KR101396880B1 - Self-assembled nanoparticles of monosaccharide/ethylene oxide alternating polyamides and methods of making and using same - Google Patents

Abstract

[화학식 2]

상기 화학식 1 및 화학식 2에서, 상기 A, B, 및 n의 정의는 발명의 상세한 설명에 기재된 바와 같다. 상기 폴리아미드는 수소결합을 이용한 자기결합(self assembled)이 가능하여, 수계 분산 자기 결합 나노입자를 형성할 수 있고, 암세포 이미지 프로브용 조영제로 활용될 수 있다.The monosaccharide / ethylene oxide alternating polyamide of the present invention is represented by the following formula (1) or (2).
[Chemical Formula 1]

(2)

In the above formulas (1) and (2), the definitions of A, B, and n are as described in the detailed description of the invention. The polyamide can be self assembled using a hydrogen bond to form aqueous dispersion self-assembled nanoparticles and can be used as a contrast agent for a cancer cell image probe.

Description

SELF-ASSEMBLED NANOPARTICLES OF MONOSACCHARIDE / ETHYLENE OXIDE ALTERNATING POLYAMIDES AND METHODS OF MAKING AND USING SAME FIELD OF THE INVENTION The present invention relates to self-assembled nanoparticles of monosaccharide / ethylene oxide alternating polyamides,

The present invention relates to a monosaccharide / ethylene oxide alternating polyamide, a self-assembled nanoparticle thereof, a production method thereof, and a use thereof, and is capable of selectively accumulating cancer due to high permeability of a new blood vessel in cancer tissue, The present invention relates to a contrastable monosaccharide / ethylene oxide alternating polyamide, nanoparticles thereof, a process for their preparation and their use.

Self-assembled nanostructures formed by biomaterials such as DNA and proteins can be easily observed in living tissues, and the self-assembly phenomenon of such biomaterials has been utilized as a method for producing nanomaterials in various applications [ : S. Zhang, Nature Biotechnology 21: 539-554 (1998)]. In other words, by simulating the self-assembly of biomaterials, it is possible to design the molecular structure of an artificial building block capable of spontaneous self-assembly. Hydrogen bonding and hydrophilic / hydrophobic attraction in the self-assembly of biomaterials are the driving force for self-assembly .

Self-assembled nanoparticles, which are generally formed by hydrophilic / hydrophobic grafts of artificial amphipatites, have been used as materials for transfer materials, including imaging probes for cancer imaging [2: J.-H. Kim et al., Progress in Polymer Science 32: 1031-1053 (2007), Document 3: S. Lee et al., Nano Letters 9: 4412-4416 (2009), Document 4: Lim et al., Chemistry of Materials 21: 5819-5825 (2009)]. Since the self-assembled nanoparticles are small in size, they are not attached to the reticuloendothelial systems in vivo, and thus the retention time of the vascular system is prolonged, and the permeability to the neovascular system in the incomplete cancer tissue is high due to rapid growth, [5] M. Ferrari, Nature Reviews Cancer 5: 161-171 (2005), 6: I. Brigger et al., Advanced Drug Delivery Reviews 54: 631-651 (2002)]. In addition, the nanoparticles accumulated in cancer tissues have a certain size, so they can not easily escape from cancer tissues and stay there for a long time. If the self-assembled nanoparticles selectively transferred to the cancer tissue and capable of staying for a long time have near-infrared fluorescent characteristics, the cancer tissue can be selectively imaged. However, since amphiphilic substances require hydrophobicity for self-assembly, they have potential limitations that cause deterioration in performance after bonding with biomaterials / cells due to non-specific gravities due to hydrophobicity.

Self-assembled nanoparticles formed by hydrogen bonding in addition to amphiphilic substances may also be useful candidates as imaging probes. In particular, unlike amphipatic materials, hydrophobicity is not required for self-assembly, and non-specific biomaterial / cell adsorption phenomenon can be excluded. However, polar solvents such as water can directly interfere with hydrogen bonding to interfere with the formation of intermolecular hydrogen bonds in the building block [SH 7: SH Gellman et al., The Journal of American Chemical Society, 113: 1164-1173 ), And self-assembled nanoparticles formed by hydrogen bonding of artificially produced monomers have been studied in organic solvents that can not participate in hydrogen bonding in large part [Literature 8: L. Brunsveld et al., Chemical Reviews 101: 4071-4097 (2001 ), Document 9: TE Kaiser et al., Angewandte Chemie International Edition 46: 5541-5544 (2007), 10: CC Lee et al., Chemical Society Reviews 38: 671-683 (2009)]. There is no example of hydrogen bonding self-assembled nanoparticles in an organic solvent used for biological application due to the toxicity of a solvent, and there is no example of producing magnetic nanoparticles in an aqueous environment for use as an imaging probe.

In order to produce self-assembled nanoparticles using hydrogen bonds, which can be utilized as imaging probes, it is required to design and develop artificial monomer units capable of forming strong intermolecular hydrogen bonds in an aqueous environment.

It is an object of the present invention to provide a monosaccharide / ethylene oxide alternating polyamide which is capable of self-bonding using hydrogen bonding force. Another object of the present invention is to provide a nanoparticle containing the polyamide, which can selectively accumulate cancer due to high permeability of neovascularization in cancer tissue, will be.

The monosaccharide / ethylene oxide alternating polyamide according to one embodiment of the present invention is represented by the following formula (1) or (2).

[Chemical Formula 1]

(2)

Wherein A is a monosaccharide atomic group, B is an oligoethylene oxide group atomic group, and n is an integer of 10 to 50, each independently in the formulas (1) and (2).

The nanoparticles according to another embodiment of the present invention include aqueous dispersed self-assembled nanoparticles comprising the monosaccharide / ethylene oxide alternating polyamide represented by Formula 1 or Formula 2, and the monosaccharide / ethylene oxide And fluorescent dyes bonded to alternating polyamides.

A process for producing a polyamide according to another embodiment of the present invention is a process for producing a polyamide, which comprises reacting a monosaccharide having a hydroxyl group capable of hydrogen bonding represented by the following formula (5) and an oligoethylene oxide-based monomer having an amine group capable of hydrogen bonding represented by the following formula And then subjecting the monomers to condensation polymerization to prepare the monosaccharide / ethylene oxide alternating polyamide represented by the above formula (1) or (2).

[Chemical Formula 5]

In Formula 5, y is an integer of 1 to 10.

[Chemical Formula 6]

In Formula 6, x is an integer of 1 to 10.

The method for producing nanoparticles according to another embodiment of the present invention includes a dye-binding step of mixing the monosaccharide / ethylene oxide alternating polyamide and a fluorescent dye in a polar solvent and then combining the monosaccharide / ethylene oxide alternating poly A step of mixing an amide and water and heating to prepare an aqueous solution in which the monosaccharide / ethylene oxide alternating polyamide is dissolved in the water, and cooling the aqueous solution to form a molecule of the dye-bonded monosaccharide / ethylene oxide alternating polyamide Are self-assembled in the water by hydrogen bonding to form aqueous dispersion-self-assembly-nanoparticles.

In another embodiment of the present invention, the contrast agent for a cancer cell image probe includes the nanoparticles.

Hereinafter, the present invention will be described in more detail with reference to the drawings.

The monosaccharide / ethylene oxide alternating polyamide according to one embodiment of the present invention is represented by the following formula (1) or (2).

[Chemical Formula 1]

(2)

Wherein A is a monosaccharide atomic group, B is an oligoethylene oxide group atomic group, and n is an integer of 10 to 50, each independently in the formulas (1) and (2).

The A may be a functional group derived from an aldaric acid represented by the following general formula (3).

(3)

In Formula 3, y is an integer of 1 to 10.

And B may be a functional group represented by the following general formula (4).

[Chemical Formula 4]

In Formula 4, x is an integer of 1 to 10.

The polyamide includes a hydroxyl group and an amide group capable of hydrogen bonding in a polyamide including alternately an atom A derived from a monosaccharide and an atom B derived from an oligoethylene oxide system and is self assembled Nanoparticles can be formed. In addition, a strong intermolecular bond can be formed through hydrogen bonding in a water-based environment by simulating structures of monosaccharides involved in various biomedical mechanisms and polyethylene oxide having high water-solubility and biocompatibility. Furthermore, it is possible to provide nanoparticles which can be chemically bonded to fluorescent dyes by at least one amine group at one end thereof, and can be selectively transferred to cancer cells to be utilized as image probes.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram showing the formation of aqueous dispersion self-assembled nanoparticles by hydrogen bonding of monosaccharide / ethylene oxide alternating polyamide. FIG. Referring to FIG. 1, in the monosaccharide / ethylene oxide alternating polyamide of the present invention, oxygen or nitrogen contained in the polyamide is self-assembled by hydrogen bonding force in a molecule to form an aqueous dispersion nanoparticle.

Another embodiment of the present invention is a nanoparticle comprising an aqueous dispersion self assembled nanoparticle comprising a monosaccharide / ethylene oxide alternating polyamide represented by Formula 1 or Formula 2, and a monodisperse / ethylene oxide alternating poly Amide. ≪ / RTI >

When the nanoparticles further include the fluorescent dye, the nanoparticles can maintain a state of staying in the target organ for a predetermined period of time, and the fluorescent dye can be chemically bonded to the nanoparticles to be observed as a fluorescent signal have.

The fluorescent dye and the monosaccharide / ethylene oxide alternating polyamide may be covalently bonded.

The fluorescent dye may be a near-infrared fluorescent dye, and the fluorescent dye may be any one selected from the group consisting of succinimidyl ester, isothiocyanate, vinyl sulfone, and combinations thereof. It may be carrying.

The near infrared fluorescent dyes have Cy5, Cy5.5, Cy7, Alexa Fluor ® 660, Alexa Fluor ® 680, Alexa Fluor ® 700, Alexa Fluor ® 750, Alexa Fluor ® 790, Bodipy ® 650/665 and the group consisting of May be selected.

The aqueous dispersed self-assembly nanoparticles may be self-assembled by a hydrogen bonding force, and the diameter of the nanoparticles may be 10 to 50 nm, and may be 10 to 20 nm. When the size of the nanoparticles is in the range of the diameter, the nanoparticles may be suitable for clinical and diagnostic applications.

A method for producing a polyamide according to another embodiment of the present invention for producing a monosaccharide / ethylene oxide alternating polyamide is characterized in that a monosaccharide capable of providing strong hydrogen bonding force between molecules and a water-soluble and biocompatible oligo- ethylene oxide -hexylene oxide-based monomers to form monosaccharide / ethylene oxide alternating polyamides.

As the monosaccharide, a monosaccharide having a carboxylic acid at both ends and a hydroxyl group can be applied, and preferably, it can be applied to aldaric acid.

The monosaccharide may be a monosaccharide represented by the following general formula (5) and containing a hydroxy group capable of hydrogen bonding.

[Chemical Formula 5]

In Formula 5, y is an integer of 1 to 10.

The monosaccharide may be substituted with methyl ester groups at both terminals in the course of the reaction. In this case, the solubility can be increased and the reactivity in the condensation polymerization can be increased.

The oligo-ethylene oxide-based monomer may have an amine group at both terminals represented by the following formula (6).

[Chemical Formula 6]

In Formula 6, x is an integer of 1 to 10.

The monomer represented by the above formula (6) contains an amine group at both ends of the monomer, and forms an amide bond with the monosaccharide during the polymerization reaction, thereby contributing to hydrogen bond formation in the molecule of the monosaccharide / ethylene oxide alternating polyamide.

In the monomer represented by the above formula (6), the number of ethylene oxide groups in the molecule can be controlled by controlling the number of x, and as the number of ethylene oxide groups is increased, the formation of hydrogen bonds between molecules by the monosaccharide on the molecular structure of polyamide . Therefore, the degree of hydrogen bonding of the polyamide can be controlled by adjusting the amount of the ethylene oxide group, which can be adjusted according to the range of x.

The oligo-ethylene oxide-based monomer is preferably selected from the group consisting of 2,2'-oxybis (ethylamine), 2,2 '- (ethylenedioxy) bis (ethylamine) 2 '- (ethylenedioxy) bis (ethylamine), 2,2' - ((oxybis (ethane-2,1-diyl)) bis (oxy) 2,1-diyl)) bis (oxy)) diethanamine, 3,6,9,12-tetraoxatetradecane-1,14- diamine), 3,6,9,12,15-pentaoxaheptadecane-1,17-diamine (3,6,9,12,15-pentaoxaheptadecane-1,17-diamine), 3,6,9,12 , 15,18-hexaoxaicosane-1,20-diamine (3,6,9,12,15,18,21) Heptaoxatricosane-1,23-diamine), 3,6,9,12,15,18,21,24 < RTI ID = 0.0 > (3,6,9,12,15,18,21- (3,6,9,12,15,18,21,24-octaoxahexacosane-1,26-diamine), 3,6,9,12,15,18,21 , 24,27-nonaoxanonacacane-1,29-dia (3,6,9,12,15,18,21,24,27-nonaoxanonacosane-1,29-dia mine), 3,6,9,12,15,18,21,24,27,30-decaoxadotriacontane-1,32-diamine (3,6,9,12,15,18,21, 24,27,30-decaoxadotriacontane-1,32-diamine), and combinations thereof.

The monosaccharide / ethylene oxide alternating polyamide represented by the formula (1) or (2) can be prepared by condensing the monosaccharide and the oligomer oxide monomer. The description of the monosaccharide / ethylene oxide alternating polyamide represented by the above formula (1) or (2) is the same as that of the nanoparticles of the present invention.

The condensation bond includes esterification of both ends of the monosaccharide using an alcohol in the presence of an acid such as sulfuric acid, and condensation polymerization reaction of the esterified monosaccharide with the ethylene oxide-based monomer.

The condensation polymerization reaction may be carried out in a polar organic solvent. The polar organic solvent is selected from the group consisting of alcohol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) And a combination thereof.

The monosaccharide and the oligoethylene oxide monomer may be condensation-polymerized in a molar ratio of 1: 1.05 to 1.3, and condensation-polymerized in a molar ratio of 1: 1.05 to 1.2. The monosaccharide may be an esterified monosaccharide. When the monosaccharide and the ethylene oxide monomer are condensation-polymerized in the molar ratio described above, an amine group may be introduced at one end or both ends of the monosaccharide / ethylene oxide alternating polyamide.

When the molar ratio of the monosaccharide to the ethylene oxide monomer is less than 1: 1.05 or more than 1.3, the molecular weight of the polyamide to be polymerized may decrease.

The polyamide thus prepared may be a monolayer / ethylene oxide alternately bonded polymer, and can form self-assembled nanoparticles by hydrogen bonding in a water system by oxygen or nitrogen element in the molecule. The aqueous dispersed nanoparticles can be efficiently produced by dispersing water-based self-assembled particles at a concentration of the polyamide of 0.13 to 10 mg · mL ^-1 .

The nanoparticles self-assembled by the hydrogen bonding can have a nonspecific biomolecule / cell adsorption blocking effect expressed in structural similarity with polyethylene glycol (PEG), and can exhibit enhanced perforation and retention (EPR) The efficiency of accumulation in cancer cells in vivo can be increased.

Another method for producing nanoparticles according to another embodiment of the present invention includes a dye bonding step, a dissolution step, and a particle forming step.

The dye bonding step includes a step of mixing and mixing the monosaccharide / ethylene oxide alternating polyamide and the fluorescent dye in a polar solvent.

In the description of the monosaccharide / ethylene oxide alternating polyamide, the fluorescent dye, and the combination thereof, the description of the overlapping portions in the description of the nanoparticles according to one embodiment of the present invention will be omitted.

Examples of the polar solvent include alcohols, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) And combinations thereof. However, the present invention is not limited thereto.

Wherein the dissolving step comprises mixing water with the dye-bonded monosaccharide / ethylene oxide alternating polyamide and heating to produce an aqueous solution in which the monosaccharide / ethylene oxide alternating polyamide is dissolved in the water.

In the dissolving step, the heating may be performed at 60 to 90 DEG C for 1 to 5 minutes. When the above-mentioned dissolution step is carried out in the range of the temperature and the time, the dye-bonded polyamide can be completely dissolved in water.

In the particle forming step, the aqueous solution is cooled so that molecules of the dye-bonded monosaccharide / ethylene oxide alternating polyamide are self assembled in the water by hydrogen bonding to form aqueous dispersion self-assembly nanoparticles . In the particle forming step, the cooling may be performed at a rate of 20 ° C / minute to 60 ° C / minute.

The nanoparticles contain nanoparticles and fluorescent dyes that maintain their self-assembled form in the aqueous system and have excellent dispersibility. The nanoparticles exhibit structural similarity with PEG and thus have a nonspecific biomolecule / cell adsorption blocking effect , Excellent accumulation efficiency in cancer cells, and can be applied to a contrast agent for cancer cell image swab. In particular, the nanoparticles can stay in cancer tissue for a certain period of time by a certain size, and can be advantageously applied to selective imaging. In addition, unlike the conventional nanoparticles used in contrast agents for cancer cell image probes, since they are not nanoparticles containing hydrophobic and ionic groups, it is possible to solve the problem of deterioration in performance after binding with biomaterials or cells with nonspecific gravitation.

The monoclonal / ethylene oxide alternating polyamides of the present invention can form magnetic binding nanoparticles using hydrogen bonding force, enable selective accumulation of cancer due to high permeability of neovascularization in cancer tissues, Cancer imaging can be enabled. In addition, it is possible to self-assemble in an aqueous solution, and water-based dispersed nanoparticles can be obtained in an efficient manner.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram showing the formation of aqueous dispersion self-assembled nanoparticles by hydrogen bonding of monosaccharide / ethylene oxide alternating polyamide. FIG.
2 is a photograph of the nanoparticles prepared in Example 1 by transmission electron microscope (TEM, CM30, PEI / Philips, 200 kV).
3 is a photograph of the nanoparticles prepared in Example 1 with a cryo-transmission electron microscope (Cryo-TEM, FV1000 system, Olympus).
FIG. 4 is a graph showing the results of MTT analysis for the number of immobilized cells of the sample (PEGA) of Example 2, Comparative Example 1 (Ctrl), and Comparative Example 2 (MA).
5 is a near-infrared fluorescence image of a mouse of Example (PEGA) according to (3) of Example 2 with time.
FIG. 6 is a graph showing the results of evaluation of the transfer characteristics of the water dispersed near-infrared fluorescence self-assembled nanoparticles of Example (PEGA) and Comparative Example (PEG) to in vivo cancer tissue in (3) of Example 2.
FIG. 7 shows the result of observing near-infrared fluorescence signals generated from each organ after removing peripheral organs including cancerous tissue from male mice of Example (PEGA) in (3) of Example 2 at each time point.

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. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

Example  1: monosaccharide / ethylene Oxide  Synthesis of alternating polyamides and water dispersion by hydrogen bonding Self-assembly of nanoparticles

(1) monosaccharide / ethylene Oxide  Synthesis of alternating polyamides

Dimethyl ester galactarate (DMGA) was synthesized by refluxing 30 g of galactaric acid (purchased from GA, Adrich) and 3 mL of concentrated sulfuric acid (purchased from Daejeon Chemical) in 720 mL of methanol (MeOH, purchased from Merck) The mixture was cooled to room temperature to obtain a solid product. The solid product was purified by recrystallization in a mixed solution of methanol (MeOH) and triethylamine (TEA, purchased from Adrich).

1 g of the purified DMGA (4.2 mmol) and 2,2 '- (ethylenedioxy) bis (ethylamine) (purchased from Sigma-Aldrich) were dissolved in methanol (MeOH) 30 mL to prepare a monosaccharide / ethylene oxide alternating polyamide (PEGAx, x = 2). The following Reaction Scheme 1 shows the reaction process of the above monosaccharide / ethylene oxide alternating polyamide (PEGA2).

[Reaction Scheme 1]

(2) Preparation of water-dispersed self-assembled nanoparticles by hydrogen bonding and evaluation thereof

Prepared in the above (1), lactase acid and 2,2 'go-to (ethylenedioxy) bis (ethylamine) the concentration of the monosaccharide / ethylene oxide alternately polyamide (PEGA2) a 2 mg · mL ^-1 synthesized from Well dispersed in water, and completely dissolved by applying heat. The PEGA2 aqueous solution was gradually cooled to room temperature to induce intermolecular hydrogen bonding of PEGA2 dissolved in the aqueous environment to prepare aqueous dispersion self-assembled nanoparticles.

The size and shape of the nanoparticles were observed with a transmission electron microscope (TEM, CM30, PEI / Philips, 200 kV) and shown in FIG. From FIG. 2, it was confirmed that the nanoparticles were spherical particles having a diameter of 10 to 20 nm. Also, a photograph of the nanoparticles observed with a cryo-TEM electron microscope (Cryo-TEM, FV1000 system, Olympus) is shown in FIG. The size and shape of the nanoparticles observed in FIG. 3 are the same as those observed in FIG. 2, and it was confirmed that the nanoparticles were spontaneously prepared in the aqueous environment before the drying process.

Example  2: Near infrared  Preparation of fluorescent nanoparticles and In vitro / In vivo Cancer accumulation  Character rating

(One) Near infrared  Fluorescent monosaccharide / ethylene Oxide  Alternating polyamide ( PEGA2 / Cy5 .5) Synthesis of

200 mg of the PEGA2 synthesized in Example 1 and 1 mg of Cy5.5-VS (vinyl sulfone) were completely dissolved in 10 mL of DMSO (dimethyl sulfoxide) and stirred at room temperature for 2 days. Cy5.5-VS reacted with PEGA2 terminal amine group to form an amide bond and was linked to polyamide, and unreacted Cy5.5-VS was removed through dialysis. In the dialysis, the solvent was dissolved in DMSO Water. After dialysis, Lyophilized PEGA2 / Cy5.5 was obtained by near-infrared fluorescence PEGA2.

(2) monosaccharide / ethylene Oxide  Evaluation of alternating polyamide nonspecific biomaterial / cell adsorption blocking effect

PEGA2 / Cy5.5 was dissolved in PBS (Phosphate buffered saline, pH 7.4) at a concentration of 50 μM to confirm the nonspecific biomolecule / cell adsorption blocking effect of the polyamide, and the surface was treated with maleic anhydride (96-well plate, Pierce) and allowed to react at room temperature for 12 hours. It was confirmed that PEGA2 / Cy5.5 was coated on the cell culture dish by reacting the terminal amine group of PEGA2 / Cy5.5 with maleic anhydride, and unreacted PEGA2 / Cy5.5 was washed out with PBS.

200 μL of a cell culture medium (DMEM) containing 1 × 10 ⁵ HeLa (human cervical epitheloid carcinoma) cells dispersed in a PEGA2 / Cy5.5-coated cell culture dish prepared in the above experiment was placed and kept for 12 hours, A sample (PEGA) was obtained and the number of cells fixed on the bottom of the cell culture dish of Example 2 was observed.

For the control experiment, the cell culture dish (MA) treated with the maleic anhydride and the cell culture dish without any treatment by the Comparative Example 1 (Ctrl) and the Comparative Example 2 (MA) The number of immobilized cells was determined by MTT assay (document 11: T. Mosmann et al., Journal of Immunological Methods 65: 55-63 (1983)). The results of the experiment are shown in FIG.

4, it was confirmed that cells were not immobilized in PEGA2 / Cy5.5-coated cell culture dishes (PEGA) unlike the other comparative examples (Ctrl and MA), and the non-specific biomaterial / And the cytotoxic blocking effect was confirmed.

The nonspecific biomolecule / cell adsorption blocking effect of such polyamides prevents the polyamide administered in vivo from accumulating in unexpected tissues, enabling stable circulation and retention in the vascular system.

(3) Dispersion of water Near infrared  Of fluorescence self-assembled nanoparticles In vivo To cancer tissue  Evaluation of transfer characteristics

In order to test the delivery of in vivo dispersed near infrared fluorescence self-assembled nanoparticles, 1 x 10 ⁶ SCC7 (Squamous Cell Carcinoma) was injected into the left hip muscle region of male rats (C3H / HeN, 5.5 weeks old, Orient Bio) Cells were subcutaneously injected.

10 days later, after confirming the growth of cancer tissue with the naked eye, the second embodiment of (1) a PEGA2 / Cy5.5 aqueous dispersion of the near-infrared magnetic nanoparticle assembly 2 mg · mL prepared ^in-male rats at a concentration of ¹ (EXplore Optix system, ART Advanced Research Technologies, Inc., Canada) was observed at a predetermined time interval for one week, as an example (PEGA).

For the control experiment, near-infrared fluorescence polyethylene oxide was synthesized by binding Cy5.5-VS to polyethylene oxide having a structure similar to that of the monosaccharide / ethylene oxide alternating polyamide, and the concentration of 2 mg · mL ^-1 was added to the tail vein (PEG) by observing near-infrared fluorescence signals in cancer tissues at regular intervals for one week. The near-infrared fluorescence image of the above example (PEGA) over time is shown in FIG. FIG. 6 is a graph showing a result of observation of near-infrared fluorescence signals of the above-mentioned Example (PEGA) and Comparative Example (PEG) with the lapse of time.

In addition, at the respective points of time before the experiment, one hour after the experiment, one day after the experiment, and one week after the start of the experiment, peripheral organs including the cancer tissue of the male rats were removed from the body during the same experiment as the above example, And the result is shown in FIG. 6.

From FIGS. 5, 6 and 7, it can be seen that the aqueous dispersed near-infrared fluorescence self-assembled nanoparticles according to the present invention start collecting selectively in cancer tissues in vivo, stay in cancer tissues for a week, there was.

In addition, the fluorescence signal of the comparative example was observed in each cancer tissue due to the nonspecific biomaterial / cell adsorption blocking effect, but it was confirmed that the nanoparticle was not formed in the same size as the nanoparticle, and thus the fluorescence signal was emitted outside the cancer tissue in a short time.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, Of the right.

Claims (17)

A monosaccharide / ethylene oxide alternating polyamide represented by the following formula (1).
[Chemical Formula 1]

Each independently of the above formula (1)
Wherein A is a monosaccharide atomic group,
B is an oligoethylene oxide-based atomic group,
And n is an integer of 10 to 50. The method according to claim 1,
In the compound represented by the general formula (1), A is a functional group derived from an aldaric acid represented by the following general formula (3).
(3)

In Formula 3, y is an integer of 1 to 10. The method according to claim 1,
In the compound represented by the general formula (1), B is a functional group represented by the following general formula (4).
[Chemical Formula 4]

In Formula 4, x is an integer of 1 to 10. Aqueous dispersion self assembled nanoparticles comprising a monosaccharide / ethylene oxide alternating polyamide represented by the following formula (1) or (2), and
The fluorescent dye bonded to the monosaccharide / ethylene oxide alternating polyamide
≪ / RTI >
[Chemical Formula 1]

(2)

In the formulas (1) and (2), each independently,
Wherein A is a monosaccharide atomic group,
B is an oligoethylene oxide-based atomic group,
And n is an integer of 10 to 50. 5. The method of claim 4,
The fluorescent dye is a near-infrared fluorescent dye,
The near-infrared fluorescent dye Cy5, Cy5.5, Cy7, Alexa Fluor ® 660, Alexa Fluor ® 680, Alexa Fluor ® 700, Alexa Fluor ® 750, Alexa Fluor ® 790, Bodipy ® 650/665 and the group consisting of ≪ / RTI > 5. The method of claim 4,
Wherein A is a functional group derived from an aldaric acid represented by the following general formula (3).
(3)

In Formula 3, y is an integer of 1 to 10. 5. The method of claim 4,
In the compound represented by Formula 1 or 2, B is a functional group represented by Formula 4 below.
[Chemical Formula 4]

In Formula 4, x is an integer of 1 to 10. 5. The method of claim 4,
Wherein the fluorescent dye and the monosaccharide / ethylene oxide alternating polyamide are covalently bonded,
Wherein the fluorescent dye comprises any one selected from the group consisting of succinimidyl ester, isothiocyanate, vinyl sulfone, and combinations thereof. 5. The method of claim 4,
Wherein said aqueous dispersion self-assembly nanoparticles maintain a self-assembled form with hydrogen bonding force. 5. The method of claim 4,
Wherein the aqueous dispersion self-assembling-nanoparticles are 10 to 50 nm in diameter. A monosaccharide having a hydroxyl group capable of hydrogen bonding represented by the following formula (5), and an oligoethylene oxide monomer having an amine group capable of hydrogen bonding represented by the following formula (6) in a molar ratio of 1: 1.05 to 1.3 To produce a monosaccharide / ethylene oxide alternating polyamide represented by the following general formula (1).
[Chemical Formula 1]

Each independently of the above formula (1)
Wherein A is a monosaccharide atomic group,
B is an oligoethylene oxide-based atomic group,
And n is an integer of 10 to 50.
[Chemical Formula 5]

In Formula 5, y is an integer of 1 to 10.
[Chemical Formula 6]

In Formula 6, x is an integer of 1 to 10. delete 12. The method of claim 11,
The condensation polymerization is carried out in a polar organic solvent, and the solvent is selected from the group consisting of alcohol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) And combinations thereof. ≪ RTI ID = 0.0 > 1. < / RTI > A dye bonding step of mixing the monosaccharide / ethylene oxide alternating polyamide prepared according to claim 11 with a fluorescent dye in a polar solvent,
A dissolution step of mixing the dye-bonded monosaccharide / ethylene oxide alternating polyamide with water and heating to prepare an aqueous solution in which the monosaccharide / ethylene oxide alternating polyamide is dissolved in the water, and
Forming a water dispersion-self-assembly-nanoparticle by self-assembling molecules of the dye-bonded monosaccharide / ethylene oxide alternating polyamide by hydrogen bonding in the water by cooling the aqueous solution
≪ / RTI > 15. The method of claim 14,
Wherein the heating in the dissolving step is performed at 60 to 90 DEG C for 1 to 5 minutes. 15. The method of claim 14,
Wherein the cooling is performed at a rate of 20 ° C / minute to 60 ° C / minute in the particle forming step. A contrast agent for a cancer cell image probe, comprising the nanoparticle according to claim 4.

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