KR102035384B1 - Microbubble-Nanoparticles complex comprising Photosensitive and Anticancer therapeutic agent - Google Patents
Microbubble-Nanoparticles complex comprising Photosensitive and Anticancer therapeutic agent Download PDFInfo
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- KR102035384B1 KR102035384B1 KR1020170080296A KR20170080296A KR102035384B1 KR 102035384 B1 KR102035384 B1 KR 102035384B1 KR 1020170080296 A KR1020170080296 A KR 1020170080296A KR 20170080296 A KR20170080296 A KR 20170080296A KR 102035384 B1 KR102035384 B1 KR 102035384B1
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- Prior art keywords
- microbubble
- photosensitizer
- lipid
- nanoparticles
- gas
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0061—5-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
Abstract
본 발명은 초음파 조영제, 광역학 치료제 및 화학적 약물 치료제로 동시에 사용가능하고, 초음파 감응을 통해 특정 암 조직에 선택적으로 약물과 광감작제를 전달할 수 있는 마이크로버블-나노입자 복합체 및 이를 포함하는 항암 치료제에 관한 것이다.
본 발명의 복합체는 마이크로 버블 내부에 초음파 조영제용 가스와 광감작제 물질을 함유하고, 마이크로 버블 표면에 결합된 나노입자는 약물을 함유하고 있으므로 초음파 조영제, 광역학 치료제 및 화학적 약물 치료제로 동시에 사용할 수 있다.
또한, 본 발명의 복합체는 초음파가 조사되면 마이크로 버블 코어 부분에 충진된 가스를 이용하여 병변 조직에 대한 초음파 영상을 제공할 수 있을 뿐만 아니라, 마이크로 버블을 좀 더 작은 크기의 미셀이나 리포좀으로 파괴하여 약물과 광감작제를 병변 조직에 효율적으로 침투 및 축적시킬 수 있다.The present invention can be used simultaneously as an ultrasound contrast agent, a photodynamic therapy agent and a chemical drug therapy, and a microbubble-nanoparticle complex which can selectively deliver drugs and photosensitizers to specific cancer tissues through ultrasound response, and an anticancer drug comprising the same It is about.
The composite of the present invention contains an ultrasonic contrast agent gas and a photosensitizer material in the microbubble, and the nanoparticles bound to the microbubble surface contain a drug, and thus can be used simultaneously as an ultrasound contrast agent, a photodynamic therapeutic agent and a chemical drug treatment agent. have.
In addition, the composite of the present invention can not only provide an ultrasound image of the lesion tissue by using a gas filled in the microbubble core portion when the ultrasound is irradiated, but also breaks the microbubble into micelles or liposomes of smaller size. Drugs and photosensitisers can efficiently penetrate and accumulate in lesion tissue.
Description
본 발명은 광감작제를 포함한 마이크로버블-나노입자 복합체 및 이를 포함하는 항암 치료제에 관한 것으로서, 보다 자세하게는, 초음파 조영제, 광역학 치료제 및 화학적 약물 치료제로 동시에 사용가능하고, 초음파 감응을 통해 특정 암 조직에 선택적으로 약물과 광감작제를 전달할 수 있는 마이크로버블-나노입자 복합체 및 이를 포함하는 항암 치료제에 관한 것이다. The present invention relates to a microbubble-nanoparticle complex including a photosensitizer and an anticancer therapeutic agent comprising the same. More specifically, the present invention may be used simultaneously as an ultrasound contrast agent, a photodynamic therapeutic agent, and a chemical drug treatment agent. The present invention relates to a microbubble-nanoparticle complex capable of selectively delivering a drug and a photosensitizer to a tissue, and an anticancer drug comprising the same.
광역학 치료법(photodynamic therapy, PDT)이란, 각종 종양에 대해 선택성 및 광증감성이 있는 광감작제(photosensitizer)를 이용해 수술 없이 암 등의 난치병을 치료할 수 있는 기술의 하나로서, 화학요법제와 같은 부작용이 없는 일종의 근치법이다. 예컨대 광감작제를 정맥주사에 의해 대상자에 투여하고, 이에 적절한 광(light)을 조사함으로써, 여기(excite)된 광감작제가 산소분자를 활성화시켜 단일항(singlet) 상태의 산소로 변환 혹은 새로운 라디칼을 만들어 암세포나 각종 종양조직만을 선택적으로 공격, 궤멸시키는 것이다.Photodynamic therapy (PDT) is a technique that can treat intractable diseases such as cancer without surgery by using photosensitizer, which is selective and photosensitive for various tumors, and has side effects such as chemotherapy. This is a kind of curiosity without. For example, by administering a photosensitizer to a subject by intravenous injection and irradiating with appropriate light, the excited photosensitizer activates oxygen molecules and converts them into singlet oxygen or new radicals. By making cancer cells or various tumor tissues selectively attack and destroy.
광역학 치료는 정상 세포를 보존하면서 병든 세포만 선택적으로 제거할 수 있어 대부분의 경우에 전신마취의 위험성을 배제할 수 있고, 간단하게 국소마취만으로도 수술할 수 있기 때문에 시술이 용이하다. 따라서 손상 장기의 적출이 필요 없고 최소 침습의 시술 후 회복이 빠르고 입원 기간을 단축시켜 환자의 복지를 증진시키는 등의 장점이 있다.Photodynamic therapy can easily remove only the diseased cells while preserving normal cells, which can rule out the risk of general anesthesia in most cases, and is easy to perform because of simple local anesthesia. Therefore, there is no need to extract the damaged organs, and the recovery after the minimally invasive procedure is quick and the hospitalization period is shortened, thereby improving the welfare of the patient.
하지만, 대부분의 광감작제들은 난용성이며, 인체 잔류시간이 길어 광독성이 크다. 또한 광감작제가 고가이고 인체 내에서 대사가 느려 광독성의 부작용이 발견되고 있으며, 체내 투입 시 광감작제의 뭉침에 의해 치료 효율이 저하되는 문제점이 있다. However, most photosensitizers are poorly soluble and have a long photoresist and are highly phototoxic. In addition, the photosensitizer is expensive and the metabolism is slow in the human body has been found side effects of phototoxicity, there is a problem that the treatment efficiency is lowered by the aggregation of the photosensitizer when injected into the body.
현재, 광감작제를 이용한 광역학 치료법은 광감작제를 정맥주사에 의해 대상자에게 투여하고, 이후 적절한 빛(light)을 조사함으로써 암세포나 종양조직을 선택적으로 공격 또는 사멸을 유도하는 것이었으나, 현재의 광역학 치료법은 빛의 투과 제한으로 부피가 큰 종양에는 사용되고 있지 못하며, 종양 내의 광감작제의 농도가 낮아 효율적인 치료 효과를 보이지 못하고 있다.Currently, photodynamic therapy using photosensitizers has been directed to selectively attack or kill cancer cells or tumor tissues by administering the photosensitizers to the subject by intravenous injection and then irradiating with appropriate light. The photodynamic therapy of is not used for bulky tumors due to the restriction of light transmission, and the low concentration of photosensitizers in the tumors does not show an effective therapeutic effect.
또한, 약물 치료법에 널리 사용되는 기존의 항암제는 항암효과를 갖지만, 세포독성을 나타내기 때문에 암세포뿐만 아니라 정상세포에도 영향을 미쳐서 원치 않는 부작용을 나타내는 경우가 많다. 예를 들면, 약물 치료를 받은 암환자는 적혈구, 백혈구 및 혈소판의 감소 등으로 세균감염, 자연출혈, 탈모, 메스꺼움 및 구토의 부작용을 겪게 된다. 따라서, 주변 정상세포에 영향을 끼치지 않고 암세포만을 선택적으로 공격하는 표적지향성 약물전달시스템(targeted drug delivery system)의 필요성이 증가되고 있다.In addition, conventional anticancer agents widely used in drug therapy have an anticancer effect, but because of their cytotoxicity, they often affect not only cancer cells but also normal cells, and thus have unwanted side effects. For example, cancer-treated patients may experience side effects of bacterial infection, spontaneous bleeding, hair loss, nausea and vomiting due to a decrease in red blood cells, white blood cells and platelets. Accordingly, there is an increasing need for a targeted drug delivery system that selectively attacks only cancer cells without affecting surrounding normal cells.
[참고특허][Reference Patent]
한국등록특허 10-1267318Korea Patent Registration 10-1267318
한국등록특허 10-1487088Korea Patent Registration 10-1487088
본 발명은 초음파 조영제, 광역학 치료제 및 화학적 약물 치료제로 동시에 사용 가능한 약물 전달체를 제공하는 것이다. The present invention provides a drug carrier that can be used simultaneously as an ultrasound contrast agent, a photodynamic therapeutic agent and a chemical drug therapeutic agent.
본 발명은 암세포에 선택적으로 전달가능한 약물 전달체를 제공하는 것이다.The present invention provides a drug delivery agent that can be selectively delivered to cancer cells.
본 발명의 하나의 양상은 One aspect of the present invention
광감작제와 초음파 조영제용 가스가 충진된 마이크로 버블 ; 및A microbubble filled with a photosensitizer and a gas for an ultrasonic contrast medium; And
상기 마이크로 버블 표면에 복 수개 부착되고 약물을 함유하는 나노입자 ; 를 포함하는 것을 특징으로 하는 마이크로버블-나노입자 복합체에 관련된다.A plurality of nanoparticles attached to the microbubble surface and containing a drug; It relates to a microbubble-nanoparticle complex comprising a.
본 발명은 광감작제와 가스가 충진되는 마이크로 버블과 약물을 함유하는 나노입자를 각각 제조하는 단계 ; 및 상기 나노입자와 상기 마이크로버블을 소정 비율로 물에 혼합하여 반응시키는 단계를 포함하는 마이크로버블-나노입자 복합체의 제조방법에 관련된다.The present invention comprises the steps of preparing nanoparticles each containing a microbubble and a drug filled with a photosensitizer and gas; And it relates to a method for producing a microbubble-nanoparticle composite comprising the step of reacting the nanoparticles and the microbubbles in water at a predetermined ratio.
다른 양상에서, 본 발명은 In another aspect, the present invention
광감작제와 초음파 조영제용 가스가 충진된 마이크로 버블 ; 및A microbubble filled with a photosensitizer and a gas for an ultrasonic contrast medium; And
상기 마이크로 버블 표면에 복 수개 부착되고 약물을 함유하는 나노입자를 포함하되,Including a plurality of nanoparticles attached to the surface of the micro-bubble and containing a drug,
상기 마이크로 버블은 조사된 초음파를 반사시켜 영상을 제공하고, 상기 마이크로 버블은 초음파에 의해 버블 구조가 파괴되면, 광감작제가 함유된 수십 나노미터의 마이셀(Micelle) 또는 리포좀(Liposome)으로 변형되어 암세포로 소노포레이션(sonoporation)되어 이동하고, 및 레이저가 상기 광감작제에 조사되면 활성산소나 라디칼 상태의 산소를 발생시켜 상기 암세포를 파괴하고,The microbubble reflects the irradiated ultrasound to provide an image, and when the bubble structure is destroyed by the ultrasound, the microbubble is transformed into micelles or liposomes of several tens of nanometers containing a photosensitizer and cancer cells. Is sonophorized and moved, and when the laser is irradiated to the photosensitizer, it generates free radicals or oxygen in the radical state to destroy the cancer cells,
상기 나노입자는 상기 초음파에 의해 암세포로 소노포레이션(sonoporation)되어 선택적으로 이동하고, 소정 시간동안 항암 약물을 방출하는 항암 치료제에 관련된다.The nanoparticles are related to anticancer drugs that are sonophorised and selectively move to cancer cells by the ultrasound and release anticancer drugs for a predetermined time.
본 발명의 복합체는 마이크로 버블 내부에 초음파 조영제용 가스와 광감작제 물질을 함유하고, 마이크로 버블 표면에 결합된 나노입자는 약물을 함유하고 있으므로 초음파 조영제, 광역학 치료제 및 화학적 약물 치료제로 동시에 사용할 수 있다.The complex of the present invention contains an ultrasonic contrast agent gas and a photosensitizer material in the microbubble, and the nanoparticles bound to the microbubble surface contain a drug, and thus can be used simultaneously as an ultrasound contrast agent, a photodynamic therapeutic agent and a chemical drug treatment agent. have.
또한, 본 발명의 복합체는 초음파가 조사되면 마이크로 버블 코어 부분에 충진된 가스를 이용하여 병변 조직에 대한 초음파 영상을 제공할 수 있을 뿐만 아니라, 마이크로 버블을 광감작제를 함유한 작은 크기의 마이셀이나 리포좀으로 파괴하여 약물과 광감작제를 병변 조직에 효율적으로 침투 및 축적시킬 수 있다.In addition, the composite of the present invention can not only provide an ultrasound image of the lesion tissue by using a gas filled in the microbubble core portion when the ultrasonic wave is irradiated, but also a micro-sized microcell containing a microsensitizer It can be broken down into liposomes to efficiently infiltrate and accumulate drugs and photosensitisers into lesion tissue.
도 1은 본 발명의 일구현예에 의한 마이크로 버블-나노입자 복합체의 개념도를 나타낸다.
도 2는 마이크로 버블-나노입자 복합체의 작용 메카니즘을 도시한 개략도이다.
도 3은 실시예 1에서 제조한 마이크로 버블-나노입자 복합체의 confocal fluorescence microscope 이미지이다.
도 4는 본 발명에서 제조된 마이크로 버블(MBs), 나노입자(HSA NPs) 및 이들이 결합된 복합체(NPs-MBs)의 입자 사이즈를 보여준다.
도 5는 초음파에 의해 파괴되기 전과 후의 마이크로 버블을 촬영한 이미지와 평균 크기를 측정한 그래프이다.
도 6은 Ce6가 담지된 마이크로 버블의 흡광 특성을 보여준다.
도 7은 Ce6-마이크로 버블에 대한 활성산소 생성 정도를 보여준다.
도 8은 마이크로 버블에 대한 초음파 조사에 따른 Sonoporation 효과에 따른 cell uptake 를 보여준다.
도 9는 3D-배양을 통한 spheroid 세포에 대한 마이크로 버블의 Sonoporation 효과로 나노입자의 침투효과를 보여준다.
도 10은 입자의 물성, 광역학치료 효능, Sonoporation 효과를 융합하여 실제 암세포 모델에 대하여 복합치료 효능이 충분히 발생하는지에 대한 세포 생존율을 측정한 결과이다.1 shows a conceptual diagram of a micro bubble-nanoparticle composite according to one embodiment of the present invention.
2 is a schematic diagram illustrating the mechanism of action of the microbubble-nanoparticle composite.
3 is a confocal fluorescence microscope image of the microbubble-nanoparticle composite prepared in Example 1. FIG.
Figure 4 shows the particle size of the micro bubbles (MBs), nanoparticles (HSA NPs) and the complexes (NPs-MBs) to which they are prepared in the present invention.
Figure 5 is a graph measuring the image and the average size of the microbubble taken before and after being destroyed by the ultrasonic wave.
Figure 6 shows the light absorption characteristics of Ce6-supported microbubble.
7 shows the degree of free radical generation for Ce 6 -micro bubbles.
Figure 8 shows the cell uptake according to the effect of sonoporation according to the ultrasonic irradiation of the micro bubble.
9 shows the penetration effect of nanoparticles by the sonoporation effect of microbubbles on spheroid cells through 3D-culture.
Figure 10 is a result of measuring the cell survival rate whether the combined treatment properties for the actual cancer cell model by fusing the physical properties, photodynamic therapy efficacy, Sonoporation effect of the particles.
본 발명은 하기의 설명에 의하여 모두 달성될 수 있다. 하기의 설명은 본 발명의 바람직한 구체 예를 기술하는 것으로 이해되어야 하며, 본 발명이 반드시 이에 한정되는 것은 아니다. The present invention can all be achieved by the following description. The following description is to be understood as describing preferred embodiments of the invention, but the invention is not necessarily limited thereto.
도 1은 본 발명의 일구현예에 의한 마이크로 버블-나노입자 복합체의 개념도를 나타내고, 도 2는 마이크로 버블-나노입자 복합체의 작용 메카니즘을 도시한 개략도이다. Figure 1 shows a conceptual diagram of a micro bubble-nanoparticle composite according to an embodiment of the present invention, Figure 2 is a schematic diagram showing the mechanism of action of the micro bubble-nanoparticle composite.
도 1을 참고하면, 본 발명의 마이크로 버블-나노입자 복합체는 마이크로 버블 및 나노입자를 포함한다. Referring to FIG. 1, the microbubble-nanoparticle composite of the present invention includes microbubbles and nanoparticles.
상기 마이크로버블은 광감작제와 가스가 충전된 마이크로스피어(microspheres), 가스 충전된 리포좀 또는 가스 포밍 에멀젼(gas-forming emulsions)일 수 있다. 바람직하게는 상기 마이크로버블은 단일층의 지질로 형성된 버블 내부에 가스가 충진되어 마이크로 크기화 된 것일 수 있다.The microbubbles may be photospheres and gas filled microspheres, gas filled liposomes or gas-forming emulsions. Preferably, the microbubbles may be micro sized by filling gas into a bubble formed of a single layer of lipid.
상기 리포좀은 인지질을 포함하는 양친매성 화합물에 의해 형성된다. 이러한 양친매성 화합물은 전형적으로 수성 매질과 본질적으로 수불용성인 유기용매 간의 계면에 배열되어, 유화된 용매 미세방울을 안정화한다. 상기 양친매성 화합물은 수성 매질과 반응할 수 있는 친수성극 머리 부분(예: 극성 또는 이온성기)과 유기 매질과 반응할 수 있는 소수성 유기 꼬리 부분(예: 탄화수소 사슬)을 가진 분자를 가진 화합물을 포함한다. 양친매성 화합물은 비혼화성인 두 가지의 액체(예: 물과 오일)의 혼합물, 액체와 기체의 혼합물 (예: 물 중에 기체 마이크로버블) 또는 액체와 불용성 입자의 혼합물 (예. 물중에 금속 나노 입자)과 같이 다른 방법으로는 통상적으로 섞일 수 없는 물질의 혼합물을 안정화시킬 수 있는 화합물이다. The liposomes are formed by amphiphilic compounds, including phospholipids. Such amphiphilic compounds are typically arranged at the interface between an aqueous medium and an inherently water insoluble organic solvent to stabilize emulsified solvent microdrops. The amphiphilic compound includes a compound having a molecule having a hydrophilic polar head portion (such as a polar or ionic group) capable of reacting with an aqueous medium and a hydrophobic organic tail portion (such as a hydrocarbon chain) capable of reacting with an organic medium. do. Amphiphilic compounds are mixtures of two immiscible liquids (eg water and oil), mixtures of liquid and gas (eg gas microbubbles in water) or mixtures of liquid and insoluble particles (eg metal nanoparticles in water) Are compounds capable of stabilizing mixtures of materials that are otherwise incompatible with other methods.
특히, 본 발명에서는 건조된 인지질 박막과 광감작제에 비활성 기체와 물을 주입한 후 초음파 처리하여 내부에 광감작제와 조영제용 가스가 충진된 리포좀을 형성할 수 있다.In particular, in the present invention, the inert gas and water are injected into the dried phospholipid thin film and the photosensitizer and then ultrasonicated to form liposomes filled with the photosensitizer and the contrast gas.
상기 리포좀은 초음파와 기계적 교반(mechanical agitation) 방법을 병용하여 마이크로 버블을 형성하게 되고, 상기 조영제용 가스는 마이크로 버블 코어 영역에 충진되고, 상기 광감작제는 소수성 유기 꼬리 부분이 구성하는 중간층 (껍질 내부)에 충진되어 담지될 수 있다. The liposomes form micro bubbles by using ultrasonic and mechanical agitation methods, the contrast gas is filled in the microbubble core region, and the photosensitizer is an intermediate layer (shell) composed of a hydrophobic organic tail portion. Filled) and can be supported.
상기 광감작제는 소수성 성질인 것을 사용할 수 있다.The photosensitizer can be used that is hydrophobic nature.
상기 광감작제는 마이크로 버블을 형성하는 지질과 화학 결합 없이 단순히 물리적으로 결합되어 있다. 초음파에 의해 상기 마이크로 버블 구조가 파괴되면, 마이크로버블이 나노크기의 리포좀이나 마이셀로 변환되는데, 이때 광감작제는 리포좀이나 마이셀의 소수성 위치에 담지되어 병변 조직에 좀 더 용이하게 이동 축척될 수 있다. The photosensitiser is simply physically bound without chemical bonding with the lipids that form the microbubbles. When the microbubble structure is destroyed by ultrasonic waves, the microbubbles are converted into nano-sized liposomes or micelles, wherein the photosensitizer is supported at the hydrophobic position of the liposomes or micelles and can be more easily moved and accumulated in the lesion tissue. .
상기 양친매성 인지질로는 공지된 화합물을 사용할 수 있으며, 일예로는 1,2-디스테아르오일-sn-글리세로-3-포스포콜린(1,2-distearoyl-sn-glycero-3-phosphocholine, DSPC), 1,2-디아실-sn-글리세로-3-포스포에탄올아민(1,2-diacyl-sn-glycero-3-phosphoethanolamine, DOPE), 1,2-디마이리스토일-sn-글리세로-3-포스파티딜에탄올아민(1,2-Dimyristoyl-snglycero-3-phosphatidylethanolamine, DMPE), 1,2-디스테아르오일-sn-글리세로-3-포스포에탄올아민(1,2- distearoyl-sn-glycero-3-phosphoethanolamine, DSPE) 등이 있다.As the amphiphilic phospholipid, a known compound may be used. For example, 1,2-distearoyl-sn-glycero-3-phosphocholine (1,2-distearoyl-sn-glycero-3-phosphocholine, DSPC), 1,2-diacyl-sn-glycero-3-phosphoethanolamine (1,2-diacyl-sn-glycero-3-phosphoethanolamine, DOPE), 1,2-dimyristoyl-sn-glycer Rho-3-phosphatidylethanolamine (1,2-Dimyristoyl-snglycero-3-phosphatidylethanolamine (DMPE), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine (1,2- distearoyl-sn) -glycero-3-phosphoethanolamine (DSPE).
또한, 상기 양친매성 인지질 화합물은 변형된 인지질 화합물을 사용할 수 있다. 변형된 인지질의 예는 폴리에틸렌글리콜(PEG)이 첨가된 변형된 인지질의 예는 폴리에틸렌글리콜 (PEG)과 함께 변형된 포스파티딜에탄올아민(DMPE-PEG) 또는 포스포에탄올아민(DSPE-PEG) 등이 있다. In addition, the amphipathic phospholipid compound may use a modified phospholipid compound. Examples of modified phospholipids include modified phospholipids with polyethylene glycol (PEG) added, modified phosphatidylethanolamine (DMPE-PEG) or phosphoethanolamine (DSPE-PEG) together with polyethylene glycol (PEG). .
바람직하게는, 본 발명에 사용되는 양친매성 인지질 화합물은 아미드 결합을 형성하기 위한 NHS(Nhydroxy succinimide)를 포함할 수 있다.Preferably, the amphiphilic phospholipid compound used in the present invention may include NHS (Nhydroxy succinimide) to form amide bonds.
본 발명에서는 상기 양친매성 화합물 이외에 부가적인 양친매성 물질을 추가로 포함할 수 있는데, 그 일예로는 리소지질, 스테아르산, 폴리에틸렌글리콜, 폴리옥시에틸렌 지방산 에스테르, 폴리옥시에틸렌 지방산스테아르레이트, 폴리옥시에틸렌 지방 알코올 등이 있을 수 있다.In the present invention, in addition to the amphiphilic compound may further include an additional amphiphilic material, for example, lysolipid, stearic acid, polyethylene glycol, polyoxyethylene fatty acid ester, polyoxyethylene fatty acid stearate, polyoxyethylene Fatty alcohols and the like.
상기 리포좀 내부에 충진되는 가스는 공지된 기체를 제한 없이 사용할 수 있으며, 일예로서 이산화탄소, 헬륨, 질소, 아르곤, 설퍼 헥사플루오라이드, 퍼플루오르화 기체를 사용할 수 있다. 상기 기체는 불소가스가 포함된 불화물이 바람직하고, 예로는 퍼플루오로프로판(C3F8), 설퍼 헥사플루오라이드(SF6), 퍼플루오로펜탄(perfluoropentane), 데카플루오로부탄 (decafluorobutane) 및 퍼플루오로헥산(perfluorohexane)가 있다.Gas filled in the liposome can be used a known gas without limitation, for example, carbon dioxide, helium, nitrogen, argon, sulfur hexafluoride, perfluorinated gas may be used. The gas is preferably a fluoride containing fluorine gas, for example, perfluoropropane (C3F8), sulfur hexafluoride (SF6), perfluoropentane, decafluorobutane and perfluoro Hexane (perfluorohexane).
상기 광감작제는 포르피린계(phorphyrins) 화합물, 클로린계 화합물, 박테리오클로린계(bacteriochlorins) 화합물, 프탈로시아닌계(phtalocyanine) 화합물, 나프탈로시아닌계(naphthalocyanines) 화합물 및 5-아미노레불린 에스테르계(5-aminoevuline esters) 화합물로 이루어진 군에서 선택될 수 있다.The photosensitiser is a porphyrin compound, a chlorine compound, a bacteriochlorins compound, a phthalocyanine compound, a naphthalocyanines compound and a 5-aminolevulin ester compound (5-aminoevuline). esters) compounds.
상기 광감작제는 Chlorin e6, hematoporphyrin, 5-Aminolevulinic acid (ALA), Purpurin, Benzoporphyrin, Phthalocyanine로 이루어진 군에서 선택될 수 있다.The photosensitizer may be selected from the group consisting of Chlorin e6, hematoporphyrin, 5-Aminolevulinic acid (ALA), Purpurin, Benzoporphyrin, Phthalocyanine.
상기 마이크로버블은 직경이 0.1~10㎛, 바람직하게는 1~10㎛일 수 있다.The microbubbles may have a diameter of 0.1 to 10 μm, preferably 1 to 10 μm.
상기 마이크로 버블은 조사된 초음파의 세기에 따라 초음파를 반사시키거나 버블 구조가 파괴될 수 있다. 예를 들면, 상기 마이크로 버블에 0.35MPa 이하의 초음파를 조사하면, 마이크로버블의 파괴없이 병변조직의 초음파 영상을 얻을 수 있다.The micro bubble may reflect the ultrasonic wave or break the bubble structure according to the intensity of the irradiated ultrasonic wave. For example, when the ultrasonic wave of 0.35 MPa or less is irradiated to the micro bubble, an ultrasound image of the lesion tissue may be obtained without breaking the microbubbles.
한편, 상기 마이크로 버블에 0.35MPa 이상의 초음파를 조사하면, 마이크로버블은 파괴될 수 있다. On the other hand, when the ultrasonic wave of 0.35MPa or more to the microbubble, the microbubbles may be broken.
상기 마이크로 버블은 초음파에 의해 버블 구조가 파괴되면, 마이크로 버블의 골격을 형성하는 리포좀은 수십 내지 수백 나노의 좀 더 작은 크기의 마이셀(Micelle) 또는 리포좀(Liposome) 형태로 변형된다. 또한, 마이크로 버블 내부에 충진된 가스는 버블 구조 파괴와 동시에 압력파를 제공하여 초음파와 같이 상기 광감작제, 마이셀, 리포좀 및 나노입자를 병변 조직 내부로 강제 주입하여 전달 효능 향상에 기여할 수 있다. When the microbubble breaks the bubble structure by ultrasonic waves, the liposomes forming the skeleton of the microbubble are transformed into micelles or liposomes of smaller size of tens to hundreds of nanometers. In addition, the gas filled inside the micro bubble provides pressure waves at the same time as the bubble structure breakdown to force injection of the photosensitiser, micelles, liposomes and nanoparticles into the lesion tissue, such as ultrasonic waves, thereby contributing to improved delivery efficiency.
레이저광이 상기 마이셀 내지 리포좀에 조사되면, 상기 마이셀 내지 리포좀에 담지되어 있는 광감작제가 여기하여 활성산소나 라디칼 상태의 산소를 발생시킬 수 있다.When laser light is irradiated to the micelles or liposomes, the photosensitizer supported on the micelles or liposomes may be excited to generate active oxygen or oxygen in a radical state.
상기 나노입자는 내부에 약물을 함유한다. 상기 나노입자는 알부민을 포함하여, 자기 집합체(self-aggregates)를 형성할 수 있다.The nanoparticles contain a drug therein. The nanoparticles can include albumin to form self-aggregates.
상기 나노입자로는 응집성이 있는 단백질을 사용할 수 있으며, 바람직하게는 혈액 내에서 장기간 순환 하면서도 응집 구조가 유지되어 약물을 안정적으로 전달할 수 있고, 암 표적성이 있는 공지된 알부민을 사용할 수 있다. 상기 알부민은 인간혈청 알부민 또는 이의 단편을 사용할 수 있다. 상기 나노입자는 직경이 156.02± 65.76nm, 바람직하게는 100~300nm일 수 있다.As the nanoparticles, a cohesive protein may be used. Preferably, the aggregated structure is maintained while circulating in the blood for a long time, thereby stably delivering the drug, and a known albumin having cancer target may be used. The albumin may be human serum albumin or a fragment thereof. The nanoparticles may have a diameter of 156.02 ± 65.76 nm, preferably 100 to 300 nm.
상기 나노입자 내부에 함유되는 약물로는 이미 공지된 알부민에 적재될 수 있는 것들을 제한 없이 사용할 수 있다. 상기 약물로는 도세탁셀(Docetaxel), 시스플라틴(cis-platin), 캠토세신(camptothecin), 파클리탁셀(paclitaxel), 타목시펜(Tamoxifen), 아나스테로졸(Anasterozole), 글리벡(Gleevec), 5-플루오로우라실(5-FU), 플록슈리딘(Floxuridine), 류프로리드(Leuprolide), 플로타미드(Flutamide), 졸레드로네이트(Zoledronate), 독소루비신(Doxorubicin), 빈크리스틴(Vincristine), 젬시타빈(Gemcitabine), 스트렙토조토신(Streptozocin), 카보플라틴(Carboplatin), 토포테칸(Topotecan), 벨로테칸(Belotecan), 이리노테칸(Irinotecan), 비노렐빈(Vinorelbine), 히도록시우레아(hydroxyurea), 발루비신(Valrubicin), 레티노익산(retinoic acid) 계열, 메소트렉세이트(Methotrexate), 메클로레타민(Meclorethamine), 클로람부실(Chlorambucil), 부술판(Busulfan), 독시플루리딘(Doxifluridine), 빈블라스틴(Vinblastin), 마이토마이신(Mitomycin), 프레드니손(Prednisone), 테스토스테론(Testosterone), 미토산트론(Mitoxantron), 아스피린(aspirin), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐부타존(phenyltazone), 시클로포스파미드(cyclophosphamide), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 및 코르티코스테로이드(corticosteroid)로 구성된 군으로부터 선택되는 어느 하나 이상일 수 있다.Drugs contained in the nanoparticles can be used without limitation those that can be loaded in the albumin already known. The drugs include docetaxel, docetaxel, cis-platin, camptothecin, camptothecin, paclitaxel, tamoxifen, anasterozole, gleevec, 5-fluorouracil (5-FU), Fluxuridine, Leuprolide, Flotamide, Zoledronate, Doxorubicin, Vincristine, Gemcitabine ), Streptozocin, Carboplatin, Topotecan, Belotecan, Irinotecan, Vinorelbine, Hyoribine, hydroxyurea, Valrubicin ), Retinoic acid series, methotrexate, mechlortreamine, methlorethamine, chlororambucil, busulfan, doxifluridine, vinblastine ( Vinblastin, Mitomycin, Prednisone, Testosterone (Testost) erone, mitoxantron, aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, indomethacin, phenyl Buttazone, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide ), Cortisone (cortisone) and corticosteroids may be any one or more selected from the group consisting of.
상기 나노입자는 링커 또는 마이크로 버블 표면의 활성화된 반응기에 의해 마이크로버블에 결합될 수 있다. 상기 반응기로는 싸이올기(thiol), 아민기(amine)이거나, 링커로는 상기 반응기를 포함하는 화합물일 수 있다.The nanoparticles may be bound to the microbubbles by an activated reactor on a linker or microbubble surface. The reactor may be a thiol group, an amine group, or a linker may be a compound including the reactor.
좀 더 구체적으로는 상기 마이크로버블과 상기 나노입자는 이들 사이에 아미드 결합(amide bond)될 수 있다. 상기 결합은 마이크로버블중의 카르복실기와 상기 알부민에 다수 포함된 아민기 사이에 일어나는 아미드 결합으로 형성될 수 있다.More specifically, the microbubbles and the nanoparticles may be amide bond (amide bond) between them. The bond may be formed by an amide bond occurring between the carboxyl group in the microbubble and the amine group contained in the albumin.
이와 같이, 본 발명의 복합체는 마이크로 버블 내부에 초음파 조영제용 가스와 광감작제 물질을 함유하고, 마이크로 버블 표면에 결합된 나노입자는 약물을 함유하고 있으므로 초음파 조영제, 광역학 치료제 및 화학적 약물 치료제로 동시에 사용할 수 있다.As described above, the composite of the present invention contains an ultrasonic contrast agent gas and a photosensitizer material in the microbubble, and the nanoparticles bound to the microbubble surface contain a drug, and thus are used as an ultrasound contrast agent, a photodynamic therapeutic agent and a chemical drug treatment agent. Can be used at the same time.
다른 양상에서, 본 발명은 광감작제와 가스가 충진되는 마이크로 버블과 약물을 함유하는 나노입자를 각각 제조하는 단계 및 상기 나노입자와 상기 마이크로버블을 소정 비율로 물에 혼합하여 반응시키는 단계를 포함하는 마이크로버블-나노입자 복합체의 제조방법에 관련된다.In another aspect, the present invention comprises the steps of preparing a nanoparticle containing a photosensitive agent and a gas-filled microbubble and a drug, respectively, and the step of reacting the nanoparticles and the microbubbles mixed with water in a predetermined ratio It relates to a method for producing a microbubble-nanoparticle composite.
상기 마이크로버블을 제조하는 단계는 지질용액과 광감작제 용액을 각각 제조하는 단계, 혼합하여 건조시키는 단계, 수화 및 초음파 처리단계 를 포함한다.The preparing of the microbubble may include preparing a lipid solution and a photosensitizer solution, mixing and drying, hydration and sonication, respectively.
상기 지질용액은 지질과 NHS를 구비하는 지질 유도체를 용매와 혼합하여 형성한다. 좀 더 자세하게는, 상기 지질용액은 지질 : NHS를 구비하는 지질유도체의 몰비를 7~9 : 1~3 범위로 유기용매(예를 들면, 클로로포름 등)에 넣어주어 형성할 수 있다.The lipid solution is formed by mixing a lipid derivative having a lipid and NHS with a solvent. In more detail, the lipid solution may be formed by putting a molar ratio of a lipid derivative including lipid: NHS in an organic solvent (eg, chloroform, etc.) in a range of 7-9: 1-3.
상기 인지질, NHS를 구비하는 인지질 유도체는 앞에서 상술한 양친매성 인지질 화합물을 사용할 수 있다. 상기 방법은 지질용액 제조시 유화제를 첨가할 수 있다. 상기 유화제로는 리소지질, 스테아르산, 폴리에틸렌글리콜, 폴리옥시에틸렌, 지방산 에스테르, 폴리옥시에틸렌 지방산 스테아르레이트, 폴리옥시에틸렌 지방 알코올 등을 사용할 수 있다.As the phospholipid derivative having the phospholipid and NHS, the amphipathic phospholipid compound described above may be used. The method may add an emulsifier when preparing the lipid solution. As the emulsifier, lysolipids, stearic acid, polyethylene glycol, polyoxyethylene, fatty acid esters, polyoxyethylene fatty acid stearates, polyoxyethylene fatty alcohols and the like can be used.
상기 광감작제 용액은 광감작제를 유기 용매(예를 들면, 메탄올 등)에 넣어 혼합하여 형성할 수 있다. The photosensitizer solution may be formed by mixing the photosensitizer in an organic solvent (for example, methanol).
상기 방법은 두 개의 용액을 소정 비율로 혼합하고, 여기에 불활성 가스를 가해준 후 소정 시간 동안 방치하여 용매를 증발시킨다.The method mixes the two solutions in a predetermined ratio, adds an inert gas to the solution, and then leaves it for a predetermined time to evaporate the solvent.
상기 방법은 상기 지질(지질+NHS를 구비하는 지질유도체의 합) 100중량부 대비 상기 광감작제를 10~20 중량부 포함되는 것이 바람직하다.The method preferably includes 10 to 20 parts by weight of the photosensitizer relative to 100 parts by weight of the lipid (lipid derivative having lipid + NHS).
상기 방법은 용매를 증발시켜 지질과 광감작제가 혼합된 박막을 수득할 수 있다. The method may evaporate the solvent to obtain a thin film mixed with a lipid and a photosensitizer.
이어서, 상기 방법은 지질과 광감작제의 혼합 박막을 물에 넣어 수화시키고, 여기에 가스를 고압으로 주입하여 초음파 처리하는 단계를 포함한다.Subsequently, the method includes hydrating a mixed thin film of lipid and a photosensitizer into water, injecting the gas at high pressure, and sonicating the same.
좀 더 구체적으로, 상기 혼합 박막이 들어 있는 용기에 PBS 1ml을 첨가한 뒤, 상층의 기체를 C3F8 gas로 치환시켜 준 뒤, mechanical agitation으로 격렬히 교반하여 광감작제가 담지된 마이크로 버블을 제조할 수 있다. More specifically, after adding 1 ml of PBS to the container containing the mixed thin film, the gas of the upper layer is replaced with C3F8 gas, and then vigorously stirred by mechanical agitation to prepare a microbubble loaded with a photosensitizer. .
또한, 본 발명의 방법은 상기 혼합 박막이 들어 있는 용기에 물, 글리콜, 글리세린 혼합액을 넣어 55~60℃의 온도를 유지하면서 녹이고, 여기에 가스(C3F8)를 200kPa로 넣어 초음파 처리하거나, 초음파와 mechanical agitation 방법을 병용하여 교반시켜 광감작제가 담지된 마이크로 버블을 제조할 수 있다.In addition, in the method of the present invention, water, glycol, and glycerin mixed solution are put into a container containing the mixed thin film to be dissolved while maintaining a temperature of 55 to 60 ° C., and gas (C3F8) is added at 200 kPa for ultrasonic treatment or ultrasonic wave and By using a combination of mechanical agitation method and stirring can be prepared a microbubble loaded with a photosensitizer.
약물을 함유하는 나노입자를 제조하는 단계는Preparation of the nanoparticles containing the drug
알부민을 물에 녹인 후 여기에 약물을 주입하여 혼합물을 제조하는 단계, 상기 혼합물의 pH를 7~10, 바람직하게는 pH 8.0~8.5로 조절한 후 알코올류를 적하시키는 단계를 포함하고, 상기 단계에 의해 상기 알부민이 자기 집합체(self-aggregates)를 형성한다.Dissolving albumin in water and injecting a drug therein to prepare a mixture, and adjusting the pH of the mixture to 7-10, preferably pH 8.0-8.5, and then dropping alcohols. The albumin forms self-aggregates.
상기 나노입자와 상기 마이크로버블을 반응시키는 단계는 링커 또는 화학 반응기가 유도된 인지질을 이용하여 나노입자를 마이크로버블 표면에 결합시킬 수 있다. 상기 링커 또는 반응기로는 싸이올기(thiol), 아민기(amine) 바이오틴(biotin)-아비딘(avidin)등이 있을 수 있다.In the step of reacting the nanoparticles with the microbubbles, the nanoparticles may be bonded to the surface of the microbubbles using a linker or a chemical reactor-induced phospholipid. The linker or reactor may be thiol, amine biotin-avidin, and the like.
좀 더 구체적으로는 상기 마이크로버블과 상기 나노입자는 이들 사이에 아미드 결합(amide bond)될 수 있다. 상기 결합은 마이크로버블중의 카르복실기와 상기 알부민에 다수 포함된 아민기 사이에 일어나는 아미드 결합으로 형성될 수 있다. 좀 더 구체적으로는, 상기 마이크로버블 표면에 존재하는 NHS가 물에 가수분해되고, 마이크로버블 표면에 잔존하는 카르복실기와 상기 나노입자에 존재하는 아민기가 아미드 결합될 수 있다.More specifically, the microbubbles and the nanoparticles may be amide bond (amide bond) between them. The bond may be formed by an amide bond occurring between the carboxyl group in the microbubble and the amine group contained in the albumin. More specifically, NHS present on the surface of the microbubbles may be hydrolyzed in water, and carboxyl groups remaining on the surface of the microbubbles and amine groups present on the nanoparticles may be amide-bonded.
상기 나노입자와 상기 마이크로버블의 혼합 비율은 결합 반응기의 몰 비로 1 : 0.5~2일 수 있다. The mixing ratio of the nanoparticles and the microbubbles may be 1: 0.5 to 2 in a molar ratio of the coupling reactor.
다른 양상에서, 본 발명은 항암 치료제(광역학 치료체)에 관련된다. 상기 항암 치료제는 앞에서 상술한 마이크로버블과 나노입자의 복합체를 사용할 수 있다.In another aspect, the present invention relates to an anticancer agent (photodynamic therapy). The anticancer agent may use a complex of the microbubbles and nanoparticles described above.
상기 마이크로 버블은 광감작제와 초음파 조영제용 가스가 내부에 충진된다.The micro bubble is filled with a gas for the photosensitizer and the ultrasonic contrast agent.
상기 나노입자는 상기 마이크로 버블 표면에 복 수개 부착되고 약물을 함유한다.The nanoparticles are plurally attached to the microbubble surface and contain a drug.
상기 마이크로 버블은 조사된 초음파를 반사시켜 영상을 제공하고, 상기 마이크로 버블은 초음파에 의해 버블 구조가 파괴되면, 광감작제가 함유된 수십 나노미터의 마이셀(Micelle) 또는 리포좀(Liposome)으로 변형되어 암세포로 소노포레이션(sonoporation)되어 이동하고, 및 레이저가 상기 광감작제에 조사되면 활성산소나 라디칼 상태의 산소를 발생시켜 상기 암세포를 파괴한다.The microbubble reflects the irradiated ultrasound to provide an image, and when the bubble structure is destroyed by the ultrasound, the microbubble is transformed into micelles or liposomes of several tens of nanometers containing a photosensitizer and cancer cells. Sonoporation is carried out, and when a laser is irradiated to the photosensitizer, it generates free radicals and oxygen in the radical state to destroy the cancer cells.
상기 나노입자는 상기 초음파에 의해 암세포로 소노포레이션(sonoporation)되어 선택적으로 이동하고, 소정 시간동안 항암 약물을 방출할 수 있다.The nanoparticles are sonoporated into the cancer cells by the ultrasonic waves, and selectively move, and release the anticancer drug for a predetermined time.
상기 항암 치료제에 관해서는 앞에서 상술한 마이크로버블과 나노입자의 복합체를 참고할 수 있다.Regarding the anticancer drug, a complex of the microbubbles and nanoparticles described above may be referred to.
이하, 본 발명의 이해를 돕기 위해 바람직한 실시예를 제시하지만, 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 본 발명이 이에 한정되는 것은 아니다. Hereinafter, preferred examples are provided to help understanding of the present invention, but the following examples are provided only for easier understanding of the present invention, and the present invention is not limited thereto.
실시예Example 1 One
마이크로 Micro 버블bubble 제조 Produce
지질로는 1,2-disteraoyl-sn-glycero-3-phosphocholine(DSPC), DSPE-PEG2000-NHS(1,2-dioleoyl-snglycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)]2000-N-hydroxysuccinimide)를 9 : 1의 molar ratio로 혼합하여 chloroform에 녹였다. Ce6는 Methanol에 5 mg/ml로 녹였다. 이후, 위 두 용액을 glass vial에 각각 50㎕, 10㎕씩 넣어 섞은 후 질소를 가해주었다. 이를 진공 조건에서 2시간 이상 보관하여 용매를 모두 증발시켜 완벽히 건조시켰다. 이 후, glass vial에 PBS 1ml을 첨가한 뒤, 상층의 기체를 C3F8 gas로 치환시켜 준 뒤, Mechanical agitation method를 이용하여 격렬히 교반함으로서 Ce6가 담지되고 C3F8이 충진된 마이크로 버블을 수득하였다.Lipids include 1,2-disteraoyl-sn-glycero-3-phosphocholine (DSPC), DSPE-PEG2000-NHS (1,2-dioleoyl-snglycero-3-phosphoethanolamine-n- [poly (ethyleneglycol)] 2000-N- hydroxysuccinimide) was dissolved in chloroform by mixing at a molar ratio of 9: 1. Ce6 was dissolved at 5 mg / ml in Methanol. Then, 50 μl and 10 μl of the above two solutions were added to the glass vial, respectively, and nitrogen was added thereto. This was kept for 2 hours or more in a vacuum condition to completely evaporate the solvent completely dried. Thereafter, after adding 1 ml of PBS to the glass vial, the upper gas was replaced with C3F8 gas, and then vigorously stirred using a mechanical agitation method to obtain Ce6 and C3F8 filled microbubbles.
추가로, 위와 같은 Ce6의 물리적 (소수성) 특성을 이용하여 이를 담지한 마이크로 버블은, 지질 분자와 Ce6간의 화학적 결합에 따른 화학반응 및 정제과정이 필요하지 않기 때문에, 제조 비용 및 시간이 매우 효율적이다. 또한, 본 방식은 유사한 특성을 보이는 광감작제를 종류에 국한되지 않고 사용이 가능하기 때문에, 화학반응을 이용한 반응기 등을 고려할 필요가 없어 적용대상물질이 매우 포괄적이다. 로딩 효율에 있어서도, 지질 대비 10% 중량비로 제조하였을 때, 약 33%의 효율을 보인다. 이는 0.5mg/ml의 지질로 제조한 버블에 있어서 16.5 ㎍/ml의 광감작제 농도를 나타내는 것으로, 광역학치료에 있어 매우 충분한 농도이다. 특히, 전신에 Ce6가 분포되는 형태가 아니라 국소적인 병변에만 전달할 수 있다는 장점 때문에, 임상적으로 사용되는 Ce6의 농도 (0.1~2.5 mg/kg)에 비하여 현저히 낮은 농도에서 치료가 가능하다.In addition, the microbubble supporting the above-mentioned physical (hydrophobic) properties of Ce6 does not require chemical reactions and purification processes due to the chemical bonding between the lipid molecules and Ce6, and thus the manufacturing cost and time are very efficient. . In addition, the present method can be used without being limited to the type of photo-sensitizer showing similar characteristics, there is no need to consider a reactor using a chemical reaction, etc. The applicable material is very comprehensive. In terms of loading efficiency, when prepared at a 10% weight ratio to lipids, the efficiency was about 33%. It shows a photosensitizer concentration of 16.5 μg / ml in a bubble made of 0.5 mg / ml lipid, which is very sufficient for photodynamic therapy. In particular, it is possible to treat at a significantly lower concentration than the concentration of Ce6 (0.1 ~ 2.5 mg / kg) used clinically because of the advantage that it can be delivered only to the local lesion, not the form of Ce6 distributed throughout the system.
나노입자 제조(Nanoparticle Manufacturing HSAHSA -- NPsNPs ))
알부민/Distilled water (DW) 용액 (40 mg/ml)을 Traut’s reagent/DW (2 mg/ml)과 pH 7~9, 상온 (25℃)의 조건에서 1:1의 부피비로 1.5시간 반응시켰다. 반응 이후, Centrifugal filter (Molecular weight cut off, MWCO: 30 kDa)를 이용하여 (4,000rpm, 5분) 원심분리를 총 2회 수행하여 미반응 Traut’s reagent를 제거하여 순수한 thiolated 알부민을 얻었다. 이 후, DOX/DW (10 mg/ml), 100㎕를 앞에서 수득한 thiolated 알부민 용액 1ml과 섞어 교반시켜 주며, 약 1시간 이후 Ethanol을 1ml/min의 속도로 첨가시켜 줌으로써 protein precipitation 현상을 이용하여 나노입자를 형성시켰다. 이 후, 상온에서 교반을 24시간 정도 진행하여 Ethanol을 증발시켜 가교결합을 형성하였다. 이후, 원심분리를 통해 (13,200 rpm, 10 분), 제조된 입자를 가라앉히고 상층용액을 분리/재분산 함으로써 미반응물을 제거하고, 최종적으로 3,000 rpm, 5분 동안의 원심분리를 통하여 가라앉은 마이크로 크기의 입자를 제거함으로써 나노입자만을 획득하였다.Albumin / Distilled water (DW) solution (40 mg / ml) was reacted with Traut's reagent / DW (2 mg / ml) for 1.5 hours in a volume ratio of 1: 1 at pH 7-9 and room temperature (25 ° C). After the reaction, centrifugation was performed twice (4,000 rpm, 5 minutes) using a Centrifugal filter (Molecular weight cut off, MWCO: 30 kDa) to remove unreacted Traut's reagent to obtain pure thiolated albumin. Thereafter, DOX / DW (10 mg / ml) and 100 µl were mixed with 1 ml of the thiolated albumin solution obtained above, and stirred. After about 1 hour, ethanol was added at a rate of 1 ml / min. Nanoparticles were formed. Thereafter, stirring was performed at room temperature for about 24 hours to evaporate Ethanol to form a crosslink. Then, by centrifugation (13,200 rpm, 10 minutes), the prepared particles are settled and the unreacted material is removed by separating / re-dispersing the supernatant solution, and finally, the micro-settled through centrifugation for 5 minutes at 3,000 rpm. Only nanoparticles were obtained by removing particles of size.
마이크로버블과With microbubbles 나노입자의 결합 Bonding Nanoparticles
앞에서 수득한 나노입자와 마이크로 버블을 1:0.5~2의 결합 반응기의 몰비로 상온에서 2시간 동안 혼합하여 아미드 결합으로 나노입자를 마이크로 버블에 결합하였다. 결합되지 않은 HSA 나노입자는 원심분리로 제거하였다.The nanoparticles obtained above and the microbubbles were mixed at room temperature in a molar ratio of 1: 0.5 to 2 for 2 hours to bind the nanoparticles to the microbubbles with amide bonds. Unbound HSA nanoparticles were removed by centrifugation.
참고로, 마이크로 버블 제작 과정 중 손실된 NHS를 보충시켜주기 위하여 사전에 EDC와 NHS를 충분히 추가하여 반응시켜 원심분리기로 잔여 EDC, NHS를 세척하면 좀 더 결합효율을 높일 수 있다.For reference, in order to make up for the NHS lost during the microbubble manufacturing process, EDC and NHS may be sufficiently added in advance to react to wash the remaining EDC and NHS in a centrifuge, thereby further increasing the coupling efficiency.
도 3은 실시예 1에서 제조한 마이크로 버블-나노입자 복합체의 confocal fluorescence microscope 이미지이다. 도 3은 마이크로 버블-나노입자의 결합을 fluorescence dye를 이용하여 결합 유무를 확인한 것으로, 형광염료(fluorescence dye)는 green color를 나타내는 FITC와 red color를 나타내는 DiIC18을 사용하였다. 나노입자 제조 시에 FITC가 결합된 bovine serum albumin을 10-20% 첨가하여 제작함으로써 HSA-NPs에 green color를 입혔으며 microbubble은 제조 시에 lipophilic한 DiIC18를 microbubble의 bilayer 사이에 적재함으로써 labeling 하였다. 도 3의 merged된 사진을 참고하면, 초록색 형광물질이 결합된 나노입자가 빨간색 형광물질이 담지된 마이크로 버블의 표면에 잘 결합되어 있는 것을 확인하였다.3 is a confocal fluorescence microscope image of the microbubble-nanoparticle composite prepared in Example 1. FIG. 3 shows the presence or absence of binding of the micro bubble-nanoparticles using a fluorescence dye, and the fluorescent dye (Fluorescent dye) used FITC representing green color and DiIC18 representing red color. The nanoparticles were prepared by adding 10-20% of FITC-bound bovine serum albumin to the green color of HSA-NPs. The microbubble was labeled by loading lipophilic DiIC18 between the microbubble bilayers. Referring to the merged picture of FIG. 3, it was confirmed that the nanoparticles combined with the green fluorescent material were well bonded to the surface of the micro bubble carrying the red fluorescent material.
도 4는 본 발명에서 제조된 마이크로 버블(MBs), 나노입자(HSA NPs) 및 이들이 결합된 복합체(NPs-MBs)의 입자 사이즈를 보여준다. 도 4를 참고하면, 마이크로 버블은 1~10㎛ 범위의 입자 사이즈를 보여주고, 나노입자는 100~400nm 범위를 보여주었다.Figure 4 shows the particle size of the micro bubbles (MBs), nanoparticles (HSA NPs) and the complexes (NPs-MBs) to which they are prepared in the present invention. Referring to Figure 4, the microbubble showed a particle size in the range of 1 ~ 10㎛, nanoparticles showed a range of 100 ~ 400nm.
도 5는 초음파에 의해 파괴되기 전과 후의 마이크로 버블을 촬영한 이미지와 평균 크기를 측정한 그래프이다. 도 5를 참고하면, 초음파에 의해 파괴되기 전의 마이크로버블의 평균 입자 사이즈는 2217.45nm 정도이며, 이미지에도 버블 입자가 선명하게 촬영되었다. 하지만, 도5 을 참고하면, 초음파가 가해진 후 마이크로 버블이 파괴된 후 측정된 입자들의 사이즈는 98.10 nm에 불과하였으며, 결과적으로, 이미지 사진에서도 입자가 촬영되지 못하였다.Figure 5 is a graph measuring the image and the average size of the microbubble taken before and after being destroyed by the ultrasonic wave. Referring to FIG. 5, the average particle size of the microbubbles before being destroyed by ultrasonic waves is about 2217.45 nm, and the bubble particles were clearly captured in the image. However, referring to FIG. 5, the size of the particles measured after the microbubble was broken after the ultrasonic wave was applied was only 98.10 nm. As a result, the particles were not photographed in the image.
도 5는 초음파에 의해 버블이 파쇄된 이후, 수 내지 수십 마이크로 크기의 버블이 수십 나노미터의 마이셀(Micelle) 혹은 리포좀(Liposome)으로 변형되는 것을 보여준다. 이와 같은 마이크로 버블의 입자 사이즈 축소는 (Enhanced permeability and retention (EPR) 효과를 이용하여) 종양 내 광감작제의 축적이 보다 용이할 수 있음을 보여준다.FIG. 5 shows that after bubbles are broken by ultrasonic waves, bubbles of several to several tens of microns are transformed into micelles or liposomes of several tens of nanometers. The particle size reduction of such microbubbles shows that the accumulation of photosensitizers in tumors (using the Enhanced permeability and retention (EPR) effect) may be easier.
도 6은 Ce6가 담지된 마이크로 버블의 흡광 특성을 보여준다. 도 6을 참고하면, 마이크로 버블에 담지된 Ce6은 약 50nm 정도에 해당하는 red-shift 현상이 관측되었다. 이러한 현상은 Ce6가 마이크로 버블의 lipid hydrophobic chain 내에 고밀도로 존재함으로써 발생하는 현상으로써, Ce6가 버블 내부, 특히, 소수성 꼬리 부분에 잘 로딩되었음을 보여준다.Figure 6 shows the light absorption characteristics of Ce6-supported microbubble. Referring to FIG. 6, a red-shift phenomenon corresponding to about 50 nm of Ce 6 supported in the microbubble was observed. This phenomenon is caused by the high density of Ce6 in the lipid hydrophobic chain of the microbubble, which shows that Ce6 is well loaded inside the bubble, especially the hydrophobic tail.
Ce6가 담지된 마이크로 버블은, 도 6에서 확인할 수 있듯이, 본래의 Ce6 흡광에서 약 6nm, 50nm shifting된 두 개의 peak를 보인다. 특히, 도 6에서는 Ce6가 담지된 버블에 초음파를 가해주어 리포좀 또는 마이셀 형태로 변화되었을 때 (도5의 결과), 여전히 shifting된 형태를 보임을 알 수 있다. 또한, Tween 20을 리포좀 구조의 붕괴를 위하여 섞어주었을 때 shifting된 peak가 없어지는 것을 통하여, Ce6가 초음파 조사 이후에도 마이크로버블이 파쇄되면서 형성되는 리포좀 또는 마이셀 내부로 자동적으로 로딩되어 존재한다는 것을 재확인 할 수 있다. As shown in FIG. 6, the Ce 6-supported microbubble shows two peaks shifted by about 6 nm and 50 nm at the original Ce 6 absorption. In particular, in Figure 6 it can be seen that when the ultrasonic wave is applied to the Ce6-supported bubble to change in the form of liposomes or micelles (result of Figure 5), it still shows the shifted form. In addition, when
도 7은 Ce6-마이크로 버블에 대한 활성산소 생성 정도를 보여준다. 7 shows the degree of free radical generation for Ce 6 -micro bubbles.
먼저, 광감작제로써 Ce6가 담지된 마이크로 버블-나노입자 복합체의 레이저 조사에 따른 세포 내 활성산소 생성을 실험적으로 검증하기 위하여 DCFDA 조사법을 활용하였다. 이는, 세포 내에 활성산소 표지제를 미리 도입시켜 활성산소의 존재에 따라 형광이 방출되는 것을 검사하는 방식이다. First, DCFDA irradiation was used to experimentally verify the generation of free radicals in the cell by laser irradiation of Ce6-supported microbubble-nanoparticle complex as a photosensitizer. This is a method of examining the release of fluorescence in accordance with the presence of active oxygen by introducing an active oxygen labeling agent in a cell in advance.
이 때 레이저는 671 nm, 100 mW/cm2로, 30초씩 처리해 주었다. At this time, the laser was treated by 30 seconds at 671 nm, 100 mW / cm 2 .
도 7을 참고하면, 대조군(CTL), 양성 대조군(Positive control group)인 TBHP(tert-Butyl hydroperoxide)에 비해서 본원발명의 Ce6-마이크로 버블(Ce6-MBs)과 나노입자-Ce6-마이크로 버블(DOX-NPs/Ce6-MBs)에 초음파를 조사하여 마이크로버블이 파쇄되어 리포좀 또는 마이셀 형태로 세포내로 들어간 경우 현저히 높은 형광을 발생함으로써 충분한 양의 활성산소가 생성됨을 확인하였다. Referring to FIG. 7, the Ce6-micro bubble (Ce6-MBs) and the nanoparticle-Ce6-micro bubble (DOX) of the present invention are compared to the control (CTL) and the positive control group (TBHP), which is a tert-Butyl hydroperoxide (positive control group). -NPs / Ce6-MBs) was irradiated with ultrasound to confirm that a sufficient amount of active oxygen was generated by generating a significantly high fluorescence when the microbubbles were broken into the cells into liposomes or micelles.
결과적으로, Ce6가 담지된 마이크로 버블과 초음파를 조사하여 마이크로버블이 파쇄된 군에서만 높은 형광이 검출됨으로써 본원발명의 복합체에 의한 광역학치료 효능이 검증되었다. As a result, high fluorescence was detected only in the microbubble-broken group by irradiating Ce6-supported microbubble and ultrasound, thereby verifying the efficacy of photodynamic therapy by the complex of the present invention.
도 8은 마이크로 버블에 대한 초음파 조사에 따른 Sonoporation 효과를 보여준다. 마이크로 버블의 존재 시, 초음파를 가해주면 버블의 파쇄에 의하여 sonoporation 효과가 발생하며, 주변 세포 혹은 조직에 대하여 높은 약물전달 효능을 기대할 수 있다. 일반 세포주에 대해서 초음파를 0.2 W/cm2,50% duty cycle로 30초씩 처리해 준 후 항암제 및 광감작제의 전달효능을 확인하였다. 8 shows the sonoporation effect of the ultrasonic irradiation on the micro bubble. In the presence of micro bubbles, sonoporation effects are generated by crushing bubbles when ultrasonic waves are applied, and high drug delivery effects can be expected for surrounding cells or tissues. Ultrasound was treated with 0.2 W / cm 2 and 50% duty cycles for 30 sec for normal cell lines, and then the anticancer and photosensitizer delivery effects were confirmed.
도 8을 참고하면, 마이크로 버블-나노입자 복합체의 경우가 초음파를 조사해 주었을 때(US(+)), 나노입자 내부의 항암제 및 마이크로 버블 내부의 광감작제의 세포 내 도입이 sonoporation 효과에 의해 극대화됨으로써 담지된 항암제 및 광감작제의 전달율이 가장 높음을 확인할 수 있었다.Referring to FIG. 8, when the microbubble-nanoparticle complex is irradiated with ultrasound (US (+)), the introduction of the anticancer agent inside the nanoparticle and the photosensitizer inside the microbubble is maximized by the sonoporation effect. As a result, the delivery rates of the supported anticancer drugs and the photosensitizers were the highest.
특히, 마이크로 버블 내부에 담지된 광감작제의 경우, 초음파를 가해주지 않은 상태로 세포에 전달되는 경우를 보면 세포 내부에 특정 구조체의 형태 (리포좀 혹은 세포 내 미세기관인 엔도좀 등)로 존재함을 알 수 있다. 이 경우 세포 내 소화 기작에 의해 전달된 광감작제가 분해, 배출되어 충분한 효과를 거둘 수 없거나 국소적인 부위에서만 활성산소가 생성되는 한계가 존재할 수 있다. 반면, 초음파를 가해주어 버블의 sonoporation 효과를 유도하였을 경우에는 광감작제의 전달량 자체가 증가할 뿐 아니라, 세포질 내에 전반적으로 퍼져서 존재하는 것을 확인할 수 있다. 즉, 초음파를 통하여 표적에 대한 광감작제의 방출이 더욱 효율적으로 일어난다는 것으로써, 이는 세포 단계에서 뿐 아니라 조직 전체적으로 더욱 효율적인 약물 전달이 가능함을 검증한다. 따라서, 레이저 조사에 의해 더욱 광범위한 병변조직 범위에 대하여 광역학치료가 가능하다는 것이다.In particular, in the case of the photosensitizer supported inside the microbubble, when it is delivered to the cell without applying ultrasonic waves, it is found that the specific structure is present inside the cell in the form of a specific structure (liposomes or endosomes, intracellular cells). Able to know. In this case, the photosensitizer delivered by the intracellular digestion mechanism may be decomposed and discharged to have a sufficient effect, or there may be a limit in which active oxygen is generated only at a localized site. On the other hand, when the ultrasonic wave is applied to induce the sonoporation effect of the bubble, the amount of delivery of the photosensitizer itself increases, and it can be confirmed that it is present throughout the cytoplasm. In other words, the release of the photosensitizer to the target through the ultrasound more efficiently, which proves that more efficient drug delivery not only at the cellular level but throughout the tissue. Therefore, photodynamic therapy is possible for a wider range of lesion tissue by laser irradiation.
도 9는 3D-배양을 통한 spheroid 세포군에 대한 마이크로 버블의 Sonoporation 효과를 보여준다. 도 9는 췌장암 조직과 유사한 환경을 모사하기 위해 3D-배양을 통한 tumor cell spheroid를 형성하고, 이에 대한 나노입자 자체의 도입 효능을 추가로 확인한 결과이다. 이 때, 초음파는 2.0 W/cm2, 50% duty cycle로 30초씩 처리해 주었다. 9 shows the sonoporation effect of microbubbles on spheroid cell populations via 3D-culture. Figure 9 is a result of further confirming the effect of introducing the nanoparticles themselves to form a tumor cell spheroid through 3D-culture to simulate the environment similar to pancreatic cancer tissue. At this time, the ultrasonic treatment was performed at 2.0 W / cm 2 and 50% duty cycle for 30 seconds.
도 9를 참고하면, 초음파에 감응하는 마이크로 버블과 결합된 나노입자(NP-MB)는 단순한 나노입자(NP)에 비해 tumor cell spheroid 내부 깊숙이까지 훨씬 많은 양이 침투함을 확인할 수 있었다.Referring to FIG. 9, it could be seen that the nanoparticles (NP-MB) combined with the microbubble sensitive to ultrasonic waves penetrate much more deeply into the tumor cell spheroid than the simple nanoparticles (NP).
혈관 내에서 초음파를 통하여 sonoporation 효과를 유도하였을 경우, 앞선 결과에서 알 수 있듯이 Ce6를 담지한 버블은 Ce6를 담지한 리포좀 형태로 변형된다. 이 때, 버블의 표면에 부착된 항암제를 담지한 나노입자는 sonoporation 효과에 의해 즉각적으로 주변 병변조직으로 전달되지만, Ce6를 담지한 리포좀은 sonoporation 효과에 의해 넓어진 혈관벽세포 간극을 통한 EPR효과 및 추가적인 버블의 연속적인 sonoporation 효과에 의해 주변 조직으로 전달된다. 특히 Ce6의 경우, 화학적으로 지질 분자에 결합되어 있는 형태에 비하여 손쉽게 버블 혹은 리포좀 내에서 주변 조직부로 방출이 용이하기 때문에, 더욱 광범위한 병변조직 및 세포에 대하여 광역학치료가 가능하다는 장점을 보인다.When the sonoporation effect is induced through the ultrasound in the blood vessel, Ce6-carrying bubble is transformed into Ce6-containing liposome form, as shown in the previous results. At this time, the nanoparticles carrying the anticancer agent attached to the surface of the bubble are immediately transferred to the surrounding lesion tissues by the sonoporation effect, but the liposomes carrying Ce6 have the effect of EPR and additional bubbles through the vascular wall cell gap enlarged by the sonoporation effect. It is transmitted to surrounding tissues by a continuous sonoporation effect. Particularly, Ce6 has a merit that photodynamic therapy is possible for a wider range of lesion tissues and cells because it is easier to release to surrounding tissues within bubbles or liposomes compared to chemically bound forms of lipid molecules.
도 10은 입자의 물성, 광역학치료 효능, Sonoporation 효과를 융합하여 실제 암세포 모델에 대하여 복합치료 효능이 충분히 발생하는지에 대한 세포 생존율을 측정한 결과이다. 도 10을 통해 암세포에 대한 복합치료 효능을 검증할 수 있다. Figure 10 is a result of measuring the cell survival rate whether the combined treatment properties for the actual cancer cell model by fusing the physical properties, photodynamic therapy efficacy, Sonoporation effect of the particles. 10 can verify the efficacy of the combination therapy for cancer cells.
미처리 대조군, DOX-나노입자와 Ce6를 포함하지 않은 마이크로 버블 복합체(DOX-NPs/MBs), DOX를 함유하지 않은 나노입자와 Ce6를 함유하는 마이크로 버블(NPs/Ce6-MBs), DOX와 Ce6을 모두 함유하는 마이크로 버블-나노입자 복합체(DOX-NPs/Ce6-MBs)에 대해 레이저, 초음파, 레이저+초음파 처리를 한 경우의 세포 생존율을 조사하였다. Untreated controls, microbubble complexes containing no DOX-nanoparticles and Ce6 (DOX-NPs / MBs), microbubbles containing D6-containing nanoparticles and Ce6 (NPs / Ce6-MBs), DOX and Ce6 Cell viability of the microbubble-nanoparticle complex (DOX-NPs / Ce6-MBs) containing all of the laser, ultrasound, and laser + ultrasound treatments was examined.
Ce6 농도는 1μDOX 약물 농도는 100μ이며, 레이저는 671 nm, 1.0 J/cm2으로 30초씩, 초음파는 0.2 W/cm2,50% duty cycle로 5초씩 처리해 주었다. 세포주는 MIA-paca-2 인간 췌장암 세포주이며, 총 48시간 배양하였다. Ce6 concentration was 1μDOX drug concentration was 100μ, laser was treated for 30 seconds at 671 nm, 1.0 J / cm 2 , and ultrasonic was treated at 0.2 W / cm 2 , 50% duty cycle for 5 seconds. The cell line is a MIA-paca-2 human pancreatic cancer cell line and incubated for a total of 48 hours.
도 10을 참고하면, 본원발명의 마이크로 버블-나노입자 복합체(DOX-NPs/Ce6-MBs)가 레이저+초음파를 조사한 경우에 다른 입자들에 비해 전반적으로 세포사멸 효율이 높았다. 이는, 단일 치료법에 비하여 복합치료의 경우가 항암효능이 더욱 높아진다는 것을 검증해준다. 또한, 본원발명의 마이크로 버블-나노입자 복합체(DOX-NPs/Ce6-MBs)가 레이저 및 초음파를 모두 가해주지 않거나 한 종류만 가해주었을 때에 비하여, 레이저/초음파를 동시에 가해준 경우가 두 가지 치료효능을 모두 유도함으로써 세포사멸 효율을 가장 높일 수 있음을 확인할 수 있었다. 특히, 본원발명의 마이크로 버블-나노입자 복합체(DOX-NPs/Ce6-MBs)가 모든 다른 군에 비하여 최소 10% 수치 이상의 세포사멸 효율 향상을 확인하였다. Referring to FIG. 10, the microbubble-nanoparticle complex (DOX-NPs / Ce6-MBs) of the present invention exhibited higher apoptosis efficiency than other particles when irradiated with laser + ultrasonic wave. This confirms that the anticancer efficacy is higher in the combination therapy than in the single treatment. In addition, the microbubble-nanoparticle complex (DOX-NPs / Ce6-MBs) of the present invention has two therapeutic effects when the laser / ultrasonic wave is applied at the same time as compared with when the laser and the ultrasonic wave are not applied or only one type is applied. By inducing all of these it was confirmed that the highest apoptosis efficiency. In particular, it was confirmed that the microbubble-nanoparticle complex (DOX-NPs / Ce6-MBs) of the present invention improves apoptosis efficiency by at least 10% compared to all other groups.
본 발명의 단순한 변형 내지 변경은 모두 본 발명의 영역에 속하는 것으로, 본 발명의 구체적인 보호범위는 첨부된 특허청구범위에 의하여 명확해질 것이다.All simple modifications and variations of the present invention fall within the scope of the present invention, and the specific scope of the present invention will be apparent from the appended claims.
Claims (16)
상기 마이크로 버블 표면에 복 수개 부착되고 약물을 함유하는 나노입자를 포함하고,
상기 마이크로버블은 단일층의 지질로 형성된 버블 내부에 상기 조영제용 가스가 충진되고, 상기 지질의 소수성 부분에 상기 광감작제가 결합되고,
상기 마이크로 버블은 조사된 초음파의 세기에 따라 초음파를 반사시키거나 버블 구조가 파괴되고,
상기 마이크로버블은 크기가 1~10㎛이고,
상기 마이크로 버블이 초음파에 의해 버블 구조가 파괴되면, 상기 마이크로버블 보다 작은 크기의 마이셀(Micelle) 형태로 변형되고, 상기 광감작제는 상기 마이셀의 소수성 영역에 담지되는 것을 특징으로 하는 마이크로버블-나노입자 복합체.A microbubble filled with a photosensitizer and a gas for an ultrasonic contrast medium; And
A plurality of nanoparticles attached to the microbubble surface and containing a drug,
The microbubble is filled with the contrast agent gas inside a bubble formed of a single layer of lipid, the photosensitive agent is bound to a hydrophobic portion of the lipid,
The micro bubble reflects the ultrasonic waves or breaks the bubble structure according to the intensity of the irradiated ultrasonic waves,
The microbubble has a size of 1 ~ 10㎛,
When the microbubble breaks the bubble structure by ultrasonic waves, the microbubble-nano is transformed into a micelle of a smaller size than the microbubble, and the photosensitizer is supported on the hydrophobic region of the micelle. Particle complex.
(self-aggregates)를 형성하고, 그 직경이 100~300nm인 것을 특징으로 하는 마이크로버블-나노입자 복합체.The self-assembly of claim 1, wherein the nanoparticle comprises albumin.
(self-aggregates) to form, the microbubble-nanoparticle composite, characterized in that the diameter is 100 ~ 300nm.
상기 나노입자와 상기 마이크로버블을 소정 비율로 물에 혼합하여 반
응시키는 단계를 포함하고,
상기 마이크로버블은 크기가 1~10㎛이고,
상기 마이크로버블을 제조하는 단계는
지질과 NHS를 구비하는 지질 유도체를 용매와 혼합하여 지질 용액을 제조하는 단계와 광감작제를 용매에 넣어 광감작제 용액을 각각 제조하는 단계 ;
상기 두 개의 용액을 혼합시켜 불활성 가스를 가해준 후 소정 시간 동안 방치하여 용매를 증발시키고 지질과 광감작제가 혼합된 박막을 수득하는 단계 ;
혼합된 박막이 들어 있는 용기 내부의 상기 불활성 가스를 초음파 조영제용 가스로 치환하는 단계 ; 및
기계적 방법으로 교반하는 단계를 포함하는 것을 특징으로 하는 마이크로버블-나노입자 복합체의 제조방법. Preparing nanoparticles each containing a microbubble and a drug filled with a photosensitizer and a gas; And
The nanoparticles and the microbubbles are mixed in water at a predetermined ratio and half
Including the step of responding,
The microbubble has a size of 1 ~ 10㎛,
Preparing the microbubble is
Preparing a lipid solution by mixing a lipid derivative having a lipid and NHS with a solvent, and preparing a photosensitizer solution by adding a photosensitizer to the solvent;
Mixing the two solutions to add an inert gas and then leaving the mixture for a predetermined time to evaporate the solvent to obtain a thin film mixed with a lipid and a photosensitizer;
Replacing the inert gas in the vessel containing the mixed thin film with an ultrasonic contrast gas; And
Method for producing a microbubble-nanoparticle composite, comprising the step of stirring by a mechanical method.
The method according to claim 12, wherein the method comprises 10 to 20 parts by weight of the photosensitizer compared to 100 parts by weight of the lipid (sum of lipid derivatives including lipid + NHS). Method for producing a microbubble-nanoparticle composite, characterized in that used.
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| KR102379296B1 (en) * | 2019-09-02 | 2022-03-29 | (주)아이엠지티 | Immuno microbubble complex and use thereof |
| KR102565700B1 (en) * | 2019-11-12 | 2023-08-17 | 서강대학교산학협력단 | Nanoparticle complex for ophthalmic formulation with improved ocular permeability through surface modification using lipid |
| KR102398743B1 (en) * | 2020-09-03 | 2022-05-16 | 충남대학교병원 | Composition for treating the dysuresia comprising microbubbles to be ultrasonic-induced |
| KR102578025B1 (en) * | 2020-12-07 | 2023-09-15 | (주)아이엠지티 | Immune checkpoint inhibitor conjugated with sonosensitizer and use thereof |
| CN114983942B (en) * | 2022-05-18 | 2023-09-05 | 中国科学院理化技术研究所 | Multifunctional microbubbles for treating helicobacter pylori infection, preparation and application thereof |
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