KR20090098929A - Mri t1 contrasting agent comprising manganese tetroxide and method for preparing thereof - Google Patents

Mri t1 contrasting agent comprising manganese tetroxide and method for preparing thereof Download PDF

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KR20090098929A
KR20090098929A KR1020080024111A KR20080024111A KR20090098929A KR 20090098929 A KR20090098929 A KR 20090098929A KR 1020080024111 A KR1020080024111 A KR 1020080024111A KR 20080024111 A KR20080024111 A KR 20080024111A KR 20090098929 A KR20090098929 A KR 20090098929A
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manganese
nanoparticles
hydrate
trimanganese tetraoxide
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KR1020080024111A
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Korean (ko)
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현택환
유태경
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서울대학교산학협력단
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Priority to KR1020080024111A priority Critical patent/KR20090098929A/en
Priority to PCT/KR2009/001277 priority patent/WO2009116755A2/en
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Abstract

A method for producing MRI T1 contrasting agent comprising manganese tetroxide is provided to mass-produce plate-like and spherical manganese tetroxide nanoparticles with a size of 6nm - 20nm. A method for producing MRI T1 contrasting agent comprising manganese tetroxide comprises a step of adding one selected from the group consisting of water, hydrogen peroxide, the aqueous solution of the hydrogen peroxide, C1-C4 alcohol and the aqueous solution of the C1-C4 alcohol to a mixture of manganese precursor, surfactant and organic solvent. The manganese precursor is selected from the group consisting of manganese(II) acetate, manganese acetate hydrate, manganese(II) acetylacetonate, manganese(II) bromide, manganese(II) carbonatehydrate, manganese(II) chloride, manganese(II)chloride hydrate, manganese(II) fluoride, manganese(II)iodide, manganese(II) nitrate hydrate and manganese(II) sulfate.

Description

사산화삼망간 나노입자를 포함하는 자기공명영상 티1 조영제 및 그 제조 방법{MRI T1 Contrasting agent comprising Manganese Tetroxide and Method for Preparing Thereof}MRI T1 Contrasting agent comprising Manganese Tetroxide and Method for Preparing Thereof}

본 발명은 사산화삼망간(mangaese tetroxide, Mn3O4) 나노입자 제조 방법에 관한 것이다. 보다 상세하게는, 본 발명은 유기용매에 망간전구체와 계면활성제를 첨가한 혼합물에 물, 과산화수소, 과산화수소의 수용액, C1 내지 C4 알콜 및 C1 내지 C4 알콜의 수용액으로 이루어진 군에서 선택되는 어느 하나를 가하여 가열하는 단계를 포함하는, 사산화삼망간 나노입자 제조 방법과, 사산화삼망간 나노입자를 포함하는 자기공명영상 T1 조영제 및 그 제조 방법에 대한 것이다.The present invention relates to a method for preparing manganese tetroxide (Mn 3 O 4 ) nanoparticles. More specifically, the present invention is selected from the group consisting of water, hydrogen peroxide, aqueous solution of hydrogen peroxide, aqueous solution of C 1 to C 4 alcohol and C 1 to C 4 alcohol in the mixture of manganese precursor and surfactant added to the organic solvent It relates to a method for producing trimanganese tetraoxide nanoparticles, comprising the step of heating by adding any one, a magnetic resonance imaging T1 contrast agent comprising the trimanganese tetraoxide nanoparticles and a method for producing the same.

저온에서 화학반응을 이용해서 나노입자를 제조하는 방법은 여러 가지가 있다. 그 중 대표적인 것이 2005년에 이유진 등이 개시한 방법이다[Youjin Lee, Jinwoo Lee, Che Jin Bae, Je-Guen Park, Han-Jin Noh, Jae-Hoon Park, and Taeghwan Hyeon, "Large-scale synthesis of uniform and crystalline magnetite nanoparticles using reverse micelles as nanoreactors under reflux conditions", Advanced Functional Materials, 15, 503, 2005]. 이 논문에서는 역미셀을 나노반응기로 사용하여 역미셀 내에서 나노입자를 제조하는 방법을 개시한다.There are many ways to produce nanoparticles using chemical reactions at low temperatures. The most representative of these is the method initiated by Yujin et al. In 2005 [Youjin Lee, Jinwoo Lee, Che Jin Bae, Je-Guen Park, Han-Jin Noh, Jae-Hoon Park, and Taeghwan Hyeon, "Large-scale synthesis of uniform and crystalline magnetite nanoparticles using reverse micelles as nanoreactors under reflux conditions ", Advanced Functional Materials, 15, 503, 2005]. In this paper, a method for producing nanoparticles in reverse micelles using reverse micelles is disclosed.

국제특허출원 제PCT/KR2004/003090호는 산화망간 나노입자 입자를 만드는 방법을 개시한다. 상기 방법은 망간염과 나트륨산을 이용해서 망간-올레일산 복합체를 제조하고, 이를 열분해 해서 산화망간 나노입자를 만드는 방법이다.International patent application PCT / KR2004 / 003090 discloses a method of making manganese oxide nanoparticle particles. The method is to prepare a manganese-oleic acid complex using manganese salt and sodium acid, and pyrolyze the manganese oxide nanoparticles.

한편, Zhang 등은 본 발명의 산화망간 나노입자를 합성하는데 필요한 반응인 금속 전구체와 올레일아민간의 반응을 개시한다[Zhihua Zhang, Meihua Lu, Hairuo Xu, and Wee-Shong Chin, "Shape-controlled synthesis of zinc oxide: a simple method for the preparation of metal oxide nanocrystals in non-aqueous medium", Chemistry A European Journal, 13, 632, 2006]. 이 논문에서는 아연 아세테이트와 올레일아민을 산화 아연 나노입자를 만드는 방법을 제시하였다.Meanwhile, Zhang et al. Disclose a reaction between a metal precursor and oleylamine, which is a reaction necessary for synthesizing manganese oxide nanoparticles of the present invention. [Zhihua Zhang, Meihua Lu, Hairuo Xu, and Wee-Shong Chin, "Shape-controlled synthesis of zinc oxide: a simple method for the preparation of metal oxide nanocrystals in non-aqueous medium ", Chemistry A European Journal, 13, 632, 2006]. In this paper, a method for making zinc oxide nanoparticles from zinc acetate and oleylamine is presented.

현재까지, 작고 균일한 산화망간 나노입자를 만드는 방법에 대해서 여러가지 기술이 개발되었다.To date, several techniques have been developed for producing small and uniform manganese oxide nanoparticles.

그러나, 이러한 선행 기술의 개발에도 불구 하고 이제까지 발표된 산화망간 나노입자를 만드는 방법은,However, despite the development of such prior art, a method of making manganese oxide nanoparticles, which has been published so far,

첫째, 제조시 질소 또는 아르곤 분위기 하에서 공기 및 물을 차단하는 조건을 요구하는 단점이 있고,First, there is a disadvantage in requiring the conditions for blocking air and water under nitrogen or argon atmosphere in the manufacture,

둘째, 반응 온도가 섭씨 수백도에 달해 에너지가 많이 소모되며,Second, the reaction temperature reaches several hundred degrees Celsius, which consumes a lot of energy,

마지막으로, 이러한 종래의 기술들은 일회의 회분식 공정(Batch process) 반 응을 통하여 제조될 수 있는 나노입자의 양이 불과 수 밀리그램 정도에 불과하여 상업적 생산 공정에 적용하기가 적절하지 아니하다는 문제점이 있다.Finally, these conventional techniques have a problem that the amount of nanoparticles that can be produced through a batch batch reaction is only a few milligrams, which makes them unsuitable for commercial production. .

따라서, 산화망간 나노 입자 제조 기술 분야에서는 수십 nm 정도 크기 이하의 크기를 가지는 산화망간 나노입자를 용이하고 저렴한 공정을 통해 제조할 수 있는 새로운 기술의 개발이 시급히 요청되고 있다.Therefore, in the field of manufacturing manganese oxide nanoparticles, there is an urgent need to develop a new technology capable of manufacturing manganese oxide nanoparticles having a size of several tens of nm or less through an easy and inexpensive process.

현재까지 상업화된 MRI 조영제는 ‘positive’ 조영제로 상자성(paramagnetic) 화합물과 ‘negative’ 조영제로 초상자성(superparamagnetic) 나노입자가 사용되고 있다. ‘positive’ 조영제인 상자성 화합물은 보통 가돌리늄 이온(Gd3 +) 나 망간 이온(Mn2 +)의 킬레이트 화합물이며, 물의 양자의 이완을 가속하여 조영제 주위에서 밝은 대조영상을 얻게 한다.Commercially available MRI contrast agents are paramagnetic compounds as 'positive' contrast agents and superparamagnetic nanoparticles as 'negative' contrast agents. 'positive' contrast agent is a paramagnetic compound is usually a chelate compounds of gadolinium ions (Gd + 3) and manganese ion (Mn + 2), to accelerate the relaxation of the water protons to obtain a bright contrast images around the contrast agents.

그런데, 가돌리늄 이온의 경우 독성이 아주 높아 이를 방지하기 위해 킬레이트 화합물이나 고분자 물질과 결합된 화합물의 형태로 사용되고 있다. 이중 Gd-DTPA는 가장 널리 쓰이고 있으며, 이의 주요 의학적 활용처는 혈액-뇌 격막(BBB)의 손상여부나 혈관시스템의 변화, 혈액의 유동이나 관류 상태의 진단이다. 이는 조영제가 화합물의 형태로 구성되어 있기 때문에 생체 내의 면역기능을 활성화시키거나, 간에서의 분해 작용을 야기하여 혈액상에서 머무르는 시간이 약 20분 정도로 짧다는 문제를 야기한다.However, gadolinium ions are highly toxic and are used in the form of chelate compounds or compounds combined with high molecular materials to prevent this. Among them, Gd-DTPA is the most widely used, and its main medical applications are blood-brain diaphragm (BBB) damage, changes in the vascular system, and blood flow or perfusion conditions. This causes the problem that, because the contrast agent is in the form of a compound, it activates immune function in vivo or causes degradation in the liver, so that the residence time on the blood is short, about 20 minutes.

망간이온(Mn2+)을 T1 조영제로 이용한 망간 강조 자기공명영상 (Manganese-enhanced MRI, MEMRI)은 뇌과학 등 다양한 영역에서 해부학적 구조와 세포의 기능 등을 연구하는데 이용되고 있다(Lin YJ, Koretsky AP, Manganese ion enhances T1-weighted MRI during brain activation: an approach to direct imaging of brain function, Magn. Reson. Med. 1997; 38: 378-388). 망간 이온을 조영제로 이용한 MEMRI의 경우 아주 뛰어난 조영특성에도 불구하고 MnCl2의 투과량이 많고 (> 88 ~ 175 mg/kg) 망간 이온이 조직에 축적이 되어 나타나는 독성으로 인하여, 동물 뇌의 조영에만 이용되고 있으며, 사람의 두뇌에 대한 활용에는 독성이나 체내 축적가능성으로 인하여 본질적인 사용상의 한계가 있다.Manganese-enhanced MRI (MEMRI) using manganese ions (Mn 2+ ) as a T1 contrast agent has been used to study anatomical structures and cell functions in various areas such as brain science (Lin YJ, Koretsky AP, Manganese ion enhances T1-weighted MRI during brain activation: an approach to direct imaging of brain function, Magn. Reson. Med. 1997; 38: 378-388). In the case of MEMRI using manganese ions as contrast medium, it is used only for the imaging of animal brain due to the high permeation rate of MnCl 2 (> 88 ~ 175 mg / kg) and the toxicity caused by accumulation of manganese ions in tissues. The use of the human brain has its inherent limitations due to its toxicity and the possibility of body accumulation.

망간을 이용한 조영제로서 사람의 간의 조영에 사용되는 Mn-DPDP(teslascan)이 상용화되어 있다. Mn-DPDP가 신체에 투여되면 Zn가 Mn을 치환하여 Zn-DPDP가 되어 신장을 통해서 배설되고, Mn2 +은 혈액과 함께 순환하다가 간, 신장, 췌장 등에 흡수되어 조영제로서 역할을 하게 된다. 이 또한 Mn2+의 독성으로 인하여 2 내지 3ml/hr 정도의 느린 속도의 주입(slow infusion) 방법이 요구된다. 통상 5μmol/kg 몸무게 (0.5ml/kg 몸무게) 정도가 사람에게 쓰일 수 있는 양인데, 이는 뇌나 기타 다른 장기에 사용하기에 턱없이 모자라는 양이다(ref. Rofsky NM, Weinreb JC, Bernardino ME et al. Hepatocellular tumors: characterization with Mn-DPDP-enhanced MR imaging. Radiology 188:53, 1993).As a contrast medium using manganese, Mn-DPDP (teslascan), which is used to contrast human liver, is commercially available. When the Mn-DPDP is administered to the body Zn is substituted by an Mn of Zn-DPDP is excreted through the kidneys, Mn 2 + is between while circulating with blood, is absorbed kidney, pancreas, etc. will act as a contrast agent. This also requires a slow infusion method of 2-3 ml / hr due to the toxicity of Mn 2+ . Normally, 5 μmol / kg body weight (0.5 ml / kg body weight) is the amount that can be used by humans, which is not enough for the brain or other organs (ref. Rofsky NM, Weinreb JC, Bernardino ME et al. Hepatocellular tumors: characterization with Mn-DPDP-enhanced MR imaging.Radiology 188: 53, 1993).

‘positive’조영제를 이용한 T1 조영은 이미지의 왜곡이 없으며 조직의 해부학적 구조와 세포의 기능을 연구하는데 적합하며, 해상도가 뛰어나 MRI에서 가장 널리 사용되고 있어서 이에 관한 많은 연구개발이 이루어지고 있으나, 현재까지의 ‘positive’조영제의 경우 상자성 금속 이온 혹은 그들의 착화합물에 기반하고 있기 때문에 독성으로 인한 인체에의 응용 한계와 혈액에 머무르는 시간이 짧으며, 착화합물의 리간드 분자에 의한 입체적 방해로 인하여 표적지향성 물질을 부착하기 어렵게 한다.T1 contrast using 'positive' contrast agent is suitable for studying anatomical structure and cell function of tissue without distortion of image, and has been widely used in MRI because of its high resolution. The 'positive' contrast agent is based on paramagnetic metal ions or their complexes, which limits their application to the human body due to toxicity and short residence time in the blood, and attaches target-oriented substances due to steric hindrance by the ligand molecules of the complex. Makes it difficult.

이와 같은 종래 기술의 문제를 극복하기 위해 미국특허 US 2003/0215392 A1은 고분자 나노 구조체에 가돌리늄 이온을 농축하여 국지적 농도를 높이면서, 입자의 형태를 유지하려는 연구 결과를 개시하고 있다. 그러나 입자의 크기가 크고, 가돌리늄 이온이 고분자 나노 구조체에 묶여 있는 형태이기 때문에 입자의 표면에서 쉽게 분리될 수 있으며, 세포투과율이 높지 않다는 문제점이 있다.In order to overcome such a problem of the prior art, US Patent US 2003/0215392 A1 discloses a study of maintaining the shape of the particles while increasing the local concentration by concentrating gadolinium ions in the polymer nanostructure. However, since the particles are large in size and gadolinium ions are bound to the polymer nanostructure, they can be easily separated from the surface of the particles, and the cell permeability is not high.

‘negative’ 조영제로 초상자성(superparamagnetic) 나노입자가 쓰이고 있으며 대표적인 예가 초상자성 산화철 나노입자 (SPIO: superparamagnetic iron oxide)이다.Superparamagnetic nanoparticles are used as 'negative' contrast agents, and a typical example is superparamagnetic iron oxide (SPIO).

미국특허 제4,951,675호는 생체적합성 초상자성 입자를 자기공명영상의 T2 조영제로 사용하였으며, 미국특허 제6,274,121호는 초상자성 입자와 이 입자의 표면에 조직 특이적 결합 물질, 진단용 또는 약제학적 활성 물질과 커플링(coupling)할 수 있는 결합자리를 포함하는 무기 또는 유기 물질로 이루어진 상자성 입자를 개시하고 있다. US Pat. No. 4,951,675 uses biocompatible superparamagnetic particles as T2 contrast agents in magnetic resonance imaging. US Pat. No. 6,274,121 uses superparamagnetic particles and tissue-specific binding agents, diagnostic or pharmaceutically active substances on their surfaces. Disclosed are paramagnetic particles made of an inorganic or organic material comprising a coupling site capable of coupling.

나노입자의 형태를 갖춘 초상자성 산화철은 그 형태가 수 내지 수백 nm 크기의 입자이기 때문에, 생체 내 체류 시간이 수시간에 이르므로 화합물의 생체 내 체류시간에 비하여 월등히 길며, 입자의 표면에 다양한 작용기와 표적물질을 결합시 킬 수 있기 때문에, 표적지향성 조영제로서 크게 각광받고 있다.Since superparamagnetic iron oxides in the form of nanoparticles are in the form of particles ranging in size from several hundreds of nm, the retention time in vivo reaches several hours, which is much longer than the retention time of the compound in vivo. Because it can bind to and the target material, it is attracting much attention as a target-oriented contrast agent.

그러나, 초상자성 나노입자의 경우, 자체의 자성 때문에 T2 이완시간이 짧아지는데 이의 부작용으로 MRI에서 자기장을 형성하여 영상을 교란시키기도 한다. 그리고 T2 강조 영상의 경우 조영된 부분이 검게 강조되는데 이렇게 검게 강조되는 부분은 체내 출혈, 체내 석화조직, 중금속 축척 부분같이 이미 검게 나타나는 부분과 혼동을 일으킬 수 있다.However, in the case of superparamagnetic nanoparticles, the T2 relaxation time is shortened due to its magnetic properties. As a side effect, the magnetic field is formed in the MRI to disturb the image. In the case of T2-weighted images, the contrasted areas are highlighted in black, which can be confused with areas that already appear black, such as bleeding in the body, petrification of the body, and accumulation of heavy metals.

또한, 자체 자성으로 인하여 조영제 부근의 자장에 뒤틀림(blooming effect)을 초래하여 신호 손실(signal loss)이나 배경이미지에 왜곡을 가져오기 때문에 해부학적 이미지에 가까운 영상을 얻을 수 없다는 문제점이 있다.In addition, due to its own magnetism, the magnetic field in the vicinity of the contrast medium (blooming effect) causes a signal loss (signal loss) or distortion in the background image, there is a problem that can not obtain an image close to the anatomical image.

따라서 본 발명의 기본적인 목적은 유기용매에 망간전구체와 계면활성제를 첨가한 혼합물에 물, 과산화수소, 과산화수소의 수용액, C1 내지 C4 알콜 및 C1 내지 C4 알콜의 수용액으로 이루어진 군에서 선택되는 어느 하나를 가하여 가열하는 단계를 포함하는, 사산화삼망간 나노입자 제조 방법을 제공하는 것이다.Therefore, the basic object of the present invention is any one selected from the group consisting of water, hydrogen peroxide, aqueous solution of hydrogen peroxide, C 1 to C 4 alcohol and C 1 to C 4 alcohol in the mixture of manganese precursor and surfactant added to the organic solvent It provides a method for producing trimanganese tetraoxide nanoparticles, comprising the step of heating by adding one.

본 발명의 또 다른 목적은 사산화삼망간 나노입자를 포함하는 자기공명영상(MRI) T1 조영제를 제공하는 것이다.Still another object of the present invention is to provide a magnetic resonance imaging (MRI) T1 contrast agent comprising trimanganese tetraoxide nanoparticles.

본 발명의 또 다른 목적은 i) 유기용매에 망간전구체와 계면활성제를 첨가한 혼합물에 물, 과산화수소, 과산화수소의 수용액, C1 내지 C4 알콜 및 C1 내지 C4 알콜의 수용액으로 이루어진 군에서 선택되는 어느 하나를 가하여 가열하여 사산화삼망간 나노입자를 제조하는 단계; 그리고 ii) 상기 사산화삼망간 나노 입자를 생체적합성 물질을 사용하여 피복시키는 단계를 포함하는 것을 특징으로 하는, 자기공명영상 T1 조영제 제조 방법을 제공하는 것이다.Another object of the present invention is i) selected from the group consisting of water, hydrogen peroxide, aqueous solution of hydrogen peroxide, aqueous solution of C 1 to C 4 alcohol and C 1 to C 4 alcohol in the mixture of manganese precursor and surfactant added to the organic solvent Adding any one of the steps to prepare trimanganese tetraoxide nanoparticles; And ii) covering the trimanganese tetraoxide nanoparticles with a biocompatible material.

전술한 본 발명의 기본적인 목적은 유기용매에 망간전구체와 계면활성제를 첨가한 혼합물에 물, 과산화수소, 과산화수소의 수용액, C1 내지 C4 알콜 및 C1 내지 C4 알콜의 수용액으로 이루어진 군에서 선택되는 어느 하나를 가하여 가열하는 단계를 포함하는, 사산화삼망간 나노입자 제조 방법을 제공함으로써 달성될 수 있다.The basic object of the present invention described above is selected from the group consisting of water, hydrogen peroxide, aqueous solution of hydrogen peroxide, aqueous solution of C 1 to C 4 alcohol and C 1 to C 4 alcohol in the mixture of manganese precursor and surfactant added to the organic solvent. It can be achieved by providing a method for producing trimanganese tetraoxide nanoparticles, comprising the step of heating by adding any one.

상기 망간전구체는 망간(II) 아세테이트(manganese(II) acetate), 망간(II) 아세테이트 하이드레이트(manganese acetate hydrate), 망간(II) 아세틸아세토네이트(manganese(II) acetylacetonate), 망간(II) 브로마이드(manganese(II) bromide), 망간(II) 카보네이트 하이드레이트(manganese(II) carbonate hydrate), 망간(II) 클로라이드(manganese(II) chloride), 망간(II) 클로라이드 하이드레이트(manganese(II) chloride hydrate), 망간(II) 플루오라이드(manganese(II) fluoride), 망간(II) 아이오다이드(manganese(II) iodide), 망간(II) 나이트레이트 하이드레이트(manganese(II) nitrate hydrate), 망간(II) 설페이트(manganese(II) sulfate) 등으로부터 선택된다.The manganese precursors are manganese (II) acetate, manganese (II) acetate hydrate, manganese (II) acetylacetonate, manganese (II) bromide ( manganese (II) bromide), manganese (II) carbonate hydrate, manganese (II) chloride, manganese (II) chloride hydrate, Manganese (II) fluoride, manganese (II) iodide, manganese (II) nitrate hydrate, manganese (II) sulfate (manganese (II) sulfate) and the like.

상기 계면활성제는 올레산(oleic acid), 옥탄산(octanoic acid), 스테아르산(stearic acid), 데칸산(decanoic acid) 등의 C3 내지 C18 카르복시산(carboxylic acid), 또는 트라이옥틸아민(tri-n-octylamine) 등의 C3 내지 C18 알킬아민(alkyl amine(RNH2)) 등으로부터 선택되는 어느 하나 또는 그들의 혼합물로부터 선택된다.The surfactant may be selected from C 3 to C 18 carboxylic acids such as oleic acid, octanoic acid, stearic acid, decanoic acid, or trioctylamine. C 3 to C 18 alkylamines (RNH 2 ) such as n-octylamine), or the like, or a mixture thereof.

상기 유기용매는 톨루엔(toluene), 자일렌(xylene), 메시틸렌(mesitylene), 벤젠(benzene) 등의 방향족화합물과, 피리딘(pyridine), 테트라하이드로퓨란(tetrahydrofurane, THF), 등의 헤테로고리화합물(heterocyclic compounds)과, 펜탄(pentane), 헥산(hexane), 헵탄(heptane), 옥탄(octane), 데칸(decane), 도데 칸(dodecane), 테트라데칸(tetradecane), 헥사데칸(hexadecane) 등으로부터 선택되는 어느 하나 또는 그들의 혼합물로부터 선택된다.The organic solvent is an aromatic compound such as toluene, xylene, mesitylene, benzene, and heterocyclic compounds such as pyridine, tetrahydrofurane (THF), and the like. from heterocyclic compounds, pentane, hexane, heptane, octane, octane, decane, dodecane, tetradecane, hexadecane and the like. Any one selected or mixtures thereof.

상기 가열 온도가 20 ℃ 내지 100 ℃인 것이 바람직하다. 100℃ 이상에서는 물, 과산화수소 등의 반응물이 증발되고, 20℃ 이하의 온도에서는 반응물들이 고형화되어 반응이 원활히 진행하지 못한다.It is preferable that the said heating temperature is 20 degreeC-100 degreeC. At 100 ° C or higher, reactants such as water and hydrogen peroxide are evaporated. At a temperature of 20 ° C or lower, the reactants solidify and the reaction does not proceed smoothly.

또한, 상기 가열 시간은 10분 내지 48시간인 것이 바람직하다. 가열 시간을 10분 이내로 제한하면 나노 입자가 성장하지 못하는 문제점이 발생하고, 48시간 이상 가열하면 나노 입자의 균일성이 떨어진다는 문제점이 있다.In addition, the heating time is preferably 10 minutes to 48 hours. If the heating time is limited to within 10 minutes, there is a problem that the nanoparticles do not grow, there is a problem that the uniformity of the nanoparticles are lowered when heated for 48 hours or more.

도 1은 본 발명의 방법에 의해 제조된 9 nm의 사산화삼망간 나노판의 투과전자현미경(Transmission Electron Microscopy) 사진이다. 도 1의 사진을 참조하면, 본 발명의 방법으로 제조된 사산화삼망간 나노판의 한 변은 9 nm 정도임을 알 수 있고 높은 결정성을 나타낸다. 반응온도를 30 ℃, 60 ℃, 75 ℃, 90 ℃ 로 조절했을 때 반응온도가 높을 수록 제조된 사산화삼망간 나노입자의 크기가 커짐을 알 수 있었다.1 is a transmission electron microscope (Transmission Electron Microscopy) photograph of the 9 nm tri-manganese tetraoxide nanoplatelets prepared by the method of the present invention. Referring to the photograph of FIG. 1, it can be seen that one side of the trimanganese tetraoxide nanoplatelets produced by the method of the present invention is about 9 nm and exhibits high crystallinity. When the reaction temperature was adjusted to 30 ° C., 60 ° C., 75 ° C., and 90 ° C., the higher the reaction temperature, the larger the size of the prepared trimanganese tetraoxide nanoparticles.

도 2 및 도 3은 본 발명의 방법으로 제조된 16 nm 및 20 nm 크기의 사산화삼망간 나노판 투과전자현미경 사진이다. 상기 사산화삼망간 나노판의 옆 모습을 보면 형성된 나노판의 두께가 4 nm 정도임을 알 수 있다.2 and 3 are transmission electron microscope photographs of tri-manganese tetramanganese tetraoxide nanoplatelets of 16 nm and 20 nm size prepared by the method of the present invention. Looking at the side of the tri-manganese tetraoxide nanoplatelet can be seen that the thickness of the formed nanoplatelet is about 4 nm.

도 4는 본 발명의 방법으로 제조된 4.5 nm 및 7 nm 크기의 사산화삼망간 나노입자의 투과전자현미경 사진을 표시하고 있다. 합성에 사용된 계면활성제의 종류를 바꾸는 것을 통해 제조된 사산화삼망간 나노입자의 크기 및 모양을 조절할 수 있었다.Figure 4 shows a transmission electron micrograph of the 4.5 nm and 7 nm trimanganese tetraoxide nanoparticles prepared by the method of the present invention. By changing the type of surfactant used in the synthesis it was possible to control the size and shape of the prepared trimanganese tetraoxide nanoparticles.

본 발명의 방법으로 제조된 사산화삼망간 나노입자의 결정구조를 확인하기 위하여, X선 회절 측정을 수행하였고 그 결과를 도 5에 나타내었다. 사산화삼망간 나노입자의 결정구조를 조사하였는데 정방 구조(tetragonal structure)임을 알 수 있다. In order to confirm the crystal structure of the trimanganese tetraoxide nanoparticles prepared by the method of the present invention, X-ray diffraction was performed and the results are shown in FIG. 5. The crystal structure of trimanganese tetraoxide nanoparticles was investigated and it can be seen that it is tetragonal structure.

본 발명의 방법에 따라 비극성 용매를 대량으로 사용하고 극성용매를 소량으로 사용하여 제조된 나노입자는 비극성 용매에 분산된다. 또한 극성용매를 대량으로 사용하고 비극성 용매를 소량으로 사용한 경우에는 비슷한 크기와 모양을 가지지만 극성용매에 분산가능한 산화망간 나노판을 얻었다(도 6).Nanoparticles prepared using a large amount of nonpolar solvent and a small amount of polar solvent according to the method of the present invention are dispersed in the nonpolar solvent. In addition, when a large amount of the polar solvent and a small amount of the non-polar solvent was used to obtain a manganese oxide nanoplatelet having a similar size and shape but dispersible in the polar solvent (Fig. 6).

전술한 본 발명의 또 다른 목적은 사산화삼망간 나노입자를 포함하는 자기공명영상(MRI) T1 조영제를 제공함으로써 달성될 수 있다.Another object of the present invention described above can be achieved by providing a magnetic resonance imaging (MRI) T1 contrast agent comprising trimanganese tetraoxide nanoparticles.

본 발명의 MRI 조영제로 사용하기에 특히 적합한 Mn3O4의 입자 크기는 바람직하게는 50nm이하, 보다 바람직하게는 40nm 이하, 가장 바람직하게는 35nm 이하이다. 또한 이러한 본 발명에 따른 MRI 조영제로서 사용하기 위한 Mn3O4 나노입자는 그 크기의 평균값에 대한 표준 편차가 15% 이하, 바람직하게는 10% 이하, 가장 바람직하게는 5% 이하의 범위 내인 것이 바람직하다.Particle sizes of Mn 3 O 4 which are particularly suitable for use as the MRI contrast agent of the present invention are preferably 50 nm or less, more preferably 40 nm or less, most preferably 35 nm or less. In addition, the Mn 3 O 4 nanoparticles for use as an MRI contrast agent according to the present invention has a standard deviation of 15% or less, preferably 10% or less, most preferably 5% or less with respect to the average value of the size thereof. desirable.

본 발명에서 Mn3O4 나노입자를 포함하는 자기공명영상 T1 조영제는 나노입자가 수용성 환경에서 분산상태가 안정하고 생체적합성 물질로 피복되기 쉽고, 표적지향성 물질과 같은 생체 내의 활성 성분과의 결합영역을 포함하고 있으며, 질병 진단제 도는 치료제로서 가공되기에도 적합하다.In the present invention, the magnetic resonance imaging T1 contrast agent including Mn 3 O 4 nanoparticles is stable in a dispersed state in a water-soluble environment and easily coated with a biocompatible material, and a binding region with an active ingredient in a living body such as a target-oriented material It is also suitable for processing as a diagnostic or therapeutic agent.

따라서 사산화삼망간 나노입자를 생체적합성 물질로 피복하여 MRI T1 조영제로 사용할 수 있다.Therefore, the manganese tetraoxide nanoparticles may be coated with a biocompatible material and used as an MRI T1 contrast agent.

상기 생체적합성 물질은, 폴리비닐알콜, 폴리락타이드(polylactide), 폴리글리콜라이드(polyglycolide), 폴리락타이드글리콜라이드공중합체(poly(lactide-co-glycolide)), 폴리안하이드라이드(polyanhydride), 폴리에스테르(polyester), 폴리에테르에스테르(polyetherester), 폴리카프로락톤(polycaprolactone), 폴리에스테르아마이드(polyesteramide), 폴리아크릴레이트(polyacrylate), 폴리우레탄(polyurethane), 폴리비닐플루오라이드(polyvinyl fluoride), 폴리비닐이미다졸(poly(vinyl imidazole)), 클로로술포네이트 폴리올레핀(chlorosulphonate polyolefin), 폴리에틸렌옥사이드(polyethylene oxide), 폴리에틸렌글리콜(poly(ethylene glycol)) 또는 덱스트란(dextran)으로 이루어진 군에서 선택되는 어느 하나 또는 이들의 혼합물 또는 이들의 공중합체로부터 선택된다.The biocompatible materials include polyvinyl alcohol, polylactide, polyglycolide, polylactide glycolide copolymer (poly (lactide-co-glycolide)), polyanhydride, Polyester, polyetherester, polycaprolactone, polyesteramide, polyacrylate, polyurethane, polyvinyl fluoride, poly Any selected from the group consisting of poly (vinyl imidazole), chlorosulphonate polyolefin, polyethylene oxide, polyethylene glycol or dextran One or a mixture thereof or a copolymer thereof.

바람직하게는 상기 생체적합성 물질은 폴리에틸렌글리콜 또는 덱스트란이다.Preferably the biocompatible material is polyethylene glycol or dextran.

본 발명에 따라 제조된 사산화삼망간 나노입자를 물에 분산시킨 후 이완도(relaxivity)를 측정하였다(도 7). 그 결과 구형 및 판형 사산화삼망간 나노입자 모두 MRI T1조영제로서 사용될 수 있음을 확인하였다.After dispersing the trimanganese tetraoxide nanoparticles prepared according to the present invention in water (relaxivity) was measured (Fig. 7). As a result, it was confirmed that both spherical and plate-shaped trimanganese tetraoxide nanoparticles can be used as MRI T1 contrast agent.

전술한 본 발명의 또 다른 목적은 i) 유기용매에 망간전구체와 계면활성제를 첨가한 혼합물에 물, 과산화수소, 과산화수소의 수용액, C1 내지 C4 알콜 및 C1 내 지 C4 알콜의 수용액으로 이루어진 군에서 선택되는 어느 하나를 가하여 가열하여 사산화삼망간 나노입자를 제조하는 단계; 그리고 ii) 상기 사산화삼망간 나노 입자를 생체적합성 물질을 사용하여 피복시키는 단계를 포함하는 것을 특징으로 하는, 자기공명영상 T1 조영제 제조 방법을 제공함으로써 달성될 수 있다.It is another object of the present invention described above is i) in the organic solvent mixture is added to the manganese precursor with the surface active agent with water, hydrogen peroxide, an aqueous solution of hydrogen peroxide, C 1 to C 4 consisting of an aqueous solution of alcohol and a C 1 within the support C 4 alcohol Adding any one selected from the group to produce trimanganese tetraoxide nanoparticles; And ii) covering the trimanganese tetraoxide nanoparticles with a biocompatible material.

상기 i)단계의 망간전구체는 망간(II) 아세테이트(manganese(II) acetate), 망간(II) 아세테이트 하이드레이트(manganese acetate hydrate), 망간(II) 아세틸아세토네이트(manganese(II) acetylacetonate), 망간(II) 브로마이드(manganese(II) bromide), 망간(II) 카보네이트 하이드레이트(manganese(II) carbonate hydrate), 망간(II) 클로라이드(manganese(II) chloride), 망간(II) 클로라이드 하이드레이트(manganese(II) chloride hydrate), 망간(II) 플루오라이드(manganese(II) fluoride), 망간(II) 아이오다이드(manganese(II) iodide), 망간(II) 나이트레이트 하이드레이트(manganese(II) nitrate hydrate), 망간(II) 설페이트(manganese(II) sulfate) 등으로부터 선택된다.Manganese precursor of step i) is manganese (II) acetate (manganese (II) acetate), manganese (II) acetate hydrate (manganese acetate hydrate), manganese (II) acetylacetonate (manganese (II) acetylacetonate), manganese ( II) manganese (II) bromide, manganese (II) carbonate hydrate, manganese (II) chloride, manganese (II) chloride hydrate (manganese (II) chloride hydrate, manganese (II) fluoride, manganese (II) iodide, manganese (II) nitrate hydrate, manganese (II) sulfate (manganese (II) sulfate) and the like.

상기 i)단계의 계면활성제는 올레산(oleic acid), 옥탄산(octanoic acid), 스테아르산(stearic acid), 데칸산(decanoic acid) 등의 C3 내지 C18 카르복시산(carboxylic acid), 또는 트라이옥틸아민(tri-n-octylamine) 등의 C3 내지 C18 알킬아민(alkyl amine(RNH2)) 등으로부터 선택되는 어느 하나 또는 그들의 혼합물로부터 선택된다.The surfactant of step i) is C 3 to C 18 carboxylic acid (carboxylic acid) or trioctyl such as oleic acid, octanoic acid, stearic acid, decanoic acid, or the like C 3 to C 18 alkylamine (RNH 2 ), such as amine (tri-n-octylamine), or the like, or a mixture thereof.

상기 i)단계의 유기용매는 톨루엔(toluene), 자일렌(xylene), 메시틸 렌(mesitylene), 벤젠(benzene) 등의 방향족화합물과, 피리딘(pyridine), 테트라하이드로퓨란(tetrahydrofurane, THF), 등의 헤테로고리화합물(heterocyclic compounds)과, 펜탄(pentane), 헥산(hexane), 헵탄(heptane), 옥탄(octane), 데칸(decane), 도데칸(dodecane), 테트라데칸(tetradecane), 헥사데칸(hexadecane) 등으로부터 선택되는 어느 하나 또는 그들의 혼합물로부터 선택된다.The organic solvent of step i) is an aromatic compound such as toluene, xylene, mesitylene, benzene, pyridine, tetrahydrofurane (THF), Heterocyclic compounds such as pentane, hexane, heptane, octane, decane, dodecane, tetradecane, tetratradecane and hexadecane (hexadecane) and the like, or a mixture thereof.

상기 i)단계의 가열 온도가 20 ℃ 내지 100 ℃인 것이 바람직하다. 100℃ 이상에서는 물, 과산화수소 등의 반응물이 증발되고, 20℃ 이하의 온도에서는 반응물들이 고형화되어 반응이 원활히 진행하지 못한다.It is preferable that the heating temperature of step i) is 20 ° C to 100 ° C. At 100 ° C or higher, reactants such as water and hydrogen peroxide are evaporated. At a temperature of 20 ° C or lower, the reactants solidify and the reaction does not proceed smoothly.

또한, 상기 i)단계의 가열 시간은 10분 내지 48시간인 것이 바람직하다. 가열 시간을 10분 이내로 제한하면 나노 입자가 성장하지 못하는 문제점이 발생하고, 48시간 이상 가열하면 나노 입자의 균일성이 떨어진다는 문제점이 있다.In addition, the heating time of step i) is preferably 10 minutes to 48 hours. If the heating time is limited to within 10 minutes, there is a problem that the nanoparticles do not grow, there is a problem that the uniformity of the nanoparticles are lowered when heated for 48 hours or more.

상기 ii)단계의 생체적합성 물질은, 폴리비닐알콜, 폴리락타이드(polylactide), 폴리글리콜라이드(polyglycolide), 폴리락타이드글리콜라이드공중합체(poly(lactide-co-glycolide)), 폴리안하이드라이드(polyanhydride), 폴리에스테르(polyester), 폴리에테르에스테르(polyetherester), 폴리카프로락톤(polycaprolactone), 폴리에스테르아마이드(polyesteramide), 폴리아크릴레이트(polyacrylate), 폴리우레탄(polyurethane), 폴리비닐플루오라이드(polyvinyl fluoride), 폴리비닐이미다졸(poly(vinyl imidazole)), 클로로술포네이트 폴리올레핀(chlorosulphonate polyolefin), 폴리에틸렌옥사이드(polyethylene oxide), 폴리에틸렌글리콜(poly(ethylene glycol)) 또는 덱스트란(dextran)으로 이루어진 군에 서 선택되는 어느 하나 또는 이들의 혼합물 또는 이들의 공중합체로부터 선택된다.The biocompatible material of step ii), polyvinyl alcohol, polylactide, polyglycolide, polylactide glycolide copolymer (poly (lactide-co-glycolide)), polyanhydride (polyanhydride), polyester, polyetherester, polycaprolactone, polyesteramide, polyacrylate, polyurethane, polyvinyl fluoride fluoride, poly (vinyl imidazole), chlorosulphonate polyolefin, polyethylene oxide, polyethylene glycol or dextran Selected from any one or a mixture thereof or a copolymer thereof.

바람직하게는 상기 생체적합성 물질은 폴리에틸렌글리콜 또는 덱스트란이다.Preferably the biocompatible material is polyethylene glycol or dextran.

본 발명의 방법에 따르면, 6 nm 에서 20 nm 에 이르는 판상 및 구형 사산화삼망간 나노입자를 대량으로 제조할 수 있다. 또한 본 발명의 사산화삼망간 나노입자는 MRI T1 조영제로 사용될 수 있다.According to the method of the present invention, plate and spherical trimanganese tetraoxide nanoparticles ranging from 6 nm to 20 nm can be prepared in large quantities. In addition, the trimanganese tetraoxide nanoparticles of the present invention can be used as MRI T1 contrast agent.

이하, 다음의 실시예를 들어 본 발명을 보다 구체적으로 설명하고자 한다. 그러나 다음의 실시예에 대한 설명은 본 발명의 구체적인 실시 태양을 특정하여 설명하고자 하는 것일 뿐이며, 본 발명의 권리범위를 이들에 기재된 내용으로 제한해석하고자 의도하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following description of the embodiments is only intended to specifically describe the specific embodiments of the present invention, it is not intended to limit the scope of the present invention to the contents described therein.

실시예Example 1: 9  1: 9 nmnm 크기를 가지는  With size 사산화삼망간Trimanganese tetraoxide 나노판의Nanoplate 합성 synthesis

1 mmol의 아세트산 망간(II)(manganese(II) acetate hydrate)을 12 mmol의 올레일아민(oleylamine)과 15 ml의 자일렌(xylene)에 녹인 후 90 ℃까지 가열하였다. 그 후 물 1.5 ml를 넣고 90 ℃에서 3시간 동안 가열하였다. 상기 반응 혼합물을 상온까지 냉각하고 에탄올(ethanol)에 침전시켜서 침전물을 분리한 후 에탄올로 세척한 후 건조시켰다.1 mmol of manganese (II) acetate hydrate was dissolved in 12 mmol of oleylamine and 15 ml of xylene and heated to 90 ° C. Then, 1.5 ml of water was added and heated at 90 ° C. for 3 hours. The reaction mixture was cooled to room temperature and precipitated in ethanol to separate the precipitate, washed with ethanol and dried.

실시예Example 2: 20  2: 20 nmnm 크기를 가지는  With size 사산화삼망간Trimanganese tetraoxide 나노판의Nanoplate 합성 synthesis

1 mmol의 아세트산 망간(II)(manganese(II) acetate hydrate)을 10 mmol의 올레일아민(oleylamine)과 2 mmol의 4-하이드록시 벤조산(4-hydroxy benzoic acid)이 녹아있는 15 ml의 자일렌(xylene)에 녹인 후 90 ℃까지 가열하였다. 그 후 물 1.5 ml를 넣고 90 ℃에서 3시간 동안 가열하였다. 상기 반응 혼합물을 상온까지 냉각하고 에탄올(ethanol)에 침전시켜서 침전물을 분리한 후 에탄올로 세척한 후 건조시켰다.1 mmol of manganese (II) acetate hydrate in 15 ml of xylene dissolved with 10 mmol of oleylamine and 2 mmol of 4-hydroxy benzoic acid After dissolving in (xylene) and heated to 90 ℃. Then, 1.5 ml of water was added and heated at 90 ° C. for 3 hours. The reaction mixture was cooled to room temperature and precipitated in ethanol to separate the precipitate, washed with ethanol and dried.

실시예Example 3: 6  3: 6 nmnm 크기를 가지는  With size 사산화삼망간Trimanganese tetraoxide 나노입자의 합성 Synthesis of Nanoparticles

1 mmol의 아세트산 망간(II)(manganese(II) acetate hydrate)을 10 mmol의 올레일아민(oleylamine)과 2 mmol의 스테아르산(stearic acid)이 녹아있는 15 ml의 자일렌(xylene)에 녹인 후 90 ℃까지 가열하였다. 그 후 물 1 ml를 넣고 90 ℃에서 3시간 동안 가열하였다. 상기 반응 혼합물을 상온까지 냉각하고 에탄올(ethanol)에 침전시켜서 침전물을 분리한 후 에탄올로 세척한 후 건조시켰다.1 mmol of manganese (II) acetate hydrate was dissolved in 15 ml of xylene dissolved in 10 mmol of oleylamine and 2 mmol of stearic acid. Heated to 90 ° C. Then 1 ml of water was added and heated at 90 ° C for 3 hours. The reaction mixture was cooled to room temperature and precipitated in ethanol to separate the precipitate, washed with ethanol and dried.

실시예Example 4: 7 내지 8  4: 7 to 8 nmnm 크기를 가지는  With size 사산화삼망간Trimanganese tetraoxide 나노입자의 합성 Synthesis of Nanoparticles

1 mmol의 아세트산 망간(II)(manganese(II) acetate hydrate)을 8 mmol의 올레일아민(oleylamine)과 4 mmol의 올레산(oleic acid)이 녹아있는 15 ml의 자일렌(xylene)에 녹인 후 90 ℃까지 가열하였다. 그 후 물 1 ml를 넣고 90 ℃에서 3시 간동안 가열하였다. 상기 반응 혼합물을 상온까지 냉각하고 에탄올(ethanol)에 침전시켜서 침전물을 분리한 후 에탄올로 세척한 후 건조시켰다.1 mmol of manganese (II) acetate hydrate was dissolved in 15 ml of xylene dissolved in 8 mmol of oleylamine and 4 mmol of oleic acid. Heated to ° C. Then 1 ml of water was added and heated at 90 ° C for 3 hours. The reaction mixture was cooled to room temperature and precipitated in ethanol to separate the precipitate, washed with ethanol and dried.

실시예Example 5: 9  5: 9 nmnm 크기를 가지는 의 크기를 가지는  Having the size of having the size of 사산화삼망간Trimanganese tetraoxide 나노판의Nanoplate 형성의 반응온도에 따른 변화 관찰 Observation of changes with reaction temperature of formation

1 mmol의 아세트산 망간(II)(manganese(II) acetate hydrate)을 12 mmol의 올레일아민(oleylamine)과 15 ml의 자일렌(xylene)에 녹인 후 각각 30 ℃, 60 ℃, 75 ℃, 90 ℃까지 가열한 후 물 1.5 ml를 넣고 각각의 온도에서 3시간 동안 유지하였다. 상기 반응 혼합물들을 상온까지 냉각하고 에탄올(ethanol)에 침전시켜서 침전물을 분리한 후 에탄올로 세척한 후 건조시켰다.1 mmol of manganese (II) acetate hydrate was dissolved in 12 mmol of oleylamine and 15 ml of xylene, respectively, followed by 30 ° C., 60 ° C., 75 ° C. and 90 ° C. After heating up to 1.5 ml of water was added and maintained at each temperature for 3 hours. The reaction mixture was cooled to room temperature and precipitated in ethanol to separate the precipitate, washed with ethanol and dried.

실시예Example 6: 다양한 망간 전구체를 사용한  6: using various manganese precursors 사산화삼망간Trimanganese tetraoxide 나노판의Nanoplate 합성 synthesis

아세트산 망간(II) 수화물(Manganese(II) acetate hydrate), 망간(II) 아세테이트(Manganese(II) acetate), 염화망간(II)(Manganese(II) chloride), 망간(II) 나이트레이트(Manganese(II) nitrate), 망간(II) 설페이트(Manganese(II) sulfate), 그리고 망간(II) 아세틸아세토네이트(Manganese(II) acetylacetonate) 각각 1 mmol씩을 12 mmol의 올레일아민(oleylamine)과 15 ml의 자일렌(xylene)에 녹인 후 90 ℃까지 가열하였다. 그 후 물 1.5 ml를 넣고 90 ℃에서 3시간 동안 유지하였다. 상기 반응 혼합물을 상온까지 냉각하고 에탄올(ethanol)에 침전시켜서 침전물을 분리한 후 에탄올로 세척한 후 건조시켰다. Manganese (II) hydrate, Manganese (II) acetate, Manganese (II) chloride, Manganese (II) nitrate II) 1 mmol of nitrate, Manganese (II) sulfate, and Manganese (II) acetylacetonate, each with 12 mmol of oleylamine and 15 ml After dissolving in xylene and heating to 90 ℃. After that, 1.5 ml of water was added and maintained at 90 ° C. for 3 hours. The reaction mixture was cooled to room temperature and precipitated in ethanol to separate the precipitate, washed with ethanol and dried.

실시예Example 7: 다양한 망간 전구체를 사용한  7: using various manganese precursors 사산화삼망간Trimanganese tetraoxide 나노판의Nanoplate 합성 synthesis

아세트산 망간(II)(Manganese(II) acetate hydrate), 망간(II) 아세테이트(Manganese(II) acetate), 염화망간(II)(Manganese(II) chloride), 망간(II) 나이트레이트(Manganese(II) nitrate), 망간(II) 설페이트(Manganese(II) sulfate), 망간(II) 아세틸아세토네이트(Manganese(II) acetylacetonate) 각 1 mmol을 12 mmol의 올레일아민(oleylamine)과 15 ml의 자일렌(xylene)에 녹인 후 90 ℃까지 가열하였다. 그 후 물 1.5 ml를 넣고 90 ℃에서 3시간 동안 유지하였다. 상기 반응 혼합물을 상온까지 냉각하고 에탄올(ethanol)에 침전시켜서 침전물을 분리한 후 에탄올로 세척한 후 건조시켰다. Manganese (II) acetate hydrate, Manganese (II) acetate, Manganese (II) chloride, Manganese (II) nitrate (Manganese (II) 1 mmol of nitrate, Manganese (II) sulfate, Manganese (II) acetylacetonate, 12 mmol of oleylamine and 15 ml of xylene After dissolving in (xylene) and heated to 90 ℃. After that, 1.5 ml of water was added and maintained at 90 ° C. for 3 hours. The reaction mixture was cooled to room temperature and precipitated in ethanol to separate the precipitate, washed with ethanol and dried.

실시예Example 8: 물에 분산된 20  8: 20 dispersed in water nmnm 크기의  Size 사산화삼망간Trimanganese tetraoxide 나노판의Nanoplate 합성 synthesis

0.5 mmol의 아세트산 망간(II)(manganese(II) acetate)을 1.5 mmol의 올레일아민(oleylamine)과 2 mmol의 4-하이드록시 벤조산(4-hydroxy benzoic acid)이 녹아있는 12 mmol의 프로판올(propanol)에 녹인 후 90 ℃에서 2시간 동안 가열하였다. 상기 반응물에 20 ml의 물을 넣고 90 ℃까지 가열한 후 과산화수소 1 ml를 넣고 3시간 동안 가열하였다.0.5 mmol of manganese (II) acetate, 12 mmol of propanol dissolved in 1.5 mmol of oleylamine and 2 mmol of 4-hydroxy benzoic acid. It was dissolved in) and heated at 90 ° C for 2 hours. 20 ml of water was added to the reaction mixture and heated to 90 ° C., followed by 1 ml of hydrogen peroxide. The mixture was heated for 3 hours.

실시예Example 9:  9: 비극성용매에In nonpolar solvents 분산된  Distributed 사산화삼망간Trimanganese tetraoxide 나노입자를 물에 분산시키는 방법 How to Disperse Nanoparticles in Water

사산화삼망간 나노입자가 분산(5 mg/ml)되어 있는 클로로포름 2 ml에 10 mg의 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]이 녹아있는 클로로포름 1 ml를 첨가한 후 건조시켜서 클로로포름을 제거하였다. 그 후 80℃에서 1시간 동안 숙성시킨 후 5 ml의 물을 첨가해 흑갈색 사산화삼망간 나노입자 수용액을 얻었다.Chloroform in which 10 mg of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol) -2000] is dissolved in 2 ml of chloroform in which trimanganese tetraoxide nanoparticles are dispersed (5 mg / ml). 1 ml was added followed by drying to remove chloroform. After aging at 80 ° C. for 1 hour, 5 ml of water was added to obtain a black brown manganese tetraoxide aqueous solution.

도 1은 본 발명의 방법에 따라 합성된 9 nm 크기의 사산화삼망간 나노판의 투과 전자 현미경(Transmission Electron Microscopy) 사진이다.1 is a Transmission Electron Microscopy photograph of a 9 nm size manganese tetraoxide nanoplatelet synthesized according to the method of the present invention.

도 2는 본 발명의 방법에 따라 합성된 16 nm 크기의 사산화삼망간 나노입자의 투과 전자 현미경 사진이다.FIG. 2 is a transmission electron micrograph of 16 nm manganese tetraoxide nanoparticles synthesized according to the method of the present invention.

도 3은 본 발명의 방법에 따라 합성된 20 nm 크기의 사산화삼망간 나노입자에 대한 저배율 및 고배율 투과 전자 현미경 사진이다.3 is a low and high magnification transmission electron micrograph of 20 nm manganese tetraoxide nanoparticles synthesized according to the method of the present invention.

도 4는 본 발명의 방법에 따라 합성된 4.5 nm 크기와 7 nm 크기의 사산화삼망간 나노입자의 투과 전자 현미경 사진이다.4 is a transmission electron micrograph of 4.5 nm and 7 nm trimanganese tetraoxide nanoparticles synthesized according to the method of the present invention.

도 5는 본 발명의 방법에 따라 합성된 사산화삼망간 나노입자의 X선 회절(XRD) 측정결과이다.5 is an X-ray diffraction (XRD) measurement result of trimanganese tetraoxide nanoparticles synthesized according to the method of the present invention.

도 6은 본 발명의 방법에 따라 합성된 20 nm의 크기의 물에 분산된 사산화삼망간 나노판의 투과 전자 현미경 사진이다.6 is a transmission electron micrograph of trimanganese tetraoxide nanoplatelets dispersed in 20 nm size water synthesized according to the method of the present invention.

도 7은 본 발명의 방법에 따라 합성된 6 nm, 11 nm의 크기의 물에 분산된 사산화삼망간 나노입자의 이완도(r1 및 r2)를 측정한 것이다.Figure 7 measures the relaxation (r1 and r2) of trimanganese tetraoxide nanoparticles dispersed in water of 6 nm, 11 nm size synthesized according to the method of the present invention.

Claims (17)

유기용매에 망간전구체와 계면활성제를 첨가한 혼합물에 물, 과산화수소, 과산화수소의 수용액, C1 내지 C4 알콜 및 C1 내지 C4 알콜의 수용액으로 이루어진 군에서 선택되는 어느 하나를 가하여 가열하는 단계를 포함하는, 사산화삼망간 나노입자 제조 방법.Heating by adding one selected from the group consisting of water, hydrogen peroxide, an aqueous solution of hydrogen peroxide, an aqueous solution of C 1 to C 4 alcohol and C 1 to C 4 alcohol, to a mixture of manganese precursor and surfactant added to the organic solvent A method of producing trimanganese tetraoxide nanoparticles, comprising. 제1항의 방법에 있어서, 상기 망간전구체가 망간(II) 아세테이트(manganese(II) acetate), 망간(II) 아세테이트 하이드레이트(manganese acetate hydrate), 망간(II) 아세틸아세토네이트(manganese(II) acetylacetonate), 망간(II) 브로마이드(manganese(II) bromide), 망간(II) 카보네이트 하이드레이트(manganese(II) carbonate hydrate), 망간(II) 클로라이드(manganese(II) chloride), 망간(II) 클로라이드 하이드레이트(manganese(II) chloride hydrate), 망간(II) 플루오라이드(manganese(II) fluoride), 망간(II) 아이오다이드(manganese(II) iodide), 망간(II) 나이트레이트 하이드레이트(manganese(II) nitrate hydrate) 및 망간(II) 설페이트(manganese(II) sulfate)로 이루어진 군에서 선택되는 어느 하나인 것을 특징으로 하는, 사산화삼망간 나노입자 제조 방법.The method of claim 1, wherein the manganese precursor is manganese (II) acetate, manganese acetate hydrate, manganese (II) acetylacetonate Manganese (II) bromide, manganese (II) carbonate hydrate, manganese (II) chloride, manganese (II) chloride hydrate (II) chloride hydrate, manganese (II) fluoride, manganese (II) iodide, manganese (II) nitrate hydrate ) And manganese (II) sulfate (manganese (II) sulfate), characterized in that any one selected from the group consisting of. 제1항의 방법에 있어서, 상기 계면활성제가 C3 내지 C18 카르복시 산(carboxylic acid) 및 C3 내지 C18 알킬아민(C3 - C18 alkyl amine(RNH2))으로 이루어진 군에서 선택되는 어느 하나 또는 그들의 혼합물인 것을 특징으로 하는, 사산화삼망간 나노입자 제조 방법.Which is selected from the group consisting of - (C 18 alkyl amine (RNH 2) C 3) Article according to the method of claim 1, wherein the surfactant is a C 3 to C 18 carboxy acid (carboxylic acid) and a C 3 to C 18 alkyl amine Method for producing trimanganese tetraoxide nanoparticles, characterized in that one or a mixture thereof. 제1항의 방법에 있어서, 상기 유기용매가, 톨루엔(toluene), 자일렌(xylene), 메시틸렌(mesitylene), 벤젠(benzene) 등의 방향족화합물과, 피리딘(pyridine), 테트라하이드로퓨란(tetrahydrofurane, THF), 등의 헤테로고리화합물(heterocyclic compounds)과, 펜탄(pentane), 헥산(hexane), 헵탄(heptane), 옥탄(octane), 데칸(decane), 도데칸(dodecane), 테트라데칸(tetradecane) 및 헥사데칸(hexadecane)으로 이루어진 군에서 선택되는 어느 하나 또는 그들의 혼합물인 것을 특징으로 하는, 사산화삼망간 나노입자 제조 방법.The method of claim 1, wherein the organic solvent is an aromatic compound such as toluene, xylene, mesitylene, benzene, pyridine, tetrahydrofuran, Heterocyclic compounds such as THF, and the like, pentane, hexane, heptane, octane, decane, dodecane, and tetradecane And hexadecane (hexadecane), characterized in that any one selected from the group consisting of or a mixture thereof, trimanganese tetraoxide nanoparticles manufacturing method. 제1항의 방법에 있어서, 상기 가열 온도가 20 ℃ 내지 100 ℃인 것을 특징으로 하는, 사산화삼망간 나노입자 제조 방법.The method of claim 1, wherein the heating temperature is 20 ° C. to 100 ° C. 3. 제1항의 방법에 있어서, 상기 가열 시간이 10분 내지 48시간인 것을 특징으로 하는, 사산화삼망간 나노입자 제조 방법.The method of claim 1, wherein the heating time is 10 minutes to 48 hours. 사산화삼망간 나노입자를 포함하는 자기공명영상(MRI) T1 조영제.Magnetic resonance imaging (MRI) T1 contrast agent comprising trimanganese tetraoxide nanoparticles. 제7항의 T1 조영제에 있어서, 상기 사산화삼망간 나노입자가 생체적합성 물질로 피복되어 있는 것임을 특징으로 하는 자기공명영상 T1 조영제.The magnetic resonance imaging T1 contrast agent according to claim 7, wherein the trimanganese tetraoxide nanoparticles are coated with a biocompatible material. 제8항의 T1 조영제에 있어서, 상기 생체적합성 물질이, 폴리비닐알콜, 폴리락타이드(polylactide), 폴리글리콜라이드(polyglycolide), 폴리락타이드글리콜라이드공중합체(poly(lactide-co-glycolide)), 폴리안하이드라이드(polyanhydride), 폴리에스테르(polyester), 폴리에테르에스테르(polyetherester), 폴리카프로락톤(polycaprolactone), 폴리에스테르아마이드(polyesteramide), 폴리아크릴레이트(polyacrylate), 폴리우레탄(polyurethane), 폴리비닐플루오라이드(polyvinyl fluoride), 폴리비닐이미다졸(poly(vinyl imidazole)), 클로로술포네이트 폴리올레핀(chlorosulphonate polyolefin), 폴리에틸렌옥사이드(polyethylene oxide), 폴리에틸렌글리콜(poly(ethylene glycol)) 그리고 덱스트란(dextran)으로 이루어진 군에서 선택되는 어느 하나 또는 이들의 혼합물 또는 이들의 공중합체를 포함하는 것임을 특징으로 하는 자기공명영상 T1 조영제.The T1 contrast agent of claim 8, wherein the biocompatible material is polyvinyl alcohol, polylactide, polyglycolide, polylactide glycolide copolymer (poly (lactide-co-glycolide)), Polyanhydride, Polyester, Polyetherester, Polycaprolactone, Polyesteramide, Polyacrylate, Polyurethane, Polyvinyl Polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonate polyolefin, polyethylene oxide, polyethylene glycol and dextran Magnetic resonance, characterized in that it comprises any one or a mixture thereof or a copolymer thereof selected from the group consisting of T1 contrast. 제8항의 T1 조영제에 있어서, 상기 생체적합성 물질이 폴리에틸렌글리콜인 것임을 특징으로 하는 자기공명영상 T1 조영제.The magnetic resonance imaging T1 contrast agent according to claim 8, wherein the biocompatible material is polyethylene glycol. 제8항의 T1 조영제에 있어서, 상기 생체적합성 물질이 덱스트란인 것임을 특 징으로 하는 자기공명영상 T1 조영제.The magnetic resonance imaging T1 contrast agent according to claim 8, wherein the biocompatible material is dextran. i) 유기용매에 망간전구체와 계면활성제를 첨가한 혼합물에 물, 과산화수소, 과산화수소의 수용액, C1 내지 C4 알콜 및 C1 내지 C4 알콜의 수용액으로 이루어진 군에서 선택되는 어느 하나를 가하여 가열하여 사산화삼망간 나노입자를 제조하는 단계; 그리고 ii) 상기 사산화삼망간 나노 입자를 생체적합성 물질을 사용하여 피복시키는 단계를 포함하는 것을 특징으로 하는, 자기공명영상 T1 조영제 제조 방법.i) To the mixture of manganese precursor and surfactant added to the organic solvent is added by heating any one selected from the group consisting of water, hydrogen peroxide, aqueous solution of hydrogen peroxide, C 1 to C 4 alcohol and C 1 to C 4 alcohol Preparing trimanganese tetraoxide nanoparticles; And ii) coating the trimanganese tetraoxide nanoparticles with a biocompatible material. 제12항의 방법에 있어서, 상기 i)단계의 망간전구체가 망간(II) 아세테이트(manganese(II) acetate), 망간(II) 아세테이트 하이드레이트(manganese acetate hydrate), 망간(II) 아세틸아세토네이트(manganese(II) acetylacetonate), 망간(II) 브로마이드(manganese(II) bromide), 망간(II) 카보네이트 하이드레이트(manganese(II) carbonate hydrate), 망간(II) 클로라이드(manganese(II) chloride), 망간(II) 클로라이드 하이드레이트(manganese(II) chloride hydrate), 망간(II) 플루오라이드(manganese(II) fluoride), 망간(II) 아이오다이드(manganese(II) iodide), 망간(II) 나이트레이트 하이드레이트(manganese(II) nitrate hydrate) 및 망간(II) 설페이트(manganese(II) sulfate)로 이루어진 군에서 선택되는 어느 하나인 것을 특징으로 하는, 자기공명영상 T1 조영제 제조 방법.The method of claim 12, wherein the manganese precursor of step i) is manganese (II) acetate, manganese (II) acetate hydrate, manganese (II) acetylacetonate (manganese) II) acetylacetonate, manganese (II) bromide, manganese (II) carbonate hydrate, manganese (II) chloride, manganese (II) Manganese (II) chloride hydrate, manganese (II) fluoride, manganese (II) iodide, manganese (II) nitrate hydrate (manganese ( II) nitrate hydrate) and manganese (II) sulfate (manganese (II) sulfate), characterized in that any one selected from the group consisting of, MRI T1 contrast agent manufacturing method. 제12항의 방법에 있어서, 상기 i)단계의 계면활성제가 C3 내지 C18 카르복시산(carboxylic acid) 및 C3 내지 C18 알킬아민(C3 - C18 alkyl amine(RNH2))으로 이루어진 군에서 선택되는 어느 하나 또는 그들의 혼합물인 것을 특징으로 하는, 사산화삼망간 나노입자 제조 방법.The method of claim method clause 12, wherein i) a surfactant of step C 3 to C 18 carboxylic acids (carboxylic acid) and a C 3 to C 18 alkyl amine (C 3 - C 18 alkyl amine (RNH 2) from the group consisting of a) Method for producing trimanganese tetraoxide nanoparticles, characterized in that any one or a mixture thereof. 제12항의 방법에 있어서, 상기 i)단계의 유기용매가, 톨루엔(toluene), 자일렌(xylene), 메시틸렌(mesitylene), 벤젠(benzene) 등의 방향족화합물과, 피리딘(pyridine), 테트라하이드로퓨란(tetrahydrofurane, THF), 등의 헤테로고리화합물(heterocyclic compounds)과, 펜탄(pentane), 헥산(hexane), 헵탄(heptane), 옥탄(octane), 데칸(decane), 도데칸(dodecane), 테트라데칸(tetradecane) 및 헥사데칸(hexadecane)으로 이루어진 군에서 선택되는 어느 하나 또는 그들의 혼합물인 것을 특징으로 하는, 사산화삼망간 나노입자 제조 방법.The method of claim 12, wherein the organic solvent of step i) is an aromatic compound such as toluene, xylene, mesitylene, benzene, pyridine, tetrahydro Heterocyclic compounds such as tetrahydrofurane (THF), pentane, hexane, heptane, octane, decane, dodecane, dodecane and tetra Decane (tetradecane) and hexadecane (hexadecane), characterized in that any one or a mixture thereof selected from the group consisting of, trimanganese tetraoxide nanoparticles manufacturing method. 제12항의 방법에 있어서, 상기 i)단계의 가열 온도가 20 ℃ 내지 100 ℃인 것을 특징으로 하는, 사산화삼망간 나노입자 제조 방법.The method according to claim 12, wherein the heating temperature of step i) is 20 ° C to 100 ° C. 제12항의 방법에 있어서, 상기 i)단계의 가열 시간이 10분 내지 48시간인 것을 특징으로 하는, 사산화삼망간 나노입자 제조 방법.The method according to claim 12, wherein the heating time of step i) is from 10 minutes to 48 hours.
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