KR102039813B1 - POC compound, manufacturing method thereof and pharmaceutical composition for preventing or treatment of inflammatory disease - Google Patents
POC compound, manufacturing method thereof and pharmaceutical composition for preventing or treatment of inflammatory disease Download PDFInfo
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- KR102039813B1 KR102039813B1 KR1020180006154A KR20180006154A KR102039813B1 KR 102039813 B1 KR102039813 B1 KR 102039813B1 KR 1020180006154 A KR1020180006154 A KR 1020180006154A KR 20180006154 A KR20180006154 A KR 20180006154A KR 102039813 B1 KR102039813 B1 KR 102039813B1
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Abstract
발명은 POC(poly(oxalate-co-curcumin)) 화합물, 이의 제조방법, 상기 화합물을 유효성분으로 포함하는 염증성 질환의 예방 또는 치료용 약학적 조성물 및 상기 화합물에 형광물질이 포겹된 영상 조영제에 관한 것이다. The present invention relates to a POC (poly (oxalate-co-curcumin)) compound, a method for preparing the same, a pharmaceutical composition for preventing or treating an inflammatory disease comprising the compound as an active ingredient, and an imaging contrast agent in which the compound is fluorescent will be.
Description
본 발명은 POC(poly(oxalate-co-curcumin)) 화합물, 이의 제조방법, 상기 화합물을 포함하는 약물전달체, 상기 화합물을 유효성분으로 포함하는 염증성 질환의 예방 또는 치료용 약학적 조성물, 상기 화합물을 유효성분으로 포함하는 간 질환의 예방 또는 치료용 약학적 조성물 및 상기 화합물에 형광물질이 포겹된 영상조영제에 관한 것이다.The present invention is a POC (poly (oxalate-co-curcumin)) compound, a preparation method thereof, a drug carrier comprising the compound, a pharmaceutical composition for the prevention or treatment of inflammatory diseases comprising the compound as an active ingredient, the compound It relates to a pharmaceutical composition for the prevention or treatment of liver disease, including as an active ingredient, and an imaging contrast agent is superimposed on the compound.
임상적으로 사용된 대다수의 약물은 짧은 혈액 순환 속도와 총체적인 대사율을 가진 저분자 화합물이다. 약물의 투여에 있어, 이런 작은 분자 약물들은 악성 조직 모두로 빠르게 확산되고 몸 전체로 균등하게 분산된다. 결과적으로 상대적으로 적은 양의 약물만이 타겟 부위에 도달하고, 이에 따른 부작용도 발생한다. 이런 한계점을 극복하고 각각의 약물의 잠재력을 향상시키기 위해 약물 전달체의 개발을 위한 많은 노력이 있었다. 대부분의 약물 전달체는 다양한 구조와 물리화학적 특성을 가진 생체적합성과 생분해성에 기초한다.The majority of drugs used clinically are low molecular weight compounds with short blood circulation and overall metabolic rate. In the administration of the drug, these small molecule drugs spread rapidly throughout all malignant tissues and are evenly distributed throughout the body. As a result, only a relatively small amount of drug reaches the target site, resulting in side effects. Many efforts have been made to develop drug delivery vehicles to overcome these limitations and to improve the potential of each drug. Most drug carriers are based on biocompatibility and biodegradability with various structural and physicochemical properties.
일반적으로 고분자 약물 전달 시스템은 마이크로와 나노미립자 약물 전달 시스템으로서 또는 복합 고분자 약물로서 분류될 수 있다. 미립자 약물 전달 시스템은 물리적으로 약물을 혼합하게 하고 미셀과 고체 입자를 포함함으로써 환경으로부터 약물을 보호한다. 한편으로 복합 고분자 약물은 가교제(linker)를 통해 고분자 주사슬의 가지에 공유결합으로 첨부된 약물을 가지고 있다. 예로는 단백질, 다당류 또는 덴드리머(dendrimer)와 폴리하이드록시프로필 메타크릴아미드 (polyhydroxypropyl methacrylamide)와 같은 합성 고분자가 있다. 이런 접근은 약물의 안정성과 약동학적 특성의 큰 개선을 이루었다. 그러나 이렇게 적은 양의 약물을 함유한 고분자 약물 전달체는 응용에 있어 약점이 될 수도 있다.In general, polymeric drug delivery systems can be classified as micro and nanoparticulate drug delivery systems or as complex polymeric drugs. Particulate drug delivery systems physically mix the drug and protect the drug from the environment by including micelles and solid particles. On the other hand, the composite polymer drug has a drug covalently attached to the branch of the polymer main chain through a linker. Examples include proteins, polysaccharides or synthetic polymers such as dendrimers and polyhydroxypropyl methacrylamide. This approach has led to significant improvements in drug stability and pharmacokinetic properties. However, polymeric drug carriers containing such small amounts of drug may be a weak point in applications.
저분자 약물의 전달을 위한 새로운 접근 방법 중 하나로 저분자 약물자체를 고분자 주사슬에 결합하여 약물을 전달하는 방법이 있다. 이러한 약물전달체가 가지는 가장 좋은 기능은 고분자 자체가 통제된 약물 전달 시스템이란 것이다. 이것은 분해 산물 그 자체가 치료제이고, 고분자는 가수 분해성 불안정한 무수물과 주쇄(backbone) 내의 에스테르 결합이 완전히 분해되기 때문이다.One of the new approaches for the delivery of low molecular weight drugs is to combine the low molecular weight drug itself with the polymer main chain to deliver the drug. The best function of these drug carriers is that the polymer itself is a controlled drug delivery system. This is because the degradation product itself is a therapeutic agent, and the polymer is completely degradable of hydrolytically labile anhydrides and ester bonds in the backbone.
기존의 생분해성 고분자들은 여러 가지 문제점을 가지고 있다. 미국 식품의약청(FDA)의 승인을 받은 생체고분자인 PLGA(Polylactide-co-glycolide)와, 나노미립구와 미셀로 제조되어 약물전달체로 많은 연구가 이루어지고 있는 PCL(Polycaprolactone), Polyorthoester 및 Polyacetal 등은 높은 가격 및 분해 후에 염증을 유발하는 분해산물이 생성되거나 가수분해 속도가 느려 약물의 방출속도가 지연되는 문제점들을 가지고 있다. 이러한 고분자들은 또한 특정부위를 표적하거나 질병부위의 환경에 감응하는 능력이 없다.Existing biodegradable polymers have various problems. PLGA (Polylactide-co-glycolide), a biopolymer approved by the US Food and Drug Administration, and PCL (Polycaprolactone), Polyorthoester, and Polyacetal, which are made of nanoparticles and micelles After the price and decomposition, there is a problem in that a degradation product that causes inflammation or a slow hydrolysis rate is delayed to release the drug. These polymers also lack the ability to target specific areas or to respond to the environment of diseased areas.
유리 산소 라디칼, 과산화수소(H2O2), 퍼옥시니트레이트(peroxinitrate), 오존과 같은 활성 산소종(Reactive oxygen species, ROS)은 세포 신호 전달에 중요한 역할을 하는 생물학적 메신저 이지만, ROS의 농도 증가는 세포에 산화적 스트레스를 증가시켜 지질, 단백질 및 DNA 등의 세포구조에 손상을 준다. 또한, 일산화질소(nitric oxide, NO)는 nitric oxide synthase(NOS)에 의하여 L-알라닌으로부터 합성되는데, 그 생물학적 중요성에도 불구하고 폐 등의 염증성 질환의 원인 물질로 알려져 있다.Reactive oxygen species (ROS), such as free oxygen radicals, hydrogen peroxide (H 2 O 2 ), peroxynitrate, and ozone, are biological messengers that play an important role in cell signal transduction, but increase the concentration of ROS Increases the oxidative stress on the cell damages the cell structure of lipids, proteins and DNA. In addition, nitric oxide (NO) is synthesized from L-alanine by nitric oxide synthase (NOS), and despite its biological significance, it is known as a causative agent of inflammatory diseases such as lung.
커큐민은 카레의 주성분인 강황의 주성분으로 항암, 항산화 및 항염증 우수한 약리작용을 하는 것으로 잘 알려져 있으나 용해도가 낮아서 약학적 응용에 문제점이 있다. 본원 발명의 발명자들은 과산화수소가 높은 염증 환경에서 과산화수소를 소거하면서 분해되어 커큐민을 생성 방출 할 수 있는 고분자를 개발함으로 써 본 발명을 완성하였다. Curcumin is the main ingredient of turmeric, which is the main ingredient of curry, and is known to have excellent pharmacological action against anticancer, antioxidant, and anti-inflammatory, but it has a low solubility, which causes problems in pharmaceutical applications. The inventors of the present invention have completed the present invention by developing a polymer capable of decomposing and releasing curcumin while releasing hydrogen peroxide in an inflammatory environment with high hydrogen peroxide.
상기와 같은 과제를 해결하기 위하여, In order to solve the above problems,
본 발명은 하기 화학식 1로 표시되는 화합물 커큐민의 단량체가 중합체 골격으로 통합된 옥살레이트 공중합체를 포함하는 나노입자를 제공한다. The present invention provides a nanoparticle comprising an oxalate copolymer in which monomers of the compound curcumin represented by the following Chemical Formula 1 are integrated into a polymer backbone.
[화학식 1][Formula 1]
또한 본 발명은 상기의 단량체가 공중합체로 통합되고, 상기 단량체는 공중합체를 합성하기 위하여 축합반응을 수행하는 것을 특징으로 나노입자를 제공한다. In another aspect, the present invention provides a nanoparticle, characterized in that the monomer is incorporated into a copolymer, the monomer performs a condensation reaction to synthesize a copolymer.
a) 옥살레이트 (Oxalate);a) oxalate;
b) 1, 4-사이클로헥산디메탄올 (1,4-cyclohexanedimethanlo); 및b) 1,4-cyclohexanedimethanol; And
c) 커큐민 (curcumin).c) curcumin.
상기 공중합체는 옥살레이트 및 1, 4-사이클로헥산디메탄올이 통합된 제 1블록; 및 옥살레이트 및 커큐민이 통합된 제 2블록을 포함하는 것이 바람직하다. The copolymer comprises a first block in which oxalate and 1,4-cyclohexanedimethanol are integrated; And a second block incorporating oxalate and curcumin.
상기 제 1블록은 하기의 화학식 2의 구조를 가지고, 상기 제 2블록은 하기의 화학식 3 구조를 가지는 것이 바람직하다. It is preferable that the first block has a structure of Formula 2 below, and the second block has a structure of Formula 3 below.
[화학식 2][Formula 2]
[화학식 3]
[Formula 3]
삭제delete
상기 공중합체는 하기의 화학식 4의 구조를 가지는 것이 바람직하다. It is preferable that the copolymer has a structure of Formula 4 below.
[화학식 4][Formula 4]
상기 나노입자는 나노입자 내에 약물 또는 바이오 영상화제를 더 포함할 수 있다. The nanoparticles may further comprise a drug or bioimaging in the nanoparticles.
상기 바이오영상화제는 형광안료(fluorescent agent), 근적외선 방출제, 방사선 트레이서, PET 조영제 및 MRI 조영제로 이루어지는 군으로부터 선택되는 것을 특징으로 할 수있다. The bioimaging may be selected from the group consisting of fluorescent pigments, near infrared emitters, radiation tracers, PET contrast agents and MRI contrast agents.
상기 나노입자를 유효성분으로 포함하는 염증성 질병 예방 또는 치료용 약학적 조성물을 제공한다. It provides a pharmaceutical composition for preventing or treating inflammatory diseases comprising the nanoparticles as an active ingredient.
상기 염증성 질병은 폐렴 또는 천식인 것을 특징으로 할 수 있다. The inflammatory disease may be characterized as pneumonia or asthma.
상기 나노입자를 유효성분으로 포함하는 간 손상의 예방 또는 치료용 약학적 조성물을 제공한다. It provides a pharmaceutical composition for preventing or treating liver damage comprising the nanoparticles as an active ingredient.
상기 간 손상은 아세트아미노펜(Acetoaminophen, APAP, Tylenol)으로부터 유발된 약물성 간 손상일 수 있다. The liver damage may be a drug liver injury caused from acetaminophen (APAP, Tylenol).
상기 바이오영상화제를 더 포함하는 나노입자를 환자에 투여하여 아세트아미노펜(Acetoaminophen, APAP, Tylenol)으로부터 유발된 약물성 간 질환의 위험이 있는 부위나 간 질환이 발생한 부위를 영상화하는 간 질환의 진단 방법을 제공한다. A method for diagnosing liver disease in which a nanoparticle further comprising the bioimaging is imaged to a patient to image a site at risk of a drug liver disease caused by acetaminophen (Acetoaminophen, APAP, Tylenol) or a site where a liver disease has occurred. To provide.
상기 나노입자를 포함하는 초음파 조영제를 제공한다. It provides an ultrasound contrast agent comprising the nanoparticles.
상기 나노입자는 과산화기 나노입자는 과산화수소(hydrogen peroxide, H2O2)에 의해 초음파를 증폭시킬 수 있다. The nanoparticles peroxide group nanoparticles can amplify the ultrasonic waves by hydrogen peroxide (H 2 O 2 ).
본 발명의 따른 POC(poly(oxalate-co-curcumin)) 나노 입자는 표적 특이적 방식으로 체내 과산화수소와 NO의 농도를 효과적으로 감소시킴으로써 부작용이 없이 항염증 및 항산화 효과를 나타내며, 표적 특이적 작용 효과로 인하여 약물전달체 및 영상조영제로서 활용할 수도 있다.POC (poly (oxalate-co-curcumin)) nanoparticles according to the present invention exhibit an anti-inflammatory and antioxidant effect without side effects by effectively reducing the concentrations of hydrogen peroxide and NO in the body in a target specific manner, with a target specific action effect. It can be used as a drug carrier and an imaging agent.
도 1은 H2O2로 활성화 되는 고분자 프로드러그(prodrug)으로서 POC(poly(oxalate-co-curcumin))의 합성 및 분해 과정의 화학구조 및 모식도이다.
도 2는 POC 나노입자의 물리적 특성의 결과로서, (a)는 1mM의 H2O2의 존재 또는 부재 하에서 동적 광산란에 의해 측정된 PBS에 현탁된 POC의 유체역학적 직경 변화이며, (b)는 POC 입자의 대표적인 주사형 전자 현미경 사진 결과이다.
도 3은 POC의 H2O2 반응성에 대한 결과로서, (a)는 H2O2의 존재 할 때의 POC로부터 커큐민의 방출 동역결과이고, (b)는 H2O2에 대한 화학 발광 POC 입자의 감도 결과이며, (C)는 POC 입자에 의한 H2O2의 소거 결과이다.
도 4는 POC 입자의 항염증 활성 결과로서, (a)는 RAW 264.7 세포에 대한 POC 입자의 세포 독성결과이며, (b)는 NIH 3T3 세포에서 POC 입자의 보호 독성 영향 결과이며, (c)는 자극 된 RAW 264.7 세포에서 ROS 생산의 억제 결과이고, (d)는 자극 된 RAW 264.7 세포에서 NO 생산의 억제결과이다.
도 5는 RAW 264.7 세포에 의한 POC 입자의 세포내 유입 결과로서, 여러 시간 시점에서 커큐민 또는 POC로 자극되거나 또는 자극되지 않은 세포의 대표 공 초점 레이저 스캐닝 현미경 사진이다.
도 6은 APAP-중독 마우스에서 POC의 치료 효과결과로서, (a)는 POC 입자 처리 후 APAP- 중독 마우스에서 혈청 ALT 수치 감소 결과이며, (b)는 간 조직의 H&E 염색 이미지 결과이다.
도 7은 간조직의 조직 검사로서, TUNEL 염색 된 간 조직의 이미지이다.
도 8은 POC 입자의 생태학적 성질결과로서, (a)는 다양한 농도의 H2O2가 존재할 때 POC 입자 (5 mg/mL)의 시간 의존적 에코 발생 결과이고, (b)는 POC 입자의 정량 된 초음파 세기결과이며, (c)는 POC 입자의 농도-의존 에코성의 결과(5 mM의 H2O2를 첨가 한 후 15 분에 초음파 영상)이고, (d)는 H2O2의 존재 하에 POC 나노 입자 농도와 에코 생성 강도 사이의 선형 관계 결과이며, (e)는 APAP- 중독 마우스의 간에 대한 대표 초음파 이미지 결과(빨간색 점선은 간 윤곽을 나타내고 노란색 화살표는 에코 생성 POC 입자를 나타냄)이다.
도 9는 BALF의 (a)단백질량 및 (b) 총 세포의 수이다.
도 10은 Diff-Quik으로 염색 된 Cytospined BALF 세포 결과이다.
도 11은 Cytospined BALF 세포의 대표 공 촛점 현미경 사진 결과이다.
도 12는 Amplex red assay에 의해 측정된 H2O2의 수준의 결과로서, (a)는 BALE에서 측정된 H2O2이고, (b)는 폐 조직에서 측정된 H2O2이다.
도 13은 Sham 또는 POC 입자의 치료를 받은 마우스에서 H&E 염색된 폐 조직의 대표적인 이미지이다. 1 is a chemical structure and schematic diagram of the synthesis and decomposition of POC (poly (oxalate-co-curcumin)) as a polymer prodrug (H 2 O 2 activated) prodrug.
FIG. 2 is a result of the physical properties of POC nanoparticles, where (a) is the hydrodynamic diameter change of POC suspended in PBS measured by dynamic light scattering in the presence or absence of 1 mM H 2 O 2 , (b) Representative scanning electron micrograph results of POC particles.
3 is a result of the H 2 O 2 reactivity of the POC, (a) is a result of the release kinetics of curcumin from the POC in the presence of H 2 O 2 , (b) is a chemiluminescent POC for H 2 O 2 the resulting sensitivity of the particles, (C) is a result of the H 2 O 2 scavenging by POC particles.
4 is a result of anti-inflammatory activity of POC particles, (a) is a cytotoxic result of POC particles to RAW 264.7 cells, (b) is a protective toxicity effect of POC particles in NIH 3T3 cells, (c) Inhibition of ROS production in stimulated RAW 264.7 cells, and (d) results in inhibition of NO production in stimulated RAW 264.7 cells.
5 is a representative confocal laser scanning micrograph of cells stimulated with or without curcumin or POC at various time points as a result of intracellular influx of POC particles by RAW 264.7 cells.
6 is a result of the treatment effect of POC in APAP-addicted mice, (a) is a result of reducing serum ALT levels in APAP-addicted mice after POC particle treatment, (b) is the result of H & E staining image of liver tissue.
7 is a histological examination of liver tissue and is an image of TUNEL stained liver tissue.
8 shows the ecological properties of POC particles, (a) is the time dependent echo generation of POC particles (5 mg / mL) when various concentrations of H 2 O 2 are present, and (b) quantification of POC particles. (C) is the concentration-dependent echo of POC particles (
9 is the (a) protein mass and (b) the total number of cells in BALF.
10 shows Cytospined BALF cells stained with Diff-Quik.
11 is a representative confocal micrograph of Cytospined BALF cells.
12 is a result of the level of H 2 O 2 measured by Amplex red assay, (a) is H 2 O 2 measured in BALE, (b) is H 2 O 2 measured in lung tissue.
13 is a representative image of H & E stained lung tissue in mice treated with Sham or POC particles.
이하, 본 발명을 상세하게 설명한다. EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.
본 발명은 하기 화학식 1로 표시되는 커큐민의 단량체가 중합체 골격으로 통합된 옥살레이트 공중합체를 포함하는 나노입자를 제공한다. The present invention provides a nanoparticle comprising an oxalate copolymer in which a monomer of curcumin represented by the following Chemical Formula 1 is integrated into a polymer backbone.
[화학식 1][Formula 1]
본 발명은 다음 단량체가 공중합체로 통합되고, 상기 단량체는 공중합체를 합성하기 위하여 축합반응을 수행하는 것을 특징으로 하는 나노입자를 제공한다:The present invention provides nanoparticles wherein the following monomers are incorporated into the copolymer, the monomers performing a condensation reaction to synthesize the copolymer:
a) 옥살레이트 (Oxalate);a) oxalate;
b) 1, 4-사이클로헥산디메탄올 (1,4-cyclohexanedimethanlo); 및b) 1,4-cyclohexanedimethanol; And
c) 커큐민 (curcumin). c) curcumin.
상기 공중합체는 옥살레이트 및 1, 4-사이클로헥산디메탄올이 통합된 1 블록; 및 옥살레이트 및 커큐민이 통합된 제 2블록을 포함하는 것이 바람직하다. The copolymer comprises one block in which oxalate and 1,4-cyclohexanedimethanol are integrated; And a second block incorporating oxalate and curcumin.
상기 제 1블록은 다음의 화학식 2의 구조를 가지고, 상기 제 2블록은 다음의 화학식 3의 구조를 가지는 것이 바람직하다. It is preferable that the first block has the structure of
[화학식 2][Formula 2]
[화학식 3] [Formula 3]
상기 공중합체는 다음의 화학식 4의 구조를 가지는 것이 바람직하다. It is preferable that the copolymer has a structure of the following
[화학식 4][Formula 4]
상기 공중합체 내의 제 1 블록과 제 블록의 몰비는 1:9 내지 9:1 일 수 있고, 바람직하게는 2:8 일수 있다. The molar ratio of the first block and the first block in the copolymer may be 1: 9 to 9: 1, preferably 2: 8.
본 발명은 상기 나노입자내에 약물 또는 바이오 영상화제를 더 포함하는 나노입자를 제공한다. 상기 약물은 항아폽토시스제(anti-apoptotic agent), 혈전용해제(clot-dissolving agent), 항산화제(anti-oxidant agent) 및 항염증제(anti-inflammatory agent)로 이루어지는 군으로부터 선택되는 것이 바람직하다. 상기 약물은 4-아미노-1,8-나프탈이미드(4-AN), N-(6-옥소-5,6-디하이드로페난트리딘-2-일)-N,N-디메틸아세트아미드 HCl(PJ34), 아우린트리카르복시산, 조직 플라스미노겐 활성화인자 단백질(tPA) 및 N-벤질옥시카보닐-발린-알라닌-아스파르트산-플루오로메틸케톤(Z-VAD-FMK)로 이루어지는 군으로부터 선택되는 것이 바람직하다.The present invention provides a nanoparticle further comprising a drug or a bio imaging agent in the nanoparticle. The drug is preferably selected from the group consisting of an anti-apoptotic agent, a clot-dissolving agent, an anti-oxidant agent and an anti-inflammatory agent. The drug is 4-amino-1,8-naphthalimide (4-AN), N- (6-oxo-5,6-dihydrophenantridin-2-yl) -N, N-dimethylacetamide From the group consisting of HCl (PJ34), aurintricarboxylic acid, tissue plasminogen activator protein (tPA) and N-benzyloxycarbonyl-valine-alanine-aspartic acid-fluoromethylketone (Z-VAD-FMK) It is preferred to be selected.
상기 약물은 4-아미노-1,8-나프탈이미드(4-AN)인 것이 바람직하다.Preferably the drug is 4-amino-1,8-naphthalimide (4-AN).
상기 바이오영상화제는 형광안료(fluorescent agent), 근적외선 방출제, 방사선 트레이서, PET 조영제 및 MRI 조영제로 이루어지는 군으로부터 선택되는 것이 바람직하다.The bioimaging is preferably selected from the group consisting of fluorescent agents, near infrared emitters, radiation tracers, PET contrast agents and MRI contrast agents.
상기 바이오영상화제는 루브렌(rubrene), 펜타센(pentacene), 인도시아닌 그린(indocyanine green), 가돌리늄(gadolinium), 테크네튬-99엠(technetium-99m) 및 플루오로데옥시글루코오스(18F)로 이루어지는 군으로부터 선택되는 것이 바람직하며, 가장 바람직하게는 루브렌 일 수 있다.The bioimaging is rubrene (pentacene), indocyanine green (indocyanine green), gadolinium (gadolinium), technetium-99m (technetium-99m) and fluorodeoxyglucose (18F) It is preferably selected from the group consisting of, and most preferably may be rubrene.
상기 바이오영상화제를 포접한 나노입자는 생체 내 또는 생체 외의 과산화수소를 영상으로 이미징(imaging)할 수 있으며, 영상으로 이미징할 수 있는 과산화수소의 최소 농도는 20nM이다.The nanoparticles encapsulated with the bioimaging agent may image hydrogen peroxide in vivo or in vitro, and the minimum concentration of hydrogen peroxide that may be imaged is 20 nM.
본 발명의 나노입자를 유효성분으로 포함하는 염증성 질병의 예방 또는 치료용 약학적 조성물을 제공한다. It provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases comprising the nanoparticles of the present invention as an active ingredient.
상기 염증성 질병은 폐렴 또는 천식일 수 있다.The inflammatory disease may be pneumonia or asthma.
상기 조성물은 염증성 질병 부위에 국부적으로 적용되는 것이 바람직하다.The composition is preferably applied locally to the inflammatory disease site.
상기 나노입자를 유효성분으로 포함하는 간 손상의 예방 또는 치료용 약학적 조성물을 제공한다. It provides a pharmaceutical composition for preventing or treating liver damage comprising the nanoparticles as an active ingredient.
간 손상은 아세트아미노펜(Acetoaminophen, APAP, Tylenol)으로부터 유발된 약물성 간 손상일 수 있다. Liver damage can be drugged liver damage caused from acetaminophen (APAP, Tylenol).
본 발명의 약학적 조성물은 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 본 발명의 약학적 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 구체예로서 과립제, 세립제, 산제, 경질캡슐제, 연질캡슐제, 시럽제, 유제, 현탁제 또는 액제 등의 경구 투여용 약학 조성물로서 투여해도 되고, 정맥내 투여, 근육내 투여, 또는 피하 투여용 주사제, 점액제, 좌제, 경피흡수제, 경점막 흡수제, 점비제, 점이제, 점안제, 흡입제, 크림제, 연고제, 파프제 등의 비경구 투여용 약학적 조성물로서 투여하는 것도 가능하다. 분말형태의 약학조성물로서 조제된 제제를 사용시에 용해하여 주사제 또는 점액제로서 사용해도 된다. 특히, 본 발명의 약학조성물은 페이스트 연고, 크림, 밀크, 파프제, 분제, 침투 패드, 용액, 겔, 분무제, 로션 또는 현탁액 형태의 제형인 것이 바람직할 수 있다.The pharmaceutical compositions of the present invention may further comprise suitable carriers, excipients and diluents commonly used. The pharmaceutical composition of the present invention may be prepared in any formulation conventionally prepared in the art, and specific examples include granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or solutions, and the like. It may be administered as a pharmaceutical composition for oral administration of, intravenous, intramuscular or subcutaneous injection, mucus, suppository, transdermal absorbent, transmucosal absorbent, nasal drops, ear drops, eye drops, inhalants, creams, It is also possible to administer it as a pharmaceutical composition for parenteral administration, such as an ointment and a pape. The formulation prepared as a pharmaceutical composition in powder form may be dissolved in use and used as an injection or mucus. In particular, the pharmaceutical composition of the present invention may be preferably in the form of a paste ointment, cream, milk, powder, powder, penetrating pad, solution, gel, spray, lotion or suspension.
본 발명의 약학적 조성물의 제조에는 고체 또는 액체의 제제용 첨가물을 사용할 수 있다. 제제용 첨가물은 유기 또는 무기 중 어느 것이어도 된다.In the preparation of the pharmaceutical compositions of the present invention, additives for the preparation of solids or liquids may be used. The additive for preparation may be either organic or inorganic.
본 발명의 약학적 조성물의 투여량은 특별히 한정되지 않지만, 성인 1일당 유효성분인 상기 물질의 중량으로서 1kg당 0.01 내지 100mg/kg, 바람직하게는 0.1 내지 10mg/kg, 더욱 바람직하게는 1.5mg/kg일 수 있다. 이 투여량을 환자의 연령, 병태, 증상에 따라 적절히 증감하는 것이 바람직하다. 상기 1일 투여량은 1일에 1회, 또는 적당한 간격을 두고 하루에 2~3회에 나눠 투여해도 되고, 수일 간격으로 간헐적으로 투여해도 된다. 그러나 본 발명의 약학적 조성물의 상기 투여량은 투여 경로, 환자의 연령, 성별, 체중, 환자의 중증도 등의 여러 관련 인자에 비추어 결정되는 것이므로 상기 투여량은 어떠한 측면으로든 본 발명의 범위를 제한하는 것으로 이해되어서는 아니 된다.The dosage of the pharmaceutical composition of the present invention is not particularly limited, but is 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg, more preferably 1.5 mg / kg, per kilogram, as the weight of the substance as an active ingredient per adult. may be kg. It is desirable to appropriately increase or decrease this dosage depending on the age, condition and symptoms of the patient. The daily dose may be administered once a day or divided into two to three times a day at appropriate intervals, or intermittently at several day intervals. However, since the dosage of the pharmaceutical composition of the present invention is determined in view of various related factors such as the route of administration, the age, sex, weight of the patient, and the severity of the patient, the dosage may limit the scope of the present invention in any aspect. It should not be understood as.
상기 바이오영화제를 더 포함하는 나노입자를 환자에 투여하여 아세트아미노펜(Acetoaminophen, APAP, Tylenol)으로부터 유발된 약물성 간 질환의 위험이 있는 부위나 간 질환이 발생한 부위를 영상화하는 간 질환의 진단 방법을 제공한다.A method for diagnosing liver disease in which a nanoparticle further comprising the biofilm agent is administered to a patient to image a site at risk of pharmacologic liver disease caused by acetaminophen (Acetoaminophen, APAP, Tylenol) or a site where liver disease has occurred. to provide.
상기 바이오영상화제는 형광안료인 것이 바람직하다.The bioimaging is preferably a fluorescent pigment.
상기 형광안료는 루브렌(rubrene)인 것이 바람직하다.The fluorescent pigment is preferably rubrene (rubrene).
상기 영상화는 광학 영상, 적외선 영상, 방사선 영상, MRI, PET로 이루어지는 군으로부터 선택되는 것이 바람직하다.The imaging is preferably selected from the group consisting of optical images, infrared images, radiation images, MRI, PET.
상기 나노입자를 포함하는 초음파 조영제를 제공한다. It provides an ultrasound contrast agent comprising the nanoparticles.
본 발명에 따른 나노입자는 과산화수소(hydrogen peroxide, H2O2)에 의해 CO2 버블을 생성하여 초음파 주파수와 공명을 이룸으로써 초음파 신호를 증폭시키는 효과가 있어, 과산화수소의 농도가 높은 병리적 환경에서 초음파 조영제로서 유용하게 사용될 수 있다.Nanoparticles according to the present invention has the effect of amplifying the ultrasonic signal by generating a CO2 bubble by hydrogen peroxide (H 2 O 2 ) to achieve the ultrasonic frequency and resonance, ultrasonic waves in a pathological environment with a high concentration of hydrogen peroxide It can be usefully used as a contrast agent.
본 발명의 조영제는 초음파 증폭 효과를 갖는 공지의 유효성분을 1종 이상 더 함유할 수 있다.The contrast agent of the present invention may further contain one or more known active ingredients having an ultrasonic amplification effect.
본 발명의 조영제는 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 또한, 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 당해 기술 분야에 알려진 적합한 제제는 문헌(Remington's Pharmaceutical Science, 최근, Mack Publishing Company, Easton PA)에 개시되어 있는 것을 사용하는 것이 바람직하다. 예를 들어 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등이 있다. 상기 조성물을 제제화할 경우에는 보통 사용하는 충전제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The contrast agent of the present invention may further comprise suitable carriers, excipients and diluents commonly used. It may also be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, external preparations, suppositories, or sterile injectable solutions according to conventional methods. Suitable formulations known in the art are preferably those disclosed in Remington's Pharmaceutical Science, recently, Mack Publishing Company, Easton PA. For example, carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil. In formulating the composition, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like in the composition. It is prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, utopsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명에서 사용되는 용어 "투여"는 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.As used herein, the term "administration" means providing a subject with any of the compositions of the present invention in any suitable manner.
본 발명의 약학적 조성물의 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 상기 조성물의 투여는 하루에 한번 투여할 수도 있고, 수 회 나누어 투여할 수도 있다.Preferred dosages of the pharmaceutical compositions of the present invention vary depending on the condition and weight of the individual, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. Administration of the composition may be administered once a day, may be divided several times.
본 발명의 조영제는 개체에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다.The contrast agent of the present invention can be administered to a subject by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections.
본 발명의 조영제는 초음파 증폭을 위하여 단독으로, 또는 약물과 병용하여 사용할 수 있으며, 상기 약물은 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), 트리암시노론(triamcinolone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 또는 코르티코스테로이드(corticosteroid) 등의 약물일 수 있다.Contrast agent of the present invention can be used alone or in combination with a drug for ultrasonic amplification, the drug is docetaxel (Docetaxel), cis-platin (camptothecin), paclitaxel (paclitaxel), tamoxifen (Tamoxifen) ), Anasterozole, Gleevec, 5-Fluorouracil (5-FU), Fluxuridine, Leuprolide, Flotamide, Zoledro Zodedronate, Doxorubicin, Vincristine, Gemcitabine, Streptozocin, Streptozocin, Carboplatin, Topotecan, Belotecan, Ilenotecan Irinotecan, vinorelbine, hydroxyurea, valrubicin, retinoic acid series, methotrexate, mechloretamine, chlorambucil ), Busulfan, Doxiflur idine, Vinblastin, Mitomycin, Prednisone, Testosterone, Mitoxantron, Aspirin, Salicylates, Ibuprofen Naproxen, fenoprofen, indomethacin, phenyltazone, cyclophosphamide, mechlorethamine, dexamethasone, dexamethasone, It may be a drug such as triamcinolone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone or corticosteroid.
또한 본 발명은 상기 초음파 조영제를 이용하는 초음파 영상 정보 획득 방법을 제공한다.The present invention also provides a method for obtaining ultrasound image information using the ultrasound contrast agent.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예, 실험예 및 제조예를 제시한다. 그러나 하기의 실시예, 실험예 및 제조예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예, 실험예 및 제조예에 의해 본 발명의 내용이 한정되는 것은 아니다. Hereinafter, preferred examples, experimental examples, and preparation examples are provided to help the understanding of the present invention. However, the following Examples, Experimental Examples and Preparation Examples are merely provided to more easily understand the present invention, but the contents of the present invention are not limited by Examples, Experimental Examples, and Preparation Examples.
재료material
커큐민 (Curcumin; total curcuminoid content 95%)은 Alfa Aesar (영국)로부터 구매했다. 테트라하이드로푸란(Tetrahydrofuran), 1,4-사이클로헥산디메탄올(1,4-cyclohexanedimethanol), 옥살릴 클로라이드(oxalyl chloride), 폴리(비닐알코올)(MW 13,000~21,000)은 시그마 알드리치사(MO. USA)로부터 구매했다. 디클로메탄 (Dichloromethane; DCM) 및 트리에틸아민(triethylamine)은 Showa(Japan)에서 구매했다. 테트라하이드로푸란은 수소화칼슘에서 증류되었다. 모든 시약들은 추가 정제 없이 사용되었다. RAW 264.7 및 NIH 3T3 세포는 한국 세포주 은행 (한국)에서 구입 하였다.Curcumin (95% total curcuminoid content) was purchased from Alfa Aesar (UK). Tetrahydrofuran, 1,4-cyclohexanedimethanol, oxalyl chloride, poly (vinyl alcohol) (MW 13,000-21,000) are available from Sigma Aldrich (MO.USA). Purchased from). Dichloromethane (DCM) and triethylamine were purchased from Showa (Japan). Tetrahydrofuran was distilled on calcium hydride. All reagents were used without further purification. RAW 264.7 and NIH 3T3 cells were purchased from the Korea Cell Line Bank (Korea).
고분자의 합성Synthesis of Polymer
커큐민(13 mmmol) 및 1,4- 시클로헥산 디메탄올 (13 mmol)을 10 ml의 잘 건조된 테트라하이드로푸란(Tetrahydrofuran, THF)에 용해시키고, 피리딘 (32 mmol)을 첨가하였다. 여기에 20 mL의 건조된 THF에 용해한 옥살릴 클로라이드(oxalyl chloride)(27.45 mmol)를 4℃에서 혼합물에 한 방울씩 첨가했다. 이 반응물은 6시간 동안 상온에서 질소 존재 하에 유지되었고, 디클로로메탄(Dichloromethane)을 이용하여 생성된 고분자를 추출한 다음 차가운 헥산(hexane)에서 침전시켜 고분자를 얻었다. POC는 주황색 고체로서 얻어졌으며 그 화학 구조는 400 MHz 1H-NMR 분광기 (Jeol, JNMECA600)로 확인되었다. POC의 분자량은 겔 투과 크로마토 그래피 (Alliance HPLC, Waters, Milford, MA)를 사용하여 측정 하였다. UV-Vis 흡광도는 분광 광도계 (RF-6500-PC, Jasco, Japan)에서 수행 하였다. 그 결과, 도 1과 같이, 커큐민은 퍼옥살레이이트 에스테를 결합을 통해 중합체의 주쇄에 공유 결합되었다. 퍼옥살레이트 결합체 옆의 메틸렌 양성자에 상응하는 약 4.2ppm의 큰 피크의 존재는 성공적인 중합을 확인해 준다. POC의 중량 평균 분자량은 약 8,500이다. Curcumin (13 mmmol) and 1,4-cyclohexane dimethanol (13 mmol) were dissolved in 10 ml of well-dried tetrahydrofuran (THF) and pyridine (32 mmol) was added. To this was added dropwise oxalyl chloride (27.45 mmol) in 20 mL of dried THF to the mixture at 4 ° C. The reaction was maintained in the presence of nitrogen at room temperature for 6 hours, the resulting polymer was extracted using dichloromethane and precipitated in cold hexane (hexane) to obtain a polymer. POC was obtained as an orange solid and its chemical structure was confirmed by a 400 MHz 1H-NMR spectrometer (Jeol, JNMECA600). The molecular weight of POC was measured using gel permeation chromatography (Alliance HPLC, Waters, Milford, MA). UV-Vis absorbance was performed on a spectrophotometer (RF-6500-PC, Jasco, Japan). As a result, as shown in Fig. 1, curcumin was covalently bonded to the main chain of the polymer through the peroxalate ester. The presence of a large peak of about 4.2 ppm corresponding to the methylene protons beside the peroxalate conjugate confirms successful polymerization. The weight average molecular weight of the POC is about 8,500.
입자 준비(Particle preparation)Particle Preparation
1 mg의 POC를 1 ml의 DCM에 용해시킨 1 mg의 POC는 5mL의 10 (w/v)% 폴리(비닐 알코올) 용액에 첨가되었다. 혼합물은 초음파 파쇄기 (Sonicator, Fisher Scientific, Sonic Dismembrator 500)를 사용하여 유화시켰다. 미세한 유제 PVA (0.5 wt%)를 형성하기 위해 용액 1용액 10ml를 초음파 저칠된 용액에 첨가하고 1 분동안 균질화 시켰다(PRO Scientific, PRO 200-호모지나이저). 남아있는 용매는 회전 증발기 (rotary evaporator)를 사용하여 제거되었다. 나노미립구는 원심분리기에 의해 4℃에서 5분 동안 11,000rpm을 통해 획득했고, 탈이온수 (deionized water)로 두 번 씻고 이를 통해 얻어진 파티클 용액을 동결건조하여 건조된 나노미립구를 얻었다. POC 입자의 형태와 크기는 가속 전압 10 kV의 주사 전자 현미경 (SEM, S-3000N, Hitachi, Japan)에 의해 관찰되었다. 입자 분석기 (Brookhaven Instruments Corporation, Holtsville, NY)를 사용하여 POC 입자의 유체 역학적 직경을 측정 하였다. POC 입자의 평균 직경은 동적 광산란에 의해 ~1.5um로 결정되었다 (도 2a). POC 입자는 둥근 구형이고, 표면이 매끄럽다 (도 2b).POC 입자는 식균 작용으로 삼켜지도록 설계되었기 때문에, 입자가 <3um 이하의 크기 범위에 있어야 하는데, 이는 대식 세포의 식균 작용에 적정한 범위이다. 1 mg of POC dissolved in 1 ml of DCM was added to 5 mL of 10 (w / v)% poly (vinyl alcohol) solution. The mixture was emulsified using an ultrasonic crusher (Sonicator, Fisher Scientific, Sonic Dismembrator 500). 10 ml of 1 solution of solution was added to the sonicated solution and homogenized for 1 minute (PRO Scientific, PRO 200-homogenizer) to form a fine emulsion PVA (0.5 wt%). The remaining solvent was removed using a rotary evaporator. Nanoparticles were obtained through centrifuge at 11,000rpm for 5 minutes at 4 ° C, washed twice with deionized water and lyophilized particle solution obtained to obtain dried nanoparticles. The shape and size of the POC particles were observed by scanning electron microscopy (SEM, S-3000N, Hitachi, Japan) with an acceleration voltage of 10 kV. The hydrodynamic diameter of POC particles was measured using a particle analyzer (Brookhaven Instruments Corporation, Holtsville, NY). The average diameter of the POC particles was determined to be ~ 1.5um by dynamic light scattering (FIG. 2A). The POC particles are round spherical and the surface is smooth (FIG. 2B). Since POC particles are designed to be swallowed by phagocytosis, the particles should be in the size range <3 μm, which is an appropriate range for phagocytosis of macrophages.
POC 입자로부터 커큐민의 방출 동역학Release Kinetics of Curcumin from POC Particles
POC 입자 (10mg)를 2mL의 PBS-Tween (0.5 % Tween 20)에 분산시킨 후 37 ℃에서 연속적으로 저었다. 지정된 시점에서 상등액 200 ㎕를 취해 동량의 신선한 PBS로 대체하고 현탁액을 1000 x g에서 5 분간 원심 분리했다. 커큐민의 농도는 435 nm의 파장에서 UV-Vis를 사용하여 결정되었다. H2O2가 입자의 크기와 안정성에 미치는 영향을 증명하기 위해, H2O2(1mM)의 존재 또는 부재하에서 POC 입자를 관찰하였다. H2O2가 없으면 POC 입자는 팽윤되어 무시할 수 있을 정도의 가수 분해를 격지만, SEM 이미지에 의해 입증된 구형을 유지 한다. 그러나 H2O2(1mM)의 존재하에서, POC 입자의 대부분은 배양 후 24시간 이네 쉽게 분해 되었고, 많은 작은 파편으로 불규칙한 모양을 보였다. POC 입자의 표면 형태와 크기의 급격한 변화는 주로 H2O2(1mM)에 의해 유되된 가수분해에 기인한 것을 알 수 있었다. H2O2의 존재 또는 부재하에 POC 입자로부터의 커큐민의 방출 속도는 커큐민 표준 용액의 농도를 비교함으로써 측정되었다. (도 3a). H2O2가 없으면 POC 입자는 12 시간에 폭발 방출을 나타내지 만 7 일 이내에 ~35 를 방출 할 수 있다. 그러나, H2O2(1mM)의 존재 하에서, 12 시간 이내에 빠른 폭발 방출이 관찰되었고 4 일 이내에 대부분의 커큐민 (75 %)이 방출되었다.POC particles (10 mg) were dispersed in 2 mL PBS-Tween (0.5% Tween 20) and stirred continuously at 37 ° C. At the
POC 입자의 HH of POC particles 22 OO 22 의 반응성Reactivity of
POC는 커큐민의 H2O2로 활성화되는 고분자 프로드럭으로 설계되었으므로 H2O2에 대한 높은 특이성과 높은 반응성으로 인해 퍼올살레이트(peroxalate) 화학 발광 반응의 원리를 이용하여 H2O2에 대한 POC의 민감성을 연구했다. 따라서 우리는 형광 루브렌으로 캡슐화 된 화학 발광 POC 입자를 공식화하고 화학 발광 POC 입자가 3 성분 퍼옥살레이트 화학 발광 반응을 수행함으로써 H2O2를 검출 할 수 있는지 여부를 조사했다. POC 입자를 0.1 M PBS (pH 7.4)에 현탁시켜 농도 1mg/mL이 되도록 하였다. 1 밀리리터의 H2O2 용액 (1 mM)을 상이한 시간 동안 POC 입자 현탁액으로 처리 하였다. 주어진 시간에 H2O2 용액 100 μL를 취하여 50 mL의 화학 발광 용액 (THF 10mL에 루브렌 2 mg 및 디페닐 퍼옥살레이트 15 mg)을 혼합했다. 삭제가능, 다음 문장이 대체 H2O2의 수준은 루미노미터 (Femtomaster FB12, Zylux Corporation, Huntsville, AL)를 이용하여 10초의 획득시간 후 화학발광강도를 측정함으로서 결정되었다.POC is designed as a polymeric prodrug which is activated by H 2 O 2 of curcumin and because of the high specificity and high reactivity with the H 2 O 2 using a buffer olsal rate (peroxalate) the principles of the chemiluminescent reaction of the H 2 O 2 The sensitivity of POC was studied. Therefore, we formulated chemiluminescent POC particles encapsulated with fluorescent rubrene and investigated whether the chemiluminescent POC particles can detect H 2 O 2 by carrying out a three-component peroxalate chemiluminescence reaction. POC particles were suspended in 0.1 M PBS (pH 7.4) to a concentration of 1 mg / mL. One milliliter of H 2 O 2 solution (1 mM) was treated with POC particle suspension for different times. At a given time, 100 μL of H 2 O 2 solution was taken and 50 mL of chemiluminescent solution (2 mg of rubrene and 10 mg of diphenyl peroxalate in 10 mL of THF) was mixed. Deleteable, the following sentence The level of alternative H 2 O 2 was determined by measuring chemiluminescence intensity after a 10 second acquisition time using a luminometer (Femtomaster FB12, Zylux Corporation, Huntsville, AL).
도 2b와 같이, 화학 발광 POC 입자는 발광 세기와 H2O2 농도 사이에 선형 상관관계를 나타내어, POC 내의 퍼옥살레이트 에스테르가 H2O2와 반응 할 수 있음을 증명한다. H2O2는 퍼옥살레이트 에스테르를 산화시키고 산화 중에 분해되기 때문에 POC 입자가 H2O2를 제거하는 능력을 검증했다. POC 입자가 H2O2를 제거하는 능력은 24 시간 동안 H2O2의 존재 하에 POC 입자와 함께 항온 처리함으로써 평가되었다. POC 입자 (1 mg)를 1 mL의 H2O2용액 (10 μM)에 현탁시키고 용액을 온화하게 저어 주면서 37 ℃에서 방치 하였다. 적절한 시간 간격으로, POC 혼합물 샘플을 1000g에서 원심 분리하고, 상등액을 새로운 튜브로 옮겼다. Amplex Red 분석법 (Invitrogen, Carlsbad, CA)에 의해 H2O2의 수준을 결정 하였다. POC 입자의 첨가 후, H2O2의 수준은 24 시간 동안 연속적이고 점진적으로 감소하였고 (도 3), 이는 POC가 과산화물 에스테르의 H2O2- 촉발 된 산화 동안 H2O2를 쉽게 소비함을 가리킨다. As shown in FIG. 2B, chemiluminescent POC particles show a linear correlation between luminescence intensity and H 2 O 2 concentration, demonstrating that the peroxalate ester in POC can react with H 2 O 2 . Since H 2 O 2 oxidizes the peroxalate ester and decomposes during oxidation, the POC particles have verified the ability to remove H 2 O 2 . The ability to remove particles is POC H 2 O 2 was evaluated by incubation with POC particles in the presence of H 2 O 2 for 24 h. POC particles (1 mg) were suspended in 1 mL of H 2 O 2 solution (10 μM) and left at 37 ° C. with gentle stirring. At appropriate time intervals, the POC mixture sample was centrifuged at 1000 g and the supernatant was transferred to a new tube. The level of H 2 O 2 was determined by Amplex Red assay (Invitrogen, Carlsbad, Calif.). After the addition of the POC particle, the level of H 2 O 2 was reduced to the continuous and gradual for 24 hours (FIG. 3), which POC is H 2 O 2 peroxide ester also easily consume the H 2 O 2 during the triggering oxidation Point to.
POC의 세포독성검사 (cytotoxicity assay)Cytotoxicity assay of POC
POC 나노 미립구의 세포독성은 3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라 졸리움 브로마이드 (MTT) 환원 분석에 의해 RAW 264.7 세포를 이용하여 측정하였다. RAW 264.7 세포는 24 웰 플레이트 (well plate)안의 1×106 세포/웰의 농도로 접종하였다. 세포에 나노 미립구를 (10mg/mL ~ 100mg/mL)의 다양한 농도로 24시간 동안 배양한 후 배양액을 제거 후 1mL의 배양액을 넣어주고 20μl MTT 시약을 넣고 4시간 배양하였다. 보라색 결정이 생성되면 디메틸 설폭사이드 용액을 1mL 씩 넣어 10분 배양 후 흡광도 570nm에서 마이크로 플레이트 리더를 이용하여 측정하였다. 그 결과, 농도가 200 ㎍/㎖ 미만인 POC 입자의 경우 세포 생존력의 현저한 감소가 관?x되지 않았다 (도 4). 이론적으로 200 ㎍의 POC 입자는 20 ug의 커큐민을 방출한다. 흥미롭게도 20 ㎍/mL 농도의 커큐민(curcumin)은 현저한 세포 독성을 나타내었으며, 이는 이전의 연구에 따르면 커큐민이 25 uM보다 높은 농도에서 독성을 나타내는 것으로 나타났다. 동량의 커큐민보다 POC의 독성이 낮은 이유는 커큐민이 느리고 지속적으로 방출되기 때문이다. H2O2에 의해 유도 된 산화 스트레스로부터 POC 입자의 보호 효과를 평가하기 위해 또 다른 MTT 분석 세트를 수행했다. 염증 조건을 모방하기 위해 세포를 H2O2(250μM)에 노출시킨 후 POC 입자로 처리 하였다 (도 4). H2O2를 이용한 자극은 세포 생존 능력을 현저하게 감소시켰다. 커큐민 (20 ㎍ / ㎖)이 세포 생존 능력에 미치는 영향은 무시할만한 수준 이었지만, POC 입자는 농도 의존적으로 H2O2 유발 독성을 현저하게 억제했다. 이러한 관찰은 POC 입자의 H2O2 소거 활성에 의해 설명 될 수 있다 (도 3).Cytotoxicity of POC nanoparticles was measured using RAW 264.7 cells by 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) reduction assay. RAW 264.7 cells were seeded at a concentration of 1 × 10 6 cells / well in a 24 well plate. After incubating the cells for 24 hours at various concentrations (10mg / mL ~ 100mg / mL) of the nanoparticles to remove the culture medium, 1mL of the culture solution was added and 20μl MTT reagent was incubated for 4 hours. When purple crystals were produced, 1 mL of dimethyl sulfoxide solution was added thereto for 10 minutes, followed by measurement using a microplate reader at 570 nm of absorbance. As a result, no significant reduction in cell viability was observed for POC particles with concentrations below 200 μg / ml (FIG. 4). Theoretically, 200 μg of POC particles release 20 ug of curcumin. Interestingly, curcumin at a concentration of 20 μg / mL showed significant cytotoxicity, which previous studies have shown that curcumin is toxic at concentrations above 25 uM. The lower toxicity of POCs than equivalent amounts of curcumin is due to the slow and sustained release of curcumin. Another set of MTT assays was performed to evaluate the protective effect of POC particles from oxidative stress induced by H 2 O 2 . Cells were exposed to H 2 O 2 (250 μM) and then treated with POC particles to mimic inflammatory conditions (FIG. 4). Stimulation with H 2 O 2 significantly reduced cell viability. The effect of curcumin (20 μg / ml) on cell viability was negligible, but POC particles significantly inhibited H 2 O 2 induced toxicity. This observation can be explained by the H 2 O 2 scavenging activity of POC particles (FIG. 3).
POC 입자의 항산화 및 항 염증 활성Antioxidant and Anti-inflammatory Activity of POC Particles
POC 입자의 시험 관내 항산화 활성은 RAW 264.7 세포를 사용하여 연구되었다 (도 4). RAW 264.7 세포를 100 μM의 H2O2로 4 시간 처리 한 후 20 μg의 커큐민, 10 μg의 POC 입자 또는 25 μg의 POC 입자와 4 시간 동안 배양했다. 세포 내 ROS 수준을 측정하기 위해, 세포를 Dichlorodihydrofluorescein diacetate (DCFH-DA)로 15 분간 어두운 곳에서 처리 하였다. 염색 된 세포를 유동 세포 계측법 (FACS Calibre Becton Dickinson, San Jose, CA)으로 분석 하였다. H2O2로 자극 된 세포는 강력한 DCFH-DA 형광으로 입증 된 많은 양의 ROS를 생성 하였다. 커큐민이 ROS 생성에 억제 효과를 나타냄에 따라 POC 입자는 농도 의존적으로 세포 내 ROS 생성을 억제하여 POC 입자의 우수한 항산화 기능을 나타내었다. RAW 264.7 세포 (24 웰 플레이트에서 4 × 105 cell/well)를 다양한 농도의 POC 입자로 처리하고 4 시간 동안 배양 하였다. POC 입자-전처리 된 세포를 1μg의 리포폴리사카라이드 (LPS 1 mg / mL)로 처리하고 20 시간 더 배양했다. 배지 내의 NO 농도는 그리스 반응 (Griess reaction)에 기초한 비색 분석법을 사용하여 측정 하였다. 총 50μL의 세포 배양 배지를 모으고, 100μL의 Griess 시약 (6mg / mL)을 첨가하고 실온에서 10 분 동안 배양하였다. 마이크로플레이트판독기 (Synergy MX, BioTek Instruments, Inc., Winooski, VT)를 사용하여 540 nm에서의 흡광도를 측정함으로써 NO 농도를 측정 하였다. 알려진 농도의 아질산나트륨을 사용하여 NO 표준 곡선을 만들고 비 처리 세포를 음성 대조군으로 사용했다. POC 처리 후 LPS-자극 된 세포에서의 NO의 수준을 그리스 시약 시스템을 사용하여 측정 하였다. 도 4d에서와 같이, LPS- 자극은 NO 수준을 극적으로 상승 시켰고, 자유 커큐민은 NO 생성에 대한 억제 효과를 나타냈다. 그러나 POC 입자는 NO 생성을 농도 의존적으로 현저하게 억제하였으며, 동량의 커큐민보다 더 강력한 억제 효과를 나타냈다. In vitro antioxidant activity of POC particles was studied using RAW 264.7 cells (FIG. 4). RAW 264.7 cells were treated with 100 μM H 2 O 2 for 4 hours and then incubated with 20 μg curcumin, 10 μg POC particles or 25 μg POC particles for 4 hours. To measure intracellular ROS levels, cells were treated with Dichlorodihydrofluorescein diacetate (DCFH-DA) for 15 minutes in the dark. Stained cells were analyzed by flow cytometry (FACS Caliber Becton Dickinson, San Jose, Calif.). Cells stimulated with H 2 O 2 produced large amounts of ROS, demonstrated by potent DCFH-DA fluorescence. As curcumin exhibited an inhibitory effect on ROS production, POC particles inhibited intracellular ROS production in a concentration-dependent manner, indicating an excellent antioxidant function of POC particles. RAW 264.7 cells (4 × 10 5 cell / well in 24 well plates) were treated with various concentrations of POC particles and incubated for 4 hours. POC particle-pretreated cells were treated with 1 μg lipopolysaccharide (LPS 1 mg / mL) and incubated for another 20 hours. NO concentration in the medium was measured using a colorimetric assay based on the Greries reaction. A total of 50 μL of cell culture medium was collected, 100 μL of Griess reagent (6 mg / mL) was added and incubated for 10 minutes at room temperature. NO concentrations were determined by measuring absorbance at 540 nm using a microplate reader (Synergy MX, BioTek Instruments, Inc., Winooski, VT). Known concentrations of sodium nitrite were used to create NO standard curves and untreated cells were used as negative controls. After POC treatment, the level of NO in LPS-stimulated cells was measured using a grease reagent system. As in FIG. 4D, LPS-stimulation dramatically raised NO levels and free curcumin showed an inhibitory effect on NO production. However, POC particles significantly inhibited NO production in a concentration-dependent manner, showing a stronger inhibitory effect than equivalent amounts of curcumin.
POC 입자의 세포유입Cell Influx of POC Particles
커큐민의 고유 형광을 이용하여 POC 입자의 세포 내 흡수 및 공 촛점 레이저 스캐닝 현미경을 사용하여 세포에서 커큐민의 방출을 조사했다. RAW 264.7 세포 (24 웰 플레이트에서 6 × 105 cell/well)를 유리 바닥 접시 (MatTek Corp., Ashland, MA)에서 배양 하였다. 250 uM의 H2O2로 세포를 전 처리한 다음 100 ㎍의 POC 입자로 2 시간 또는 6 시간 처리 하였다. 세포를 새로운 배지로 2 회 세척하고 공 초점 레이저 주사 현미경 (LSM 510 Meta, Carl Zeiss, Inc. Germany)하에 관찰 하였다. 도 5는 POC 입자와 함께 인큐베이션 한 후 비 자극 및 H2O2-자극 된 RAW 264.7 세포의 형광 이미지를 도시한다. 배양 2 시간 후, 세포의 기포화 (perphery)에서 강한 형광이 관찰되었으며, 이는 엔도좀에서 식균 작용과 내부(interallization)를 나타내는 것이다. 6시간 후, 녹색 형광이 세포질에 분산되어, POC 입자의 endosomal escpae와 endosomal compartment에 커큐민이 세포질로 전돨되었다. 또한 자극된 세포가 이전 연구와 함께 함께, 비 스트레스를 받지 않은 세포보다 유의하게 높은 속도로 POC 입자를 내부화 시킨 다는 것을 발견했다. 흥미롭게도, H2O2- 자극 된 세포는 자극받지 않은 세포보다 현저히 높은 형광을 나타냈다. 비 표적화 된 세포는 분산 된 형광을 보였으나, 형광 강도는 6 시간 후에 증가하지 않았다. 그러나 H2O2 자극 세포는 POC 입자에서 더 많은 커큐민이 방출되어 고유의 형광을 회복했기 때문에 6 시간 째 세포질 영역에서 상당히 향상된 형광을 보였다 (도 5). 이러한 관찰은 POC 입자가 염증의 주요 요인 인 대 식세포에 의해 흡수 될 수 있고 커큐민을 방출하기 위해 H2O2에 의해 가수 분해가 진행됨을 보여준다. Intracellular uptake of POC particles using curcumin's intrinsic fluorescence and release of curcumin in the cells using confocal laser scanning microscopy. RAW 264.7 cells (6 × 10 5 cell / well in 24 well plates) were incubated in glass bottom plates (MatTek Corp., Ashland, Mass.). Cells were pretreated with 250 uM of H 2 O 2 and then treated with 100 μg of POC particles for 2 or 6 hours. Cells were washed twice with fresh medium and observed under confocal laser scanning microscopy (LSM 510 Meta, Carl Zeiss, Inc. Germany). 5 shows fluorescence images of non-stimulated and H 2 O 2 -stimulated RAW 264.7 cells after incubation with POC particles. After 2 hours of culture, strong fluorescence was observed in the cell's perphery, indicating phagocytosis and internalization in the endosome. After 6 hours, green fluorescence was dispersed in the cytoplasm, and curcumin was transferred to the cytoplasm in the endosomal escpae and endosomal compartments of the POC particles. Stimulated cells, along with previous studies, also found that they internalize POC particles at significantly higher rates than non-stressed cells. Interestingly, H 2 O 2 -stimulated cells showed significantly higher fluorescence than unstimulated cells. Untargeted cells showed scattered fluorescence, but fluorescence intensity did not increase after 6 hours. However, H 2 O 2 stimulating cells showed significantly enhanced fluorescence in the cytoplasmic region at 6 hours because more curcumin was released from the POC particles to restore intrinsic fluorescence (FIG. 5). These observations show that POC particles can be taken up by macrophages, a major factor of inflammation, and hydrolyzed by H 2 O 2 to release curcumin.
APAP 유발 간 손상의 POC 입자의 치료 효과Therapeutic Effects of POC Particles on APAP-induced Liver Injury
APAP 유도 된 간 기능 장애의 마우스 모델을 사용하여 POC 입자의 치료제로서의 가능성을 조사했다. 수컷 ICR 생후 8 주 된 생쥐 (30g)는 Orient Experimental Animal Breeding Center (Korea)로부터 입수 하였다. 모든 동물은 습도 50 ± 10 %의 상대 습도와 20 내지 22 ℃의 케이지에 보관했다. 실험 이전에, 마우스를 12 시간 동안 금식시켰다. 꼬리 정맥을 통해 마우스 (n = 4)에 커큐민 (0.75 mg/kg) 또는 POC 입자 (5mg/kg)를 주사 하였다. 1 시간 후 APAP (22.5 mg / mL) 400 μL를 복강 내 주사하여 급성 간 기능 부전을 유도 하였다. 마우스를 혈액 희생시키고 24 시간에 기관을 수집하여 분석 하였다.혈청 ALT (alanine transaminase)는 마이크로 플레이트 리더 (Synergy MX, BioTek Instruments, Inc., Winooski, VT)를 사용하여 ALT 효소 분석 키트 (Asan Pharma, Seoul, Korea)로 측정 하였다. 간 조직을 4 % 포르말린 (Sigma-Aldrich, St. Louis, MO)으로 고정시키고 파라핀에 끼웠다. 조직 절편을 만들고 헤 마톡 실린과 에오신 (H & E)으로 염색 하였다. 도 6a에 도시 된 바와 같이, APAP- 중독은 혈청 내 ALT 수준을 극적으로 상승 시켰으며, 커큐민은 ALT 수준을 유의하게 억제 하였다. POC 입자는 ALT 수준을 현저하게 감소 시켰으며 동량의 커큐민보다 유의하게 높은 치료 효과를 나타냈다. APAP에 의한 간 손상에 대한 POC 입자의 치료 효과를 확인하기 위해 간 조직을 이용하여 조직 검사를 시행 하였다. POC 입자는 간세포 형태학에서 눈에 띄는 변화를 일으키지 않았지만, APAP 중독은 간세포의 광범위한 파괴 및 백혈구의 침윤을 유도했다 (도 5b). Free curcumin은 APAP에 의한 간 손상으로부터 온건 한 보호 효과를 나타내었다. 그러나 POC 입자는 간세포를 APAP에 의한 간 손상으로부터 보호함으로써 상당한 치료 효과를 나타냈다. Apoptosis는 APAP에 의한 간 손상에서 세포 사멸을 담당하는 메커니즘 중 하나이다. 간에서 apoptotic 세포 사멸에 POC 입자의 효과를 조사하기 위해, 우리는 간 조직의 deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) 염색을 사용하여 정량화 하였다. 도 7에 나타낸 바와 같이, APAP 처리 군에서는 유의 한 세포 자멸사가 관찰되었고, 커큐민은 간세포에 적당한 억제 효과를 나타냈다. 대조적으로, POC 입자는 현저히 간 세포 사멸을 억제했다. 그 결과는 H & E 염색 된 간 조직에서 평가 된 결과와 일치하였으며, POC 입자가 APAP 손상을 예방하기 위해 매우 강력한 항 염증 및 항 - 세포 자멸사 활성을 발휘한다는 것을 명확히 입증 하였다. 더욱이, 우리는 HO-1, 산화 스트레스 [46]을 방해하는 세포 보호 활성을 이끌어 스트레스 반응 단백질의 발현에 POC 입자의 효과를 평가 하였다. 도 5에 도시 된 바와 같이, APAP- 중독 마우스의 간 조직은 HO-1의 수준이 유의하게 상승하여 산화 스트레스를 나타내는 것으로 나타났다. 커큐민은 HO-1 발현에 적당한 억제 효과를 나타냈다. 그러나 POC 입자 처리는 HO-1 발현을 현저히 하향 조절하였으며, 이는 ORS를 제거하고 간을 메메 독성으로부터 보호 할 수 있음을 보여준다. POC 입자의 전신 독성을 평가하기 위해 다른 기관의 조직학적 검사도 시행 하였다. 도 6에 나타낸 바와 같이, POC 처리 군의 폐, 심장 및 신장 조직은 미처리 대조군과 비교하여 현저한 조직 학적 차이가 관찰되지 않았다. 이러한 관찰은 POC 입자가 우수한 생체 적합성을 가짐을 나타낸다. A mouse model of APAP-induced liver dysfunction was used to investigate its potential as a therapeutic for POC particles. Male ICR 8-week-old mice (30 g) were obtained from the Orient Experimental Animal Breeding Center (Korea). All animals were stored in cages of 20-22 ° C. with a relative humidity of 50 ± 10% humidity. Prior to the experiment, mice were fasted for 12 hours. Mice (n = 4) were injected with curcumin (0.75 mg / kg) or POC particles (5mg / kg) through the tail vein. After 1 hour, 400 μL of APAP (22.5 mg / mL) was intraperitoneally injected to induce acute liver failure. Mice were sacrificed for blood and organs were collected and analyzed at 24 hours. Serum alanine transaminase (ALT) was analyzed using an ALT enzyme assay kit (Asan Pharma, using a microplate reader (Synergy MX, BioTek Instruments, Inc., Winooski, VT)). Seoul, Korea). Liver tissue was fixed with 4% formalin (Sigma-Aldrich, St. Louis, Mo.) and embedded in paraffin. Tissue sections were made and stained with hematoxylin and eosin (H & E). As shown in Figure 6a, APAP-intoxication dramatically raised serum ALT levels, and curcumin significantly inhibited ALT levels. POC particles significantly reduced ALT levels and showed a significantly higher therapeutic effect than equivalent amounts of curcumin. To determine the therapeutic effect of POC particles on liver damage caused by APAP, a biopsy was performed using liver tissue. POC particles did not cause noticeable changes in hepatocellular morphology, but APAP poisoning induced extensive destruction of hepatocytes and infiltration of leukocytes (FIG. 5B). Free curcumin showed moderate protection against liver damage caused by APAP. However, POC particles have shown significant therapeutic effects by protecting hepatocytes from liver damage by APAP. Apoptosis is one of the mechanisms responsible for cell death in liver damage caused by APAP. To investigate the effect of POC particles on apoptotic cell death in the liver, we were quantified using deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining of liver tissue. As shown in FIG. 7, significant apoptosis was observed in the APAP treatment group, and curcumin showed a moderate inhibitory effect on hepatocytes. In contrast, POC particles significantly inhibited liver cell death. The results were consistent with the results evaluated in H & E stained liver tissue, clearly demonstrating that POC particles exert very potent anti-inflammatory and anti-cell apoptosis activity to prevent APAP damage. Moreover, we assessed the effect of POC particles on the expression of HO-1, a stress-responsive protein that leads to cell protective activity that interferes with oxidative stress [46]. As shown in FIG. 5, liver tissue of APAP-addicted mice was shown to significantly increase the level of HO-1, indicating oxidative stress. Curcumin showed a moderate inhibitory effect on HO-1 expression. However, POC particle treatment significantly down-regulated HO-1 expression, demonstrating that it can eliminate ORS and protect the liver from medotoxicity. Histological examinations of other organs were also performed to assess the systemic toxicity of POC particles. As shown in FIG. 6, no significant histological differences were observed in the lung, heart and kidney tissues of the POC treated group compared to the untreated control. This observation indicates that POC particles have good biocompatibility.
생체 내 및 생체 내에서 POC 입자의 초음파 이미징Ultrasound Imaging of POC Particles in Vivo and in Vivo
Peroxalate 에스테르는 H2O2와 빠르게 반응하여 CO2를 생성하는 것으로 알려져 있다. 따라서, 이산화탄소가 POC의 과산화물 에스테르와 H2O2의 반응에 의해 생성되어 축적되어 POC 입자에 나노 또는 마이크로 버블을 형성하여 변형 가능성과 압축성으로 인해, 음향 장의 공명에 의한 초음파 신호 강도를 향상 시킨다고 추론했다. 상기의 가설을 증명하기 위해, 먼저 H2O2의 존재 또는 부재 하에서 아가로오스겔 팬텀에서 POC 입자의 에코 형성을 평가했다. 피부와 조직층을 자극하기 위해 아가로오스 겔 팬텀을 준비했다. 아가로스 용액 (3 중량 %)을 가열하여 기포를 제거한 후 500μL 미세 원심 분리 관에 묻힌 금형에 옮겼다. 겔 형성이 완료되면 튜브를 조심스럽게 제거했다. PBS에 현탁 된 다양한 농도의 POC 입자를 H2O2의 존재 또는 부재 하에 아가로즈 겔의 웰에 넣었다. APAP-중독 간장의 초음파 영상화를 위해 POC 입자 (5mg/kg)를 정맥 주사 하였다. 초음파 이미징은 Sonix TOUCH (Ultrasonix, 캐나다), 14 MHz의 L14-5 / 38 변환기 (128 요소, 7.2 MHz : 중심 주파수)를 사용하여 후방 산란 모드 (B 모드)에서 수행되었다. H2O2의 부재하에, POC 입자는 에코 형성성이 아니며, 2 시간 동안 눈에 띄는 초음파 조영 증강으로 입증되지 않았다 (도 8a). 그러나 POC 입자는 시간 의존적이며 H2O2에 농도 의존적으로 증가하였다. POC 입자는 높은 농도의 H2O2에서 더 높은 초음파 신호 강도를 보였다. 예를 들어, POC 입자는 30 분에 H2O2가없는 것보다 10 mM의 H2O2로 10 배 더 높은 초음파 신호 강도를 나타났다. 이러한 관찰은 과산화물 에스테르의 H2O2에 의해 유발 된 산화로부터 POC 입자에서 생성 된 이산화탄소 기포가 에코 발생 반사에 충분함을 분명히 시사한다. H2O2가 존재할 때, POC 입자는 15 분에서 명백한 에코 신호를 나타내었고 에코 신호는 60 분 동안 지속될 수 있었다. 초음파 신호의 느리고 점진적인 향상은 입자의 고체 소수성 내부와 H2O2의 느린 확산과 POC 입자의 안정성에 기인한다. 또한 POC 입자가 에코 원성과 농도 사이에 선형 상관관계를 나타냄을 관찰했다 (그림 8c.d).Peroxalate ester is known to produce a CO 2 to quickly react with the H 2 O 2. Therefore, it is inferred that carbon dioxide is produced and accumulated by the reaction of peroxide ester of POC with H 2 O 2 to form nano or micro bubbles in POC particles, thereby improving the ultrasonic signal strength due to acoustic field resonance due to the deformability and compressibility. did. To demonstrate the above hypothesis, the echo formation of POC particles in the agarose gel phantom was first evaluated in the presence or absence of H 2 O 2 . Agarose gel phantoms were prepared to stimulate the skin and tissue layers. The agarose solution (3% by weight) was heated to remove bubbles and transferred to a mold embedded in a 500 μL microcentrifuge tube. The tube was carefully removed when gel formation was complete. POC particles of various concentrations suspended in PBS were placed in the wells of an agarose gel in the presence or absence of H 2 O 2 . POC particles (5 mg / kg) were injected intravenously for ultrasound imaging of APAP-addicted liver. Ultrasound imaging was performed in backscattering mode (B mode) using Sonix TOUCH (Ultrasonix, Canada), an L14-5 / 38 transducer at 14 MHz (128 elements, 7.2 MHz: center frequency). In the absence of H 2 O 2 , POC particles are not echogenic and have not been demonstrated with noticeable ultrasound contrast enhancement for 2 hours (FIG. 8A). However, POC particles were time dependent and concentration dependent on H 2 O 2 . POC particles showed higher ultrasonic signal intensities at higher concentrations of H 2 O 2 . For example, POC particles showed 10 times higher ultrasonic signal intensity with 10 mM H 2 O 2 than without H 2 O 2 at 30 minutes. This observation clearly suggests that the carbon dioxide bubbles generated in POC particles from oxidation induced by H 2 O 2 in peroxide esters are sufficient for echogenic reflections. When H 2 O 2 was present, the POC particles showed a clear echo signal at 15 minutes and the echo signal could last 60 minutes. The slow and gradual improvement of the ultrasonic signal is due to the solid hydrophobic interior and slow diffusion of H 2 O 2 and the stability of the POC particles. We also observed that POC particles showed a linear correlation between echogenicity and concentration (Figure 8c.d).
LPS 유발 폐 손상의 마우스 모델Mouse Model of LPS-induced Lung Injury
6주 내지 8주령의 C57BL / 6 수컷 마우스를 Orient Experimental Animal Breeding Center로 부터 얻었다. 모든 동물은 20 ~ 22 ℃, 상대 습도 50 ± 10 %의 와이어 케이지에 사육하였다. 상기 마우스는 케타민(ketamine) 90 mg/kg 및 자일라진(Xylazine) 1mg/kg을 복강내 주사하여 감작하였다. 기관 절제술을 시행 한 다음 멸균 인산염 완충 식염수 (PBS)에 현탁시킨 내 독소 LPS를 기관 내로 주입 하였다. 30 분간의 LPS 처리 후, 마우스는 각 제제 (30μg의 커큐민/ 커큐민 함량의 30μg을 포함하는 POC)를 기관 내 주입 하였다. 멸균된 PBS로 처리된 동물은 대조군으로 간주 하였다. 추가 분석을 위해 혈액 샘플, 기관지 폐포 세척액 (BALF) 및 폐 조직 폐포 세척액 (BALF) 및 폐 조직을 수집하기 위해 치료 후 6 시간 후에 동물을 희생시켰다.C57BL / 6 male mice from 6 to 8 weeks of age were obtained from the Orient Experimental Animal Breeding Center. All animals were housed in wire cages with a relative humidity of 50 ± 10% at 20-22 ° C. The mice were sensitized by intraperitoneal injection of ketamine 90 mg / kg and xylazine 1 mg / kg. After tracheotomy, an endotoxin LPS suspended in sterile phosphate buffered saline (PBS) was injected into the trachea. After 30 minutes of LPS treatment, mice were injected intratracheally with each preparation (30 μg of curcumin / POC containing 30 μg of curcumin content). Animals treated with sterile PBS were considered controls. Animals were sacrificed 6 hours after treatment to collect blood samples, bronchial alveolar lavage (BALF) and lung tissue alveolar lavage (BALF) and lung tissue for further analysis.
BALF 수집, 세포 수, 측정 및 단백질 분석BALF collection, cell count, measurement and protein analysis
우하 폐엽을 제거한 후 기관 캐뉼라를 통해 0.1 mM EDTA를 함유 한 PBS 1 ml를 폐로 세척하여 BALF를 수집 하였다. 세포를 수집하고 4 ℃에서 500 ㎍, 5 분간 원심 분리하여 풀링 된 BALF로부터 농축시키고 1 ㎖ PBS에 재현탁시켰다. BALF 액을 5,000 x g에서 10 분간 원심 분리하고 단백질 분석을 위해 즉시 사용하거나 -80 ℃에서 동결시켰다. 상등액 중의 단백질 농도는 Smart BCA Assay Kit를 사용하여 측정 하였다. 모조 군에서 낮은 단백질 수준이 관찰 되었지만, LPS 치료는 폐에서 염증을 유발하였으며 이는 단백질 수준의 상승으로 입증되었다. 커큐민 처리군에서 단백질 수준의 유의한 변화는 없었다. 그러나, POC 입자로 폐를 치료하면 단백질 농도가 현저하게 검되었다. 단백질 농도의 감소는 염증 세포의 수가 적기 때문이며, 이는 POC가 항염증성 커큐민을 폐포대식세포에 직접 방출하면서 염증을 억제한다는 것을 입증한다(도 9). 혈구계에 의해 총 세포 수를 세었고 백혈구 백분율수(differential cell count)은 Diff-Quik stain과 함께 cytospin 염색으로 수행되었다. 커큐민은 형광이기 때문에, 공 초점 레이저 스캐닝 현미경 하에서 POC 입자의 내재화가 관찰되었다. 가짜 그룹(PBS 처리한 그룹)에서는 세포 침투가 거의 나타나지 않았으나, LPS를 처리한 마우스에서는 호산구의 개체군이 유의하게 증가했다. 그러나 POC 입자의 처리에 의해 호산구가 현저하게 감소하였다. POC입자는 커큐민 보다 호산구에서 더 많은 감소를 보였다. 호산구의 모집은 POC 입자의 처리에 의해 거의 완전히 저해되었다. 그 결과는 Diff-Quik으로 염색 된 cytospined BALF 세포에 의해 뒷받침되었다 (도 10). PBS과 LPS로 처리 한 군은 관찰 가능한 형광성 신호를 나타내지 않았지만 커큐민으로 처리 한 군에서는 작은 신호가 관찰되었다. 그러나, POC 입자 처리 군에서 POC의 내재화로 인한 형광 신호 강도가 상승 하였다 (도 11). After removing the lower right lobe, BALF was collected by pulmonary washing 1 ml of PBS containing 0.1 mM EDTA through tracheal cannula. Cells were collected and concentrated from pooled BALF by centrifugation at 500 μg for 5 min at 4 ° C. and resuspended in 1 ml PBS. BALF liquor was centrifuged at 5,000 x g for 10 minutes and used immediately for protein analysis or frozen at -80 ° C. Protein concentration in the supernatant was measured using the Smart BCA Assay Kit. Although low protein levels were observed in the sham group, LPS treatment induced inflammation in the lungs, which was evidenced by elevated protein levels. There was no significant change in protein levels in the curcumin treated group. However, treatment of the lungs with POC particles significantly marked protein concentrations. The decrease in protein concentration is due to the low number of inflammatory cells, demonstrating that POC inhibits inflammation by releasing anti-inflammatory curcumin directly into alveolar macrophages (FIG. 9). Total cell counts were counted by hemocytometer and differential cell count was performed by cytospin staining with Diff-Quik stain. Since curcumin is fluorescent, internalization of POC particles was observed under a confocal laser scanning microscope. Cell penetration did not appear in the sham group (PBS-treated group), but the LPS-treated mice significantly increased the population of eosinophils. However, treatment of POC particles significantly reduced eosinophils. POC particles showed more reduction in eosinophils than curcumin. The recruitment of eosinophils was almost completely inhibited by the treatment of POC particles. The results were supported by cytospined BALF cells stained with Diff-Quik (FIG. 10). The group treated with PBS and LPS did not show an observable fluorescent signal, but a small signal was observed in the group treated with curcumin. However, in the POC particle treatment group, the fluorescence signal intensity due to internalization of POC was increased (FIG. 11).
산화제 스트레스 측정Oxidant stress measurement
Amplex Red (Invitrogen, Carlsbad, CA) 분석법을 사용하여 BALF 및 폐 조직에서 세포 내 ROS 수준을 측정 하였다. 폐 조직을 균질화시키고 (PRO Scientific, PRO 200, Oxford, CT), 원심 분리하여 조직 도랍을 제거하고, 상등액을 분석에 사용 하였다. 100 μM Amplex Red 시약 (0.1 mM N- 아세틸 -3,7- 디 히드 록시 페녹 사진, 0.2 U / mL 양 겨자무과산화효소(horseradish peroxidase), 50 mM 인산 나트륨 pH 7.4)의 작업 용액을 각 웰에 첨가하고, 실온에서 20 분 동안 배양 하였다. 마이크로 플레이트 판독기 (Synergy MX, BioTek Instrument, Inc., Winooski, VT)를 사용하여 590 nm에서 형광 방출 강도를 측정 하였다. H2O2의 표준 농도를 플롯하고 조직의 H2O2 농도를 표준 농도에 대해 플롯했다. LPS-sensitization은 가짜 그룹에 비해 H2O2의 수준을 현저히 상승시켰다. 그러나 POC 나노 입자는 H2O2의 생성을 현저하게 억제하였으며, H2O2의 현저한 감소는 폴리머 백본에서 방출 된 퍼옥살레이트 에스테르 및 커큐민의 H2O2- 제거 활성에 기인한다 (도 12).Intracellular ROS levels were measured in BALF and lung tissue using Amplex Red (Invitrogen, Carlsbad, CA) assay. Lung tissue was homogenized (PRO Scientific,
폐 조직 병리학Lung Tissue Pathology
폐 조직 표본을 10 % 포르말린에 고정시키고 파라핀에 끼우고 5μm 두께의 절편으로 자른다. 탈 파라핀 화 후, 슬라이드를 헤마톡실린 및 에오신으로 염색 하였다. 폐의 형태 학적 변화를 광학 현미경으로 관찰 하였다. Sham 그룹은 간 조직의 정상적인 미세 형태를 보였으나 LPS에 의한 폐의 알레르기성 염증에서 호산구가 동반 된 면역 세포의 특징적인 침윤이 인정되었다. LPS- 처리 마우스에서, 기관지 염증의 전형적인 징후 (광범위한 상피 손상, 내강 협착,기도 벽의 부종 및 점액 장애)을 나타내었다. 커큐민의 기관 내 투여는 기도 구조의 변화에 미치는 영향이 적었다. 그러나 POC 입자는 폐 염증의 현저한 감소, 폐포의 비후 감소 및 상피 손상의 감소에 의해 입증 된 바와 같이 상당한 치료 효과를 보였다.Lung tissue specimens are fixed in 10% formalin, embedded in paraffin and cut into 5 μm thick sections. After deparaffinization, the slides were stained with hematoxylin and eosin. Morphological changes in the lungs were observed under an optical microscope. The Sham group showed normal microscopic morphology of liver tissue, but the characteristic infiltration of eosinophils with immune cells was recognized in allergic inflammation of the lungs by LPS. In LPS-treated mice, typical signs of bronchial inflammation (extensive epithelial injury, lumen narrowing, edema of the airway wall and mucus disorders) were shown. Intratracheal administration of curcumin had little effect on changes in airway structure. However, POC particles showed a significant therapeutic effect, as evidenced by a marked reduction in pulmonary inflammation, a decrease in the alveolar thickening and a decrease in epithelial damage.
Claims (10)
옥살레이트 및 1, 4-사이클로헥산디메탄올이 통합된 제 1블록; 및 옥살레이트 및 커큐민이 통합된 제 2블록;으로 구성되는 POC(poly(oxalate-co-curcumin)) 공중합체를 포함하는 나노입자:
[화학식 4]
.Represented by the following formula (4),
A first block incorporating oxalate and 1,4-cyclohexanedimethanol; And a second block in which oxalate and curcumin are integrated; a nanoparticle comprising a poly (oxalate-co-curcumin) (POC) copolymer comprising:
[Formula 4]
.
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