WO2008093905A1 - Biocompatible aliphatic brush polymers and manufacturing methods thereof - Google Patents

Biocompatible aliphatic brush polymers and manufacturing methods thereof Download PDF

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Publication number
WO2008093905A1
WO2008093905A1 PCT/KR2007/000735 KR2007000735W WO2008093905A1 WO 2008093905 A1 WO2008093905 A1 WO 2008093905A1 KR 2007000735 W KR2007000735 W KR 2007000735W WO 2008093905 A1 WO2008093905 A1 WO 2008093905A1
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polymer
coch
biocompatible
brush
group
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PCT/KR2007/000735
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French (fr)
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WO2008093905A8 (en
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Moonhor Ree
Heesoo Kim
Gahee Kim
Hyunchul Kim
Kyoung Sik Jin
Samdae Park
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Postech Academy-Industry Foundation
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Publication of WO2008093905A8 publication Critical patent/WO2008093905A8/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/04—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers only
    • C08G65/22—Cyclic ethers having at least one atom other than carbon and hydrogen outside the ring
    • C08G65/24—Epihalohydrins
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/3332—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carboxamide group
    • C08G65/33324—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carboxamide group acyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33348—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing isocyanate group
    • C08G65/33351—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing isocyanate group acyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
    • C08G65/3344—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing oxygen in addition to sulfur
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G2261/10—Definition of the polymer structure
    • C08G2261/13—Morphological aspects
    • C08G2261/136—Comb-like structures
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Definitions

  • the present invention relates to an aliphatic brush polymer having an amine-based derivative as a brush end group, and more particularly, to an aliphatic brush polymer having biocompatible property through an amine- based derivative introduced to a brush.
  • SAMs Self Assembled Monolayers
  • the biggest property of SAMs is that a surface having desired property can be obtained by introducing a single molecule having self-assembly property onto a substrate surface. Accordingly, a surface having biocompatible property can be obtained by introducing a single molecule having various functionalities.
  • SAMs unlike such property, SAMs have a shortcoming in that their chemical stability is weak and they have structural defects, as well as have a shortcoming in that they are not applicable to a living body.
  • a is an integer of 0 to 8 representing the length of alkyl in a backbone
  • Y is -CH 2 - or -0-
  • X is selected from the group consisting of - CH 2 S(CH 2 )HiO-, -CH 2 O(CH 2 )IIiO-, -CH 2 COO(CH 2 )m ⁇ -, -(CH 2 )m0-, -0C0(CH 2 )m0-, - C00(CH 2 )m0-, -NHCO(CH 2 )m ⁇ - and -NHCOO(CH 2 )m ⁇ - (wherein m is an integer of 0 to 20);
  • R is selected from the group consisting of -COCH 2 NH 2 , -COCH(NH 2 )CH 3 , -COCH(NH 2 )CH(CH S ) 2 , -COCH(NH 2 )CH 2 CH(CH 3 ) 2 , -COCH(NH 2 )CH(CH 3
  • the brush polymer has a weight average molecular weight of 5,000 to 5,000,000, and preferably 5,000 to 500,000 so that it can be processed as a biomaterial.
  • the brush polymer is represented by formula II below:
  • X represents -CH 2 S(CH 2 )m ⁇ -, (wherein m is an integer of 0 to 20); R is selected from the group consisting of -COCH 2 NHCH 3 , -COCH 2 N(CHs) 2 , - COCH 2 NHCOCH 3 and -CONHCH 2 CHs; Z is -H; n represents polymerization degree.
  • the brush polymer is poly[oxy(methylamino-ll- undecylesterthiomethyDethylene] (hereinafter refers to 'PMUTE') represented by formula III below,
  • a method of preparing an aliphatic brush polymer having an amine-based derivative as a brush end group comprising preparing an aliphatic polymer; incorporating a functional group into the aliphatic polymer through reaction between the aliphatic polymer and a brush; and incorporating an amine-based derivative into the incorporated functional group.
  • a method of preparing a biocompatible brush polymer comprising reacting an aliphatic brush polymer represented by formula VII below with the functional group and a compound selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, sarcosine, dimethyl glycine, acetyl glycine, ethyl isocyanate and a mixture thereof:
  • a is an integer of 0 to 8 representing the length of alkyl in a backbone
  • Y is -CH 2 - or -CK X is selected from the group consisting of - CH 2 S(CH 2 )m0-, -CH 2 O(CH 2 )m ⁇ -, -CH 2 COO(CH 2 )m ⁇ -, -(CH 2 )m0-, -0C0(CH 2 )m0-, - C00(CH 2 )m0-, -NHC0(CH 2 )m0- and -NHCOO(CH 2 )m ⁇ - (wherein m is an integer of 0 to 20); Z is -H or the said -XH; and n represents polymerization degree.
  • the brush polymer of the formula I is prepared by reacting an aliphatic polymer represented by formula VIII below:
  • Vffl (Vffl) where a is an integer of 0 to 8 representing the length of alkyl in a backbone, and preferably 1; Y is -CH 2 - or -0-, and preferably -0-; Z is -H or CH 2 L; L represents a halogen group, and preferably Cl; and n represents polymerization degree; with a compound represented by formula IX below:
  • m is an integer of 0 to 20
  • a material selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, sarcosine, dimethyl glycine, acetyl glycine, ethyl isocyanate and a mixture thereof.
  • the aliphatic polymer can be prepared in a known polymerization way.
  • a low molecular aliphatic polymer can be preferably prepared by ring opening reaction.
  • the low molecular aliphatic polymer can be synthesized by cation ring opening polymerization employing triphenyl carbenium hexaf luorophosphate (TCHP) as described in reaction scheme I below: Reaction scheme I
  • the polymerization is performed by putting epichlorohydrin into a container, drying it at 5°C in nitrogen atmosphere, and adding and stirring methylene chloride solution in which an initiator is dissolved. A specimen after the reaction was completed was dissolved in a small amount of methylene chloride, and the solution was again precipitated in methanol to purify and the resultant product was dried in vacuum to obtain the low molecular aliphatic polymer. Purifying a monomer is needed before reaction, and attention should be paid to exothermic reaction of an initial reactant.
  • reaction scheme II the reaction between an aliphatic polymer and a brush incorporates a hydroxyalkyl brush into a side chain as described in reaction scheme II below by a sulfide bond.
  • a hydroxy group can be incorporated into the side chain of the synthesized aliphatic polymer through reaction between hydroxyundecyl thioleate and chloride (Cl): Reaction scheme II
  • reaction product prepared by the reaction scheme II proceeds esterification reaction with a material selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, sarcosine, dimethyl glycine, acetyl glycine, ethyl isocyanate and a mixture thereof as described in reaction scheme III: Reaction scheme III
  • R XOCH 2 NH CH 3 , -COCH 2 N(CH 3 ) 2 . -COCH 2 N HCOCH 3 , -CONHCH 2 CH 3
  • a brush polymer represented by the formul a I below for a biomater i al having biocompat ibi I i ty as a biomater i al and a medical mater i al :
  • R ( I ) where a is an integer of 0 to 8 representing the length of alkyl in a backbone; Y is -ChV or -CH X is selected from the group consisting of - CH 2 S(CH 2 )IIiO-, -CH 2 O(CH 2 )m ⁇ -, -CH 2 COO(CH 2 )m ⁇ -, -(CH 2 )m0-, -0C0(CH 2 )m0-, - C00(CH 2 )m0-, -NHC0(CH 2 )m0- and -NHCOO(CH 2 )m ⁇ - (wherein m is an integer of 0 to 20); R is selected from the group consisting of -COCH 2 NH 2 , -COCH(NH 2 )CH 3 , -COCH(NH 2 )CH(CH S ) 2 , -COCH(NH 2 )CH 2 CH(CH 3 ) 2 , -COCH(NH 2 )CH(CH 3
  • a brush polymer according to the present invention can be prepared in the form of various moldings or films through molding and casting method employing a proper temperature or pressure.
  • the films prepared by employing the brush polymer according to the present invention can be prepared on various substrates through various coating methods, and preferably in the form of a film having excellent selective biocompatible property among surface properties.
  • a biocompatible brush polymer according to an embodiment of the present invention can be used as biocompatible materials by which various forms of processed products, e.g., a tooth, an artificial joint and an implant, to be inserted or incorporated within a living body are prepared or coated.
  • the brush polymer or a biomaterial employing the same preferably a polymer film shows an ability of inhibiting pathogenic bacteria.
  • the brush polymer or the biomaterial employing the same can inhibit adsorption, attachment or adhesion of the pathogenic bacteria.
  • the pathogenic bacteria can provide inhibition layers for various bacteria including P. aeruginosa, S. aureus, S. epidermidis, E. faecalis, andE.coli.
  • the brush polymer or the biomaterial employing the same preferably a polymer film shows an inhibiting ability against a blood protein or a blood platelet.
  • the brush polymer or the biomaterial employing the same can inhibit the adsorption, attachment or adhesion of the blood protein or the blood platelet.
  • the biocompatible brush polymer or the biomaterial employing the same, preferably a polymer film can inhibit adsorption, attachment or adhesion of Staphylococcus and variant thereof, for example, DKM_1, DKM_3, DKM_11, DKM_12, DKM_19 and DKM_31.
  • the biocompatible brush polymer or the biomaterial employing the same preferably a polymer film shows an activity to a cell.
  • the brush polymer or the biomaterial employing the same can activate the cell to adsorb, attach or adhere.
  • the biocompatible brush polymer can show an activity to Hep-2 cell.
  • the biocompatible brush polymer or the biomaterial employing the same, preferably a polymer film shows an activity to an animal cell, for example, the skin and hypodermic component of the dorsum of a mouse.
  • an aliphatic brush polymer having an amine-based derivative as a brush end group and a method of preparing the same.
  • the present novel material can be employed in developing various products since various forms of moldings can be prepared, and it can be processed from a sheet to a nanofilm, and can be also variously coated due to its excellent processibi lity. Further, the applicability of the material is limitless since it can embody surface properties required in desired application due to its self-assembly ability and various functional groups at the brush end.
  • the material can be applied as a biomaterial and a medical material since the attachment, adsorption and adhesion properties to various pathogenic bacteria, various blood proteins and blood platelet can be inhibited or prevented by employing control function of surface properties, while it gives excellent attachment, adsorption and adhesion properties to living body cells.
  • FIG. 1 is a graph showing the adsorption results of the pathogenic bacteria P. aeruginosa, S. aureus, S. epidermidis, E. faecalis, E.coli to PMUTE, PDUTE, PAUTE and PEUTE films.
  • FIGS. 2 to 5 are optical microscopic photographs taken 8 days after adsorption of Hep-2 cell to PMUTE, PDUTE, PAUTE and PEUTE films.
  • FIGS. 6 to 9 are optical microscopic photographs of blood platelets taken 8 days after adsorption of Hep-2 cell to PMUTE, PDUTE, PAUTE and PEUTE films.
  • FIG. 10 is a graph showing the adsorption results of control ATCC and the variant Staphylococcus to PMUTE, PDUTE, PAUTE and PEUTE films, and to DKJLl, DKM_3, DKM_11, DKM_12, DKM_19 and DK1L31.
  • FIGS. 11 to 14 are optical microscopic photographs taken 4 weeks after PMUTE, PDUTE, PAUTE and PEUTE films were incorporated and adsorbed to the skin and hypodermis of the dorsum of a mouse.
  • Step 1 40 ml (512 mmol) of epichlorohydrin were poured into 100 mi of round bottom flask, and the flask was cooled to 5°C at nitrogen atmosphere. Methylene chloride solution, in which 2.56 mmol of an initiator were dissolved, was added to the cooled flask, and then the flask was stirred for 4 days at room temperature. Raw specimen was dissolved in small amount of methylene chloride, the solution was again precipitated in methanol to purify, and then the precipitate was dried for 8 hours at 40°C under vacuum to obtain a purified product.
  • Step 2 11-hydroxyundecylthioleate (1,382 mg, 5.4 mmol) was dissolved in 10 ml of dimethyl acetamide (hereinafter abbreviated as DMAc). PECH (500 mg, 5.4 mmol) and 2 ml of DMAc solution were added thereto. The mixture was stirred for 2 hours at room temperature, was extracted with chloroform, and was washed with water.
  • DMAc dimethyl acetamide
  • Step 3 the product from Step 2 (500 mg, 1.92 mmol), dimethyl glycine (206 mg) , N-(3-dimethylaminopropyl)-N-ethylcarbodi imide hydrochloride (hereinafter abbreviated as EDC, 586 mg), and N,N- dimethylaminopyridine (hereinafter abbreviated as DMAP, 187 mg) were dissolved in 40 ml of methylene chloride.
  • EDC N-(3-dimethylaminopropyl)-N-ethylcarbodi imide hydrochloride
  • DMAP N,N- dimethylaminopyridine
  • PAUTE can be also obtained in the same method as described above.
  • 1H NMR 300 MHz, CDC13
  • ⁇ 4.16-4.15 t, 2H
  • ⁇ 4.03 d, 2H
  • ⁇ 3.73- 3.64 m, 5H
  • ⁇ 2.72-2.51 m, 4H
  • ⁇ 2.04 s, 3H
  • ⁇ 1.64-1.56 m, 4H
  • ⁇ 1.27 s, 14H
  • IR (film): v 2941, 1745, 1466, 1388, 1281, 1138, 718, 493
  • Step 3 the product from Step 2 (500 mg, 1.92 mmol) and ethyl isocyanate (172 mg) were dissolved in 40 ml of tetrahydrofuran. The solution was stirred for 24 hours at 60°C , and then the solution was filtered through CeI ite and extracted with chloroform. The solvent was removed under reduced pressure, and the remaining product was purified through flash column. The product was dried for 8 hours at 40 ° C under vacuum to obtain PEUTE.
  • the brush polymer described above was dissolved in chloroform solvent to give lwt% solution. This solution was subjected to dip coating on a slide glass, and the slide glass was dried for a day in a vacuum oven at 60 ° C .
  • the surface of the polymer film prepared like this was measured for surface wettability by employing a contact angle-measuring device. The surface wettability was measured by comparing angles before and after dipping into a buffer at pH 7.4 for 20 minutes, and three parts per one film were measured and then the measured values were averaged. The results for this experiment were shown in Table 1. [Table 1]
  • a polymer film was prepared through the same procedure as described above.
  • the prepared film was tested for biocompatibi lity through adsorption experiment employing five pathogenic bacteria.
  • Example 5 The polymer film prepared in Example 3 was examined for cell compatibility by employing HEp-2 cells. In the experiment, each polymer film was disinfected with 70% ethyl alcohol, and then put into T-25 flask. Hep-2 cells suspension having a concentration of 0.5 X 10 6 cells/m ⁇ .
  • a polymer film was prepared by spin coating a polymer solution dissolved in chloroform in a concentration of 1 wt% on a silicon wafer.
  • the compatibility of the polymer film to blood was ascertained by using a blood platelet isolated from blood.
  • the polymer film disinfected with 70% ethyl alcohol was put into 6 wells,
  • Example 7 A polymer film was prepared through the same procedure as described in Example 4. 6 variants of the Staphylococcus extracted from a patient were subjected to the same adsorption experiment as described in Example 4 to investigate the adsorption property of the bacteria parasitic to a human body. The calculated values were shown in FIG. 4.

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  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
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Abstract

There are provided an aliphatic brush polymer material, a method of preparing the same, and a product employing the same material. The aliphatic brush polymer material has biocompatible property through an amine-based derivative introduced to a brush.

Description

[DESCRIPTION] [Invention Tit Ie]
BIOCOMPATIBLE ALIPHATIC BRUSH POLYMERS AND MANUFACTURING METHODS THEREOF
[Technical Field]
The present invention relates to an aliphatic brush polymer having an amine-based derivative as a brush end group, and more particularly, to an aliphatic brush polymer having biocompatible property through an amine- based derivative introduced to a brush. [Background Art]
Presently, a method employing SAMs (Self Assembled Monolayers) is most widely used in a research for biocompatible property. The biggest property of SAMs is that a surface having desired property can be obtained by introducing a single molecule having self-assembly property onto a substrate surface. Accordingly, a surface having biocompatible property can be obtained by introducing a single molecule having various functionalities. However, unlike such property, SAMs have a shortcoming in that their chemical stability is weak and they have structural defects, as well as have a shortcoming in that they are not applicable to a living body.
[Disclosure] [Technical Problem]
It is an object of the invention to provide a brush polymer having biocompatibi lity.
It is another object of the invention to provide an aliphatic brush polymer having an amine-based derivative as a brush end group.
It is still another object of the invention to provide a method of preparing an aliphatic brush polymer having an amine-based derivative as a brush end group.
It is still yet another object of the invention to provide an aliphatic brush polymer material that produces a surface having chemical and physical stability due to its self-assembly property, has various surface properties and easy processibi lity, and simultaneously enhances applicability to a living body. [Technical Solution]
In order to accomplish the above objects, according to one aspect of the invention, there is provided a brush polymer represented by formula I below:
Figure imgf000003_0001
where a is an integer of 0 to 8 representing the length of alkyl in a backbone; Y is -CH2- or -0-; X is selected from the group consisting of - CH2S(CH2)HiO-, -CH2O(CH2)IIiO-, -CH2COO(CH2)mθ-, -(CH2)m0-, -0C0(CH2)m0-, - C00(CH2)m0-, -NHCO(CH2)mθ- and -NHCOO(CH2)mθ- (wherein m is an integer of 0 to 20); R is selected from the group consisting of -COCH2NH2, -COCH(NH2)CH3, -COCH(NH2)CH(CHS)2, -COCH(NH2)CH2CH(CH3)2, -COCH(NH2)CH(CH3)CH2CH3, - COCH(NH2)CH2CH2SCH3, -COCH2NHCH3, -COCH2N(CHS)2, -COCH2NHCOCHS and - CONHCH2CH3; Z is -H or the said -X-R; and n represents polymerization degree.
In the above aspect of the present invention, the brush polymer has a weight average molecular weight of 5,000 to 5,000,000, and preferably 5,000 to 500,000 so that it can be processed as a biomaterial.
In an embodiment of the present invention, the brush polymer is represented by formula II below:
Figure imgf000004_0001
(II) wherein X represents -CH2S(CH2)mθ-, (wherein m is an integer of 0 to 20); R is selected from the group consisting of -COCH2NHCH3, -COCH2N(CHs)2, - COCH2NHCOCH3 and -CONHCH2CHs; Z is -H; n represents polymerization degree.
In a preferable embodiment of the present invention, the brush polymer is poly[oxy(methylamino-ll- undecylesterthiomethyDethylene] (hereinafter refers to 'PMUTE') represented by formula III below,
Figure imgf000004_0002
poly[oxy(dimethylamino-ll-undecylesterthiomethyl)ethylene](hereinafter refers to 'PDUTE') represented by formula IV below,
Figure imgf000005_0001
poly[oxy(acetyIaminoamino-11-undecy1esterthiomethy1 )ethylene](hereinafter refers to 'PAUTE') represented by formula V below, or
Figure imgf000005_0002
polytoxyCethylamino-ll-undecylesterthiomethyDethylene] (hereinafter refers to 'PEUTE' ) represented by formula VI below:
Figure imgf000005_0003
According to another aspect of the invention, there is provided a method of preparing an aliphatic brush polymer having an amine-based derivative as a brush end group comprising preparing an aliphatic polymer; incorporating a functional group into the aliphatic polymer through reaction between the aliphatic polymer and a brush; and incorporating an amine-based derivative into the incorporated functional group.
According to still another aspect of the invention, there is provided a method of preparing a biocompatible brush polymer comprising reacting an aliphatic brush polymer represented by formula VII below with the functional group and a compound selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, sarcosine, dimethyl glycine, acetyl glycine, ethyl isocyanate and a mixture thereof:
Figure imgf000006_0001
(VI) where a is an integer of 0 to 8 representing the length of alkyl in a backbone; Y is -CH2- or -CK X is selected from the group consisting of - CH2S(CH2)m0-, -CH2O(CH2)mθ-, -CH2COO(CH2)mθ-, -(CH2)m0-, -0C0(CH2)m0-, - C00(CH2)m0-, -NHC0(CH2)m0- and -NHCOO(CH2)mθ- (wherein m is an integer of 0 to 20); Z is -H or the said -XH; and n represents polymerization degree.
In an embodiment of the present invention, the brush polymer of the formula I is prepared by reacting an aliphatic polymer represented by formula VIII below:
(CH2)a—C —Y
CH2L
(Vffl) where a is an integer of 0 to 8 representing the length of alkyl in a backbone, and preferably 1; Y is -CH2- or -0-, and preferably -0-; Z is -H or CH2L; L represents a halogen group, and preferably Cl; and n represents polymerization degree; with a compound represented by formula IX below:
MRH (IX) wherein M represents a Group I metal, and preferably Na; R is -S(CH2)m0-
(wherein m is an integer of 0 to 20); and reacting the reaction product with a material selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, sarcosine, dimethyl glycine, acetyl glycine, ethyl isocyanate and a mixture thereof.
In an embodiment of the present invention, the aliphatic polymer can be prepared in a known polymerization way. A low molecular aliphatic polymer can be preferably prepared by ring opening reaction. In a preferable embodiment of the present invention, the low molecular aliphatic polymer can be synthesized by cation ring opening polymerization employing triphenyl carbenium hexaf luorophosphate (TCHP) as described in reaction scheme I below: Reaction scheme I
Figure imgf000007_0001
The polymerization is performed by putting epichlorohydrin into a container, drying it at 5°C in nitrogen atmosphere, and adding and stirring methylene chloride solution in which an initiator is dissolved. A specimen after the reaction was completed was dissolved in a small amount of methylene chloride, and the solution was again precipitated in methanol to purify and the resultant product was dried in vacuum to obtain the low molecular aliphatic polymer. Purifying a monomer is needed before reaction, and attention should be paid to exothermic reaction of an initial reactant.
In the present invention, the reaction between an aliphatic polymer and a brush incorporates a hydroxyalkyl brush into a side chain as described in reaction scheme II below by a sulfide bond. In an embodiment of the present invention, a hydroxy group can be incorporated into the side chain of the synthesized aliphatic polymer through reaction between hydroxyundecyl thioleate and chloride (Cl): Reaction scheme II
Figure imgf000007_0002
In the present invention, the reaction product prepared by the reaction scheme II proceeds esterification reaction with a material selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, sarcosine, dimethyl glycine, acetyl glycine, ethyl isocyanate and a mixture thereof as described in reaction scheme III: Reaction scheme III
Figure imgf000008_0001
R=XOCH2NH CH3, -COCH2N(CH3)2. -COCH2N HCOCH3, -CONHCH2CH3
According to st i l l another aspect of the invent ion , there are provided uses of a brush polymer represented by the formul a I below for a biomater i al having biocompat ibi I i ty as a biomater i al and a medical mater i al :
L-
-hofcu-i-Yf
X
R ( I ) where a is an integer of 0 to 8 representing the length of alkyl in a backbone; Y is -ChV or -CH X is selected from the group consisting of - CH2S(CH2)IIiO-, -CH2O(CH2)mθ-, -CH2COO(CH2)mθ-, -(CH2)m0-, -0C0(CH2)m0-, - C00(CH2)m0-, -NHC0(CH2)m0- and -NHCOO(CH2)mθ- (wherein m is an integer of 0 to 20); R is selected from the group consisting of -COCH2NH2, -COCH(NH2)CH3, -COCH(NH2)CH(CHS)2, -COCH(NH2)CH2CH(CH3)2, -COCH(NH2)CH(CH3)CH2CH3, - COCH(NH2)CH2CH2SCH3, -COCH2NHCH3, -C0CH2N(CH3)2, -COCH2NHCOCH3 and - CONHCH2CH3; Z is -H or the said -X-R; and n represents polymerization degree.
A brush polymer according to the present invention can be prepared in the form of various moldings or films through molding and casting method employing a proper temperature or pressure. The films prepared by employing the brush polymer according to the present invention can be prepared on various substrates through various coating methods, and preferably in the form of a film having excellent selective biocompatible property among surface properties.
A biocompatible brush polymer according to an embodiment of the present invention can be used as biocompatible materials by which various forms of processed products, e.g., a tooth, an artificial joint and an implant, to be inserted or incorporated within a living body are prepared or coated.
In the present invention, the brush polymer or a biomaterial employing the same, preferably a polymer film shows an ability of inhibiting pathogenic bacteria. In an embodiment of the present invention, the brush polymer or the biomaterial employing the same can inhibit adsorption, attachment or adhesion of the pathogenic bacteria. In an embodiment of the present invention, the pathogenic bacteria can provide inhibition layers for various bacteria including P. aeruginosa, S. aureus, S. epidermidis, E. faecalis, andE.coli.
In another embodiment of the present invention, the brush polymer or the biomaterial employing the same, preferably a polymer film shows an inhibiting ability against a blood protein or a blood platelet. In an embodiment of the present invention, the brush polymer or the biomaterial employing the same can inhibit the adsorption, attachment or adhesion of the blood protein or the blood platelet.
In still another embodiment of the present invention, the biocompatible brush polymer or the biomaterial employing the same, preferably a polymer film can inhibit adsorption, attachment or adhesion of Staphylococcus and variant thereof, for example, DKM_1, DKM_3, DKM_11, DKM_12, DKM_19 and DKM_31.
In the present invention, the biocompatible brush polymer or the biomaterial employing the same, preferably a polymer film shows an activity to a cell. In an embodiment of the present invention, the brush polymer or the biomaterial employing the same can activate the cell to adsorb, attach or adhere. In the embodiment of the present invention, the biocompatible brush polymer can show an activity to Hep-2 cell. In the present invention, the biocompatible brush polymer or the biomaterial employing the same, preferably a polymer film shows an activity to an animal cell, for example, the skin and hypodermic component of the dorsum of a mouse.
[Advantageous Effects]
According to the present invention, there are provided an aliphatic brush polymer having an amine-based derivative as a brush end group, and a method of preparing the same. The present novel material can be employed in developing various products since various forms of moldings can be prepared, and it can be processed from a sheet to a nanofilm, and can be also variously coated due to its excellent processibi lity. Further, the applicability of the material is limitless since it can embody surface properties required in desired application due to its self-assembly ability and various functional groups at the brush end. Particularly, the material can be applied as a biomaterial and a medical material since the attachment, adsorption and adhesion properties to various pathogenic bacteria, various blood proteins and blood platelet can be inhibited or prevented by employing control function of surface properties, while it gives excellent attachment, adsorption and adhesion properties to living body cells.
[Description of Drawings] FIG. 1 is a graph showing the adsorption results of the pathogenic bacteria P. aeruginosa, S. aureus, S. epidermidis, E. faecalis, E.coli to PMUTE, PDUTE, PAUTE and PEUTE films.
FIGS. 2 to 5 are optical microscopic photographs taken 8 days after adsorption of Hep-2 cell to PMUTE, PDUTE, PAUTE and PEUTE films. FIGS. 6 to 9 are optical microscopic photographs of blood platelets taken 8 days after adsorption of Hep-2 cell to PMUTE, PDUTE, PAUTE and PEUTE films.
FIG. 10 is a graph showing the adsorption results of control ATCC and the variant Staphylococcus to PMUTE, PDUTE, PAUTE and PEUTE films, and to DKJLl, DKM_3, DKM_11, DKM_12, DKM_19 and DK1L31.
FIGS. 11 to 14 are optical microscopic photographs taken 4 weeks after PMUTE, PDUTE, PAUTE and PEUTE films were incorporated and adsorbed to the skin and hypodermis of the dorsum of a mouse.
[Best Mode] The present invention will be described in greater detail with reference to the following examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.
Examples Example 1
Preparation of PDUTE
(Step 1): 40 ml (512 mmol) of epichlorohydrin were poured into 100 mi of round bottom flask, and the flask was cooled to 5°C at nitrogen atmosphere. Methylene chloride solution, in which 2.56 mmol of an initiator were dissolved, was added to the cooled flask, and then the flask was stirred for 4 days at room temperature. Raw specimen was dissolved in small amount of methylene chloride, the solution was again precipitated in methanol to purify, and then the precipitate was dried for 8 hours at 40°C under vacuum to obtain a purified product.
(Step 2): 11-hydroxyundecylthioleate (1,382 mg, 5.4 mmol) was dissolved in 10 ml of dimethyl acetamide (hereinafter abbreviated as DMAc). PECH (500 mg, 5.4 mmol) and 2 ml of DMAc solution were added thereto. The mixture was stirred for 2 hours at room temperature, was extracted with chloroform, and was washed with water. The solvent was removed from the solution, the remaining product was precipitated in hexane, and then the precipitate was dried for 8 hours at 40°C under vacuum to obtain a purified product (Step 3); the product from Step 2 (500 mg, 1.92 mmol), dimethyl glycine (206 mg) , N-(3-dimethylaminopropyl)-N-ethylcarbodi imide hydrochloride (hereinafter abbreviated as EDC, 586 mg), and N,N- dimethylaminopyridine (hereinafter abbreviated as DMAP, 187 mg) were dissolved in 40 ml of methylene chloride. The solution was stirred for 72 hours at room temperature, and then the solution was filtered through CeI ite and extracted with chloroform. The solvent was removed under reduced pressure, and the remaining product was purified through flash column. The product was dried for 8 hours at 40°C under vacuum to obtain PDUTE. 1H NMR (300 MHz, CDC13) δ 4.14-4.09 (t, 2H), δ 3.73-3.64 (m, 5H), δ 3.16 (s, 2H), δ 2.72-2.51 (m, 4H), δ 1.64-1.56 (m, 4H), δ 1.27 (s, 14H); IR (film): v = 2943, 1755, 1461, 1387, 1283, 1128, 708, 496. PMUTE can be also obtained in the same method as described above. 1H NMR (300 MHz, CDC13) δ 4.31-4.28 (t, 2H), δ 3.73-3.64 (m, 5H), δ 3.42 (s, 2H), δ 2.72-2.51 (m, 4H), δ 2.43-2.40 (m, 2H), δ 2.03 (m, IH), δ 1.64-1.56 (m, 4H), δ 1.27 (s, 14H); IR (film): v = 2933, 1758, 1468, 1382, 1278, 1125, 708, 489.
PAUTE can be also obtained in the same method as described above. 1H NMR (300 MHz, CDC13) δ 4.16-4.15 (t, 2H), δ 4.03 (d, 2H), δ 3.73- 3.64 (m, 5H), δ 2.72-2.51 (m, 4H), δ 2.04 (s, 3H), δ 1.64-1.56 (m, 4H), δ 1.27 (s, 14H); IR (film): v = 2941, 1745, 1466, 1388, 1281, 1138, 718, 493
Example 2
Preparation of PEUTE Syntheses at the Step 1 and 2 were performed in the same way as in Step 1 and 2 in Example 1.
(Step 3) the product from Step 2 (500 mg, 1.92 mmol) and ethyl isocyanate (172 mg) were dissolved in 40 ml of tetrahydrofuran. The solution was stirred for 24 hours at 60°C , and then the solution was filtered through CeI ite and extracted with chloroform. The solvent was removed under reduced pressure, and the remaining product was purified through flash column. The product was dried for 8 hours at 40°C under vacuum to obtain PEUTE.
1H NMR (300 MHz, CDC13) δ 4.12-4.06 (t, 2H), δ 3.73-3.64 (m, 5H), δ 3.01 (m, 2H), δ 2.72-2.51 (m, 4H), δ 1.64-1.56 (m, 4H), δ 1.27 (s,
17H): IR (film): v = 2944, 1751, 1468, 1379, 1289, 1123, 711, 494
Example 3
The brush polymer described above was dissolved in chloroform solvent to give lwt% solution. This solution was subjected to dip coating on a slide glass, and the slide glass was dried for a day in a vacuum oven at 60°C . The surface of the polymer film prepared like this was measured for surface wettability by employing a contact angle-measuring device. The surface wettability was measured by comparing angles before and after dipping into a buffer at pH 7.4 for 20 minutes, and three parts per one film were measured and then the measured values were averaged. The results for this experiment were shown in Table 1. [Table 1]
Figure imgf000012_0001
Example 4
A polymer film was prepared through the same procedure as described above. The prepared film was tested for biocompatibi lity through adsorption experiment employing five pathogenic bacteria. The film was put into a medium containing five pathogenic bacteria quantified in concentration of 0.5 X 106 cells/ml (A660 = 0.15) by employing UV-VIS spectrophotometer and adsorption experiment was performed for 4 hours in 37°C incubator. After adsorption experiment, the polymer film was picked out and detached by employing an ultrasonic device, and the detached bacteria was inoculated on a semi-solid medium and grown for a day in 37°C incubator, and bacterial colonies grown on the medium were counted, and then adsorption % was calculated comparing with the initially inoculated bacterial count. The calculated values are shown in FIG. 1. Example 5 The polymer film prepared in Example 3 was examined for cell compatibility by employing HEp-2 cells. In the experiment, each polymer film was disinfected with 70% ethyl alcohol, and then put into T-25 flask. Hep-2 cells suspension having a concentration of 0.5 X 106 cells/mϋ. (A660 = 0.15) in a proper medium was also put into the T-25 flask, and the behavior of Hep-2 cells on the polymer film was observed over time. After observation up to 8 days, the polymer film was picked out from the flask, and the viability of cells adsorbed on the surface of the polymer film was examined by employing a tryphan blue stain, and then the polymer film was again put into a buffer solution to ascertain the cell stability over time. The optical microscopic photograph of a cell on the respective polymer film observed up to 8 days was shown in FIG. 2. Example 6 The brush polymer represented by the formula I was examined for its compatibility to blood. In the experiment, a polymer film was prepared by spin coating a polymer solution dissolved in chloroform in a concentration of 1 wt% on a silicon wafer. The compatibility of the polymer film to blood was ascertained by using a blood platelet isolated from blood. The polymer film disinfected with 70% ethyl alcohol was put into 6 wells,
100//4 of blood plasma were dropped to each well to cover overall film, and then adsorption was performed for 1 hour in 37°C incubator. After 1 hour, 6 wells were picked out, washed two times with a buffer solution, and then immobilized by employing 1% glutaraldehyde. After complete drying for 2 days through lyophi lization, the platelet adsorbed on the surface of the polymer film was observed by employing a scanning electronic microscope. The microscopic photographs for the platelet observed on each polymer film were shown in FIGS. 3a, 3b, 3c and 3d. Example 7 A polymer film was prepared through the same procedure as described in Example 4. 6 variants of the Staphylococcus extracted from a patient were subjected to the same adsorption experiment as described in Example 4 to investigate the adsorption property of the bacteria parasitic to a human body. The calculated values were shown in FIG. 4. Example 8
An experiment for biocompatibi lity of each polymer film was performed an in vivo experiment by employing a mouse based on the in vitro experiment performed in Examples 4 to 7. The polymer film was prepared by cutting a polyethylene terephthalate film to a circle in diameter of 7 mm, and then dip coating with the same polymer solution as used in the above examples. Two parts between a skin and hypodermis of the dorsum of a mouse were excised and two polymer films were inserted in each mouse. Each polymer film was investigated for biocompatibi lity including Siam over time, e.g., 1, 2, 4 and 8 weeks. The results at 4 weeks were shown in FIGS. 5a, 5b, 5c and 5d.
Although the present invention has been described with reference to several embodiments of the invention, the description is illustrative of the invention and is not to be construed as limiting the invention. Various modifications and variations may occur to those skilled in the art, without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

[CLAIMS] [Claim 1]
A polymer compound represented by formula I below:
Figure imgf000015_0001
where a is an integer of 0 to 8 representing the length of alkyl in a backbone; Y is -CH2- or -CK X is selected from the group consisting of - CH2S(CH2)InO-, -CH2O(CH2)mθ-, -CH2COO(CH2)mθ-, -(CH2)m0-f -0C0(CH2)m0-, - COO(CH2)IIiO-, -NHCO(CH2)mθ- and -NHCOO(CH2)mθ- (wherein m is an integer of 0 to 20); R is selected from the group consisting of -COCH2NH2, -COCH(NH2)CH3, -COCH(NH2)CH(CHS)2, -COCH(NH2)CH2CH(CHS)2, -COCH(NH2)CH(CH3)CH2CH3, - COCH(NH2)CH2CH2SCH3, -COCH2NHCH3, -COCH2N(CHS)2, -COCH2NHCOCH3 and - CONHCH2CHs; Z is -H or the said -X-R; and n represents polymerization degree.
[Claim 2]
The polymer compound according to claim 1, wherein the polymer compound has a weight average molecular weight of 5,000 to 1,000,000.
[Claim 3] The polymer compound according to claim 1, wherein a is 1; Y is -0- ; X is -CH2S(CH2)m0- (wherein m is an integer of 0 to 20); R is selected from the group consisting of -COCH2NHCH3, -C0CH2N(CH3)2, -C0CH2NHCOCH3 and - CONHCH2CH3; Z is -H; n represents polymerization degree.
[Claim 4] The polymer compound according to claim 1, wherein the polymer compound is poly[oxy(methylamino-ll-undecylesterthiomethyl)ethylene] .
[Claim 5]
The polymer compound according to claim 1, wherein the polymer compound is poly[oxy(dimethylamino-ll-undecylesterthiomethyl)ethylene] .
[Claim 6]
The polymer compound is according to claim 1, wherein the polymer compound is poly[oxy(acetylaminoamino-ll-undecylesterthiomethyl )ethylene] .
[Claim 7]
The polymer compound is according to claim 1, wherein the polymer compound is poly[oxy(ethylamino-ll-undecylesterthiomethyl)ethylene] .
[Claim 8]
A biocompatible brush polymer represented by formula I below:
Figure imgf000016_0001
where a is an integer of 0 to 8 representing the length of alkyl in a backbone; Y is -CH2- or -0-; X is selected from the group consisting of - CH2S(CH2)ITiO-, -CH2O(CH2)InO-, -CH2COO(CH2)InO-, -(CH2)m0-, -0C0(CH2)m0-, - C00(CH2)m0-, -NHCO(CH2)mθ- and -NHCOO(CH2)mθ- (wherein m is an integer of 0 to 20); R is selected from the group consisting of -COCH2NH2, -COCH(NH2)CH3, -COCH(NH2)CH(CH3)2, -COCH(NH2)CH2CH(CHS)2, -COCH(NH2)CH(CH3)CH2CH3, - COCH(NH2)CH2CH2SCH3, -COCH2NHCH3, -C0CH2N(CH3)2, -COCH2NHCOCH3 and - CONHCH2CH3; Z is -H or the said -X-R; and n represents polymerization degree.
[Claim 9]
The biocompatible brush polymer according to claim 8, wherein the brush polymer is poly[oxy(methylamino-ll-undecylesterthiomethyl)ethylene] , poly[oxy(dimethylamino-ll-undecylesterthiomethyl )ethylene] , poly[oxy(acetylaminoamino-ll-undecylesterthiomethyl )ethylene] , or poly[oxy(ethylamino-ll-undecylesterthiomethyl)ethylene] .
[Claim 10]
The biocompatible brush polymer according to claims 8 or 9, wherein the brush polymer has an ability of inhibiting adsorption, attachment or adhesion to the pathogenic bacteria.
[Claim 11]
The biocompatible brush polymer according to claim 10, wherein the pathogenic bacteria is P.aeruginosa, S.aureus, S. epidermidis, E. faecal is, or E.coli .
[Claim 12]
The biocompatible brush polymer according to claim 10, wherein the pathogenic bacteria is Staphylococcus.
[Claim 13]
The biocompatible brush polymer according to claims 9 or 10, wherein the brush polymer has an ability of inhibiting adsorption, attachment or adhesion to a blood protein and the blood platelet.
[Claim 14]
The biocompatible brush polymer according to claims 9 or 10, wherein the brush polymer has an ability of enhancing adsorption, attachment or adhesion to a cell.
[Claim 15]
The biocompatible brush polymer according to claim 14, wherein the cell is HEp-2 cell.
[Claim 16] The biocompatible brush polymer according to claim 14, wherein the cell is a cell of the skin and hypodermis of the dorsum of a mouse.
[Claim 17]
A biomaterial comprising a biocompatible polymer according to claims 8 or 9.
[Claim 18]
A biocompatible material prepared by processing the biomaterial according to claim 17.
[Claim 19] The biocompatible material according to claim 18, wherein the biocompatible material is a polymer film, a coating film, a molding and an attachment or implant to a human body. [Claim 20]
A method of preparing a biocompatible brush polymer comprising reacting an aliphatic brush polymer represented by formula VII below with the functional group and a compound selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, sarcosine, dimethyl glycine, acetyl glycine, ethyl isocyanate and a mixture thereof:
Figure imgf000017_0001
(vπ) where a is an integer of 0 to 8 representing the length of alkyl in a backbone; Y is -CH2- or -0-; X is selected from the group consisting of - CH2S(CH2)IIiO-, -CH2O(CH2)mθ-, -CH2COO(CH2)mθ-, -(CH2)m0-, -0C0(CH2)m0-, - COO(CH2)IIiO-, -NHC0(CH2)m0- and -NHCOO(CH2)mθ- (wherein m is an integer of 0 to 20); Z is -H or the said -XH; and n represents polymerization degree. [Claim 21]
A method of preparing a brush polymer comprising reacting an aliphatic polymer represented by formula VIII below:
Figure imgf000017_0002
where a is an integer of 0 to 8 representing the length of alkyl in a backbone; Y is -CH2- or -0-; Z is -H; L represents a halogen group, and preferably Cl; and n represents polymerization degree; with a compound represented by formula IX below: MRH (IX) wherein M represents a Group I metal, and preferably Na; R is -S(CH2)mO- (wherein m is an integer of 0 to 20); and reacting the reaction product with a compound selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, sarcosine, dimethyl glycine, acetyl glycine, ethyl isocyanate and a mixture thereof. [Claim 22]
The method of preparing a brush polymer according to claim 15, wherein the aliphatic polymer is prepared by ring opening reaction. [Claim 23]
A use of a polymer compound according to any one of claims 1 to 7 as a biomaterial .
PCT/KR2007/000735 2007-02-01 2007-02-09 Biocompatible aliphatic brush polymers and manufacturing methods thereof WO2008093905A1 (en)

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