KR101920425B1 - Photothermal-heating particles coated stent and preparation method thereof - Google Patents

Abstract

The present invention provides a stent comprising: a stent base; A first layer comprising a catechol-based compound coupled to the stent substrate and a first material covalently coupled to the catechol-based compound; And a second layer comprising a second material bonded on the first layer by an electrostatic attraction, the method comprising the steps of: providing a stent having uniformly coated optical thermal particles over the entire stent substrate, It can be applied to optical thermal therapy because it shows a heating effect by near infrared rays.

Description

[0001] PHOTOTHERMAL-HEATING PARTICLES COATED STENT AND PREPARATION METHOD THEREOF [0002]

TECHNICAL FIELD The present invention relates to a stent applicable to thermal therapy using near infrared rays, and more particularly, to a stent coated with optical thermal particles uniformly over the entire surface-modified stent substrate and a method for manufacturing the stent.

As medical technology advances, the life expectancy of humans increases, and as the population of older age increases, the stenting of blood vessels and nonvascular systems is increasing.

Generally, a stent is inserted into a blood vessel or a non-blood vessel, etc., in order to solve a stenosis problem in which a blood vessel or a non-blood vessel is clogged due to a blood clot or cancer tissue. The inserted stent enlarges the inner diameter of the stenosis to secure the opening, thereby allowing the fluid necessary for blood, food, or metabolism to flow.

In recent years, studies on the development of functional stents for local treatment of cancer tissues and inhibition of tissue hyperplasia have been actively carried out in addition to the basic functions of the stent fixed in the human body.

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U.S. Published Patent Application No. 2015-0182673 (published on July 27, Korean Laid-Open Patent Publication No. 2013-0092511 (published on August 20, 2013)

It is an object of the present invention to provide a stent in which optical thermal particles are uniformly coated on a stent base and a method for manufacturing the same.

In addition, the stent is inserted into narrowed blood vessels and non-blood vessels to support the inner wall to secure the opening of the stent. In addition, since the stent has a local heating effect by external near-infrared irradiation, And a method for manufacturing the same.

In order to achieve the above object,

Stent base;

A first layer comprising a catechol-based compound coupled to the stent substrate and a first material covalently coupled to the catechol-based compound; And

And a second layer comprising a second material bound on the first layer by an electrostatic attraction.

Further, in one embodiment,

Modifying the surface of the stent base by binding a catechol-based compound on the stent base using a solution containing a catechol-based compound;

Covalently bonding a first material to the catechol-based compound to form a first layer comprising the catechol-based compound and the first material; And

And coating the second material on the first layer by an electrostatic attraction to form a second layer.

According to the present invention, by using a substance covalently bonded to a stent substrate and a catechol-based compound surface-modified with a catechol-based compound, optical thermal particles can uniformly be coated over the entire stent substrate by electrostatic attraction.

In addition, the stent coated with the optical thermal particles exhibits a heat generating effect by irradiation with external near-infrared rays, so that the stent can be applied to optical thermal treatment.

Furthermore, the stent coated with the optical thermal particles can be inserted into narrowed blood vessels and non-blood vessels to support the inner wall, thereby securing the openness of the constriction.

Figure 1 is a schematic diagram of dopamine oxidation polymerization.
2 is a schematic view of a structure in which a catechol-based compound is bound to a stent base and a first substance is bound to the catechol-based compound.
3 is an electron micrograph of branched gold nanoparticles.
4 is a graph showing the absorbance of branched gold nanoparticles.
5 is a photograph showing the uniformity of coating of the stent.
6 is a graph showing the heat generation efficiency of the stent.

Hereinafter, the present invention will be described in detail by way of examples. The embodiments can be modified into various forms as long as the gist of the invention is not changed.

As used herein, " comprising " means that other elements may be included unless otherwise specified.

The terms first, second, etc. are used herein to describe various components, and the components should not be limited by the term. The terms are used only for the purpose of distinguishing one component from another.

The present invention provides a stent comprising: a stent base; A first layer comprising a catechol-based compound coupled to the stent substrate and a first material covalently coupled to the catechol-based compound; And a second layer comprising a second material bonded on the first layer by an electrostatic attraction.

A stent according to one embodiment includes a stent base; A first layer comprising a catechol-based compound coupled to the stent substrate and a first material covalently coupled to the catechol-based compound; And a second layer comprising a second material bonded on the first layer by electrostatic attraction.

The stent substrate may be a commonly used stent substrate, and is not particularly limited.

According to one embodiment, the stent base material comprises a non-degradable polymer; But are not limited to, polyglycolide, polylactide (PLLA), poly p-dioxanone, polycaprolactone, trimethylene carbonate, polyhydroxyalkanoates ), Polypropylene fumarate, polyortho esters, other polyesters, polyanhydride, polyphosphazenes, polyalkylcyanoacrylates, polyacrylates, At least one member selected from the group consisting of poloxamers, polyamino L-tyrosine, modified polysaccharides, oxidized cellulose, gelatin and collagen. Biodegradable polymers; Or a metal containing at least one selected from the group consisting of nitinol, stainless steel, cobalt-chrome, and magnesium.

For example, the stent substrate may comprise a metal, and preferably, but not limited to, nitinol.

Further, the catechol-based compound is bound to the stent base.

The catechol-based compound is a compound having a catechol group, and includes catechol and derivatives thereof.

The catechol group means a group in which a hydroxyl group (-OH) is substituted at an ortho position of a benzene ring. For example, the catechol group may be a 1,2-dihydroxybenzene group.

Wherein the catechol-based compound comprises a catechol group and the catechol group is attached to the stent base.

In addition, the catechol-based compound may further include an amine group, but is not limited thereto.

For example, the catechol-based compound may include at least one selected from the group consisting of dopamine, norepinephrine, and dihydroxylphenylalanine, but is not limited thereto.

Specifically, the dihydroxyl phenylalanine may be L-3,4-dihydroxyl phenylalanine.

As another example, the catechol-based compound may include, but is not limited to, a compound represented by the following Formula 1:

 [Chemical Formula 1]

N in Formula 1 is an integer of 1 to 10. Specifically, n in the general formula (1) may be an integer of 1 to 6, more specifically, an integer of 1 to 4, but is not limited thereto.

The catechol-based compound bonded to the stent base may be present in a polymerized form by an oxidative polymerization reaction.

For example, when dopamine is used as the catechol-based compound, the surface-modified stent substrate may include polypodamine by oxidation polymerization.

See FIG. 1 for a specific reaction schematic diagram of the dopamine oxidation polymerization reaction.

By binding the catechol-based compound to the stent base material, a specific substance can be covalently bonded to the catechol-based compound, and the optical and thermal particles can be uniformly and strongly coated by electrostatic attraction with the specific material do. In addition, since the polymer-type polycatecoate coating has a light absorbing property in the near-infrared ray, the heat-generating effect can be improved in photothermal treatment.

The first layer is characterized in that it comprises, in addition to the catechol-based compound bonded to the stent base, a first substance covalently bonded to the catechol-based compound.

The first substance is a substance capable of forming a covalent bond with the catechol-based compound.

Specifically, the first material includes an amine group or a thiol group.

Wherein the first substance is a compound containing an amine group or a compound containing a thiol group and the compound containing the amine group is a compound selected from the group consisting of polyethyleneimine (PEI), chitosan, ethylenediamine and propylenediamine Wherein the thiol group-containing compound is selected from the group consisting of butanethiol, cyanobutanethiol, propanedithiol, cysteamine, aminopropanethiol hydrochloride, (Dimethylamino) ethanethiol hydrochloride, and aminohexanethiol hydrochloride. However, the present invention is not limited thereto.

As another example, the butanethiol may be 1-butanethiol, the cyanobutanethiol may be 4-cyano-1-butanethiol, the propanedithiol may be 1,3-propanedithiol , The aminopropane thiol hydrochloride may be 3-amino-1-propanethiol hydrochloride and the (dimethylamino) ethanethiol hydrochloride may be 2- (dimethylamino) ethanethiol hydrochloride, and the aminohexanethiol The hydrochloride may be 6-amino-1-hexanethiol hydrochloride, but is not limited thereto.

The amine group includes a primary amine group and a secondary amine group. Specifically, the amine group may be a primary amine group.

For example, the polyethyleneimine (PEI) may be represented by the following formula:

(2)

.

.

M in Formula 2 is an integer of 1 to 200. Specifically, m in the general formula (2) may be an integer of 1 to 100. More specifically, m in formula (2) may be an integer of 1 to 46, but is not limited thereto.

The first substance is a substance covalently bonded to the catechol-based compound, and the covalently bonded structure is shown in Fig.

The first material may have a branched structure and may be covalently bonded to the benzene ring side of the catechol-based compound through an amine group or a thiol group by a Michael-type addition reaction.

The unit mass ratio per unit volume of the first layer comprising the catechol-based compound bonded to the stent base material and the first substance covalently bonded to the catechol-based compound is 0.3 to 0.7 mg / stent (mg). Specifically, the unit mass ratio of the first layer to the stent may be 0.43 to 0.57 mg / stent (mg), but is not limited thereto.

The unit mass ratio per stent of the first layer means the content ratio of the first layer per mg of the stent substrate.

When the content of the first layer is within the above range, it is possible to uniformly coat the surface of the stent without clumping.

The second material may be bonded onto the first layer by electrostatic attraction. In particular, the second material may be dispersed on the first layer by electrostatic attraction. The second material is uniformly dispersed in the first layer and exhibits a higher heat generation efficiency as it is coated.

The surface of the first layer and the second material have different charges from each other.

For example, when the surface of the first layer is positively charged, the second material is negatively charged. Conversely, when the surface of the first layer is negatively charged, the second material is positively charged.

Specifically, the surface of the first layer may be positively charged.

For example, the first material may be positively charged through a covalent bond with a polymer material having an amine group.

As another example, the first material may be branched polyethyleneimine (PEI), which is positively charged by ionization of primary, secondary or tertiary amine groups of the polymeric material having the amine group.

The second material may be negatively charged. In this case, the second material can be bonded to the surface of the positively charged first layer by electrostatic attraction and form a second layer.

The second material is an optical thermal particle.

The optical thermal particle is a particle that absorbs light in the near infrared region and emits heat.

The near-infrared region indicates a region having a wavelength range of 700 to 1,000 nm.

The region is harmless to the human body and corresponds to a suitable wavelength range when the stent according to the embodiment is inserted into blood vessels or non-blood vessels in the human body and applied to a hyperthermia treatment.

The second material is an optical thermal particle with negative charge, which is bonded to the first layer by an electrostatic attractive force, and exhibits a heat generating effect by a near-infrared laser.

For example, the second material may be at least one selected from the group consisting of branched gold nanoparticles, carbon nanotubes, oxidized graphene, and gold nanorods.

As another example, the second material may be a branched gold nanoparticle (bGNP).

The branched gold nanoparticles include a three-dimensionally non-spherical branch structure. Specifically, the specific structure of the branched gold nanoparticles is shown in FIG.

The branched gold nanoparticles may form a negative charge by deoxycholic acid.

The average diameter of the second material is 1 to 100 nm. Specifically, the average diameter of the second material may be 20 to 50 nm, but is not limited thereto.

The unit mass ratio of the second substance per stent is 0.01 to 0.05 mg / stent (mg). Specifically, the unit mass ratio of the second material per stent may be 0.017 to 0.028 mg / stent (mg), but is not limited thereto.

The unit mass ratio of the second substance per stent means the content ratio of the second substance per 1 mg of the stent substrate.

When the content of the second material is in the above range, the ambient temperature can be increased to 60 to 65 ° C by applying an external wavelength of 808 nm with an energy of 0.5 W to the prepared stent for 1 to 4 minutes.

When the content of the second material is in the above range, it is suitable to show the light heat effect necessary for thermal treatment.

The second material effectively absorbs near-infrared wavelengths and generates heat.

The optical thermal particles have an absorption wavelength in a wavelength range of 800 to 900 nm.

4 is a graph showing the absorbance of branched gold nanoparticles.

In Figure 4, the empty cuvette is a control, the PDA-coated cuvette is a solution containing a polydodamine coating, the sGNP-coated cuvette is a solution containing a non-branched spherical gold nanoparticle coating, the bGNP- RTI ID = 0.0 > a < / RTI >

4, it was confirmed that the absorbance of the bGNP-coated cuvette was the best in the near-infrared region of 800 to 900 nm in the wavelength region where the skin permeability was excellent, though the absorbance varied according to the wavelength range.

If the absorbance of the branched gold nanoparticles is excellent in the near infrared region, the efficiency of absorbing the light in the specific region and converting the light into heat is high, so that the heating effect in the near infrared region is also excellent.

The stent according to the present invention comprises a first layer comprising a catechol-based compound bonded to the stent base material and a first substance covalently bonded to the catechol-based compound, whereby the optical thermal particles are uniformly Lt; / RTI >

The stent according to the present invention is inserted into a narrowed blood vessel and supports the inner wall to prevent stenosis of the blood vessel. In addition, the stent exhibits exothermic effect by external near-infrared rays to change the necrosis or physiological function of the surrounding tissue. Can be used to treat a variety of diseases including cancer. In addition, since hyperthermia treatment is performed using external near-infrared rays which are harmless to the human body and can penetrate deep tissues during thermal treatment, it is possible to minimize the concern of burns and destruction of normal tissues and treat diseases located in deep tissues.

In one embodiment, a method of manufacturing a stent,

Modifying the surface of the stent base by binding a catechol-based compound on the stent base using a solution containing a catechol-based compound;

Covalently bonding a first material to the catechol-based compound to form a first layer comprising the catechol-based compound and the first material; And

And coating the second material on the first layer by an electrostatic attraction to form a second layer.

In the above-described stent manufacturing method, the description of the stent substrate, the catechol-based compound, the first substance, the first layer and the second substance is described in the stent.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  1. Nitinol In the stent Polydopamine  After coating, Branched PEI  Mediated branched gold nanoparticles are coated Stent

1.1. Catechol-based compound coating

Dopamine hydrochloride (15 mg) was mixed with 15 ml of an aqueous solution having a pH of 8.5, and a self-expanding nitinol stent was inserted into the mixture and stirred for 8 hours. After 8 hours, the primary poly dopamine-coated stent was naturally dried and then the second poly dopamine coating was performed in the same manner.

1.2. Catechol-based compounds Branched PEI  Combination

500 mg of branched polyethylenimine (PEI) was dissolved in 50 ml of tertiary distilled water. Secondary polydopamine-coated stents were placed in 15 ml of the above solution and stirred for 8 hours to bind PEI branched to polydodamine.

1.3. Branched  Manufacture of gold nanoparticle coating solution

10 mg of gold (III) chloride trihydrate was mixed with 3 ml of tertiary distilled water to prepare (1) a solution. 25 mg of silver nitrate was mixed with 15 ml of tertiary distilled water to prepare a solution (2). 53 mg of L-ascorbic acid was mixed with 3 ml of tertiary distilled water to prepare a solution (3).

1.4. Branched  Formation of gold nanoparticle coating layer

The stent with branched PEI was washed with tertiary distilled water and then coated with branched gold nanoparticles. 15 mg of sodium deoxycholate detergent was dissolved in 15 ml of tertiary distilled water, and a self-expanding nitinol stent (surface having a cation) coated with polydodamine and branched PEI was inserted and stirred. 0.6 ml of the solution (1) prepared in 1.3, 0.09 ml of the solution (2) and 0.96 ml of the solution (3) were sequentially added to the mixed solution containing the stent to form branched gold nanoparticles (particles having anions) Electrostatic interactions were used to obtain a self-expanding nitinol stent coated with branched gold nanoparticles.

Comparative Example  One. Nitinol In the stent Polydopamine  After coating, Branched  Coated with gold nanoparticles Stent

A stent was prepared in the same manner as in Example 1 except that the PEI branched to the catechol-based compound was bound.

Experimental Example  1. Uniformity of Coating

The stent photographs prepared in Example 1 and Comparative Example 1 are shown in FIG. 5, respectively.

As can be seen from FIG. 5, in the case of Comparative Example 1, which is a stent without branched PEI, it was confirmed that the branched gold nanoparticles were not sufficiently coated. Also, in Example 1, which is a stent containing branched PEI, it was confirmed that the branched gold nanoparticles were uniformly coated.

Experimental Example  2. Heat efficiency

The heat generation efficiency of the stent manufactured in Example 1 and Comparative Example 1 was measured.

The heat generation efficiency was measured in real time for a certain period of time using a thermal camera while irradiating 0.5 W (Watt) of near infrared rays while maintaining a distance of 1 cm.

The results are shown in Fig.

In FIG. 6, red indicates the heat generating efficiency of Example 1, and blue indicates the heat generating efficiency of Comparative Example 1.

Specifically, in Example 1, the heating efficiency was 46 ° C on average, whereas in Comparative Example 1, the heating efficiency was 41 ° C on average.

From the above results, it was confirmed that the stent coated with the gold nanoparticles branched by the electrostatic attraction through the branched PEI showed excellent heat generation efficiency when the near-infrared laser was applied.

Claims (15)

Stent base;
A first layer comprising a catechol-based compound coupled to the stent substrate and a first material covalently coupled to the catechol-based compound; And
And a second layer comprising a second material bonded on the first layer by electrostatic attraction,
Wherein the second material is an optical thermal particle, the optical thermal particle is a particle that absorbs light in a near infrared region and emits heat,
Wherein the unit mass ratio of the second substance per stent is 0.01 to 0.05 mg / stent (mg)
Stent.
The method according to claim 1,
In the stent base,
Non-degradable polymers;
But are not limited to, polyglycolide, polylactide (PLLA), poly p-dioxanone, polycaprolactone, trimethylene carbonate, polyhydroxyalkanoates ), Polypropylene fumarate, polyortho esters, other polyesters, polyanhydride, polyphosphazenes, polyalkylcyanoacrylates, polyacrylates, At least one member selected from the group consisting of poloxamers, polyamino L-tyrosine, modified polysaccharides, oxidized cellulose, gelatin and collagen. Biodegradable polymers; or
A metal containing at least one member selected from the group consisting of nitinol, stainless steel, cobalt-chrome and magnesium.
Stent.
The method according to claim 1,
Wherein the catechol-based compound comprises a catechol group,
Wherein the catheter is attached to the stent base
Stent.
The method of claim 3,
Wherein the catechol-based compound further comprises an amine group
Stent.
The method according to claim 1,
Wherein the catechol-based compound comprises at least one member selected from the group consisting of dopamine, norepinephrine, and dihydroxylphenylalanine
Stent.
The method according to claim 1,
Wherein the first material comprises an amine group or a thiol group
Stent.
The method according to claim 1,
Wherein the first substance is a compound containing an amine group or a compound containing a thiol group,
Wherein the amine group-containing compound is at least one selected from the group consisting of polyethyleneimine (PEI), chitosan, ethylenediamine, and propylenediamine,
Wherein the thiol group-containing compound is selected from the group consisting of butanethiol, cyanobutanethiol, propanedithiol, cysteamine, aminopropanethiol hydrochloride, (dimethylamino) ethane At least one selected from the group consisting of (dimethylamino) ethanethiol hydrochloride and aminohexanethiol hydrochloride)
Stent.
The method according to claim 1,
Wherein the surface of the first layer is positively charged,
Wherein the second material is negatively charged,
Stent.
The method according to claim 1,
Wherein an average diameter of the optical thermal particles as the second material is 1 to 100 nm,
Stent.
The method according to claim 1,
Wherein the near-infrared region has a wavelength range of 700 to 1,000 nm,
Stent.
The method according to claim 1,
Wherein the second material is at least one selected from the group consisting of branched gold nanoparticles, carbon nanotubes, oxidized graphene, and gold nanorods
Stent.
Modifying the surface of the stent base by binding a catechol-based compound on the stent base using a solution containing a catechol-based compound;
Covalently bonding a first material to the catechol-based compound to form a first layer comprising the catechol-based compound and the first material; And
Coating the second material on the first layer by an electrostatic attraction to form a second layer,
Wherein the second material is an optical thermal particle, the optical thermal particle is a particle that absorbs light in a near infrared region and emits heat,
Wherein the unit mass ratio of the second substance per stent is 0.01 to 0.05 mg / stent (mg)
A method for manufacturing a stent.
13. The method of claim 12,
Wherein the surface of the first layer is positively charged,
Wherein the second material is negatively charged
A method for manufacturing a stent.
delete 13. The method of claim 12,
Wherein the second material is at least one selected from the group consisting of branched gold nanoparticles, carbon nanotubes, oxidized graphene, and gold nanorods
A method for manufacturing a stent.

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