KR101973846B1 - Polymer-iron oxide nano-complex, uses thereof and preparation method thereof - Google Patents
Polymer-iron oxide nano-complex, uses thereof and preparation method thereof Download PDFInfo
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 title claims abstract description 149
- 238000002360 preparation method Methods 0.000 title 1
- 239000002131 composite material Substances 0.000 claims abstract description 61
- 229940031182 nanoparticles iron oxide Drugs 0.000 claims abstract description 43
- 239000002086 nanomaterial Substances 0.000 claims abstract description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 32
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- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- 229920000642 polymer Polymers 0.000 claims description 19
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
- C08J3/128—Polymer particles coated by inorganic and non-macromolecular organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
- A61K49/0043—Fluorescein, used in vivo
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/20—Compounding polymers with additives, e.g. colouring
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
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Abstract
본 발명에 따른 고분자-산화철 복합 나노구조체는 다수의 산화철 나노입자체가 포함될 수 있을 뿐만 아니라, 포집되는 산화철 나노입자의 양을 넓은 범위에서 조절할 수 있고, 이입된 산화철 나노입자의 양에 따라 자기장 반응성 및 자성을 정밀하고 용이하게 조절 가능하며, 또한, 산화철 나노입자가 외부 자기장내에서 보이는 특별한 성질인 '물리적 차폐 (physical blocking)'를 이용하여 고분자-산화철 복합체 표면에 처리된 단백질의 활성을 조절할 수 있고, 다양한 자성을 갖는 고분자-산화철 복합 나노입자체를 동시에 사용함으로써 특이적 적층 구조 형성 및 표면 처리된 단백질의 활성 조절이 가능한바, 기존에 사용되던 산화철 기반의 생체 의학적 치료 및 진단에 널리 응용될 수 있을 것으로 기대된다.The polymer-iron oxide composite nano structure according to the present invention can contain a large number of iron oxide nanoparticles, can control the amount of collected iron oxide nanoparticles over a wide range, and can control magnetic field reactivity Iron oxide nanoparticles can be used to control the activity of the treated protein on the surface of the polymer-iron oxide complex using 'physical blocking' which is a special property that iron oxide nanoparticles show in the external magnetic field. It is possible to form a specific laminate structure and control the activity of the surface-treated protein by simultaneously using the polymer-iron oxide complex nano-particles having various magnetic properties, and is widely applied to biomedical treatment and diagnosis based on iron oxide It is expected to be possible.
Description
본 발명은 고분자-산화철 복합 나노구조체, 이의 이용방법, 및 이의 제조방법에 관한 것이다.The present invention relates to a polymer-iron oxide composite nano-structure, a method of using the same, and a method for producing the same.
산화철 나노입자는 나노크기로 인해 발생하는 전자기적 특성, 생체적합성, 우수한 이미징 효과로 인해 생체 의학적 치료 및 진단 분야에서 주목받는 물질 중 하나이다. 이러한 산화철 나노입자의 다양한 활용은 대부분 나노크기 입자가 갖는 특별한 성질인 '초상자성 (superparamagnetism)'에서 기인한다. 그러나 단일 산화철 나노입자가 갖는 자성의 한계로 인하여 산화철 기반의 약물전달 시스템이나 바이오 이미징 시스템의 응용에 한계가 있다. Iron oxide nanoparticles are one of the materials of interest in biomedical treatment and diagnosis due to the electromagnetic properties, biocompatibility and excellent imaging effect caused by the nanoscale. The various applications of these iron oxide nanoparticles are mostly due to the 'superparamagnetism' which is a special property of nano-sized particles. However, due to the limitation of magnetic properties of single iron oxide nanoparticles, application of iron oxide based drug delivery system or bioimaging system is limited.
상기와 같은 한계를 극복하기 위하여 산화철 나노입자를 다중으로 포획하는 기술들이 개발되어 왔으나, 각 기술마다 포획할 수 있는 산화철 나노입자의 개수 및 자기장 반응성에 대한 한계가 여전히 존재한다. 예를 들어, 메사추세츠 공과대학 화학과의 CHEN, Ou, et al. 연구진에서는 산화철 나노입자의 소수성 효과에 따른 응집 현상을 이용하여 산화철 나노입자들로 이루어진 산화철 나노입자 군집을 합성하였으나, 이 경우 규칙적이고 균일한 형태의 군집이 합성되지만 내부에 포획되는 산화철 나노입자의 개수나 비율을 조절하여 자기장에 대한 반응성을 조절하기에는 어려움이 있었다.Techniques have been developed for capturing multiple iron oxide nanoparticles in order to overcome the above limitations. However, there are still limitations on the number of iron oxide nanoparticles that can be captured for each technique and the magnetic field reactivity. For example, CHEN, Ou, et al., Chem. The researchers synthesized iron oxide nanoparticle assemblies composed of iron oxide nanoparticles using the coagulation phenomenon due to the hydrophobic effect of iron oxide nanoparticles. In this case, however, a regular and uniform type of cluster was synthesized, but the number of iron oxide nanoparticles It has been difficult to control the reactivity to the magnetic field by controlling the ratio.
이에, 기존 산화철 기반의 생체 의학적 응용에서 가진 한계, 외부 자기장에 대한 약한 반응성을 극복하여 보다 신속하고 정확한 약물전달 및 바이오 이미징 효과를 나타낼 수 있는 나노구조체가 요구되고 있는 실정이다(한국공개특허 제10-2007-0106412호 참조).Accordingly, there is a demand for nanostructures capable of exhibiting faster and more accurate drug delivery and bio-imaging effects over the limitations of existing iron oxide-based biomedical applications and weak reactivity to external magnetic fields (Korean Patent Laid-Open No. 10 -2007-0106412).
본 발명자들은 종래기술의 문제점을 극복하기 위하여, 다수의 산화철 나노입자체가 포함될 수 있을 뿐만 아니라, 포집되는 산화철 나노입자의 양을 넓은 범위에서 조절할 수 있는 고분자 기반 플랫폼을 개발함으로써 본 발명을 완성하였다.In order to overcome the problems of the prior art, the present inventors have completed the present invention by developing a polymer-based platform capable of not only containing a plurality of iron oxide nanoparticles themselves but also controlling the amount of collected iron oxide nanoparticles over a wide range .
따라서 본 발명의 목적은 고분자-산화철 복합 나노입자; 및 상기 고분자-산화철 복합 나노입자 표면에 코팅된 실리카 코팅층을 포함하는, 고분자-산화철 복합 나노구조체를 제공하는 것이다.Accordingly, an object of the present invention is to provide a polymer-iron oxide composite nanoparticle; And a silica coating layer coated on the surface of the polymer-iron oxide composite nano-particles.
본 발명의 다른 목적은 에멀젼을 이루는 유기용매 내에 나노구조체의 지지체로 사용되는 고분자 및 산화철 나노입자를 혼합하고, PVA (poly vinyl alcohol) 수용액을 첨가하고 교반시키며, 상기 유기용매를 증발시켜 반응시키는 단계; 및 고분자-산화철 복합 나노구조체의 표면 개질을 용이하게 하기 위하여 계면활성제로 사용된 PVA 고분자를 기반으로 실리카를 코팅하는 단계를 포함하는, 고분자-산화철 복합 나노구조체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing a polymer emulsion, which comprises mixing a polymer and iron oxide nanoparticles used as a support of a nanostructure in an organic solvent for forming an emulsion, adding an aqueous solution of PVA (poly vinyl alcohol) ; And a method of manufacturing a polymer-iron oxide composite nano structure comprising coating silica on the basis of a PVA polymer used as a surfactant to facilitate surface modification of the polymer-iron oxide composite nano structure.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
상기와 같은 본 발명의 목적을 달성하기 위해서, 본 발명은 고분자-산화철 복합 나노입자; 및 상기 고분자-산화철 복합 나노입자 표면에 코팅된 실리카 코팅층을 포함하는, 고분자-산화철 복합 나노구조체를 제공한다.In order to accomplish the above object, the present invention provides a polymer-iron oxide composite nanoparticle; And a silica coating layer coated on the surface of the polymer-iron oxide composite nano-particles.
본 발명의 일실시예에 있어서, 상기 고분자는 PLGA (Poly lactic-L-glycolic acid)일 수 있다.In one embodiment of the present invention, the polymer may be PLGA (poly lactic-L-glycolic acid).
본 발명의 다른 실시예에 있어서, 상기 고분자-산화철 복합 나노구조체는 표면에 형광체를 더 포함할 수 있다.In another embodiment of the present invention, the polymer-iron oxide composite nano structure may further include a phosphor on its surface.
본 발명의 또 다른 실시예에 있어서, 상기 형광체는 플루오레신(fluorescein), 텍사스레드(TexasRed), 로다민(rhodamine), 알렉사(alexa), 시아닌(cyanine), 보디피(BODIPY), 또는 쿠마린(coumarin)일 수 있다.In another embodiment of the present invention, the phosphor is selected from the group consisting of fluorescein, Texas Red, rhodamine, alexa, cyanine, BODIPY, (coumarin).
본 발명의 또 다른 실시예에 있어서, 상기 고분자-산화철 복합 나노구조체의 크기는 200 내지 300 nm일 수 있다.In another embodiment of the present invention, the size of the polymer-iron oxide composite nano structure may be 200 to 300 nm.
또한, 본 발명은 에멀젼을 이루는 유기용매 내에 나노구조체의 지지체로 사용되는 고분자 및 산화철 나노입자를 혼합하고, PVA (poly vinyl alcohol) 수용액을 첨가하고 교반시키며, 상기 유기용매를 증발시켜 반응시키는 단계; 및 고분자-산화철 복합 나노구조체의 표면 개질을 용이하게 하기 위하여 계면활성제로 사용된 PVA 고분자를 기반으로 실리카를 코팅하는 단계를 포함하는, 고분자-산화철 복합 나노구조체의 제조방법을 제공한다.The present invention also relates to a method for preparing a polymer electrolyte membrane, which comprises mixing a polymer and iron oxide nanoparticles used as a support of a nanostructure in an organic solvent for forming an emulsion, adding an aqueous solution of polyvinyl alcohol (PVA) and stirring the organic solvent, And a step of coating silica on the basis of a PVA polymer used as a surfactant to facilitate surface modification of the polymer-iron oxide composite nano-structure.
본 발명의 일실시예에 있어서, 상기 유기용매는 클로로폼 (chloroform)일 수 있다.In one embodiment of the present invention, the organic solvent may be chloroform.
본 발명의 다른 실시예에 있어서, 상기 고분자는 PLGA (Poly lactic-L-glycolic acid)일 수 있다.In another embodiment of the present invention, the polymer may be PLGA (poly lactic-L-glycolic acid).
본 발명의 또 다른 실시예에 있어서, 상기 고분자-산화철 복합 나노구조체는 표면에 형광체를 더 포함할 수 있다.In another embodiment of the present invention, the polymer-iron oxide composite nano structure may further include a phosphor on its surface.
본 발명의 또 다른 실시예에 있어서, 상기 형광체는 플루오레신(fluorescein), 텍사스레드(TexasRed), 로다민(rhodamine), 알렉사(alexa), 시아닌(cyanine), 보디피(BODIPY), 또는 쿠마린(coumarin)일 수 있다.In another embodiment of the present invention, the phosphor is selected from the group consisting of fluorescein, Texas Red, rhodamine, alexa, cyanine, BODIPY, (coumarin).
본 발명의 또 다른 실시예에 있어서, 상기 고분자-산화철 복합 나노구조체의 크기는 200 내지 300 nm일 수 있다.In another embodiment of the present invention, the size of the polymer-iron oxide composite nano structure may be 200 to 300 nm.
본 발명에 따른 고분자-산화철 복합 나노구조체는 다수의 산화철 나노입자체가 포함될 수 있을 뿐만 아니라, 포집되는 산화철 나노입자의 양을 넓은 범위에서 조절할 수 있고, 이입된 산화철 나노입자의 양에 따라 자기장 반응성 및 자성을 정밀하고 용이하게 조절 가능하며, 또한, 산화철 나노입자가 외부 자기장내에서 보이는 특별한 성질인 '물리적 차폐 (physical blocking)'를 이용하여 고분자-산화철 복합체 표면에 처리된 단백질의 활성을 조절할 수 있고, 다양한 자성을 갖는 고분자-산화철 복합 나노입자체를 동시에 사용함으로써 특이적 적층 구조 형성 및 표면 처리된 단백질의 활성 조절이 가능한바, 기존에 사용되던 산화철 기반의 생체 의학적 치료 및 진단에 널리 응용될 수 있을 것으로 기대된다.The polymer-iron oxide composite nano structure according to the present invention can contain a large number of iron oxide nanoparticles, can control the amount of collected iron oxide nanoparticles over a wide range, and can control magnetic field reactivity Iron oxide nanoparticles can be used to control the activity of the treated protein on the surface of the polymer-iron oxide complex using 'physical blocking' which is a special property that iron oxide nanoparticles show in the external magnetic field. It is possible to form a specific laminate structure and control the activity of the surface-treated protein by simultaneously using the polymer-iron oxide complex nano-particles having various magnetic properties, and is widely applied to biomedical treatment and diagnosis based on iron oxide It is expected to be possible.
도 1은 고분자-산화철 복합 나노구조체 제작방법 및 효과를 나타낸 도이다.
도 2는 동적 광 산란 (DLS)을 통해 측정한 고분자-산화철 복합체 (PLGA-산화철 복합체)의 크기 (a) 및 2주 후의 크기 변화 (b)를 나타낸 도이다.
도 3은 산화철 나노입자의 비율을 다르게 하여 합성한 고분자-산화철 복합체 (PLGA-산화철 복합체)의 크기를 동적 광 산란 (DLS)을 통해 측정한 결과를 나타낸 도이다.
도 4는 실리카 코팅된 고분자-산화철 복합체 (PLGA-산화철 복합체)를 투과전자현미경 (TEM)을 통해 확인한 도이다.
도 5는 내부의 산화철 양을 다르게 조절한 서로 다른 고분자-산화철 복합체 (PLGA-산화철 복합체)를 투과전자현미경 (TEM)을 통해 확인한 도이다.
도 6은 산화철 나노입자의 비율을 늘려서 합성한 고분자-산화철 복합체 (PLG-산화철 복합체) 표면에 실리카 코팅 후, 배율을 달리하여 투과전자현미경 (TEM)을 통해 확인한 도이다.
도 7은 내부의 산화철 양을 다르게 (10-100 mg) 조절한 서로 다른 고분자-산화철 복합체 (PLGA-산화철 복합체)의 외부자기장에 대한 반응성을 나타낸 도이다.
도 8은 산화철 나노입자의 비율을 다르게 조절한 서로 다른 고분자-산화철 복합체 (PLGA-산화철 복합체)의 외부자기장에 대한 반응성을 나타낸 도이다.
도 9는 두 가지 서로 다른 자기장 반응성을 갖는 고분자-산화철 복합체 (PLGA-산화철 복합체)에 형광인자인 FITC 및 RBITC를 각각 부착한 뒤, 외부 자기장을 걸었을 때 측정되는 형광세기의 변화를 나타낸 도이다.
도 10은 서로 다른 자기장 반응성을 갖는 두 종류의 고분자-산화철 복합체 (PLGA-산화철 복합체)에 형광인자인 FITC 및 RBITC를 각각 부착한 뒤, 외부에 자기장을 가했을 때 형성되는 적층구조를 형광현미경으로 통해 확인한 도이다.BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view showing a method for producing a polymer-iron oxide composite nano structure and its effect.
FIG. 2 is a diagram showing the size (a) and the size change (b) of the polymer-iron oxide composite (PLGA-iron oxide composite) measured through dynamic light scattering (DLS) after two weeks.
FIG. 3 is a graph showing the results of dynamic light scattering (DLS) measurement of the size of a polymer-iron oxide composite (PLGA-iron oxide composite) synthesized with different ratios of iron oxide nanoparticles.
4 is a view showing a silica-coated polymer-iron oxide composite (PLGA-iron oxide composite) through a transmission electron microscope (TEM).
FIG. 5 is a view showing transmission electron microscopy (TEM) of different polymer-iron oxide complexes (PLGA-iron oxide composite) in which the amount of iron oxide inside is adjusted differently.
FIG. 6 is a view of a polymer-iron oxide composite (PLG-iron oxide composite) synthesized by increasing the ratio of iron oxide nanoparticles to a surface of silica coated with silica and observing the magnification through a transmission electron microscope (TEM).
FIG. 7 is a graph showing the reactivity of different polymer-iron oxide complexes (PLGA-iron oxide composite) with different amounts of inner iron oxide (10-100 mg) to an external magnetic field.
FIG. 8 is a graph showing the reactivity of different polymer-iron oxide complexes (PLGA-iron oxide composite) with different ratios of iron oxide nanoparticles to an external magnetic field.
FIG. 9 is a graph showing a change in fluorescence intensity measured when an external magnetic field is applied after attaching fluorescent elements FITC and RBITC to polymer-iron oxide complex (PLGA-iron oxide complex) having two different magnetic field reactivities .
FIG. 10 is a graph showing the relationship between the fluorescence intensity of the polymer-iron oxide complex (PLGA-iron oxide complex) and the FITC and RBITC of the two kinds of polymer-iron oxide complexes having different magnetic field reactivities It is also confirmed.
본 발명자들은 산화철 나노입자를 다중으로 포획할 수 있는 산화철 나노입자를 개발하기 위해 연구한 결과 본 발명을 완성하게 되었다.The inventors of the present invention have studied to develop iron oxide nanoparticles capable of capturing multiple iron oxide nanoparticles, and have completed the present invention.
따라서 본 발명은 고분자-산화철 복합 나노입자; 및 상기 고분자-산화철 복합 나노입자 표면에 코팅된 실리카 코팅층을 포함하는, 고분자-산화철 복합 나노구조체을 제공하는 것을 그 특징으로 한다.Therefore, the present invention relates to a polymer-iron oxide composite nanoparticle; And a silica coating layer coated on the surface of the polymer-iron oxide composite nano-particles. The present invention also provides a polymer-iron oxide composite nano-structure.
또한, 본 발명은 에멀젼을 이루는 유기용매 내에 나노구조체의 지지체로 사용되는 고분자 및 산화철 나노입자를 혼합하고, PVA (poly vinyl alcohol) 수용액을 첨가하고 교반시키며, 상기 유기용매를 증발시켜 반응시키는 단계; 및 고분자-산화철 복합 나노구조체의 표면 개질을 용이하게 하기 위하여 계면활성제로 사용된 PVA 고분자를 기반으로 실리카를 코팅하는 단계를 포함하는, 고분자-산화철 복합 나노구조체의 제조방법을 제공한다.The present invention also relates to a method for preparing a polymer electrolyte membrane, which comprises mixing a polymer and iron oxide nanoparticles used as a support of a nanostructure in an organic solvent for forming an emulsion, adding an aqueous solution of polyvinyl alcohol (PVA) and stirring the organic solvent, And a step of coating silica on the basis of a PVA polymer used as a surfactant to facilitate surface modification of the polymer-iron oxide composite nano-structure.
이때, 상기 제조방법은 본 발명에 따른 고분자-산화철 복합 나노구조체를 제조할 수 있다면, 적절하게 단계의 순서 및/또는 구성을 변경할 수 있으며 상기 단계에 제한되는 것은 아니다.At this time, if the polymer-iron oxide composite nanostructure according to the present invention can be produced, the manufacturing method may be suitably changed in order and / or configuration of the steps, and the present invention is not limited thereto.
본 발명에 따른 고분자-산화철 복합 나노구조체는 질병의 치료 및 진단을 위해 사용될 수 있으며, 이를 위해 본 발명의 일실시예에서는 산화철 나노입자를 다중으로 포획할 수 있도록 고분자-산화철 나노입자를 제조한 다음 실리카로 상기 나노입자 표면을 코팅하였다 (실시예 2 참조). 이때, 본 발명의 일실시예에서는 지지체로 고분자인 PLGA (Poly lactic-L-glycolic acid)를 이용하였으나, 생체 내 사용가능한 나노사이즈의 고분자라면 이에 제한되지 않고 사용할 수 있으며, 제조된 고분자-산화철 복합체의 크기는 체내에 주입할 수 있는 크기 및 모양이라면 적절하게 조절 가능 하지만, 바람직하게는 직경이 200 nm 내지 300 nm인 구형으로 제조할 수 있다.The polymer-iron oxide composite nanostructure according to the present invention can be used for the treatment and diagnosis of diseases. For this purpose, in one embodiment of the present invention, polymer-iron oxide nanoparticles are prepared so as to capture multiple iron oxide nanoparticles The surface of the nanoparticles was coated with silica (see Example 2). In this case, PLGA (poly lactic-L-glycolic acid), which is a polymer, is used as a support in the present invention. However, any nano-sized polymer that can be used in vivo can be used without limitation, Can be appropriately adjusted if it is a size and shape that can be injected into the body, but it can preferably be formed into a spherical shape having a diameter of 200 nm to 300 nm.
또한, 본 발명의 고분자-산화철 복합 나노구조체는 표면에 형광체를 더 포함할 수 있으며, 바람직하게 상기 형광체는 플루오레신(fluorescein), 텍사스레드(TexasRed), 로다민(rhodamine), 알렉사(alexa), 시아닌(cyanine), 보디피(BODIPY) 또는 쿠마린(coumarin)일 수 있고, 더욱 바람직하게는 6-FAM, Texas 615, Alexa Fluor 488, Cy5, 또는 Cy3일 수 있으나, 생체 내 사용 가능한 형광체라면 이에 한정되지 않고 당업자가 적절하게 변경하여 사용할 수 있다.In addition, the polymer-iron oxide composite nano structure of the present invention may further include a fluorescent substance on its surface. Preferably, the fluorescent substance includes fluorescein, Texas Red, rhodamine, alexa, Cyanine, BODIPY or coumarin, and more preferably 6-FAM, Texas 615, Alexa Fluor 488, Cy5, or Cy3, And those skilled in the art can appropriately change and use it.
따라서 본 발명의 고분자-산화철 복합 나노구조체는 다수의 산화철 나노입자체가 포함될 수 있을 뿐만 아니라, 포집되는 산화철 나노입자의 양을 넓은 범위에서 조절할 수 있고, 이입된 산화철 나노입자의 양에 따라 자기장 반응성 및 자성을 정밀하고 용이하게 조절 가능한 특징을 가지는 것이다.Therefore, the polymer-iron oxide composite nano structure of the present invention can contain a large number of iron oxide nanoparticles, can control the amount of collected iron oxide nanoparticles over a wide range, And the magnetic property can be precisely and easily adjusted.
나아가 본 발명의 고분자-산화철 복합 나노구조체는 산화철 나노입자가 외부 자기장내에서 보이는 특별한 성질인 '물리적 차폐 (physical blocking)'를 이용하여 고분자-산화철 복합체 표면에 처리된 단백질의 활성을 조절할 수 있고, 다양한 자성을 갖는 고분자-산화철 복합 나노입자체를 동시에 사용함으로써 특이적 적층 구조 형성 및 표면 처리된 단백질의 활성 조절이 가능한 특징을 가진다.Further, the polymer-iron oxide composite nanostructure of the present invention can control the activity of the protein treated on the surface of the polymer-iron oxide complex by using 'physical blocking' which is a special property of the iron oxide nanoparticles seen in the external magnetic field, It is possible to form a specific laminate structure and to control the activity of a surface-treated protein by simultaneously using a polymer-iron oxide complex nano-particle having various magnetic properties.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.
[실시예][Example]
본 실시예에서는 효과적인 산화철 기반의 생체 의학적 복합체 제조를 위해, 클로로폼에 녹인 산화철 나노입자와 PLGA (Poly lactic-L-glycolic acid)를 다중 이멀젼 용액 증착법을 통해 PVA (poly vinyl alcohol) 내부에 포획시켜 고분자-산화철 복합체를 합성하였으며, 이때 사용된 산화철 나노입자의 양이나 클로로폼의 부피를 조절하여 고분자-산화철 복합체의 자기장 반응성을 조절하였다. In this embodiment, for the production of an effective iron oxide-based biomedical complex, iron oxide nanoparticles and PLGA (poly lactic-L-glycolic acid) dissolved in chloroform are captured in PVA (poly vinyl alcohol) The polymer - iron oxide complexes were synthesized by controlling the amount of iron oxide nanoparticles used and the volume of chloroform used to control the magnetic field reactivity of the polymer - iron oxide complex.
외부 자기장 내에서 산화철 나노입자의 경우 '초상자성'이 발현되고, 이에 따라 인접한 산화철 나노입자와 전자기적 인력에 의해 뭉치게 되는데, 이때 외부에 노출되는 산화철 나노입자의 표면적이 감소하게 된다. 따라서 산화철 나노입자의 표면에 단백질이 부착된 경우, 기질이 포함된 용액 내에서 외부에 자기장이 걸리면 기질용액으로 노출된 단백질의 면적이 감소하고, 상기 단백질의 발현을 감소시킬 수 있게 된다. 따라서 이와 같은 고분자-산화철 복합체의 '물리적 차폐 (physical blocking)' 효과를 이용하여 단백질의 발현조절의 새로운 방법을 제시하고자 하였다.In the case of iron oxide nanoparticles in the external magnetic field, 'superparamagnetism' is expressed, and thus the iron oxide nanoparticles are aggregated by the adjacent iron oxide nanoparticles and the surface area of the iron oxide nanoparticles exposed to the outside is reduced. Therefore, when a protein is adhered to the surface of iron oxide nanoparticles, if an external magnetic field is applied in a solution containing the substrate, the area of the protein exposed to the substrate solution decreases and the protein expression can be reduced. Therefore, we propose a new method of controlling protein expression by using the 'physical blocking' effect of the polymer-iron oxide complex.
실시예 1. 산화철 나노입자의 합성Example 1 Synthesis of Iron Oxide Nanoparticles
1-1. 올레산철 (Iron oleate)의 합성1-1. Synthesis of iron oleate
140 ml의 헥산, 80 ml의 에탄올, 60 ml의 증류수를 500 ml 플라스크에 넣고 교반시킨 후, 10.8 g의 FeCl3·6H2O와 36.5 g의 올레산나트륨 (sodium oleate)을 플라스크에 넣고 녹이고, 4 시간 동안 60 ℃로 유지시켰으며, 이때 용액이 끓지 않도록 주의하였다. 4 시간 교반 후, 분별깔때기를 이용해 하층에 분리되는 증류수와 에탄올을 제거하고 2회 세척하였다. 이후 회전 증발 농축기를 이용해 헥산을 증발시켜 올레산철 (iron oleate)을 얻었다. 140 ml of hexane, 80 ml of ethanol and 60 ml of distilled water were placed in a 500 ml flask and stirred. 10.8 g of FeCl 3 .6H 2 O and 36.5 g of sodium oleate were added to the flask and dissolved. Lt; RTI ID = 0.0 > 60 C < / RTI > for a period of time. After stirring for 4 hours, distilled water and ethanol were removed from the lower layer using a separating funnel and washed twice. Then, hexane was evaporated using a rotary evaporator to obtain iron oleate.
1-2. 산화철 나노입자의 합성1-2. Synthesis of iron oxide nanoparticles
36 g의 올레산철을 5.7 g의 올레산 (oleic acid), 200 g의 1-옥타데신 (1-octadecene)에 넣고, 빠르게 교반하여 녹이고, 1 분에 3.3 ℃씩 상승시켜 320 ℃까지 가열한 후, 320 ℃에서 30 분간 온도를 유지한 뒤 서서히 식혔다. 합성된 산화철 나노입자 용액을 비커에 옮기고 헥산을 넣은 뒤, 용액의 색이 변할 때까지 아세톤을 넣어주고, 다시 용액의 색이 변할 때까지 에탄올을 넣어준 후, 비커 아래에 자석을 대어 상층액을 버렸다. 상기와 같은 방법으로 2회 세척한 뒤, 소량의 클로로폼을 넣고 분산시켰다.36 g of iron oleate was added to 5.7 g of oleic acid and 200 g of 1-octadecene. The resulting mixture was rapidly stirred and dissolved. The mixture was heated to 3.3 ° C in one minute at a temperature of 320 ° C, The temperature was maintained at 320 DEG C for 30 minutes and then slowly cooled. Transfer the synthesized iron oxide nanoparticle solution to a beaker, add hexane, add acetone until the color of the solution changes, add ethanol until the color of the solution changes, then place the magnet under the beaker, I abandoned it. After washing twice in the same manner as above, a small amount of chloroform was added and dispersed.
실시예 2. PLGA (Poly lactic-L-glycolic acid)를 사용한 고분자-산화철 복합체의 합성Example 2. Synthesis of polymer-iron oxide complex using PLGA (Poly lactic-L-glycolic acid)
2-1. 고분자-산화철 복합 나노입자 합성2-1. Synthesis of Polymer-Iron Oxide Composite Nanoparticles
2-1-1. 산화철의 비율을 높여 합성하는 방법2-1-1. A method of synthesizing by increasing the ratio of iron oxide
PLGA (Poly lactic-L-glycolic acid) 20 mg 및 산화철 100 mg을 클로로폼 (0.125, 0.25, 0.5, 1, 2, 및 4 ml)에 녹이고, 이어서 3 %의 PVA (poly vinyl alcohol) 수용액 4.5 ml를 넣고 2 분간 볼텍싱 (vortexing) 후, 초음파 분산방법으로 2 분간 분산시켰다. 분산된 용액을 다시 20 ml의 1 % PVA (poly vinyl alcohol) 수용액에 넣고 12 시간동안 자석 교반기 (magnetic stirrer)가 아닌 교반기를 사용하여 교반시키며 클로로폼을 증발시켰다. 12 시간 교반 후 4 ℃, 15000 g에서 30 분씩 3 회 원심분리하여 세척하였으며, 이후 4 ℃에서 보관하였다.20 mg of PLGA (poly lactic-L-glycolic acid) and 100 mg of iron oxide were dissolved in chloroform (0.125, 0.25, 0.5, 1, 2 and 4 ml) and then 4.5 ml of a 3% aqueous solution of polyvinyl alcohol Followed by vortexing for 2 minutes, followed by dispersion for 2 minutes using an ultrasonic dispersion method. The dispersed solution was added to 20 ml of 1% aqueous solution of polyvinyl alcohol (PVA), stirred for 12 hours using a stirrer instead of a magnetic stirrer, and the chloroform was evaporated. After 12 hours of stirring, the cells were washed by centrifugation three times at 4 ° C and 15,000 g for 30 minutes, and then stored at 4 ° C.
2-1-2. 산화철의 양을 증가시켜 합성하는 방법2-1-2. How to synthesize by increasing the amount of iron oxide
PLGA (Poly lactic-L-glycolic acid) 20 mg 및 산화철 10, 30, 50, 70 또는 100 mg을 클로로폼 2 ml에 녹인 후, 3 %의 PVA (poly vinyl alcohol) 수용액 4.5 ml를 넣고 2 분간 볼텍싱 (vortexing) 후, 초음파 분산방법으로 2 분간 분산시켰다. 분산된 용액을 다시 20 ml의 1 % PVA (poly vinyl alcohol) 수용액에 넣고 12 시간동안 자석 교반기 (magnetic stirrer)가 아닌 교반기를 사용하여 교반시키며 클로로폼을 증발시켰다. 12 시간 교반 후 4 ℃, 15000 g에서 30 분씩 3 회 원심분리하여 세척하였으며, 이후 4 ℃에서 보관하였다.20 mg of PLGA (poly lactic-L-glycolic acid) and 10, 30, 50, 70 or 100 mg of iron oxide were dissolved in 2 ml of chloroform, 4.5 ml of a 3% aqueous solution of polyvinyl alcohol (PVA) After vortexing, it was dispersed for 2 minutes by an ultrasonic dispersion method. The dispersed solution was added to 20 ml of 1% aqueous solution of polyvinyl alcohol (PVA), stirred for 12 hours using a stirrer instead of a magnetic stirrer, and the chloroform was evaporated. After 12 hours of stirring, the cells were washed by centrifugation three times at 4 ° C and 15,000 g for 30 minutes, and then stored at 4 ° C.
2-2. 산화철-고분자 복합 나노입자의 실리카 표면 처리 방법2-2. Silica surface treatment of iron oxide-polymer composite nanoparticles
20 ml의 에탄올에 4 mg의 산화철-고분자 복합체를 넣고 700 rpm으로 교반시키면서 3 ml의 증류수를 넣은 후, 1 ml의 30 % 암모니아 수용액과 500 μl의 테트라에틸 오소실리케이트 (tetraethyl orthosilicate, TEOS)를 순서대로 천천히 넣어주었다. 이후 20 분간 교반시키고 20 ℃, 15000 g에서 30 분씩 3 회 원심분리하여 세척하였으며, 이후 6 시간 동안 magnetic 세척 후, 4 ℃에서 보관하였다.After adding 4 mg of iron oxide-polymer complex into 20 ml of ethanol and adding 3 ml of distilled water with stirring at 700 rpm, 1 ml of aqueous 30% ammonia solution and 500 μl of tetraethyl orthosilicate (TEOS) I put it slowly. Then, the mixture was stirred for 20 minutes and centrifuged three times for 30 minutes at 20 ° C and 15,000 g. After that, the mixture was washed for 6 hours and stored at 4 ° C.
실시예 3. 고분자-산화철 복합체에 형광인자 부착Example 3. Attachment of a fluorescent moiety to a polymer-iron oxide complex
3-1. Fluorescein isothiocyanate (FITC)에 silane source 치환3-1. Silane source substitution in Fluorescein isothiocyanate (FITC)
FITC 19.5 mg을 50 ml의 에탄올에 녹인 뒤 800 rpm으로 교반하고, 11.5 μl의 (3-아미노프로필)트라이에톡시실란 ((3-Aminopropyl)triethoxysilane, APTES)을 천천히 주입한 후, 빛을 차단한 뒤, 42 ℃에서 24 시간 교반한 후, 빛에 노출되지 않도록 주의하여 보관하였다. After dissolving 19.5 mg of FITC in 50 ml of ethanol and stirring at 800 rpm, 11.5 μl of (3-aminopropyl) triethoxysilane (APTES) was slowly injected and then blocked with light Thereafter, the mixture was stirred at 42 ° C for 24 hours, and then carefully stored so as not to be exposed to light.
40.4 ml의 에탄올 및 2 ml의 증류수를 800 rpm에서 교반시키고, 250 μl의 아세트산을 천천히 주입한 후, 상기 방법에 의해 합성된 실란 (silane source)으로 치환된 FITC 용액 6.6 ml를 천천히 넣고 5 분간 교반하였다. 이후, 상기 실시예 2-2에서 합성된 실리카 코팅된 고분자-산화철 용액 1 ml를 천천히 넣고 2 시간 교반한 후, 20 ℃, 15000 g에서 에탄올을 이용하여 30 분씩 3 회 원심분리하여 세척하였다.40.4 ml of ethanol and 2 ml of distilled water were stirred at 800 rpm and 250 μl of acetic acid was slowly injected. Then, 6.6 ml of the FITC solution substituted by the silane source synthesized by the above method was slowly added and stirred for 5 minutes Respectively. Thereafter, 1 ml of the silica-coated polymer-iron oxide solution synthesized in Example 2-2 was slowly added and stirred for 2 hours and then washed by centrifugation three times for 30 minutes using ethanol at 20 ° C and 15,000 g.
3-2. Rhodamine b isothiocyanate (RBITC)에 silane source 치환3-2. Silane source substitution for Rhodamine b isothiocyanate (RBITC)
RBITC 19.5 mg을 15 ml의 에탄올에 녹인 뒤 800rpm으로 교반하고, 50 μl의 (3-아미노프로필)트라이에톡시실란 ((3-Aminopropyl)triethoxysilane, APTES)을 천천히 주입한 후, 빛을 차단한 뒤, 상온에서 48 시간 교반한 후, 빛에 노출되지 않도록 주의하여 보관하였다.After 19.5 mg of RBITC was dissolved in 15 ml of ethanol, the mixture was stirred at 800 rpm, and 50 μl of (3-aminopropyl) triethoxysilane (APTES) was slowly injected. , Stirred at room temperature for 48 hours, and then carefully stored so as not to be exposed to light.
40.4 ml의 에탄올 및 2 ml의 증류수를 800 rpm에서 교반시키고, 250 μl의 아세트산을 천천히 주입한 후, 상기 방법에 의해 합성된 실란 (silane source)으로 치환된 FITC 용액 6.6 ml를 천천히 넣고 5 분간 교반하였다. 이후, 상기 실시예 2-2에서 합성된 실리카 코팅된 고분자-산화철 용액 1 ml를 천천히 넣고 2 시간 교반한 후, 20 ℃, 15000 g에서 에탄올을 이용하여 30 분씩 3 회 원심분리하여 세척하였다. 40.4 ml of ethanol and 2 ml of distilled water were stirred at 800 rpm and 250 μl of acetic acid was slowly injected. Then, 6.6 ml of the FITC solution substituted by the silane source synthesized by the above method was slowly added and stirred for 5 minutes Respectively. Thereafter, 1 ml of the silica-coated polymer-iron oxide solution synthesized in Example 2-2 was slowly added and stirred for 2 hours and then washed by centrifugation three times for 30 minutes using ethanol at 20 ° C and 15,000 g.
실시예 4. 고분자-산화철 복합체의 크기 변화 확인Example 4. Confirmation of Size Change of Polymer-Iron Oxide Composite
동적 광 산란 (Dynamic light scattering, DLS)을 통해, 상기 실시예 2에서 합성한 고분자-산화철 복합체의 크기 및 2주 후의 크기 변화를 확인하였다. The size of the polymer-iron oxide composite synthesized in Example 2 and the size change after 2 weeks were confirmed through dynamic light scattering (DLS).
그 결과, 먼저 산화철의 양을 증가시켜 합성하는 경우, 도 2에 나타낸 바와 같이, 산화철의 양을 10 배까지 증가시켜 고분자-산화철 복합체 (PLGA-산화철 복합체)를 합성했음에도 불구하고 복합체의 전체 크기는 일정한 것을 확인할 수 있었다. 또한, 2 주의 시간 후에도 복합체의 크기는 변화 없이 안정하게 구조를 유지하는 것을 확인할 수 있었다. As a result, in the case of synthesizing by increasing the amount of iron oxide, the total size of the composite, although synthesizing the polymer-iron oxide composite (PLGA-iron oxide composite) by increasing the amount of iron oxide to 10 times as shown in FIG. 2 I could confirm something constant. Also, it was confirmed that even after 2 weeks, the size of the composite remains stable without change.
반면, 산화철의 비율을 높여 합성하는 경우, 도 6에 나타낸 바와 같이, 에멀젼 용매 증발법 (Emulsion solvent evaporation method)의 특성상, 용매로 사용된 클로로폼의 양을 일정 범위 이상으로 바꾸는 경우, 복합체의 크기가 크게 변하는 것을 확인할 수 있었다.6, when the amount of chloroform used as a solvent is changed over a certain range, the size of the complex is increased as shown in FIG. 6 because of the nature of the emulsion solvent evaporation method And the like.
나아가, 실리카 코팅된 고분자-산화철 복합체 (PLGA-산화철 복합체)를 투과전자현미경 (transmission electron microscopy, TEM)을 통해 확인한 결과, 도 5에 나타낸 바와 같이, 상기 모든 고분자-산화철 복합체 (PLGA-산화철 복합체)가 실리카로 고르게 코팅되어 있음을 확인할 수 있었다.Further, the silica-coated polymer-iron oxide composite (PLGA-iron oxide composite) was examined by transmission electron microscopy (TEM). As a result, all the polymer- Was uniformly coated with silica.
실시예 5. 고분자-산화철 복합체 내의 산화철 크기 변화 확인Example 5. Confirmation of Change in Size of Iron Oxide in Polymer-Iron Oxide Composite
투과전자현미경(transmission electron microscopy, TEM)을 통해, 상기 실시예 2에서 합성한 고분자-산화철 복합체 내의 산화철의 양 및 복합체의 크기 변화를 확인하였다. The amount of iron oxide and the size of the complex in the polymer-iron oxide composite synthesized in Example 2 were confirmed through transmission electron microscopy (TEM).
그 결과, 먼저 산화철의 양을 증가시켜 합성하는 경우, 도 4에 나타낸 바와 같이, 왼쪽부터 10, 30, 50, 70, 및 100 mg의 산화철 나노입자를 사용하여 합성한 고분자-산화철 복합체 (PLGA-산화철 복합체)를 관찰하였으며, 산화철의 양을 증가시킬수록 복합체 내부에 포집된 산화철의 양은 증가함에도 복합체 전체의 크기는 일정한 것을 확인할 수 있었다.As a result, when the amount of iron oxide was increased, as shown in FIG. 4, the polymer-iron oxide complex (PLGA-10) synthesized using iron oxide nanoparticles of 10, 30, 50, 70, The amount of iron oxide collected in the complex increases with increasing amount of iron oxide, but the size of the complex as a whole is constant.
반면, 산화철의 비율을 높여 합성하는 경우, 도 8에 나타낸 바와 같이, 에멀젼 용매 증발법 (Emulsion solvent evaporation method)의 특성상, (a)(b)(c)(d)(e)(f) 순으로 유액 내의 산화철 나노입자 비율이 증가하는 것을 확인할 수 있었다.On the other hand, in the case of synthesizing by increasing the ratio of iron oxide, as shown in FIG. 8, the characteristics of the emulsion solvent evaporation method are as follows: (a) (b) And the ratio of iron oxide nanoparticles in the emulsion was increased.
실시예 6. 고분자-산화철 복합체의 외부자기장에 대한 반응성 확인Example 6. Confirmation of reactivity of polymer-iron oxide complex to external magnetic field
4.5 ml 큐벳 (cuvette)에 상기에 기재된 방법대로 합성된 고분자-산화철 복합체 (PLGA-산화철 복합체) 500 μl를 넣고, 4 ml의 물을 넣은 후 충분히 섞어주었다. 기포가 생기지 않도록 주의하면서 큐벳의 캡을 닫고, 분광기 (spectrometer)를 이용해 500 nm 파장에서의 시간에 따른 흡광도 변화를 측정하였다. 초기 10 분간 용액의 흡광도가 일정해질 때까지 기다린 후, 고분자-산화철 복합체 (PLGA-산화철 복합체)가 담긴 큐벳의 위쪽에 자석을 올려 자기장을 가한 후, 2 시간 50 분간 흡광도의 변화를 확인하였다.To a 4.5-ml cuvette, 500 μl of the polymer-iron oxide complex (PLGA-iron oxide complex) synthesized according to the method described above was added, and 4 ml of water was added thereto, followed by thorough mixing. The cap of the cuvette was closed with care to avoid bubbles and the change in absorbance with time at a wavelength of 500 nm was measured using a spectrometer. After waiting for the initial absorbance of the solution to be constant for 10 minutes, the magnet was placed on the cuvette containing the polymer-iron oxide complex (PLGA-iron oxide complex), and the magnetic field was applied.
그 결과, 먼저 산화철의 양을 증가시켜 합성하는 경우, 도 3에 나타낸 바와 같이, 내부의 산화철 양을 다르게 (10-100 mg) 조절하면서, 고분자-산화철 복합체 (PLGA-산화철 복합체) 내부에 포집된 산화철의 양을 늘렸을 때, 포집된 산화철의 양이 증가할수록 자기장에 대한 반응성이 증가함을 확인할 수 있었다. As a result, in the case of synthesizing by increasing the amount of iron oxide, the amount of iron oxide collected inside the polymer-iron oxide composite (PLGA-iron oxide composite) was controlled while the amount of iron oxide inside was varied (10-100 mg) When the amount of iron oxide was increased, the reactivity to the magnetic field increased as the amount of collected iron oxide increased.
반면, 산화철의 비율을 높여 합성하는 경우, 도 7에 나타낸 바와 같이, 고분자-산화철 복합체 (PLGA-산화철 복합체)의 내부에 산화철의 비율이 높을수록 자기장에 대한 반응성이 증가하는 것을 확인할 수 있었으며, 단순히 산화철의 양만 증가시킨 경우보다 더 확연한 차이를 발생시키는 것을 알 수 있었다.On the other hand, when synthesized by increasing the ratio of iron oxide, as shown in FIG. 7, it was confirmed that the reactivity to the magnetic field increases as the ratio of iron oxide increases in the polymer-iron oxide composite (PLGA-iron oxide composite) It was found that the difference was more pronounced than when the amount of iron oxide was increased.
이때, 상기 결과값은, 자석에 반응하지 않고 남아있는 입자의 수를 시간에 따라 측정하여 초기 입자 수에 대한 상댓값으로 나타내었다.At this time, the resultant value was expressed as an average value of the initial number of particles by measuring the number of remaining particles without reacting with the magnet over time.
실시예Example 7. 7. 형광인자가Fluorescence factor 부착된 고분자-산화철 복합체를 이용한 외부 자기장에 의한 By an external magnetic field using an attached polymer-iron oxide complex 형광세기Fluorescence intensity 변화 확인 Confirm change
4.5 ml 큐벳 (cuvette)에 상기 실시예 3에서 합성된, 형광인자 부착된 서로 다른 자기장 반응성을 갖는 두 고분자-산화철 복합체 (PLGA-산화철 복합체)를 각각 250 μl 씩 넣고 증류수 4 ml를 넣은 후 충분히 섞어주었다. 기포가 생기지 않도록 주의하면서 큐벳의 캡을 닫고, FITC의 형광파장인 520 nm 및 RBITC의 형광파장인 570 nm에서 동시에 형광세기의 시간에 따른 변화를 측정하였다. 초기 10 분간 용액의 흡광도가 일정해질 때까지 기다린 후, 고분자-산화철 복합체 (PLGA-산화철 복합체)가 담긴 큐벳의 위쪽에 자석을 올려 자기장을 가한 후, 2 시간 50 분간 형광세기의 변화를 확인하였다.To a 4.5-ml cuvette, 250 μl of each of the two polymer-iron oxide complexes (PLGA-iron oxide complex) having different magnetic field reactivity and having fluorescence factors synthesized in Example 3 were added, and 4 ml of distilled water was added thereto. gave. The cuvette cap was closed while taking care not to bubble, and the change in fluorescence intensity over time was measured simultaneously at 520 nm, which is the fluorescence wavelength of FITC, and 570 nm, which is the fluorescence wavelength of RBITC. After waiting for the initial absorbance of the solution to remain constant for 10 minutes, a magnetic field was applied to the top of the cuvette containing the polymer-iron oxide complex (PLGA-iron oxide complex) and the fluorescence intensity was changed for 2 hours and 50 minutes.
그 결과, 도 9에 나타낸 바와 같이, 더 강한 자기장 반응성을 가지는 고분자-산화철 복합체 (PLGA-산화철 복합체)에 부착된 RBITC의 경우, FITC에 비해 형광의 세기가 빠르게 감소하는 것을 확인할 수 있었다.As a result, as shown in FIG. 9, it was confirmed that the fluorescence intensity of RBITC attached to the polymer-iron oxide complex (PLGA-iron oxide complex) having stronger magnetic field reactivity was faster than that of FITC.
이러한 결과는, 산화철의 비율을 다르게 하여 합성된 고분자-산화철 복합체 (PLGA-산화철 복합체)를 사용할 경우, 부착된 형광인자도 자석에 딸려오는 속도가 달라질 것인바, 이를 이용하여 특이한 적층구조를 형성할 수 있음을 시사한다.These results indicate that when a polymer-iron oxide composite (PLGA-iron oxide composite) synthesized with different ratios of iron oxide is used, the rate of attachment of the attached fluorescent material to the magnet will be different, and a specific laminate structure is formed .
실시예 8. 형광인자가 부착된 고분자-산화철 복합체를 이용한 적층구조 형성과 확인Example 8. Formation and confirmation of laminated structure using polymer-iron oxide complex with fluorescent agent
이에, 상기 실시예 7의 결과를 바탕으로, 실시예 3에서 합성된, 형광인자 부착된 서로 다른 자기장 반응성을 갖는 두 고분자-산화철 복합체 (PLGA-산화철 복합체) 각각 100 μl와 15 %의 SDS PAGE gel solution 300 μl를 섞고 끝을 막은 마이크로 피펫 팁에 주입하였다. 이후 외부에 자기장을 걸고 20 분 후에 온도를 올려 SDS PAGE gel solution을 겔로 굳힌 후, 팁을 자르고 겔 속에 형성된 적층구조를 형광현미경을 통해 확인하였다.On the basis of the results of Example 7, 100 μl of each of the two polymer-iron oxide complexes (PLGA-iron oxide complex) having different magnetic field reactivity, which were synthesized in Example 3, and 15% of SDS PAGE gel solution (300 μl) were mixed and injected into a micropipette tip with a stopper. Then, a magnetic field was externally applied and after 20 minutes, the temperature was raised to solidify the SDS PAGE gel solution into gel, and then the tip was cut and the lamination structure formed in the gel was confirmed by fluorescence microscope.
그 결과, 도 10에 나타낸 바와 같이, 자기장 반응성이 큰 고분자-산화철 복합체 (PLGA-산화철 복합체)에 부착된 RBITC (도 10a) 및 자기장 반응성이 작은 고분자-산화철 복합체(PLGA-산화철 복합체)에 부착된 FITC (도 10b)를 확인할 수 있었다. As a result, as shown in Fig. 10, it was confirmed that RBITC (Fig. 10A) attached to the polymer-iron oxide composite (PLGA-iron oxide composite) having a large magnetic field reactivity and the polymer- FITC (Fig. 10B).
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해되어야 한다.It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.
Claims (11)
고분자-산화철 복합 나노구조체의 표면 개질을 용이하게 하기 위하여 계면활성제로 사용된 PVA 고분자를 기반으로 실리카를 코팅하는 단계를 포함하고,
상기 유기용매는 클로로폼 (chloroform)이고,
상기 고분자는 PLGA (Poly lactic-L-glycolic acid)인 것을 특징으로 하는, 고분자-산화철 복합 나노구조체의 제조방법.
Mixing the polymer and iron oxide nanoparticles used as a support of the nanostructure in an organic solvent constituting the emulsion, adding an aqueous solution of polyvinyl alcohol (PVA) and stirring, and evaporating the organic solvent to react; And
And coating the silica on the basis of the PVA polymer used as a surfactant to facilitate the surface modification of the polymer-iron oxide composite nano structure,
The organic solvent is chloroform,
Wherein the polymer is PLGA (poly lactic-L-glycolic acid).
상기 제조방법은 고분자-산화철 복합 나노구조체 표면에 형광체를 부착하는 단계를 더 포함하는 것을 특징으로 하는, 고분자-산화철 복합 나노구조체의 제조방법.
The method according to claim 6,
The method of manufacturing a polymer-iron oxide composite nanostructure according to any one of claims 1 to 3, further comprising the step of attaching a phosphor to the surface of the polymer-iron oxide composite nano structure.
상기 형광체는 플루오레신(fluorescein), 텍사스레드(TexasRed), 로다민(rhodamine), 알렉사(alexa), 시아닌(cyanine), 보디피(BODIPY), 및 쿠마린(coumarin)으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 고분자-산화철 복합 나노구조체의 제조방법.
10. The method of claim 9,
The phosphor is selected from the group consisting of fluorescein, Texas Red, rhodamine, alexa, cyanine, BODIPY, and coumarin. Wherein the polymer-iron oxide composite nano-structure is a polymer-iron oxide composite nanostructure.
상기 고분자-산화철 복합 나노구조체의 직경은 200 내지 300 nm인 것을 특징으로 하는, 고분자-산화철 복합 나노구조체의 제조방법.The method according to claim 6,
Wherein the polymer-iron oxide composite nano-structure has a diameter of 200 to 300 nm.
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