°C. Here, potassium naphthalenide (0.3M in THF) is added dropwise through a syringe until a bright green color persists. Thereafter, a compound (1.8 g, 16 mmol) represented by Formula 3a was added and reacted at 40° C. for 24 hours, then quenched with methanol and precipitated with hexane to obtain precursor copolymer 1. The precursor copolymer 1 is represented by Chemical Formula 1-1-1, wherein x and y are 8. ( Mn _{, 1 H NMR} =21,800g/mol, Mn _,GPC = 20,000 g/mol, PDI(Ð, polydispersity index)=1.04)

1H NMR (400 MHz, CDCl3) of the precursor copolymer 1: δ 5.985.83 (m, 1H), 5.315.21 (d, 1H), 5.215.12 (d, 1H), 4.033.96 (d, 1H) ), 3.703.38 (m, 96H)

[Formula 3a]

[Formula 1-1-1]

(2) Then, the precursor copolymer 1 (5 g, 0.23 mmol), thioacetic acid (0.84 g, 11.04 mmol, 3.0 equivalents relative to the N moiety of the precursor copolymer 1), and 2,2-dimethoxy-2 -Phenylacetophenone (DMPA, 47mg, 0.184mmol, 0.05 equivalents relative to the N moiety of the precursor copolymer 1 above) was added to 70mL of methanol. After degassing through nitrogen bubbling, the reaction was performed while irradiating UV light (λ = 365 nm) for about 2 hours until the alkene peak completely disappeared in 1H NMR analysis. Thereafter, methanol is removed under reduced pressure, the concentrated mixture is precipitated twice with cold ether, and the precipitate is dried under high vacuum for 1 day to obtain precursor copolymer 1'. The precursor copolymer 1' is represented by the following Chemical Formula 1-1-2, wherein x and y are 8. (Isolation yield: 80-90%, Mn _{, 1H NMR} = 23,030 g/mol, Mn _{, GPC} = 21,100 g/mol, PDI(Ð, polydispersity index)=1.12)

1H NMR (400 MHz, CDCl3) of the precursor copolymer 1': δ 3.703.38 (m, 82H), 2.95 (t, J = 6.9 Hz, 2H), 1.88 (s, 3H), 1.020.93 (m , 2H)

[Formula 1-1-2]

(3) After that, the precursor copolymer 1' (4g, 0.17mmol) was dissolved in a mixed solvent (50mL) of methanol and water in a 1:1 volume ratio, and sodium hydroxide (NaOH, 0.44mg, 11.12mmol, 11.12mmol, the precursor air 4.0 equivalent relative to the thioester moiety of the compound 1') was added and hydrolyzed while heating at 70 ° C for 24 hours. After cooling to room temperature, 1M HCl solution was added to adjust the pH of the mixture to 8.5, and dithiothreitol (DTT, 0.86g, 5.56mmol, produced by hydrolysis of the precursor copolymer 1') was maintained at room temperature for 12 hours. 2 equivalents relative to the thiol moiety). Thereafter, using a dialysis membrane (Fisher Scientific, MWCO 12K dialysis membrane), the mixture was purified with methanol and then purified with water for 2 days, and the purified solid was lyophilized to obtain copolymer 1.

Copolymer 1 is represented by the following Chemical Formula 1-1-3, wherein x and y are 8. ( M _n = 22,150 g/mol)

[Formula 1-1-3]

Synthesis Example 2

(1) Precursor in the same manner as in Synthesis Example 1 (1), except that the compound represented by Formula 3a (3.15 g, 28 mmol) was used instead of the compound represented by Formula 3a (1.8 g, 16 mmol). Copolymer 2 is obtained. The precursor copolymer 2 is represented by Chemical Formula 1-1-1, wherein x and y are 14. ( Mn _{, 1 H NMR} = 21,670 g/mol, Mn _{, GPC} = 20,500 g/mol, PDI(Ð, polydispersity index)=1.05)

(2) After that, Precursor Copolymer 2 was prepared in the same manner as in Synthesis Example 1 (2), except that Precursor Copolymer 2 (2.8 g, 0.13 mmol) was used instead of Precursor Copolymer 1 (5 g, 0.23 mmol). ' get The precursor copolymer 2' is represented by Chemical Formula 1-1-2, and x and y are 14 in Chemical Formula 1-1-2. ( Mn _{, 1 H NMR} = 23,830 g/mol, Mn _{, GPC} = 22,500 g/mol, PDI(Ð, polydispersity index)=1.19)

(3) After that, the copolymer was obtained in the same manner as in (3) of Synthesis Example 1, except that the precursor copolymer 2' (2.4 g, 0.099 mmol) was used instead of the precursor copolymer 1' (4 g, 0.17 mmol). 2 was prepared. Copolymer 2 is represented by Chemical Formula 1-1-3, wherein x and y are 14. ( M _n = 23,750 g/mol)

Synthesis Example 3

(1) Precursor in the same manner as in Synthesis Example 1 (1), except that the compound represented by Formula 3a (4.5 g, 40 mmol) was used instead of the compound represented by Formula 3a (1.8 g, 16 mmol). Copolymer 3 is obtained. The precursor copolymer 3 is represented by Chemical Formula 1-1-1, wherein x and y are 20. ( Mn _{, 1 H NMR} = 24,600 g/mol, Mn _{, GPC} = 21,600 g/mol, PDI(Ð, polydispersity index)=1.04)

(2) Then, the precursor copolymer 3' in the same manner as in Synthesis Example 1 (2), except that the precursor copolymer 3 (2.26 g, 0.09 mmol) was used instead of the precursor copolymer 1 (5 g, 0.23 mmol). The precursor copolymer 3' is represented by Chemical Formula 1-1-2, and in Chemical Formula 1-1-2, x and y are 20. ( M _{n , 1H NMR} = 27,680 g/mol, Mn _{, GPC} = 25,000 g/mol, PDI(Ð, polydispersity index)=1.07)

(3) After that, the copolymer was obtained in the same manner as in Synthesis Example 1 (3), except that the precursor copolymer 3' (1.9 g, 0.07 mmol) was used instead of the precursor copolymer 1' (4 g, 0.17 mmol). 3 was prepared. Copolymer 3 is represented by Chemical Formula 1-1-3, wherein x and y are 20. ( M _n = 25,360 g/mol)

Synthesis Example 4

(1) Precursor in the same manner as in Synthesis Example 1 (1), except that the compound represented by Formula 3a (9.9 g, 88 mmol) was used instead of the compound represented by Formula 3a (1.8 g, 16 mmol). Copolymer 4 is obtained. The precursor copolymer 4 is represented by Chemical Formula 1-1-1, wherein x and y are 44.

(2) Then, precursor copolymer 4 was prepared in the same manner as in Synthesis Example 1 (2), except that the precursor copolymer 4 (1.25 g, 0.04 mmol) was used instead of the precursor copolymer 1 (5 g, 0.23 mmol). ' get The precursor copolymer 4' is represented by Chemical Formula 1-1-2, and x and y are 44 in Chemical Formula 1-1-2.

(3) After that, the copolymer was obtained in the same manner as in (3) of Synthesis Example 1, except that the precursor copolymer 4' (1.14 g, 0.03 mmol) was used instead of the precursor copolymer 1' (4 g, 0.17 mmol). 4 was prepared. Copolymer 4 is represented by Chemical Formula 1-1-3, wherein x and y are 44. ( M _n =31,790g/mol)

Preparation of hydrogel

Copolymer 1 obtained in Synthesis Example 1 was mixed with 0, 2, 3, 4, 5, 6, 7, 9, and 15 equivalents of DTT with respect to the thiol moiety contained in Copolymer 1, respectively, in phosphate buffered saline at pH 7.0. (Phosphate-buffered saline, PBS) and dissolved in a solution to prepare the hydrogels of Examples 1-1 to 1-9 having a copolymer content of about 3 wt%. In addition, the hydrogels of Examples 2-1 to 2-9, 3-1 to 3-9, and 4-1 to 4-9 were obtained in the same manner using the copolymers 2 to 4 obtained in Synthesis Examples 2 to 4. to manufacture The prepared hydrogel is equilibrated at room temperature for 96 hours or more.

Evaluation 1. Gel Formability

Evaluate the gel formation of the hydrogel according to the amount of DTT added during hydrogel preparation and temperature.

Evaluation 1-1: Gel formation according to DTT content

The hydrogels of Examples 1-1, 1-2, 1-4, 1-6, 2-1, 2-2, 2-4, 2-6, 2-9, 3-9, and 4-4 After each was placed in a transparent vial, the vial was inverted for 20 seconds and the formation of the gel was observed.

2 is a diagram of Examples 1-1, 1-2, 1-4, 1-6, 2-1, 2-2, 2-4, 2-6, 2-9, 3-9, and 4-4 This is a picture observed from the front 4 days after mixing the vial containing the hydrogel with a vortex mixer.

Referring to FIG. 2, it can be seen that as the lengths of x and y increase in the copolymer represented by Chemical Formula 1-1-3, the gel formation property of the hydrogel increases. While not wishing to be bound by any particular theory, it is believed that the gel is produced by spontaneous self-assembly of disulfide bonds between thiol groups of the copolymer during hydrogel preparation. In addition, as the amount of added DTT increases, more thiol groups exist than disulfide bonds between the copolymers in the hydrogel, and it is thought that the hydrogel will have more sol form than gel form.

Evaluation 1-2: Gel formation according to temperature

The hydrogel of Example 1-2 was loaded between two parallel plates having a diameter of 25 mm arranged at an interval of about 1 mm on an MCR302 rheometer (Anton Paar, Austria). Use Peltier accessories to control temperature and use covers to minimize moisture evaporation. The temperature dependence in G' and G'' is measured at a frequency of 1 Hz and a ramp rate of 2° C./min. Here, G' means storage modulus, and G'' means loss modulus.

3 is a graph showing changes in G' and G″ values of the hydrogel of Example 1-2 according to temperature.

Referring to FIG. 3, since G' has a value greater than G'' in the measured temperature range of 0 to 60 °C, it can be confirmed that the hydrogel of Example 1-2 is in the form of a gel in the above temperature range. In addition, since both G' and G'' values are maintained relatively parallel and independently in the above temperature range, it can be confirmed that a stable state is maintained in the above temperature range. Accordingly, it is considered that the hydrogel of Example 1-2 is suitable for application as a general biomaterial.

Assessment 2: Liquidity

Hydrogels of Examples 1-2, 1-5, 1-7, and 1-8 between two parallel plates having a diameter of 25 mm arranged at an interval of about 1 mm in an MCR302 rheometer (Anton Paar, Austria) to load Use Peltier accessories to control temperature and use covers to minimize moisture evaporation. Measure the values of G' and G'' as a function of frequency from 0.1 to 100 rad/s at strain amplitudes of 0.5% and 1%. Here, G' and G'' are as described above.

4 is a graph showing changes in G' and G'' values of the hydrogels of Examples 1-2, 1-5, 1-7, and 1-8 according to frequency.

Referring to FIG. 4, the hydrogel of Example 1-2 having a low content of DTT has both G' and G'' values relatively parallel and independently maintained, resulting in a stable and robust gel form in the measured frequency range. You can check to keep. On the other hand, in the hydrogels of Examples 1-7 and 1-8 with a high content of DTT, the G'' value is more dominant than G', and terminal relaxation occurs in G' ~ ω ² and G'' ~ ω ¹ As this is observed, it can be confirmed that the hydrogels of Examples 1-7 and 1-8 have a fluid sol form.

In addition, referring to FIG. 4, it can be seen that the higher the content of added DTT, the longer the frequency at which G' and G'' cross, and the relaxation time of the hydrogel is the frequency at which G' and G'' cross. Inversely proportional to, it can be seen that the relaxation time of the hydrogel is short.

Although not wishing to be bound by a particular theory, the higher the content of added DTT, the smaller the number of disulfide bonds formed by thiol groups of Copolymer 1, resulting in relaxation of the hydrogel, and thus, the hydrogel containing Copolymer 1 It is believed that liquidity increases.

Evaluation 3: Self-healing properties

Prepare the hydrogel of Example 1-3 having a red color using rhodamine B, and prepare the hydrogel of Example 1-3 that is transparent without using rhodamine B . The red hydrogel of Example 1-3 and the transparent hydrogel of Example 1-3 were placed side by side in a sealed container and observed after 24 hours.

Figure 5 is a photograph of the red-colored hydrogel of Example 1-3 and the transparent hydrogel of Example 1-3, which are attached side by side in a sealed container, pulled from both sides after 24 hours.

Referring to Figure 5, it can be seen that the hydrogels placed side by side are bonded to each other and have self-healing properties.

Evaluation 4: Redox Sensitivity

Prepare the hydrogel of Example 1-3 having a red color using rhodamine B, and prepare the hydrogel of Example 1-3 that is transparent without using rhodamine B . The red hydrogel of Example 1-3 and the transparent hydrogel of Example 1-3 were attached side by side in a sealed container, and the interface was treated with hydrogen peroxide (H ₂ O ₂ ) Observation after 24 hours do.

Figure 6 shows the hydrogel of Example 1-3 and the hydrogel of Example 1-3, which are red in color and are attached side by side by treating the interface with hydrogen peroxide (H ₂ O ₂ ) in a sealed container, and the hydrogel of Example 1-3 after 24 hours. This is a picture taken from and observed.

Referring to FIG. 6, unlike in FIG. 5, it can be seen that the hydrogels placed side by side in which the interface is treated with hydrogen peroxide (H ₂ O ₂ ) do not have self-healing properties. Accordingly, it can be confirmed that the hydrogels of Examples 1-3 have sensitivity to the redox agent and can control the self-healing properties and mechanical properties of the hydrogel by treating the redox agent.

Evaluation 5: Injectability

By applying strains of 1% and 300% at a frequency of 1 Hz at intervals of 3 minutes, the shear reactivity of the hydrogel of Example 1-2 and the possibility of injection by extrusion were confirmed.

7 is a graph showing changes in G' and G″ values of the hydrogels of Examples 1-2 according to pressure changes. Here, G' and G'' are as described above.

Referring to FIG. 7, it can be confirmed that the hydrogel of Example 1-2 is converted from a gel form to a sol form when shear force is applied, and returns to the gel form when the shear force disappears. Accordingly, the hydrogel of Example 1-2 will have a sol form by pressure when injected by extrusion, and will return to a gel form immediately after injection, confirming that the hydrogel has injectability.

In addition, the hydrogel of Example 1-2 having a red color was injected into water using rhodamine B with an 18G needle and observed one day later.

Fig. 8a is a photograph immediately after injecting the red hydrogel of Example 1-2 into water, and Fig. 8b is a photograph after 24 hours.

Referring to a of FIG. 8, it can be confirmed that the hydrogel of Example 1-2 is converted into a sol form by the pressure applied when injected with a needle, injected into a desired form, and then returned to the gel form immediately after injection, , Referring to b of FIG. 8, it can be confirmed that the shape of the gel is maintained even after 24 hours, except that the color is faded due to the diffusion of rhodamine B. Accordingly, it is thought that the hydrogel of Example 1-2 can be applied as a drug delivery reservoir and a tissue engineering material through extrusion-based 3D printing.

Evaluation 6: Reversible redox reactivity

The hydrogel of Example 1-8 was treated with hydrogen peroxide in an amount of 9, 4.5, 4, 2, and 0, respectively, relative to the thiol moiety of the copolymer, and measured using an MCR302 rheometer (Anton Paar, Austria) at intervals of about 1 mm. Each hydrogel is loaded between two parallel plates with a diameter of 25 mm placed between them. Use Peltier accessories to control temperature and use covers to minimize moisture evaporation. Measure the values of G' and G'' as a function of frequency from 0.1 to 100 rad/s at strain amplitudes of 0.5% and 1%. Here, G' and G'' are as described above.

9 is a graph showing the change in G' and G'' values of the hydrogels of Examples 1-8 according to the amount of hydrogen peroxide treated according to frequency;

10 is a graph showing the relaxation time of the hydrogels of Examples 1-8 according to the amount of DTT added and the amount of hydrogen peroxide treated.

Comparing FIGS. 9 and 10 with the aforementioned FIG. 4 , it can be confirmed that the reducing effect of DTT in the hydrogel is offset by the equivalent amount of hydrogen peroxide treated. That is, it can be confirmed that the hydrogels of Examples 1-8 have reversible redox reactivity according to the addition of an oxidizing agent and a reducing agent.

Assessment 7: biocompatibility

Human dermal fibroblasts (HDF, Lonza, Switzerland) and green fluorescent protein-labeled human umbilical vein endothelial cells (GFP-HVC, Angio Proteomie, USA) were respectively loaded with the hydrogels of Examples 1-3, The number of cells is measured after 1 day and 3 days, respectively.

11 shows that the hydrogel of Example 1-3 was added to human dermal fibroblasts and green fluorescent protein-labeled human umbilical vein endothelial cells, respectively, and the number of cells was measured 5 times, respectively, 1 day and 3 days later, and the average values were obtained. It is a graph showing the standard deviation as an error range. In Fig. 11, the control group was not treated with the hydrogels of Examples 1-3.

Referring to FIG. 11, even if the hydrogel of Example 1-3 is treated, it can be confirmed that the number of cells is hardly reduced compared to the control group. Accordingly, the hydrogel of Example 1-3 has low cytotoxicity Bar, it can be confirmed that it has excellent biocompatibility.

Although the preferred embodiments of the present invention have been described in detail above, the present invention is not limited thereto, and various modifications and improvements of those skilled in the art using the basic concept of the present invention defined in the following claims are also the rights of the present invention. that falls within the scope

100: polymer according to the present embodiment

Claims (18)

It includes two or more moieties represented by Formula 1 below, and a linking group present between the two or more moieties,
The linking group is a copolymer comprising a structural unit represented by Chemical Formula 2:
[Formula 1]

In Formula 1,
X is a single bond or a substituted or unsubstituted, saturated or unsaturated C1 to C6 aliphatic hydrocarbon group,
Y is a substituted or unsubstituted C1 to C18 alkylene group,
m is an integer greater than or equal to 1;
* is the connection point:
[Formula 2]
* ---[O-(C _n H _2n )-]---*
In Formula 2,
n is an integer of 2 or more and 4 or less;
* is a connection point.
The copolymer of claim 1, wherein X in Formula 1 is a substituted or unsubstituted C1 to C4 alkylene group, a substituted or unsubstituted C2 to C4 alkenylene group, or a combination thereof.
The copolymer of claim 1, wherein X in Formula 1 is a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, or a combination thereof.
The copolymer of claim 1, wherein Y in Formula 1 is a substituted or unsubstituted C2 to C8 alkylene group.
In claim 1, Y in Formula 1 is a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, a substituted or unsubstituted pentylene group, or a substituted or unsubstituted hexylene group. , or a copolymer that is a combination thereof.
The copolymer of claim 1, wherein m in Formula 1 is an integer of 5 to 50.
The copolymer of claim 1, wherein the linking group has a number average molecular weight of 250 to 100,000 g/mol.
The copolymer of claim 1, wherein the copolymer has a number average molecular weight of 500 to 200,000 g/mol.
The copolymer of claim 1, wherein the copolymer has a polydispersity of 1 to 2.
Reacting a substituted or unsubstituted polyalkylene glycol with a compound represented by Formula 3 below, and
Dithiothreitol (DTT), Glutathione (GSH), Tris(2-carboxyethyl)phosphine (TCEP), Beta-Mercaptoethanol (BME) , or a method for producing a copolymer comprising the step of treating a reducing agent containing a combination thereof:
[Formula 3]

In Formula 3,
X is a single bond or a substituted or unsubstituted, saturated or unsaturated C1 to C6 aliphatic hydrocarbon group,
Z ¹ is a substituted or unsubstituted, saturated or unsaturated C1 to C18 aliphatic hydrocarbon group, a substituted or unsubstituted, saturated or unsaturated C1 to C18 heteroaliphatic hydrocarbon group, or a combination thereof;
Z ² is hydrogen or a monovalent organic group;
a and b are each independently 0 or 1.
11. The method of claim 10, wherein the substituted or unsubstituted polyalkylene glycol is polyethylene glycol, polypropylene glycol, methoxy polyethylene glycol, ethoxy polyethylene glycol, propoxy polyethylene glycol, methoxy polypropylene glycol, ethoxy polypropylene glycol, Propoxy polypropylene glycol, or a method for producing a copolymer that is a combination thereof.
In claim 10, Z ¹ of Formula 3 is a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group, a substituted or unsubstituted butylene group, a substituted or unsubstituted pentylene group, or a substituted or unsubstituted hexylene group. Group, or a method for producing a copolymer that is a combination thereof.
11. The method of claim 10, wherein Z ² of Formula 3 is a substituted or unsubstituted C2 to C18 alkenyl group or a C2 to C13 monovalent organic group containing at least one carbonyl group.
The method of claim 10, wherein when b in Formula 3 is 1, a is 1.
In claim 10, when b in Formula 3 is 0, after reacting the substituted or unsubstituted polyalkylene glycol with a compound represented by Formula 3,
A method for producing a copolymer further comprising the step of treating a substituted or unsubstituted thioester compound.
16. The method of claim 15, wherein the thioester compound is represented by Formula 4 below.
[Formula 4]

In Formula 4,
R ¹ and R ² are each independently hydrogen or a substituted or unsubstituted C1 to C12 alkyl group.
In claim 16, R ¹ of Formula 4 is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted propyl group, a substituted or unsubstituted butyl group, or a combination thereof,
A method for producing a copolymer in which R ² is hydrogen.
A redox-sensitive hydrogel comprising the copolymer of any one of claims 1 to 9.

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