KR101456333B1 - Ligand compound containing iodine and polymer, nano-particle complex containing the compound, and contrast media comprising the complex - Google Patents

Abstract

The present invention relates to a ligand compound including a biocompatible polymer and iodine, a nanoparticle complex containing the ligand compound, and a contrast agent for X-ray computed tomography comprising the nanoparticle complex, wherein the nanoparticle composite according to the present invention comprises And has a CT number of 1500 or more while having a uniform particle size distribution at a certain level.

Description

[0001] The present invention relates to a ligand compound containing iodine and a polymer, a nanoparticle complex containing the compound, and a contrast agent containing the complex,

The present invention relates to a ligand compound comprising a biocompatible polymer and iodine, a nanoparticle complex comprising the ligand compound, and a contrast agent comprising the nanoparticle complex.

Nanoparticles are becoming increasingly important as new molecular probes in the human body in terms of both experimental and clinical aspects. In the imaging method using nanoparticles as probes, semiconductors such as quantum dots, magnetic or fluorescent magnetic particles, gold nanoparticles and nanoshells are used. However, studies on nanoparticles that can be used in computed tomography (CT) have not yet been conducted. Current CT contrast agents are basically composed of small iodine molecules. This contrast agent is responsible for the absorption of x-rays, but it can affect microvessels due to size irregularities and rapid circulation in the human body, and it can not be targeted to specific sites. In addition, since there is a case of causing an irritable shock reaction due to toxicity of iodine, it is necessary to reduce the concentration of iodine while showing sufficient CT intensity.

The related technologies for reducing such side effects are as follows.

Prior Art Document 1 discloses a Bismuth Sulfide nanoparticle technique in which a surface is coated with a PVP polymer to replace a commercial contrast agent. As shown in the above-mentioned document 1, when the bismuth sulfide was observed by x-ray fluoroscopy, the degree of x-ray absorption was about the same as that of the 2.36 M iodine solution (300 mg I ml ^-1 ) when the concentration of bismuth was 0.55 M 5100 HU), indicating that the concentration is very high. As shown in FIG. 5, the bismuth sulfide according to the above synthesis method is a flat plate-like shape and can be dispersed in a polar solvent. In this connection, various methods for synthesizing bismuth and controlling its size and shape have been known (see prior art documents 2 to 9).

In this document, images were obtained from liver, lymph nodes and capillaries of rats injected with polymer-coated bismuth sulfide nanoparticles and the blood CT values were improved from -27 ± 77 HU (Hounsfield Units) to 530 ± 150 HU . In addition, the structures of the ventricles and major arteries and veins were clear, and the half-life in the blood of rats was 140 ± 15 min, which is significantly longer than the commercial iodine solution (<10 min). In addition, 12 to 24 hours after intravenous administration, polymer-coated bismuth sulfide nanoparticles were found to be absorbed and distributed in phagocytic cells (liver, spleen, lymph nodes). For example, the signal intensity of the liver increased from -22 ± 77 HU to 740 ± 210 HU after 24 hours. The reason for this increase is probably due to the fact that polymer-coated bismuth sulfide nanoparticles were absorbed into macrophages (Kupffer cells) and hepatocytes. .

However, in the case of the particles mentioned in the above document, it is known that the concentration of bismuth is high, which may have a toxic effect on the human body, and can particularly affect the targeted liver, spleen and lymph nodes. Therefore, it is necessary to develop a bismuth particle which can be used as a low concentration.

[Prior Art Literature]

1. ODED RABIN, J. MANUEL PEREZ, JAN GRIMM, GREGORY WOJTKIEWICZ AND RALPH WEISSLEDER, Nature Materials 5 (2006) 118-122)

2. B. F. Variano, D. M. Hwang, C. J. Sandroff, P. Wiltzius, T. W. Jing, and N. P. Ong, The Journal of Physical Chemistry, Vol. 91, No. 26, 1987 6465-6458

3. Rong Chen, Man Ho So, Chi-Ming Che and Hongzhe Sun, J. Mater. Chem. 15 (2005) 4540-4545,

4. Shi Huaqiang, Zhou Xiaodong, Xun Fu, Wang Debao, Hu Zhengshui, Materials Letters 60 (2006) 1793-1795,

5. Yan Sun, Qiaofeng Han, Juan Lu, Xujie Yang, Lude Lu, Xin Wang, Materials Letters 62 (2008) 3730-3732,

6. Qiaofeng Han, Jian Chen, Xujie Yang, Lude Lu, and Xin Wang, J. Phys. Chem. C 111 (2007) 14072-14077,

7. Rong He, Xuefeng Qian *, Jie Yin, Zikang Zhu, Journal of Crystal Growth 252 (2003) 505-510

8. Reihaneh Malakooti, Ludovico Cademartiri, Yasemin Akcakir, Srebri Petrov, Andrea Migliori, and Geoffrey A. Ozin, Adv. Mater. 18 (2006) 2189-2194

9. Michael B. Sigman, Jr. and Brian A. Korgel, Chem. Mater. 17 (2005) 1655-1660

SUMMARY OF THE INVENTION It is an object of the present invention to provide a ligand compound for producing high-efficiency nanoparticles capable of exhibiting a sufficient CT effect even with only low-concentration nanoparticles.

Another object of the present invention is to provide a nanoparticle complex comprising the ligand compound and a method for producing the same.

It is still another object of the present invention to provide a contrast agent for X-ray computed tomography comprising the nanoparticle complex.

In order to achieve the above object, the present invention provides a ligand compound represented by the following general formula (1).

[Chemical Formula 1]

In Formula 1,

R ₁ and R ₅ are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 18 carbon atoms, or -N (R ₇ ) R ₈ ,

R ₇ and R ₈ are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 18 carbon atoms, or -C (O) R ₉ ,

R ₉ is hydrogen, -OH, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 18 carbon atoms,

R ₃ is hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 18 carbon atoms, or -OOR ₁₀ ,

R ₁₀ is a biocompatible polymer,

R ₂ , R ₄ and R ₆ are each a halogen atom.

Specifically, for example, in Formula 1,

R ₁ and R ₅ are each independently hydrogen, an alkyl group having 1 to 4 carbon atoms, or -N (R ₇ ) R ₈ ,

R ₇ and R ₈ are each independently hydrogen, an alkyl group having 1 to 4 carbon atoms, or -C (O) R ₉ ,

R ₉ is -OH or an alkyl group having 1 to 4 carbon atoms,

R ₃ is hydrogen, an alkyl group having 1 to 4 carbon atoms, or -OOR ₁₀ ,

R ₁₀ is - [OCH ₂ CH ₂ ] _n -OH (n is an integer of 2 or more)

R ₂ , R ₄ and R ₆ may each be an iodine ligand compound.

More specifically, for example, a ligand compound represented by the following formula (2) can be used.

(2)

The biocompatible polymers usable in the present invention include polyethylene glycol, polypropylene glycol, polyoxyethylene, polytrimethylene glycol, polylactic acid, polyacrylic acid, polyamino acid, polyurethane, polyphosphazene, polylysine, polyalkylene oxide, poly Polyglycolic acid, pectin, alginic acid, agar, galactan, mannitol, mannitol, mannitol, mannitol, mannitol, , Xanthan gum, betacyclodextrin, amylose, glycol chitosan, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, cellulose acetate phthalate, gelatin, protamine sulfate, salts and derivatives thereof And copolymers. &Lt; RTI ID = 0.0 &gt; have.

The present invention also provides nanoparticles and nanoparticle composites comprising the ligand compounds.

In the nanoparticle complex according to the present invention, the ligand compound may have a structure to surround the surface of the nanoparticles.

In the present invention, bismuth sulfide nanoparticles and the like can be used as the nanoparticles.

The nanoparticle complex according to the present invention may comprise 1 to 50% by weight of nanoparticles and 50 to 99% by weight of a ligand compound.

The CT value of the nanoparticle complex according to the present invention may be 1500 HU or higher, preferably 3000 HU or higher.

The present invention also provides a method for producing a nanoparticle complex comprising the steps of synthesizing nanoparticles, synthesizing a ligand compound containing a biocompatible polymer and a halogen element, and mixing the nanoparticles and a ligand compound .

In the process for preparing nanoparticles in the nanoparticle composite according to the present invention, a polar solvent or a nonpolar solvent can be used.

The present invention also provides a contrast agent comprising the nanoparticle complex.

The contrast agent according to the present invention can be usefully used in X-ray computed tomography.

In the contrast agent according to the present invention, the nanoparticle complex may be dispersed in a polar solvent or a non-polar solvent.

The contrast agent of the present invention can remarkably improve the kinetics of the drug metabolism and the shock side effect due to the application of high concentration, which is the biggest disadvantage of the conventional X-ray computed tomography contrast agent based on the iodide molecule, It is possible to perform active targeting by passive targeting by conjugation with biomolecules for targeting and vasoconstriction by retention effect in vivo, The limitation due to the non-specific body distribution of the contrast agent can be remarkably improved.

1 is a synthesis diagram of a nanoparticle complex in which a bismuth sulfide nanoparticle is wrapped and bound with a biocompatible polymer and a ligand compound containing iodine according to an embodiment of the present invention.
FIG. 2 is a transmission electron microscope (TEM) photograph showing two types of bismuth sulfide nanoparticles dispersed well in a non-polar solvent and having different sizes. The synthesis method of these particles is described in step (1) of the following examples.
3 is a TEM photograph of bismuth sulfide nanoparticles well dispersed in a non-polar solvent. The synthesis method of these particles is described in step (1) of the following examples.
4 is a TEM photograph of a bismuth sulfide nanoparticle well dispersed in a nonpolar solvent. The synthesis method of these particles is described in step (1) of the following examples.
5 is a TEM photograph of bismuth sulfide nanoparticles well dispersed in a polar solvent (water) of the prior art document 1.
6 is a TEM photograph of a bismuth sulfide nanoparticle well dispersed in a polar solvent, particularly water. The synthesis method of these particles is described in step (2) of the following example.
FIG. 7 is a graph showing the results of a comparison between a bismuth sulfide nanoparticle (BS) dispersed in a nonpolar solvent, a bismuth sulfide nanoparticle (BS-PEG) bonded with a biocompatible polymer, a bis (BS-PEG-I Ligand). &Lt; / RTI &gt;
FIG. 8 shows a graph showing the results of a comparison between a small bismuth sulfide nanoparticle (BS) dispersed in a nonpolar solvent, a bismuth sulfide nanoparticle (BS-PEG) bonded with a biocompatible polymer, and a ligand compound including a biocompatible polymer and iodine CT graphs of the Bismuth sulfide nanoparticles (BS-PEG-I Ligand).
FIG. 9 is a graph showing the results of a comparison between a large bismuth sulfide nanoparticle (BS) dispersed in a nonpolar solvent, a bismuth sulfide nanoparticle (BS-PEG) bonded with a biocompatible polymer, and a ligand compound including a biocompatible polymer and iodine CT graphs of the Bismuth sulfide nanoparticles (BS-PEG-I Ligand).
10 is a CT photograph of a large bismuth sulfide nanoparticle (BS-PEG-I) dispersed in a non-polar solvent and bound to a ligand compound containing a biocompatible polymer and iodine.
FIG. 11 is a graph showing the results of a comparison between a large bismuth sulfide nanoparticle (BS) dispersed in a polar solvent (water) and a bismuth sulfide nanoparticle (BS-PEG-I Ligand) bonded with a ligand compound containing a biocompatible polymer and iodine CT picture.

Hereinafter, the present invention will be described in detail.

The present invention relates to a ligand compound for producing high-efficiency nanoparticles exhibiting a sufficient CT effect at a low concentration, a nanoparticle complex containing the ligand compound, and a contrast agent comprising the nanoparticle complex.

The ligand compound of the present invention is a compound represented by the above formula (1).

Wherein R ₁ and R ₅ are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 18 carbon atoms, or -N (R ₇ ) R ₈ , and R ₇ and R ₈ are each independently is hydrogen, aryl, or -C (O) of the alkyl group having 1 to 12 carbon atoms, having 6 to 18 carbon atoms and R _9, R ₉ is hydrogen, -OH, an alkyl group having 1 to 12 carbon atoms, or aryl having 6 to 18 And R ₃ is hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 18 carbon atoms, or -OOR ₁₀ , R ₁₀ is a biocompatible polymer, and R ₂ , R ₄ and R ₆ are each a halogen atom . Halogen is a Group 17 element of the periodic table and refers to both fluorine (F), chlorine (Cl), bromine (Br), iodine (I) and astatine (At).

Specifically, for example, the ligand compound of the present invention is represented by the general formula (1) wherein R ₁ and R ₅ are each independently hydrogen, an alkyl group having 1 to 4 carbon atoms, or -N (R ₇ ) R ₈ , R ₇ and R ₈ (O) R ₉ , R ₉ is -OH or an alkyl group having 1 to 4 carbon atoms, R ₃ is hydrogen, an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms, or -OOR ₁₀ , R ₁₀ is - [OCH ₂ CH ₂ ] _n -OH (n is an integer of 2 or more), and R ₂ , R ₄ and R ₆ are each an iodine element.

More specifically, for example, the ligand compound of the present invention may be a compound containing polyethylene glycol (PEG) as a biocompatible polymer and iodine as a halogen element, as shown in Formula 2 above.

The biocompatible polymers usable in the present invention may be natural polymers, modified polymers from natural polymers, and / or synthetic polymers.

Examples of the natural polymers include chitosan, salts thereof and derivatives thereof; Dextran and its derivatives; Acacia gum; Tragacanthin; Hyaluronic acid, salts thereof and derivatives thereof; Pectin, salts thereof and derivatives thereof; Alginic acid, salts thereof and derivatives thereof; Agar; Galactomannans, salts thereof and derivatives thereof; Xanthan, salts thereof and derivatives thereof; Beta-Cyclodextrin, salts thereof and derivatives thereof; And amylose (water-soluble starch), salts thereof and derivatives thereof.

Examples of the polymer modified from the natural polymer include glycoll chitosan, a salt thereof and a derivative thereof; Carboxymethyl cellulose (CMC), its salts and derivatives thereof; Hydroxyethylcellulose (HEC), salts thereof and derivatives thereof; Hydroxypropyl cellulose (HPC), salts thereof and derivatives thereof; Hydroxypropyl methylcellulose (HPMC); Methylcellulose, salts thereof and derivatives thereof; Cellulose acetate phthalate, salts thereof and derivatives thereof; Gelatin, salts thereof and derivatives thereof; And protamine sulfate.

Examples of the synthetic polymer include poly (beta-hydroxyethylmethacrylate) (PHEMA); poly (beta-hydroxyethylmethacrylate); Polyacrylamide (PA); Polyvinyl alcohol (PVA); Polyacrylic acid (PAA), salts thereof and derivatives thereof; Polyvinylpyrrolidone (PVP); Polyethylene oxide (PEO); Polyethyleneglycol (PEG); Polypropylene glycol; Polyolefins such as poly (ethylene oxide-b-propylene oxide) and polylysine; polyoxyethylene; polytrimethylene glycol; polylactic acid; polyamino acids; poly Urethane, polyphosphazene, and the like.

The present invention also provides nanoparticles and nanoparticle composites comprising the ligand compounds.

In the nanoparticle complex according to the present invention, the ligand compound may have a structure to surround the surface of the nanoparticles. In the linkage structure between the nanoparticles and the ligand compound, the polymer bound to the ligand may be entangled on the nanoparticle surface. That is, the ligand compound may be surface-coated on the nanoparticles.

As the nanoparticles in the present invention, bismuth sulfide nanoparticles, nano gold particles and the like can be used.

The size of the nanoparticles may be, for example, 1,000 nm or less, preferably 500 nm or less. On the other hand, the size of the nanoparticle complex containing the ligand compound may be about 100 to 300 nm in terms of radiological image. The size of the bismuth particles themselves is 40 to 60 nm, but when a complex is formed with a ligand compound containing a polymer, a complex having a size of about 100 to 300 nm can be formed. In terms of imaging, nanoparticle complexes of sizes between 100 and 300 nm may be better suited for targeting into macrophages than sizes of nanoparticle complexes. However, in fact, if you give up targeting of macrophages, the smaller size may be better. On the other hand, among the methods for producing nanoparticles, nanoparticles having a large size and dispersed in a non-polar solvent can be advantageously obtained in a large capacity.

The shape of the nanoparticles may be spherical. Spherical shape is less likely to cause trouble in human body than fiber or irregular shape. Also, spherical shape is generally convenient for surface modification.

The nanoparticle complex according to the present invention comprises 1 to 50% by weight of nanoparticles and 50 to 99% by weight of a ligand compound, preferably 5 to 30% by weight of a nanoparticle and 70 to 95% by weight of a ligand compound, To 20% by weight of the ligand compound and 80 to 90% by weight of the ligand compound. The reason for using excessive amounts of ligand compounds is to increase the amount of iodine to increase the CT level.

The CT value of the nanoparticle complex according to the present invention may be 1500 HU or higher, preferably 3000 HU or higher. In CT, what is the degree of X-ray absorption of each pixel is important, and the extent of such absorption is called HU (Hounsfield Units) after the inventor who invented the CT value or CT.

The present invention also provides a method for synthesizing a nanoparticle, comprising a first step of synthesizing a nanoparticle, a second step of synthesizing a ligand compound comprising a biocompatible polymer and a halogen element, and a second step of synthesizing a nanoparticle complex by mixing the nanoparticle and a ligand compound. The method comprising the steps of:

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram of a nanoparticle complex in which a biomaterial is surrounded by a ligand compound containing a biocompatible polymer and iodine, wherein the toxic Bismuth sulfide is a non-toxic ligand compound , A non-toxic nanoparticle complex can be formed.

In the process for preparing nanoparticles in the nanoparticle composite according to the present invention, a polar solvent or a nonpolar solvent can be used. Examples of the polar solvent include water, alcohol, aqueous ammonia, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, hexamethylphospholamide, Oleylamine, carbon tetrachloride, benzene, hexane and the like can be used.

In order for the prepared nanoparticles to be well dispersed in a non-polar solvent, it is preferable to use a non-polar solvent when preparing nanoparticles. Likewise, in order for the prepared nanoparticles to be well dispersed in a polar solvent, it is preferable to use a polar solvent when preparing nanoparticles.

As an example of a production method using a nonpolar solvent, the bismuth compound is first dissolved in a non-polar solvent and then heated. At this time, the particle size can be controlled at a temperature increasing rate. Next, the sulfur or sulfur compound is dissolved in a non-polar solvent, and then the solution is added to a previously prepared bismuth solution and stirred. After the reaction is completed, the precipitate is filtered through centrifugation.

As an example of a production method using a polar solvent, a bismuth compound is first dissolved in a polar solvent. Next, after the sulfur or sulfur compound is dissolved in the polar solvent, it is added to the previously prepared bismuth solution with strong stirring. After stirring for a certain time, it is obtained in the form of particles through filtration and freeze-drying. On the other hand, spherical nanoparticles can be obtained by adding 1.3 to 6.5 mL of 3-mercaptopropionic acid to the Bismuth solution before adding the sulfur or sulfur compound.

The present invention also provides a contrast agent comprising the nanoparticle complex. The contrast agent may include the nanoparticle complex and, if necessary, a solvent. For example, the contrast agent used in the human body may include a solvent applicable to the human body such as water or a phosphate buffer saline. Particularly, the form of the contrast agent in which the nanoparticle composite is dispersed in water can be advantageous in that it is applicable to the human body.

The contrast agent according to the present invention can be usefully used in X-ray computed tomography.

Hereinafter, the present invention will be described in more detail by way of examples, but the scope of the present invention is not limited by the following examples.

[Example]

(Oleylamine), bismuth chloride (BiCl ₃ ), sulfur, ammonia (NH ₄ OH), 3-mercaptopropionic acid, bismuth (III) Citric acid, Bismuth (III) citrate, sodium sulphide, diatrizoic acid, dimethylsulfoxide, N, N-dicyclohexyl carbodiimide ) And polyethylene glycol-monolaurate (Sigma-Aldrich) were used. All the water used in the experiment was deionized water.

(1) Preparation of bismuth sulfide nanoparticles dispersed in a non-polar solvent

6.34 mmol of BiCl ₃ was dissolved in oleic amine, which is a non-polar solvent, and then heated to 170 ° C. At this time, the particle size was controlled at the temperature increasing rate. The temperature was then maintained for 30 minutes. 1.27 mmol of sulfur was dissolved in olayamine and added to the previously reacted BiCl ₃ solution. After the addition, the mixture was stirred at 300 rpm using a magnetic stirrer, the temperature was lowered to 130 캜 and the temperature was maintained for 30 minutes. After the reaction was completed, the precipitate was filtered through centrifugation and only the supernatant was left. The resulting precipitate is a large bismuth sulfide particle. Bismuth sulfide particles of small size are precipitated when ethanol is added to the supernatant.

Although prior art document 8 (Reihaneh Malakooti et al.) Describes precipitates as undissolved impurities, when the CT of the precipitate (large bismuth sulfide particle) after the actual experiment was taken, the numerical value was very high (1235 HU) as judged by Bismuth .

(2) Preparation of bismuth sulfide nanoparticles dispersed in a polar solvent (water)

Bismuth (III) citrate 0.5 M was dissolved in 10 mL of 1N NH ₄ OH. 6.5 mL of 3-mercaptopropionic acid was added to the solution, followed by rapid stirring for 1 hour. After dissolving 320 mg of sodium sulfide in 70 mL of deionized water, the solution was added with vigorous stirring. After the addition, the mixture was stirred for 24 hours. After filtration, they were obtained in the form of particles through lyophilization and stored. The synthesized particles can be seen in Fig. The synthesized particles have a spherical shape unlike the particles shown in FIG.

A synthetic method such as that of the prior art document 1 was used, and in an amount of 3-mercaptopropionic acid, a different amount from the above literature was applied. That is, 650 ml was used in the above document but 6.5 ml of 1/100 was used in the present invention. As a result, the shape and size of the particles were different. As can be seen from FIG. 6, spherical particles were synthesized and size distribution was different from the result of the literature of FIG.

(3) Preparation of ligand containing biocompatible polymer and iodine

2 mmol of diatrizoic acid was dissolved in 20 ml of DMSO (Dimethylsulfoxide). In another container, 2.4 mmol of N, N-dicyclohexylcarbodiimide was placed in 10 ml of DMSO and stirred vigorously. After mixing the two solutions, 2.4 mmol (molecular weight: 680) of polyethylene glycol-monolaurate and DMSO were added under nitrogen composition. In this case, the kind of the polymer used is not limited to polyethylene glycol-monolaurate, and polyethylene glycol including dodecanoate is applicable. The mixture was stirred for two days. After stirring, the mixture was centrifuged for 40 minutes and washed with water. The washing procedure was repeated three times, and then the freeze-dried method was obtained and stored in the form of particles. This ligand can be named as 3- (3,5-diacetamido-2,4,6-triiodophenylperoxy) polypropyldodecanoate as the compound represented by the formula (2). In this case, the iodine compound is not limited to the above-mentioned examples but can be applied to any compound including a benzene ring such as 1,3,5-triiodo-2,4,6-trimethylbenzene and iodide is not ionized.

(4) Preparation of ligand-bound nanoparticles

50 mg of the bismuth sulfide nanoparticles of step (2) and 450 mg of the biocompatible polymer and iodine ligand in step (3) were added to 1 mL of deionized water and stirred vigorously for 24 hours. The resulting solution had a very high CT value of 3303 HU.

[Experimental Example]

1. Analysis

The size and shape of the materials were observed by operating a high resolution TEM (HR-TEM) of JEOL JEM-300 at 300 kV. The sample for HR-TEM analysis was obtained by dropping a drop of aqueous solution onto the copper grid and then sufficiently evaporating at room temperature.

2. TEM image observation of bismuth sulfide nanoparticles

FIG. 2 is a TEM photograph in which two types of bismuth sulfide nanoparticles well dispersed in a non-polar solvent are mixed. The synthesis method of these particles is described in step (1) of the above embodiment. These particles are a mixture of large and small nanoparticles described below.

3 is a TEM photograph of bismuth sulfide nanoparticles well dispersed in a non-polar solvent. The synthesis method of these particles is described in step (1) of the above embodiment. The size is between approximately 100 and 200 nm, and the shape of the plate shape of the square is mixed with various types of particle shapes.

4 is a TEM photograph of a bismuth sulfide nanoparticle well dispersed in a nonpolar solvent. The synthesis method of these particles is described in step (1) of the above embodiment. The size is very homogeneous within approximately 20 nm and the shape of the particles is well dispersed in a very uniform spherical shape.

5 is a TEM photograph of a polar solvent, particularly Bismuth sulfide nanoparticles well dispersed in water. The synthesis method of these particles is a method known in the prior art document 1, and shows the shape of a rectangular plate-like particle.

6 is a TEM photograph of a bismuth sulfide nanoparticle well dispersed in a polar solvent, particularly water. The synthesis method of these particles is described in step (2) of the above embodiment. The size is uniform between 40 and 60 nm, and the shape of the particles is uniform.

3. CT results of bismuth sulfide nanoparticles

1) In the case of bismuth sulfide particles dispersed in a non-polar solvent

FIG. 7 is a graph showing the results of a comparison between the bismuth sulfide nanoparticles (BS) dispersed in the non-polar solvents of FIGS. 2 to 4, the bismuth sulfide nanoparticles (BS-PEG) bound to the biocompatible polymer, and the ligands containing biocompatible polymers and iodine (BS-PEG-I Ligand), which is a bismuth sulfide nanoparticle.

The types of particles are shown in the following table.

Line number One BS Small particle 20 nm 2 BS Big particle ~ 200 nm 3 BS Small particle 20 nm + PEG 4 BS Small particle 20 nm + PEG + I Ligand 5 BS Big particle 200 nm + PEG 6 BS Big particle 200 nm + PEG + I Ligand

Column number One 2 3 4 5 6 7 Particle concentration (%) 100 50 25 12.5 6.25 3.125 1.563

In the order of the columns, the leftmost one is the original concentration (representing the concentration of the original solution obtained by one synthetic experiment at 100%), and then the sample is diluted in half. For example, the 3 rd-4 column sample is BS Small particle 20 nm + PEG, 25%. Detailed CT values are shown in Figs. 8 and 9. CT was measured using computed tomography (Somatom Sensation 64, Siemens Medical Solution, Forchheim, Germany) in Yonsei Severance Department of Radiology.

Figure 8 is a graph showing the results of a comparison between a small bismuth sulfide nanoparticle (BS) dispersed in a nonpolar solvent, a bismuth sulfide nanoparticle (BS-PEG) bonded with a biocompatible polymer, a bis CT scans of murine sulfide nanoparticles (BS-PEG-I Ligand). At this time, the original concentration of bismuth sulfide was obtained by dispersing bismuth sulfide, which can be obtained once in the step (1) of the above example, in 10 ml of hexane. In the case of small bismuth sulfide particles, Was very small and relatively low compared to large bismuth sulfide particles.

FIG. 9 is a graph showing the results of a comparison between a large bismuth sulfide nanoparticle (BS) dispersed in a nonpolar solvent, a bismuth sulfide nanoparticle (BS-PEG) bonded with a biocompatible polymer, a bis CT scans of murine sulfide nanoparticles (BS-PEG-I Ligand). 8, it can be seen that the concentration of bismuth sulfide is very high, and the concentration of the bismuth sulfide nanoparticles which can be obtained once in the step (1) of the above example is also dispersed in 10 ml of hexane And there was a large amount to be obtained, indicating a high value.

In addition, in the case of bismuth sulfide nanoparticles bound to a biocompatible polymer, and a bismuth sulfide nanoparticle bound to a ligand containing a biocompatible polymer and iodine, the concentration of the bismuth sulfide nanoparticles is about one third lower than that of the original bismuth sulfide particle Since it contains bismuth sulfide, you should think about multiplying the figure on the graph by about three times. However, even when multiplying by 3 times, the Bismuth sulfide nanoparticles bound to the biocompatible polymer are much lower in number than the Bismuth sulfide particles, suggesting that the PEG interferes with X-ray absorption, resulting in lower values.

10 is a CT photograph of a large bismuth sulfide particle (BS-PEG-I) dispersed in a non-polar solvent and bound to a ligand containing a biocompatible polymer and iodine. The concentrations of the samples are shown in the following table.

Column number One 2 3 4 5 6 7 Particle concentration (%) 100 50 25 12.5 6.25 3.125 1.563

As can be seen in the figure, the first crude solution seems to be well dispersed, but the more the dilution becomes apparent, the more clearly the precipitate appears. The precipitation of the particles is due to the aggregation of the particles, and it is difficult to use as a molding agent because there is no uniform dispersion. Particularly, in order to be used for a human body as an actual contrast agent, it should be dispersed well in water, not a non-polar solvent such as hexane. Therefore, the bismuth particles dispersed in the non-polar solvent should be phase-transformed by binding a polymer (water-dispersed in the above example, PEG) which is well dispersed in water, Therefore, a method of introducing bismuth particles dispersed in a polar solvent and dispersing it well without phase transition as in step (2) of the embodiment was sought.

2) For bismuth sulfide particles dispersed in a polar solvent (water)

FIG. 11 is a graph showing the relationship between the large bismuth sulfide nanoparticles (BS) shown in FIG. 6 dispersed in a polar solvent (water) and the bismuth sulfide nanoparticles (BS-PEG-I Ligand).

Three lines on the first row are a mixture of Bismuth sulfide 0.1 M and a mixture of a biocompatible polymer and an iodine-containing ligand 0.222 M, Bismuth sulfide 0.1 M and a biocompatible polymer and a ligand containing iodine 0.444 M, Bismuth sulfide 0.1 M and a mixture of a biocompatible polymer and a ligand 1.1 M containing iodine, one of the two rows being a 0.1 M solution of bismuth sulfide. That is, the biocompatible polymers and iodine-containing ligands were added to the same concentration of bismuth sulfide at different concentrations. The respective values are shown in the following table.

Bismuth Sulfide (BS) (M) PEG-I (M) CT number (HU) One 0.1 0.222 1417 2 0.1 0.444 1908 3 0.1 1.1 3303 4 0.1 0 411

In the above table, it can be seen that as the concentration of the ligand including the biocompatible polymer and iodine increases, the CT value becomes significantly higher. In the case of the BS-PVP described in the literature, it was 530 ± 150 HU when Bi ^{3 +} was 57 μmol. For the particles in the table above, when the concentration of Bi ^{3 +} was 200 μmol (BS 0.1 M = Bi ^{3 +} 200 μmol), the CT value was up to 3303 HU depending on the amount of PEG-I ligand attached. Therefore, it can be seen that the CT performance of the developed particles is better even if the CT value of the literature (polar solvent / bismuth + PVP) is calculated by simply quadrupling.

In addition, the complex according to the present invention is expected to be relatively easily dispersed in water to be applied to human body, and the toxicity of bismuth is expected to be relatively low, while the CT value is increased due to the ligand having the iodine group and the biocompatible polymer . It is expected that the rate of circulation in the body will be significantly lower due to bismuth sulfide particles as compared with commercial contrast agents using iodide particles (see prior art document 1).

Claims (14)

A ligand compound represented by the following formula (1):
[Chemical Formula 1]

In Formula 1,
R ₁ and R ₅ are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 18 carbon atoms, or -N (R ₇ ) R ₈ ,
R ₇ and R ₈ are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 18 carbon atoms, or -C (O) R ₉ ,
R ₉ is hydrogen, -OH, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 18 carbon atoms,
R ₃ is hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 18 carbon atoms, or -OOR ₁₀ ,
R ₁₀ is a biocompatible polymer,
R ₂ , R ₄ and R ₆ are each a halogen element,
The biocompatible polymer may be selected from the group consisting of polyethylene glycol, polypropylene glycol, polyoxyethylene, polytrimethylene glycol, polylactic acid, polyacrylic acid, polyamino acid, polyurethane, polyphosphazene, polylysine, polyalkylene oxide, polysaccharide, Polyglycolic acid, polyglycolic acid, polyglycerol, polyglycerol, polyglycerol, polyglycerol, polyglycerol, polyglycerol, polyglycerol, And at least one member selected from the group consisting of dextrin, amylose, glycol chitosan, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, cellulose acetate phthalate, gelatin, protamine sulfate, It is selected from the group.
The method according to claim 1,
R ₁ and R ₅ are each independently hydrogen, an alkyl group having 1 to 4 carbon atoms, or -N (R ₇ ) R ₈ ,
R ₇ and R ₈ are each independently hydrogen, an alkyl group having 1 to 4 carbon atoms, or -C (O) R ₉ ,
R ₉ is -OH or an alkyl group having 1 to 4 carbon atoms,
R ₃ is hydrogen, an alkyl group having 1 to 4 carbon atoms, or -OOR ₁₀ ,
R ₁₀ is - [OCH ₂ CH ₂ ] _n -OH (n is an integer of 10 or more)
R ₂ , R ₄ and R ₆ are each an iodine element.
The method according to claim 1,
A ligand compound represented by the following formula (2).
(2)

delete A nanoparticle complex comprising the nanoparticle and the ligand compound of claim 1.
6. The method of claim 5,
Wherein the ligand compound surrounds the surface of the nanoparticle.
6. The method of claim 5,
Wherein the nanoparticle is a bismuth sulfide nanoparticle.
6. The method of claim 5,
1 to 50% by weight of nanoparticles and 50 to 99% by weight of a ligand compound.
6. The method of claim 5,
Wherein the CT value is at least 1500 HU.
Synthesizing nanoparticles,
Synthesizing a ligand compound represented by formula (1) according to claim 1, and
A method for producing a nanoparticle composite comprising the steps of: mixing nanoparticles with a ligand compound.
11. The method of claim 10,
Wherein a polar solvent or a non-polar solvent is used in the step of synthesizing the nanoparticles.
A contrast agent comprising the nanoparticle complex of claim 5.
13. The method of claim 12,
A contrast agent characterized by being used in X-ray computed tomography.
13. The method of claim 12,
Wherein the nanoparticle complex is dispersed in a polar solvent or a non-polar solvent.

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