KR102129854B1 - Decontaminating agent of radionuclide and method for producing the same - Google Patents

Abstract

The present invention relates to a hydrogel bead for removing radionuclides, and a manufacturing method thereof. The hydrogel bead for removing radionuclides according to the present invention is effective in removing radionuclides in a living body as well as radionuclides dissolved in contaminated rivers, rivers, lakes and wetlands.

Description

Decontaminating agent of radionuclide and method for producing the same}

The present invention relates to a radionuclide decontamination agent and a method for manufacturing the same, and more particularly, to a hydrogel bead for removing radionuclides containing multi-component particles embodying three different components in one particle and a method for manufacturing the same will be.

As the demand for smart materials increases in the biomedical industry, the development of multifunctional particle manufacturing technology has been developed as a method to solve this. The multifunctional particle is a material showing two or more functionalities in one particle, and a typical example is Janus particle. Finally, it is meant to ultimately realize the production of customized materials to satisfy the different needs of each patient, and the manufacture of customized materials using hydrogels has been made for application to the bio industry. Joshi et al. proposed a multifunctional microsphere for biosensing, drug delivery and magnetic resonance imaging in a single system [Acta Biomater. 7 (2011) 3955].

Prussian Blue is a hydrate of ferrocyanide, which has the effect of shortening the biological half-life of cesium 137 from 110 days to 30 days, and has been used to reduce radioactivity exposure by cesium by taking it in a purified state when coated with cesium. In addition, the Industrial Technology Research Institute, an independent administrative corporation in Japan, developed Prussian blue nanoparticles that show selective adsorption to cesium, and developed various adsorption compositions for cesium adsorption to selectively adsorb and adsorb cesium in contaminated water or leachate contaminated with radioactive cesium. Did. In Korean Patent Publication No. 10-2005-120312, anion exchange is possible for selective adsorption of radioactive cesium or strontium among radionuclides by adsorbing anion hexacyano iron (II), which is anion, to an anion exchange resin and adsorbing a transition metal, Co. Sieve. However, the ion exchanger has a limitation in adsorbing cesium distributed in a low concentration in the radioactive waste wing or water with selective and high efficiency, and has a disadvantage that it cannot be applied to adsorption of radionuclides in vivo.

Alginate is a typical hydrogel and is a complex polysaccharide composed of mannuronic acid and glucuronic acid. It has a feature of real-time crosslinking through binding with a divalent cation. To date, various technologies ranging from equiaxed air-flow-enhanced dripping, static electricity-improving dripping, vibration, atomization using rotating discs or rotating nozzles, and jet cutter systems have been developed to date. Limitations exist. Therefore, there is a need to develop a device that is easy, simple, and can be manufactured quickly and has a low manufacturing cost.

The problem to be solved by the present invention is to provide a hydrogel bead for radionuclide removal.

The problem to be solved by the present invention is to provide a method for producing a hydrogel bead for removing radionuclides.

Another problem to be solved by the present invention is to provide an apparatus for manufacturing a hydrogel bead for radioactive removal.

The present invention to solve the above problems,

A first hydrogel comprising prussian blue;

A second hydrogel comprising a radionuclide in vitro excretion promoter; And

A third hydrogel comprising magnetic nanoparticles; containing,

The first hydrogel, the second hydrogel, and the third hydrogel provide hydrogel beads for radionuclide removal, which are particles formed by fusion with each other.

According to the present invention, the hydrogel beads for removing radionuclides are porous, and include a first region comprising a single component of the first hydrogel;

A second region comprising a single component of the second hydrogel; And

It includes; a third region comprising a single component of the third hydrogel; the first hydrogel, the second hydrogel and the third hydrogel may be cross-linked by a divalent cation.

According to the present invention, the hydrogel beads for removing radionuclides further include a first hybrid region in which a first hydrogel and a second hydrogel are mixed at a junction of the first region and the second region; A second hybrid region in which a second hydrogel and a third hydrogel are mixed is additionally present at a junction between the second region and the third region; A third hybrid region in which the first hydrogel and the third hydrogel are mixed is additionally present at the junction of the first region and the third region; A fourth hybrid region in which the first hydrogel, the second hydrogel, and the third hydrogel are mixed may be additionally present at the junction of the first region, the second region, and the third region.

According to the present invention, the radionuclide may be selected from the group consisting of radioactive strontium, cesium, plutonium, americium, uranium, radium, thorium and combinations thereof.

According to the present invention, the prussian blue may be a porous prussian blue having a hollow or mesoporous structure.

According to the present invention, the radionuclide ex vivo excretory agent may be diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), or a combination thereof.

According to the present invention, the magnetic nanoparticles are selected from the group consisting of Fe ₂ O ₃ , Fe ₃ O ₄ , FePt, CoPt, MnFe ₂ O ₄ , CoFe ₂ O ₄ , NiFe ₂ O ₄ ZnFe ₂ O ₄ and combinations thereof It can be.

According to the present invention, the hydrogel beads for removing radionuclides may include 25 to 45 parts by volume of the first hydrogel, 25 to 45 parts by volume of the second hydrogel, and 25 to 45 parts by volume of the third hydrogel.

According to the present invention, the hydrogel may be a polymer-based hydrogel selected from alginate, agarose, hyaluronic acid, collagen and combinations thereof.

In addition, the present invention is a first syringe containing a first polymer containing prussian blue; A second syringe containing a second polymer containing a radionuclide extracorporeal excreter; And preparing a third syringe containing a third polymer containing magnetic nanoparticles.

The first syringe; Inserting a micro-spindle nozzle into each of the second and third syringes and fixing them to the bracket so that the discharge ports of the three micro-spindle nozzles have an angle of 110 to 130°;

The first syringe; Pumping the second syringe and the third syringe to discharge the first polymer, the second polymer, and the third polymer to form one droplet; And

The droplets are added onto a divalent cation aqueous solution to form a hydrogel.

The polymer is selected from alginate, agarose, hyaluronic acid, collagen, and combinations thereof, and provides a method for producing hydrogel beads for removing radionuclides.

According to the present invention, the droplet comprises a first region comprising a single component of the first polymer; A second region comprising a single component of the second polymer; And a third region including a single component of the third polymer.

According to the present invention, a region in which the first polymer and the second polymer are mixed is additionally present at the junction between the first region and the second region,

A second hybrid region in which the second polymer and the third polymer are mixed is additionally present at the junction between the second region and the third region,

A third hybrid region in which the first polymer and the third polymer are mixed is additionally present at the junction of the first region and the third region,

A first hybrid region in which the first polymer, the second polymer, and the third polymer are mixed may be additionally present at the junction of the first region, the second region, and the third region.

In addition, the present invention includes a first syringe containing a first hydrogel containing prussian blue and a first microinjection needle connected to the first syringe;

A second syringe containing a second hydrogel containing a radionuclide extracorporeal excreted agent and a second microinjection needle connected to the second syringe;

A third syringe containing a third hydrogel containing magnetic nanoparticles and a third fine needle needle connected to the third syringe;

Includes; brackets for fixing the first, second and third fine needle nozzles,

Each of the first, second and third fine needle nozzles of the first, second and third fine needle nozzles are in close contact with each other or the ends are in contact with each other so that the hydrogels injected from each nozzle are united together to form a single droplet. Provided is an apparatus for manufacturing hydrogel beads for removing radionuclides.

According to the present invention, the first fine needle needle and the second fine needle needle; A second fine needle needle and a third fine needle needle; And outlets of the first micro-needle needle nozzle and the third micro-needle needle nozzle may be fixed to the bracket so as to have an angle of 110 to 130°, respectively.

In one embodiment of the present invention, the bracket has two holes through which a micro-injection needle can be inserted, and the angles of the holes and the holes each have an angle of 110 to 130°, and the ejection openings of the micro-injection nozzles are adjacent to each other or have ends. It may be designed to reach.

According to the present invention, the discharge port of the first fine needle needle, the second fine needle needle or the third fine needle needle may be 20 G to 23 G.

Hydrogel beads for radionuclide removal according to the present invention include Prussian blue, radionuclide extracorporeal excretion accelerator and magnetic nanoparticles in the particles, and are highly efficient and highly selective radionuclide compared to conventional cesium or radionuclide extracorporeal excretion promoter The adsorption and discharge is possible, and the biocompatibility is excellent. In addition, since it is possible to control the magnetism, it is easy in the industry because it is easy to control beads and to collect beads adsorbed with radionuclides. Therefore, the hydrogel beads for removing radionuclides according to the present invention are effective not only for radionuclides dissolved in contaminated rivers, rivers, lakes, wetlands, etc., but also for removal of radionuclides in vivo.

1A is a conceptual view of a micro-injection needle injection device according to an embodiment of the present invention, FIG. 1B is an image of a micro-injection nozzle injection device manufactured according to an embodiment of the present invention, and FIG. This is an image of a fine needle needle injection device manufactured according to an embodiment viewed from the side.
2A to 2C are images of beads prepared according to one comparative example and an embodiment of the present invention, FIG. 2D is the particle size of the prepared beads, and FIG. 2E is the size (black dot) of the beads actually manufactured and experimentally It is the result of comparing the calculated size (red dot).
3 is an image of an bead of an embodiment made in accordance with an embodiment of the present invention. 3A is an optical image showing the distribution of the total components, FIG. 3B is an SEM-EDX composite microscope image, FIG. 3C is an SEM image of a site with three components, and FIGS. 3D, 3E and 3F are respectively Prussian A first hydrogel region including blue, a second hydrogel region including a radionuclide ex vivo accelerator; And a third hydrogel region including magnetic nanoparticles at high magnification.
4 is a result confirming the release behavior of the DTPA drug as an accelerator for cesium adsorption and radionuclide excretion of radiogels for removal of radionuclides. 4D is a cesium adsorption isotherm of beads. 4B shows adsorption kinetics as a function of time. 4C is a UV-vis absorbance measured at 230 nm. 4D is the time vs. output efficiency for the number of particles, and the inset is the anti-first order reaction rate. DTPA drug was detected by UV-vis spectrometer at 230 nm.
5 is a result confirming the magnetic properties of the hydrogel beads for removing radionuclides according to the present invention. 5A-5C are time sequence images showing the linear motion of a single particle. 5D is an image showing particle recovery using an external magnetic field. 5F and 5F are images showing the magnetic rotational behavior of particles in a rotating magnetic field.
6 is a side view of a nozzle injection apparatus according to an embodiment of the present invention.
7 is a top view of a nozzle injection apparatus according to an embodiment of the present invention.

The present invention,

A first hydrogel comprising prussian blue;

A second hydrogel comprising a radionuclide in vitro excretion promoter; And

A third hydrogel comprising magnetic nanoparticles; containing,

The first hydrogel, the second hydrogel, and the third hydrogel provide hydrogel beads for radionuclide removal, which are particles formed by fusion with each other.

According to the present invention, the first hydrogel, the second hydrogel or the third hydrogel may be the same or different from each other.

According to the present invention, the first hydrogel, the second hydrogel or the third hydrogel is not particularly limited as long as it is a biocompatible material, but is based on a polymer selected from alginate, agarose, hyaluronic acid, collagen and combinations thereof. It may be a hydrogel, preferably an alginate-based hydrogel. Alginate is a typical hydrogel, a complex polysaccharide composed of mannuronic acid and glucuronic acid, which is excellent in biocompatibility, easy to supply, low in price, and prussian blue according to the present invention. The radionuclide is preferable because it contains an extracorporeal excreted agent and magnetic nanoparticles and is stable and exhibits excellent radionuclide removal efficiency.

According to the present invention, the hydrogel beads for removing radionuclides are porous, and include a first region comprising a single component of the first hydrogel; A second region comprising a single component of the second hydrogel; And a third region comprising a single component of the third hydrogel, wherein the first hydrogel, the second hydrogel, and the third hydrogel may be cross-linked by divalent cations. According to the present invention, the divalent cation is not particularly limited as long as it can crosslink alginate or the like with a hydrogel, and may be, for example, calcium ion.

According to the present invention, the hydrogel beads for removing radionuclides further include a first hybrid region in which a first hydrogel and a second hydrogel are mixed at a junction of the first region and the second region; A second hybrid region in which a second hydrogel and a third hydrogel are mixed is additionally present at a junction between the second region and the third region; A third hybrid region in which the first hydrogel and the third hydrogel are mixed is additionally present at the junction of the first region and the third region; A fourth hybrid region in which the first hydrogel, the second hydrogel, and the third hydrogel are mixed may be additionally present at the junction of the first region, the second region, and the third region.

According to the present invention, the radionuclide may be selected from the group consisting of radioactive strontium, cesium, plutonium, americium, uranium, radium, thorium and combinations thereof, but is not limited thereto. Radioactive strontium is Sr 89 and Sr 90, and radioactive cesium is Cs 134 and Cs 137.

According to the present invention, Prussian Blue represents a blue pigment whose main component is potassium hexacyano iron (II) iron iron (III). Prussian Blue is an effective remover of cesium and is often used to remove radioactive cesium (Cs 137, ¹³⁷ Cs) from the gastrointestinal tract by oral administration. According to the present invention, the prussian blue may be a porous prussian blue, for example, a porous prussian blue having a hollow or mesoporous structure. According to another embodiment of the present invention, Prussian Blue can be coated with polyvinylpyrrolidone. According to the present invention, the first hydrogel containing prussian blue is particularly effective in the selective adsorption of radioactive cesium, so it is preferable to be included in the beads.

According to the present invention, the radionuclide ex vivo excreted agent may be, but is not limited to, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), or a combination thereof, and is typically in vitro of radionuclides in vivo. If it is used for excretion, it can be applied.

According to the present invention, the magnetic nanoparticles are selected from the group consisting of Fe ₂ O ₃ , Fe ₃ O ₄ , FePt, CoPt, MnFe ₂ O ₄ , CoFe ₂ O ₄ , NiFe ₂ O ₄ ZnFe ₂ O ₄ and combinations thereof It may be, preferably iron oxide. In the present invention, the term'magnetic nanoparticles' means a metal nanocomposite having magnetism, and may be formed of a metal, a magnetic material, or a magnetic alloy. Materials capable of forming the magnetic nanoparticles may be included without limitation, and may be, for example, a magnetic material as a nanoparticle having a spinel structure or a reverse spinel structure.

In the present invention, the term'adsorption' refers to a phenomenon in which molecules of a gas or a solution adhere to a solid surface, and a solid substance that accepts adsorption is called an adsorbent. The adsorbent has a large surface area to be adsorbed per unit volume, which acts as an excellent adsorbent. The beads according to the present invention can increase the adsorption surface area when the prussian blue in the first hydrogel of the first region has porosity.

According to the present invention, the hydrogel beads for removing radionuclides may include 25 to 45 parts by volume of the first hydrogel, 25 to 45 parts by volume of the second hydrogel, and 25 to 45 parts by volume of the third hydrogel, Preferably, the first hydrogel, the second hydrogel and the third hydrogel may be included in the same amount.

The hydrogel beads for radionuclide removal according to the present invention are configured based on biocompatible hydrogels, and may be used as pharmaceuticals for oral administration for removal of radioactive isotopes in vivo. The hydrogel beads for removing radionuclides according to the present invention can effectively induce adsorption of radioactive isotopes in vivo within a short time through magnetic control using an external magnetic field. In addition, it can be decomposed in vivo to release Prussian Blue and radionuclide ex vivo excretion agent, decontamination of various radioactive isotopes including cesium is possible, and magnetic nanoparticles can be recovered 100% by applying a static magnetic field. .

In addition, the present invention is a first syringe containing a first polymer containing prussian blue; A second syringe containing a second polymer containing a radionuclide extracorporeal excreter; And preparing a third syringe containing a third polymer containing magnetic nanoparticles.

The first syringe; Inserting a micro-spindle nozzle into each of the second and third syringes and fixing them to the bracket so that the discharge ports of the three micro-spindle nozzles have an angle of 110 to 130°;

The first syringe; Pumping the second syringe and the third syringe to discharge the first polymer, the second polymer, and the third polymer to form one droplet; And

The droplets are added onto a divalent cation aqueous solution to form a hydrogel.

The polymer is selected from alginate, agarose, hyaluronic acid, collagen, and combinations thereof, and provides a method for producing hydrogel beads for removing radionuclides.

According to the present invention, the polymer may be in a solution state, and preferably, the Reynolds number (Re) is 1 or less. This induces laminar flow behavior within the micrometer-sized needle and can prevent significant mixing between the flows of neighboring polymer solutions.

According to the present invention, as the amount of the injected solution increases, gravity can dominate the surface tension to form droplets.

According to the present invention, the first polymer, the second polymer or the third polymer is not particularly limited as long as it has biocompatibility and can form a hydrogel, and may be polymers of the same or different raw materials. According to the present invention, the polymer may be a polymer selected from alginate, agarose, hyaluronic acid, collagen and combinations thereof, preferably alginate-based polymer. Alginate is a typical hydrogel, a complex polysaccharide composed of mannuronic acid and glucuronic acid, which is excellent in biocompatibility, easy to supply, low in price, and prussian blue according to the present invention. The radionuclide is preferable because it contains an extracorporeal excreted agent and magnetic nanoparticles and is stable and exhibits excellent radionuclide removal efficiency.

In one embodiment of the invention the droplet comprises a first region comprising a single component of a first polymer; A second region comprising a single component of the second polymer; And a third region including a single component of the third polymer.

In an embodiment of the present invention, a region in which the first polymer and the second polymer are mixed is additionally present at the junction between the first region and the second region,

A second hybrid region in which the second polymer and the third polymer are mixed is additionally present at the junction between the second region and the third region,

A third hybrid region in which the first polymer and the third polymer are mixed is additionally present at the junction of the first region and the third region,

A first hybrid region in which the first polymer, the second polymer, and the third polymer are mixed may be additionally present at the junction of the first region, the second region, and the third region.

According to the present invention, the first polymer, the second polymer, and the third polymer are provided as a solution, and the generation of the hybrid region can be minimized by controlling the Reynolds number to 1 or less.

In the present invention, the Prussian blue, radionuclide in vitro excretory agent and magnetic nanoparticles are as defined above.

In the present invention, the droplet is the first polymer, the second polymer so that the generated beads include 25 to 45 parts by volume of the first hydrogel, 25 to 45 parts by volume of the second hydrogel and 25 to 45 parts by volume of the third hydrogel. The amount of the polymer and the third polymer may be adjusted.

In addition, the present invention, a first syringe containing a first hydrogel containing Prussian Blue and a first microinjection needle connected to the first syringe;

A second syringe containing a second hydrogel containing a radionuclide extracorporeal excreted agent and a second microinjection needle connected to the second syringe;

A third syringe containing a third hydrogel containing magnetic nanoparticles and a third fine needle needle connected to the third syringe;

Includes; brackets for fixing the first, second and third fine needle nozzles,

Each of the first, second and third fine needle nozzles of the first, second and third fine needle nozzles are in close contact with each other or the ends are in contact with each other so that the hydrogels injected from each nozzle are united together to form a single droplet. Provided is an apparatus for manufacturing hydrogel beads for removing radionuclides.

6 and 7 are side and top views of a hydrogel bead manufacturing apparatus for removing radionuclides according to one embodiment of the present invention. The first to third fine needle nozzles 1 are fixed to the bracket 2 and spray a hydrogel in the direction of the arrow to form droplets through the bracket.

According to the present invention, the first fine needle needle and the second fine needle needle; A second fine needle needle and a third fine needle needle; And outlets of the first micro-needle needle nozzle and the third micro-needle needle nozzle may be fixed to the bracket so as to have an angle of 110 to 130°, respectively.

In one embodiment of the present invention, the bracket has two holes through which a micro-injection needle can be inserted, and the angles of the holes and the holes each have an angle of 110 to 130°, and the ejection openings of the micro-injection nozzles are adjacent to each other or have ends. It may be designed to reach.

According to the present invention, the material of the bracket is not particularly limited as long as it can fix the micro-injection needle nozzle, and various materials such as epoxy resin, polymer, plastic, and steel can be used. In the embodiment of the present invention, the nozzle was fixed using an epoxy resin.

According to the present invention, the syringe can be equipped with a finely adjustable syringe pump in order to improve the precision of the injection amount and injection speed. The syringe pump can be individually attached to the syringe, the injection amount and injection speed can be adjusted, and the beads produced through on-off control are single-component particles (on-off-off), dual-component particles (on-on) -off) or tri-component particles (on-on-on) to be coded to operate.

In the present invention, a micro syringe pump was installed to control the amount of droplets.

In one embodiment of the present invention, the micro-injection needle nozzle may have a straight shape, but may have a shape bent at an angle of 80 to 100°, for example, a shape bent with a base (a) ruler.

The discharge port of the first fine needle needle, the second fine needle needle or the third fine needle needle may be 20 G to 23 G, and a commercial needle may be used.

The device according to the invention can form droplets at a rate of 40 to 70 drops per minute.

In the present invention, beads were manufactured using three syringes and a fine needle needle, but it is also possible to manufacture beads using three or more (eg, four, five) syringes and a fine needle needle. .

Hereinafter, the present invention will be described in more detail by examples. However, the following examples are intended to illustrate the present invention more easily, and the contents of the present invention are not limited by the examples.

matter

Sodium alginate, anhydrous calcium chloride (Mw = 110.98), iron (III) ferrocyanide (PB, insoluble prussian blue), diethylenetriaminepentaacetic acid (DTPA, Mw = 393.35), ferric chloride hexahydrate, MNPs, magnetic nanoparticles, Mw = 270.30) and methylene blue (MB) were purchased from Sigma-Aldrich and used without further purification. Inert cesium ( ¹³³ Cs) was purchased from o2si smart solution. The cesium solution was prepared by diluting a standard solution (1000 mg/L) with deionized water. Distilled water was used in all experiments.

Preparation of tetrapod needle injectors

Three commercially available syringe needles (KOVAX-NEEDLE　, 23 gauge) were bent at 90° each and inserted into a plastic support (1 mL pipette tip). The outer/inner diameter of the needle is 0.64 mm and 0.32 mm. Using an epoxy resin, the needles are oriented at 120° to each other, and a tetrapod-type needle injector was prepared by grafting and fixing with an epoxy resin to maintain a tetrapod-like arrangement. The fabricated device is shown in FIG. 1. 1A is a conceptual view of a micro-injection needle injection device according to an embodiment of the present invention, FIG. 1B is an image of a micro-injection nozzle injection device manufactured according to an embodiment of the present invention, and FIG. This is an image of a fine needle needle injection device manufactured according to an embodiment viewed from the side. Polymers having different functional components were discharged from the three needle outlets to form a single droplet and dropped. The blue color is a polymer containing Prussian blue, the red color is a polymer containing magnetic nanoparticles, and the white color is a radioactive nuclide in vitro excretion promoter. It can be seen with the naked eye that the beads contain three components.

Example 1.

The particles were functionally encoded to have compartments to produce the hydrogel beads for radionuclide removal according to the present invention. First, three different sodium alginate solutions were prepared. Specifically, 0.2% by weight of Prussian Blue (PB), 1% by weight of radionuclide in vitro excretion promoter (DTPA) and 7% by weight of sodium alginate solution containing magnetic nanoparticles (MNPm) were prepared. Using a microsyringe pump (Kd Scientific, Inc., Korea) and an injector prepared earlier, a single multiphase air stream with three phases was formed, and as a monodisperse spherical droplet (droplet) when gravity exceeded the surface tension of the mixture. It was added dropwise, and left to stand in a 5% by weight aqueous calcium chloride solution for 10 minutes to polymerize with Ca ²⁺ to form a hydrogel bead. The prepared beads were washed 3 times with deionized water and lyophilized. The prepared beads are shown in Figure 2C. It can be observed that three components were formed as a single component in a bead, and one particle was formed.

Comparative Example 1.

Beads were prepared in the same manner as in Example 1, but particles were prepared as a single component. This is shown in Figure 2A. The white beads are hydrogel beads made of sodium alginate containing radionuclide in vitro excretion accelerator, brown is hydrogel beads made of sodium alginate containing magnetic nanoparticles, and the darkest (blue) is Prussian Blue It is a hydrogel bead made of sodium alginate containing.

Comparative Example 2.

Prepared in the same manner as in Example 1, the particles were prepared with a dual component. This is shown in Figure 2B. White is a sodium alginate-based hydrogel zone containing radionuclide in vitro excretion promoter, and brown is a sodium alginate-based hydrogel zone containing magnetic nanoparticles.

Test Example 1. Characterization

Particle morphology was determined using a scanning electron microscope (SEM, S-4800, Hitachi, Tokyo, Japan) operating at an acceleration voltage of 5 kV. Cross section and elemental analysis of the regions of each component of the particles was performed using Energy Dispersive X-ray (EDX, QuantaX200, Bruker, Germany) using samples immobilized on the resin at 60° C. Was set. The Fourier transform infrared spectrum was obtained using an FT-IR spectrometer (FT/IR-6600, JASCO Corp., Japan) in the wavelength range 400 to 4000 cm ^-1 under atmospheric conditions using KBr tablets. Determination of the polydispersity of the resulting particles was taken with a digital camera. The average diameter and standard deviation of the particles in the optical image were measured using open source image analysis software ImageJ.

Particle size

23 G needle, after forming droplets at a volume flow rate of 1 ml/min, after optical analysis, Comparative Example 1 was 2.0 to 2.5 mm (average 2.26±0.04 mm), Comparative Example 2 was 2.5 to 3.0 mm (average 2.76) ±0.05 mm), the beads according to Example 1 were confirmed to form beads of uniform size having a size of 3.5 nm to 4.0 mm (average 3.72±0.09 mm) (FIG. 2D).

HR-SEM analysis

The beads according to Example 1 were imaged using a high resolution scanning electron microscope (HR-SEM), which is shown in Figure 3A.

3B is a result of element mapping using SEM-EDX composite microscope, the beads according to Example 1 were found to be 3.5 nm to 4.0 mm, preferably 3.5 to 3.8 mm, and iron, nitrogen, and calcium through element mapping , The presence and location of carbon and oxygen. The elemental distribution includes a first hydrogel containing prussian blue, a second hydrogel containing radionuclide ex vivo accelerator; And the third hydrogel containing magnetic nanoparticles is separated, stably compartmentalized and encapsulated without interference, and the presence of calcium means establishment of crosslinking of the polymer network.

3C to 3F are SEM images of Example 1. Figure 3C is a SEM image of a site with three components, Figures 3D, 3E and 3F are respectively a first hydrogel region including Prussian Blue, a second hydrogel region including a radionuclide in vitro excretion promoter; And a third hydrogel region including magnetic nanoparticles at high magnification. The SEM image confirms that the beads according to the present invention have a well-developed porous three-dimensional structure. This internal structure is open and highly interconnected, suggesting that beads can be a suitable vehicle for drug, adsorbate or nutrient delivery. 3D, 3E and 3F show that nano-sized PB and MNPs particles in beads according to the present invention are widely dispersed and integrated in a polymer network.

Test Example 2. Cesium adsorption capacity test

Adsorption experiments include cesium ion concentrations (0.01, 0.1, 0.5, 1, 5, 10, 50, 100, 500 mg/L) and contact time (5, 10, 20 min, 40 min, 60 min, 120 min, 240 min) , 480 min) was performed to adsorb the cesium ion of the beads prepared. To this end, cesium ion solutions were prepared at different concentrations. Isothermal experiments were performed by stirring for 24 hours using a stirrer. Other parameters such as full speed (30 rpm), dry adsorbent dose (200 mg), temperature (23.5 °C), pH (5.3) and solution volume (50 mL) were kept constant. CP-MS, PerkinElmer ELAN 6100, Massachusetts, USA) was used to determine the final concentration of Cs ions in solution after isotherm and exercise experiments.

Adsorption behavior was evaluated using Langmuir and Freundlich isotherm models. The nonlinear form of the Langmuir and Friedrich isotherms is defined by the following equations 1 and 2.

Equation (1)

In the formula, q _e (mg/g) is the amount of adsorbate at equilibrium, C _e (mg/L) is the equilibrium concentration of adsorbate, and q _max (mg/g) and b (L/mg) are related to adsorption capacity. Langmuir constant and adsorption affinity.

Equation (2)

q _e (mg/g) is the amount of adsorbate at equilibrium, C _e (mg/L) is the equilibrium concentration of adsorbent, the Friedrich constant KF represents the adsorption capacity (mg/g), and n is an isothermal parameter of adsorption strength Is a variable.

4A shows the adsorption capacity of the beads of Example 1 (200 mg) as a function of initial cesium concentration. The adsorption capacity was found to depend on the cesium concentration over the entire range of concentrations investigated, and the equilibrium adsorption capacity of cesium ion removal was determined to be 7.80 mg/g. The adsorption rate of cesium by the beads of Example 1 according to the present invention was investigated while contacting for 8 hours, and the results are shown in FIG. 4B. The cesium adsorption rate increased gradually up to 200 minutes of reaction and soon became saturated. These results mean that the beads of Example 1 according to the present invention can effectively remove cesium ions.

Test Example 3. DTPA release behavior test

The release mechanism used the Korsmeyer-Peppas model to measure the DTPA release behavior in the presence of various amounts of particles (5, 10 and 15). The experiment was carried out in an aqueous solution (50 mL), the rotation speed was set to 30 rpm, and the temperature was set to 36±0.5°C. An aliquot was collected at 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, and 40 minutes. DTPA concentration was determined by measuring absorbance at 230 nm using a UV-Vis spectrometer (V-770, JASCO Corp., Japan). Results are expressed as mean±standard deviation of 5 independent measurements. DTPA release efficiency was calculated using the following equation 3.

Equation (3)

In the formula, m _t is the amount of DTPA released at time t, and m _∞ is the total amount of DTPA contained in the particles.

4C shows the DTPA release behavior from the beads of Example 1 in aqueous solution for 40 minutes at room temperature. The UV-vis spectrum of DTPA showed the maximum absorption peak at 230 nm. The drug was gradually released during the initial 20 minutes. As a result of calculating the standard calibration curve for DTPA release, it was confirmed that the plot shows good linearity of R2 = 0.9934 for DTPA concentration.

Figure 4D is the result of confirming the DTPA sustained release from the beads of Example 1 under an aqueous solution. DTPA release from different numbers of beads showed the highest release rate during the first 20 minutes and the final release after 40 minutes. DTPA release efficiency did not change significantly with increasing number of beads. The final DPTA emissions for the use of 5, 10 and 15 beads were 90.04%, 90.67% and 91.19%, respectively.

In the Korsmeyer-Peppas model, the slope (n) is Fickian diffusion (n ≤ 0.43), anomalous transport (0.43 <n <0.85), case II (relaxation) transport (n = 0.85) and super case II transport (n> 0.85) . 4D inset shows experimental data plotted as log release efficiency versus log time for the first 20 minutes of DTPA release. According to the n values (i.e., n5 particles = 0.6573, n10 particles = 0.7118 and n15 particles = 0.8405), predominant abnormal transport in this system was also found in intracellular protein diffusion and diffusion through porous media.

Test Example 4. Magnetic drive

Example 1 An external magnetic field was used to confirm the magnetic action of the beads. Under the influence of the applied external magnetic field, the beads moved in a straight line (Figs. 5A and 5B), and within 0.3 seconds, the area (compartment) containing the magnetic nanoparticles was changed in the same direction as the direction of the applied magnetic field. This demonstrates that the beads of Example 1 according to the present invention can be efficiently recovered. In addition, each bead can receive an external magnetic field and exhibit independent rotational behavior, such as a magnetic stirrer. Since the axis of the rotating magnetic field is perpendicular to the particles, a rotating magnetic field can be used to statically align the stir plate, as shown in Figure 5D, and control the rotational speed of the particles, as shown in Figures 5E and 5F. have.

The above results show that the hydrogel beads for radionuclide removal according to the present invention efficiently promote drug release, accelerate the radionuclide removal reaction, have excellent adsorption capacity, and are easy to recover and remove.

Claims (15)

A first hydrogel comprising prussian blue;
A second hydrogel comprising a radionuclide in vitro excretion promoter; And
A third hydrogel comprising magnetic nanoparticles; containing,
The first hydrogel, the second hydrogel and the third hydrogel are hydrogel beads for removing radionuclides, which are formed by fusion with each other to form particles.
The hydrogel beads are porous and include a first region comprising a single component of the first hydrogel; A second region comprising a single component of the second hydrogel; And a third region comprising a single component of the third hydrogel, wherein the first hydrogel, the second hydrogel, and the third hydrogel are crosslinked by divalent cations to remove radionuclides. Hydrogel beads. delete According to claim 1,
A first hybrid region in which the first hydrogel and the second hydrogel are mixed is additionally present at the junction of the first region and the second region,
A second hybrid region in which the second hydrogel and the third hydrogel are mixed is additionally present at the junction of the second region and the third region,
A third hybrid region in which the first hydrogel and the third hydrogel are mixed is additionally present at the junction of the first region and the third region,
Hydrogel beads for radionuclide removal, wherein a fourth hybrid region in which a first hydrogel, a second hydrogel and a third hydrogel are mixed is additionally present at a junction of the first region, the second region, and the third region. . According to claim 1,
The radionuclide is selected from the group consisting of strontium, cesium, plutonium, americium, uranium, radium, thorium and combinations thereof, hydrogel beads for removing radionuclides. According to claim 1,
Prussian Blue is a porous Prussian Blue having a hollow or mesoporous structure, a hydrogel bead for removing radionuclides. According to claim 1,
Radionuclide extracorporeal excretion accelerator is diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA) or a combination thereof, hydrogel beads for removing radionuclides. According to claim 1,
The magnetic nanoparticles are selected from the group consisting of Fe ₂ O ₃ , Fe ₃ O ₄ , FePt, CoPt, MnFe ₂ O ₄ , CoFe ₂ O ₄ , NiFe ₂ O ₄ ZnFe ₂ O ₄ and combinations thereof. Hydrogel beads for nuclide removal. According to claim 1,
Hydrogel beads for removing radionuclides, comprising 25 to 45 parts by volume of the first hydrogel, 25 to 45 parts by volume of the second hydrogel, and 25 to 45 parts by volume of the third hydrogel. According to claim 1,
The hydrogel is a polymer-based hydrogel selected from alginate, agarose, hyaluronic acid, collagen, and combinations thereof, and hydrogel beads for removing radionuclides. A first syringe containing a first polymer containing prussian blue; A second syringe containing a second polymer containing a radionuclide extracorporeal excreter; And preparing a third syringe containing a third polymer containing magnetic nanoparticles.
The first syringe; Inserting a micro-spindle nozzle into each of the second and third syringes and fixing them to the bracket so that the discharge ports of the three micro-spindle nozzles have an angle of 110 to 130°;
The first syringe; Pumping the second syringe and the third syringe to discharge the first polymer, the second polymer, and the third polymer to form one droplet; And
The droplets are added onto a divalent cation aqueous solution to form a hydrogel.
The polymer is selected from alginate, agarose, hyaluronic acid, collagen and combinations thereof, a method for producing a hydrogel bead for radionuclide removal. The method of claim 10,
The droplet comprises a first region comprising a single component of the first polymer; A second region comprising a single component of the second polymer; And a third region comprising a single component of the third polymer. The method of manufacturing a hydrogel bead for removing radionuclides. The method of claim 10,
A region in which the first polymer and the second polymer are mixed is additionally present at the junction of the first region and the second region,
A second hybrid region in which the second polymer and the third polymer are mixed is additionally present at the junction between the second region and the third region,
A third hybrid region in which the first polymer and the third polymer are mixed is additionally present at the junction of the first region and the third region,
The first region, the second region and the third region of the junction, the first polymer, the second polymer and the fourth hybrid region in which the third polymer is mixed is further present, the manufacturing method. A first syringe containing a first polymer containing prussian blue and a first micro-injection needle connected to the first syringe;
A second syringe containing a second polymer containing a radionuclide extracorporeal excretory agent and a second microinjection needle connected to the second syringe;
A third syringe containing a third polymer containing magnetic nanoparticles and a third fine needle needle connected to the third syringe;
Includes; brackets for fixing the first, second and third fine needle nozzles,
For ejection of radionuclides equipped with a microinjection nozzle injection system, the respective ejection openings of the first, second and third microinjection nozzles are adjacent to each other so that the polymers ejected from each nozzle unite with each other to form a single droplet. Hydrogel bead manufacturing apparatus. The method of claim 13,
The first fine needle needle and the second fine needle needle; A second fine needle needle and a third fine needle needle; And Hydrogel bead manufacturing apparatus for removing radionuclides equipped with a micro-injection nozzle injection system, that the outlet of the first micro-injection needle and the third micro-injection needle is fixed to the bracket to have an angle of 110 to 130 °, respectively. The method of claim 13,
Hydrogel bead manufacturing apparatus for removing radionuclides equipped with a micro-injection nozzle injection system, the discharge port of the first micro-injection needle, the second micro-injection needle or the third micro-injection needle is 20 G to 23 G.

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