KR20230105518A - Composition for the treatment of autoimmune diseases and mitochondria using theragnostic gold nanomedical particles - Google Patents
Composition for the treatment of autoimmune diseases and mitochondria using theragnostic gold nanomedical particles Download PDFInfo
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Abstract
본 발명은 테라그노스틱 골드 나노메디칼입자를 이용한 자가면역질환과 미토콘드리아 치료용 조성물에 관한 것으로서, 본 발명의 금 나노입자는 류마티스 관절염이 유도된 동물모델에서, 관절염 지수 및 유병률을 감소시키고, 관절 조직을 보호하는 것을 확인하였다. 또한, 류마티스 관절염 모델에서 감소한 것으로 알려진 미토콘드리아의 활성을 증가시키며, Th17 세포의 발현을 억제시키는 것을 확인하였다. 또한, 염증성 사이토카인인 IL-1β, IL-17, IL-6 및 TNF-α의 양을 감소시키고, 혈청 내 citrulinet vimentin specific IgG의 양을 감소시키는 것을 확인하여, 관절염의 치료 효과를 확인하였다.The present invention relates to a composition for treating autoimmune diseases and mitochondria using theragnostic gold nanomedical particles. was confirmed to protect. In addition, it was confirmed that mitochondrial activity, which is known to be decreased in the rheumatoid arthritis model, was increased, and expression of Th17 cells was suppressed. In addition, it was confirmed that the amounts of inflammatory cytokines IL-1β, IL-17, IL-6, and TNF-α were reduced, and the amount of citrulinet vimentin specific IgG in serum was reduced, thereby confirming the therapeutic effect of arthritis.
Description
본 발명은, 테라그노스틱 골드 나노메디칼입자를 이용한 자가면역질환과 미토콘드리아 치료용 조성물에 관한 것이다.The present invention relates to a composition for treating autoimmune diseases and mitochondria using theragnostic gold nanomedical particles.
전 세계적으로 면역과민반응으로 인한 질환이 증가하고 있지만, 이러한 질환들의 발생에 대한 근본적인 원인 규명이 충분히 이루어지지 않은 상태이다. 현재 과도한 면역반응에 의한 질환의 치료방법으로는 면역억제제를 단독 또는 병용 투여함으로써 상기 질환에 의해 야기되는 각종 증상을 완화 내지 감소시키는 것이다. Diseases caused by immune hypersensitivity reactions are increasing worldwide, but the fundamental causes of the occurrence of these diseases have not been sufficiently identified. Currently, as a treatment method for diseases caused by an excessive immune response, various symptoms caused by the diseases are alleviated or reduced by administering an immunosuppressive agent alone or in combination.
면역억제제란 항원의 작용에 대하여 숙주가 항체를 만드는 능력(체액성 면역반응) 또는 세포성 면역반응을 일으키는 능력을 저하시키거나 차단하기 위해 사용되는 다양한 물질들을 말한다. 이러한 면역억제제는 장기이식분야 뿐만 아니라 루푸스, 류마티스 관절염 등과 같은 자가면역질환과, 아토피, 알러지 등의 피부과민 반응에도 유용하게 사용될 수 있다. 우수한 면역억제제는 면역반응의 불균형을 조절할 수 있어야 하고, 인체에 대한 안전성이 확보되어야 하며, 장기간 치료시에 질환의 재발 발생 빈도가 낮아야 한다.Immunosuppressive agents refer to various substances used to reduce or block the ability of a host to produce antibodies against the action of an antigen (humoral immune response) or to induce a cellular immune response. These immunosuppressants can be usefully used not only in the field of organ transplantation, but also in autoimmune diseases such as lupus and rheumatoid arthritis, and skin hypersensitivity reactions such as atopy and allergy. An excellent immunosuppressive agent should be able to control the imbalance of the immune response, should be safe for the human body, and should have a low frequency of disease recurrence during long-term treatment.
현재 사용되고 있는 면역억제제로는 사이클로스포린 A와 FK506 등이 있는데, 이들은 복잡한 화학구조를 가진 천연물 유래의 화합물로서 원료 수급의 측면에서 고비용이 드는 문제점이 있어 비경제적이고, 장기투여로 인해 각종 부작용이 야기될 수 있다는 위험성을 내포하고 있다. 따라서 낮은 독성 및 면역관용 유도와 함께 경제적인 생산이 가능한 새로운 면역억제제의 개발이 절실히 요구되고 있는 실정이다. Currently used immunosuppressants include cyclosporin A and FK506, which are compounds derived from natural products with complex chemical structures that are uneconomical due to the high cost in terms of raw material supply and long-term administration, which can cause various side effects. There is a risk that there is Therefore, there is an urgent need for the development of new immunosuppressants capable of economical production with low toxicity and induction of immune tolerance.
한편, 각종 병원체에 대한 생체 방어 시스템으로 면역계에서 중심적 역할을 담당하는 세포군의 하나로 T 세포가 있다. T 세포는 인체의 흉선에서 생성되며 일련의 분화 과정을 거치면서 고유의 특성을 지닌 T 세포로 분화하게 되는데, 분화를 완료한 T 세포는 그 기능에 따라 크게 1형 보조 세포(Th1)와 2형 보조 세포(Th2)로 구분된다. 이 중에서 Th1 세포의 주된 기능은 세포 매개성 면역에 관여하고, Th2 세포는 체액성 면역에 관여하며, 면역계에서 이러한 두 세포 집단은 서로 과 활성화되지 않도록 서로 견제를 통해 면역계의 균형을 유지하고 있다. On the other hand, T cells are one of the cell groups that play a central role in the immune system as a biological defense system against various pathogens. T cells are produced in the human thymus and differentiate into T cells with unique characteristics through a series of differentiation processes. It is divided into helper cells (Th2). Among them, the main function of Th1 cells is involved in cell-mediated immunity, and Th2 cells are involved in humoral immunity.
따라서 면역질환의 대부분은 이러한 두 가지 면역 세포간의 불균형에 기인하는 것으로 볼 수 있는데, 예를 들어 Th1 세포의 활성이 비정상적으로 증가하는 경우 자가면역질환이 발생할 수 있고, Th2 세포의 활성이 비정상적으로 증가하는 경우 과민반응에 의한 면역질환이 발생하는 것으로 알려져 있다. Therefore, most of the immune diseases can be seen as being caused by an imbalance between these two immune cells. For example, when the activity of Th1 cells is abnormally increased, autoimmune diseases can occur, and the activity of Th2 cells is abnormally increased. It is known that immune diseases caused by hypersensitivity reactions occur.
한편, Th1 세포의 분화에 대한 최근 연구 결과에 따르면, Th1 세포의 활성을 조절할 수 있는 새로운 그룹인 면역조절 T 세포(Treg)의 존재가 알려지면서 이를 이용한 면역질환의 치료에 대한 연구가 대두되고 있는데, Treg 세포는 비정상적으로 활성화된 면역세포의 기능을 억제하여 염증 반응을 제어하는 특성이 있어, Treg 세포의 활성을 증가시키는 작용을 통해 면역질환을 치료하고자 하는 연구들이 많이 진행되고 있다.On the other hand, according to recent research results on the differentiation of Th1 cells, as the existence of immunoregulatory T cells (Tregs), a new group capable of regulating the activity of Th1 cells, has been known, research on the treatment of immune diseases using them has emerged. , Treg cells have the property of controlling the inflammatory response by suppressing the function of abnormally activated immune cells, and many studies are being conducted to treat immune diseases through the action of increasing the activity of Treg cells.
또한, Treg 세포 이 외에 T 세포의 분화 과정에서 만들어지는 또 다른 그룹으로 Th17 세포가 있는데, Th17 세포는 미분화 T세포의 분화 과정에서 Treg 세포의 분화와 유사한 과정을 거치며 형성되는 것으로 알려져 있다. 즉, Treg 세포와 Th17 세포의 분화는 공통적으로 TGF-β의 존재 하에서 이루어지지만, Treg 세포의 경우 IL-6을 필요로 하지 않는 반면, Th17 세포의 경우에는 TGF-β와 함께 IL-6가 존재하는 상황에서 분화를 한다. 또한, 분화된 Th17 세포는 IL-17을 분비하는 것을 특징으로 한다. In addition, there are Th17 cells as another group formed during the differentiation process of T cells other than Treg cells. It is known that Th17 cells are formed during the differentiation process of undifferentiated T cells through a process similar to that of Treg cells. That is, the differentiation of Treg cells and Th17 cells is commonly achieved in the presence of TGF-β, but IL-6 is not required for Treg cells, whereas IL-6 is present together with TGF-β for Th17 cells. differentiate in the circumstances. Also, differentiated Th17 cells are characterized by secreting IL-17.
Th17 세포는 Treg 세포와는 달리 면역질환에서 보이는 염증반응의 최전방에서 관여하여 염증 반응의 신호를 최대화시켜 질병의 진행을 가속화시키는 것이 밝혀지고 있다. 그러므로 자가면역질환 중 Treg 세포에 의해 제어되지 않는 자가면역질환의 경우, Th17 세포 활성의 억제를 표적으로 한 자가면역질환의 치료제 개발이 크게 부각되고 있다.It has been revealed that Th17 cells, unlike Treg cells, are involved in the forefront of the inflammatory response seen in immune diseases, maximizing the signal of the inflammatory response and accelerating the progression of the disease. Therefore, in the case of autoimmune diseases that are not controlled by Treg cells among autoimmune diseases, the development of a therapeutic agent for autoimmune diseases targeting inhibition of Th17 cell activity has been greatly highlighted.
한편, 미토콘드리아 내부에 세포사와 밀접한 관계를 갖는 신호전달기전들이 존재하고 우리가 이들 신호를 해석하고 제어할 수 있다면 질병치료에 응용할 수 있다(Biochimica et Biophysica Acta, 2006; Cell, 2005; Trends Biochem Sci, 2005; Nature Med, 2005; Nature, 2005; J Clin Invest, 2005; Heart Lung Circ, 2005; J Nat Cancer Inst, 2005, Science, 2005). 미토콘드리아 기능저하는 단일한 증상이나 질병이 아닌 인체 내 다양한 기관에서 다양한 질병으로 나타날 수 있어, 병든 미토콘드리아와 연관된 병소 및 질병 특이적이 치료법의 가능성이 제기되고 있으나 현재까지 정확한 타깃이나 합당한 치료기술 개발이 시급한 상태이다. 특히 세포내 증가한 활성산소종으로 인한 산화스트레스의 증가는 최근 심혈관·대사질환은 물론 퇴행성신경 질환에서의 세포학적·분자생물학적 근본 기전으로 제시되고 있으나, 현재까지 임상 및 전임상 단계에서 사용되는 대사성치료제 또는 항산화제 치료는 효과는 아직 논란의 여지가 있다. 따라서 손상되지 않은 미토콘드리아를 이식하거나, 미토콘드리아 기능을 직접 제어할 수 있는 막단백질 및 기질 단백질의 발현을 조절할 수 있는 미세표적화치료(micro-targeting therapy)로서의 유전자 치료법은 영구적 또는 반영구적 치료법으로서 가능성이 높은 전략일 수 있다.On the other hand, there are signal transduction mechanisms closely related to cell death inside mitochondria, and if we can interpret and control these signals, it can be applied to disease treatment (Biochimica et Biophysica Acta, 2006; Cell, 2005; Trends Biochem Sci, 2005; Nature Med, 2005; Nature, 2005; J Clin Invest, 2005; Heart Lung Circ, 2005; J Nat Cancer Inst, 2005, Science, 2005). Mitochondrial dysfunction is not a single symptom or disease, but can appear as a variety of diseases in various organs in the human body, and the possibility of pathological and disease-specific treatments related to diseased mitochondria has been raised. It is a state. In particular, the increase in oxidative stress due to increased intracellular reactive oxygen species has recently been suggested as a fundamental cytological and molecular biological mechanism in cardiovascular and metabolic diseases as well as neurodegenerative diseases. The efficacy of antioxidant treatment is still controversial. Therefore, gene therapy as a micro-targeting therapy that can transplant intact mitochondria or regulate the expression of membrane and matrix proteins that can directly control mitochondrial function is a strategy with high potential as a permanent or semi-permanent treatment. can be
본 발명의 목적은, 금 나노입자(Gold nano-particle)을 유효성분으로 포함하는 관절염의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition for preventing or treating arthritis, comprising gold nano-particles as an active ingredient.
본 발명의 다른 목적은, 금 나노입자(Gold nano-particle)을 유효성분으로 포함하는 관절염의 예방 또는 개선용 식품조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving arthritis, containing gold nano-particles as an active ingredient.
상기의 목적을 달성하기 위하여, 본 발명은 금 나노입자(Gold nano-particle)을 유효성분으로 포함하는 관절염의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating arthritis, comprising gold nano-particles as an active ingredient.
또한, 본 발명은 금 나노입자(Gold nano-particle)을 유효성분으로 포함하는 관절염의 예방 또는 개선용 식품조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving arthritis, including gold nano-particles as an active ingredient.
본 발명의 금 나노입자는 류마티스 관절염이 유도된 동물모델에서, 관절염 지수 및 유병률을 감소시키고, 관절 조직을 보호하는 것을 확인하였다. 또한, 류마티스 관절염 모델에서 감소한 것으로 알려진 미토콘드리아의 활성을 증가시키며, Th17 세포의 발현을 억제시키는 것을 확인하였다. 또한, 염증성 사이토카인인 IL-1β, IL-17, IL-6 및 TNF-α의 양을 감소시키고, 혈청 내 citrulinet vimentin specific IgG의 양을 감소시키는 것을 확인하여, 관절염의 치료 효과를 확인하였기에, 관련 산업에 유용하게 이용할 수 있다.It was confirmed that the gold nanoparticles of the present invention reduced the index and prevalence of arthritis and protected joint tissues in an animal model in which rheumatoid arthritis was induced. In addition, it was confirmed that mitochondrial activity, which is known to be decreased in the rheumatoid arthritis model, was increased, and expression of Th17 cells was suppressed. In addition, it was confirmed that the amount of inflammatory cytokines IL-1β, IL-17, IL-6 and TNF-α was reduced, and the amount of citrulinet vimentin specific IgG in serum was reduced, thereby confirming the therapeutic effect of arthritis, It can be usefully used in related industries.
도 1은 본 발명의 금 나노입자의 UV-Vis Absorption 분석 및 SEM(scanning electron microscope) 관찰 결과를 나타낸 도이다(A: UV-Vis Absorption, B: SEM 결과).
도 2는 류마티스 관절염이 유도된 마우스에 금 나노입자를 처리하여, 관절염 지수(arthritis score) 및 유병율(incidence)을 확인한 도이다(A: 관절염 지수 확인, B: 유병율 확인).
도 3은 류마티스 관절염이 유도된 마우스에 금 나노입자를 처리하여, 관절 손상 정도를 헤막토실린&에오신 염색과 사프라닌 O 염색으로 확인한 도이다(A: 염색 결과, B: 관절 손상 지수 정량화)
도 4는 류마티스 관절염이 유도된 마우스에 금 나노입자를 처리하여, 비장 세포의 미토콘드리아 기능 향상을 확인한 도이다(A: ATP 양 증가 확인, B: ATP 합성능 증가 확인).
도 5는 류마티스 관절염이 유도된 마우스에 금 나노입자를 처리하여, 비장세포에서의 미토콘드리아 호흡양을 OCR assay로 확인한 도이다.
도 6은 류마티스 관절염이 유도된 마우스에 금 나노입자를 처리하여, 비장세포에서의 Th17 세포 발현을 유세포 분석으로 분석한 도이다(A: 유세포 분석 결과, B: 발현량 정량화)
도 7은 류마티스 관절염이 유도된 마우스에 금 나노입자를 처리하여, 관절 내 염증성 사이토카인의 양을 면역조직화학염색으로 확인한 도이다(A: 염색 결과, B: 염증성 사이토카인 발현 정량화).
도 8은 류마티스 관절염이 유도된 마우스에 금 나노입자를 처리하여, 혈청 내 citrulinet vimentin specific IgG의 양을 확인한 도이다.1 is a diagram showing the results of UV-Vis Absorption analysis and SEM (scanning electron microscope) observation of the gold nanoparticles of the present invention (A: UV-Vis Absorption, B: SEM results).
FIG. 2 is a diagram illustrating arthritis score and incidence by treating rheumatoid arthritis-induced mice with gold nanoparticles (A: arthritis score confirmed, B: prevalence confirmed).
Figure 3 is a diagram showing the degree of joint damage by treating rheumatoid arthritis-induced mice with gold nanoparticles, and confirming the degree of joint damage by hematoxylin & eosin staining and safranin O staining (A: staining result, B: quantification of joint damage index)
FIG. 4 is a diagram illustrating the improvement of mitochondrial function of spleen cells by treating rheumatoid arthritis-induced mice with gold nanoparticles (A: confirming an increase in the amount of ATP; B: confirming an increase in the ability to synthesize ATP).
5 is a diagram confirming mitochondrial respiration in splenocytes by OCR assay by treating rheumatoid arthritis-induced mice with gold nanoparticles.
6 is a diagram illustrating the analysis of Th17 cell expression in splenocytes by flow cytometry analysis by treating rheumatoid arthritis-induced mice with gold nanoparticles (A: result of flow cytometry, B: quantification of expression level)
7 is a diagram illustrating the amount of inflammatory cytokines in a joint treated with gold nanoparticles in a mouse induced with rheumatoid arthritis by immunohistochemical staining (A: staining result, B: quantification of inflammatory cytokine expression).
8 is a diagram confirming the amount of citrulinet vimentin specific IgG in serum by treating a mouse with rheumatoid arthritis with gold nanoparticles.
본 발명은, 금 나노입자(Gold nano-particle)을 유효성분으로 포함하는 관절염의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating arthritis, comprising gold nano-particles as an active ingredient.
본 발명에서 사용되는 용어 “예방”은 본 발명의 조성물의 투여로 특정 질환의 증상을 억제하거나 진행을 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" refers to any action that suppresses symptoms or delays the progression of a specific disease by administering the composition of the present invention.
본 발명에서 사용되는 용어 “치료”는 본 발명의 조성물의 투여로 특정 질환의 증상을 호전 또는 이롭게 변경시키는 모든 행위를 의미한다.The term "treatment" used in the present invention refers to all activities that improve or beneficially change the symptoms of a specific disease by administering the composition of the present invention.
본 발명의 “나노입자(nano-particle)”는 입자크기가 나노미터(nanometer) 단위로 표기될 수 있는 미세입자를 말한다."Nano-particle" of the present invention refers to fine particles whose particle size can be expressed in nanometer units.
본 발명의 약학 조성물에는 유효성분 이외에 보조제(adjuvant)를 추가로 포함할 수 있다. 상기 보조제는 당해 기술분야에 알려진 것이라면 어느 것이나 제한 없이 사용할 수 있으나, 예를 들어 프로인트(Freund)의 완전 보조제 또는 불완전 보조제를 더 포함하여 그 효과를 증가시킬 수 있다.The pharmaceutical composition of the present invention may further include an adjuvant in addition to the active ingredient. As long as the adjuvant is known in the art, any one may be used without limitation, but, for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the effect.
본 발명에 따른 약학 조성물은 유효성분을 약학적으로 허용된 담체에 혼입시킨 형태로 제조될 수 있다. 여기서, 약학적으로 허용된 담체는 제약 분야에서 통상 사용되는 담체, 부형제 및 희석제를 포함한다. 본 발명의 약학 조성물에 이용할 수 있는 약학적으로 허용된 담체는 이들로 제한되는 것은 아니지만, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The pharmaceutical composition according to the present invention may be prepared in the form of incorporating the active ingredient into a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers usable in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀전, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or sterile injection solutions according to conventional methods, respectively. .
제제화할 경우에는 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 그러한 고형 제제는 유효성분에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘 카르보네이트, 수크로스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 일반적으로 사용되는 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수용성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수용성용제, 현탁제로는 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브유와 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.When formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations contain at least one or more excipients such as starch, calcium carbonate, sucrose, lactose, and gelatin in addition to active ingredients. It can be prepared by mixing etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc. In addition to commonly used diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. can Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for suppositories, witepsol, tween 61, cacao paper, laurin paper, glycerogelatin, and the like may be used.
본 발명에 따른 약학 조성물은 개체에 다양한 경로로 투여될 수 있다. 투여의 모든 방식이 예상될 수 있는데, 예를 들면 경구, 정맥, 근육, 피하, 복강 내 주사에 의해 투여될 수 있다.The pharmaceutical composition according to the present invention can be administered to a subject by various routes. All modes of administration are contemplated, eg oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
본 발명에 따른 약학 조성물의 투여량은 개체의 연령, 체중, 성별, 신체 상태 등을 고려하여 선택된다. 상기 약학 조성물 중 포함되는 유효성분의 농도는 대상에 따라 다양하게 선택할 수 있음은 자명하며, 바람직하게는 약학 조성물에0.01 ~ 5,000 ㎍/ml의 농도로 포함되는 것이다. 그 농도가 0.01 ㎍/ml 미만일 경우에는 약학 활성이 나타나지 않을 수 있고, 5,000 ㎍/ml를 초과할 경우에는 인체에 독성을 나타낼 수 있다.The dosage of the pharmaceutical composition according to the present invention is selected in consideration of the age, weight, sex, and physical condition of the subject. It is obvious that the concentration of the active ingredient included in the pharmaceutical composition can be variously selected according to the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 μg/ml. If the concentration is less than 0.01 μg/ml, pharmacological activity may not appear, and if the concentration exceeds 5,000 μg/ml, toxicity to the human body may be exhibited.
본 발명의 일실시예에 따르면, 상기 금 나노입자는 20 내지 40 nm의 입자 크기를 갖는 것일 수 있고, 바람직하게는 25 내지 35의 입자크기를 갖는 것일 수 있으나, 이에 제한되지는 않는다.According to one embodiment of the present invention, the gold nanoparticles may have a particle size of 20 to 40 nm, preferably 25 to 35 nm, but are not limited thereto.
본 발명의 일실시예에 따르면, 상기 조성물은 관절염 지수(arthritis score) 및 유병율(incidence)를 감소시키는 것일 수 있다.According to one embodiment of the present invention, the composition may reduce arthritis score and incidence.
본 발명의 일실시예에 따르면, 상기 조성물은, 미토콘드리아의 기능을 증가시키는 것일 수 있고, 상기 미토콘드리아의 기능 증가는, ATP 양(ATP contents), ATP 합성능(ATP synthesis) 및 미토콘드리아의 호흡양의 증가인 것일 수 있다.According to one embodiment of the present invention, the composition may be to increase the function of mitochondria, and the increase in the function of mitochondria, the amount of ATP (ATP contents), ATP synthesis capacity (ATP synthesis) and the amount of respiration of the mitochondria may be an increase.
본 발명의 일실시예에 따르면, 상기 조성물은, Th17 세포의 발현을 억제시키는 것일 수 있다.According to one embodiment of the present invention, the composition may inhibit the expression of Th17 cells.
본 발명의 일실시예에 따르면, 상기 조성물은, 염증성 사이토카인의 양을 감소시키는 것일 수 있고, 상기 염증성 사이토카인은 IL-1β(interleukin 1 beta), IL-17(interleukin 17), IL-6(interleukin 6) 및 TNF-α(tumor necrosis factor-α)로 이루어진 군에서 선택된 것일 수 있으나, 이에 제한되지는 않는다.According to one embodiment of the present invention, the composition, may be to reduce the amount of inflammatory cytokines, the inflammatory cytokines IL-1β (interleukin 1 beta), IL-17 (interleukin 17), IL-6 It may be selected from the group consisting of (interleukin 6) and TNF-α (tumor necrosis factor-α), but is not limited thereto.
본 발명의 일실시예에 따르면, 상기 조성물은, 혈청 내 citrulinet vimentin specific IgG의 양을 감소시키는 것일 수 있다.According to one embodiment of the present invention, the composition may reduce the amount of citrulinet vimentin specific IgG in serum.
본 발명의 일실시예에 따르면, 상기 관절염은, 류마티스 관절염 (Rheumatoid Arthritis) 또는 골관절염(osteoarthritis) 것일 수 있고, 바람직하게는 류마티스 관절염이나, 이에 제한되지는 않는다.According to one embodiment of the present invention, the arthritis may be rheumatoid arthritis or osteoarthritis, preferably rheumatoid arthritis, but is not limited thereto.
또한, 본 발명은, 금 나노입자(Gold nano-particle)을 유효성분으로 포함하는 관절염의 예방 또는 개선용 식품조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving arthritis, including gold nano-particles as an active ingredient.
본 발명에서 사용되는 용어 “개선”은 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term "improvement" refers to any action that at least reduces the severity of a parameter related to the condition being treated, for example, a symptom.
본 발명의 식품 조성물은 본 발명의 유효성분을 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.In addition to containing the active ingredient of the present invention, the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like conventional food compositions.
상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 본 발명의 식품 조성물은 상기 약학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등이 있다.Examples of the aforementioned natural carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the flavoring agents described above, natural flavoring agents (thaumatin), stevia extracts (eg rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can advantageously be used. The food composition of the present invention can be formulated in the same way as the pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gum, candy, ice cream, alcoholic beverages, vitamin complexes and health supplements, etc. there is
또한 상기 식품 조성물은 유효성분인 추출물 외에 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition, the food composition, in addition to the active ingredient extract, various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, Alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like may be contained. In addition, the food composition of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages, and vegetable beverages.
본 발명의 기능성 식품 조성물은 관절염의 예방 또는 치료 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공될 수 있다. 본 발명에서 '건강기능성 식품 조성물'이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. 상기 '식품 첨가물 공전'에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료 제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다. 예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다. 캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다. 환 형태의 건강기능식품은 본 발명의 유효성분과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다. 과립 형태의 건강기능식품은 본 발명의 유효성분의 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The functional food composition of the present invention may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or treating arthritis. In the present invention, 'health functional food composition' refers to a food manufactured and processed using raw materials or ingredients having useful functionality for the human body according to Health Functional Food Act No. 6727, and the structure and function of the human body It refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients or physiological functions. The health functional food of the present invention may contain ordinary food additives, and the suitability as a food additive is determined according to the general rules of the Food Additive Code and General Test Methods approved by the Food and Drug Administration, unless otherwise specified. It is judged according to standards and standards. Examples of the items listed in the 'Food Additive Code' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, kaoliang pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations. For example, a health functional food in the form of a tablet is obtained by granulating a mixture obtained by mixing the active ingredient of the present invention with an excipient, a binder, a disintegrant, and other additives in a conventional manner, and then adding a lubricant or the like to compression molding, or as described above. The mixture can be directly compression molded. In addition, the health functional food in the form of a tablet may contain a flavoring agent and the like as needed. Among health functional foods in the form of capsules, hard capsules can be prepared by filling a mixture in which the active ingredient of the present invention is mixed with additives such as excipients in a normal hard capsule. It can be prepared by filling the mixture mixed with gelatin in a capsule base. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary. The health functional food in the form of a pill can be prepared by molding a mixture of the active ingredient of the present invention mixed with an excipient, a binder, a disintegrant, etc. by a conventionally known method, and can be coated with sucrose or other coating agent if necessary, Alternatively, the surface may be coated with a material such as starch or talc. Health functional food in the form of granules can be prepared in granular form by a conventionally known method of mixing the active ingredient of the present invention with excipients, binders, disintegrants, etc., and, if necessary, flavoring agents, flavoring agents, etc. can
이하, 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail by examples. These examples are merely for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
<제조예 1> 금 나노입자(Gold nano-particle)의 제조<Preparation Example 1> Preparation of gold nano-particle
본 발명자들은 금 나노입자(Gold nano-particle, Gold-NP)가 관절염에 효과가 있는지 확인하기 위하여, 금 나노입자를 제조하였다. 구체적으로 Seed mediated growth 방법을 이용하여 합성하였으며, 17 nm 크기의 구형 금 나노 입자 제작을 위하여, 95℃의 100 ml의 금 전구체(HAuCl4, 0.01 wt%)에 3 ml의 시트르산(Citrate, 0.01g/ml)을 첨가한 뒤 20분간 반응 시켰다. 그 후 추가적인 입자의 성장을 위하여, 이온이 제거된 물(deionized water, DI water) 90 ml에 합성된 17 nm 구형 금 나노입자 10 ml과 상기 금 전구체를 0.01 g/ml의 농도로 0.833 ml 첨가하였다. 그 후 하이드록시아민 하이드로클로라이드(hydroxylamine hydrochloride)를 0.2 M의 농도로 1 ml 첨가하여 20분간 반응시켰다. 그 후 UV-Vis Absorption 및 전자현미경(Scanning Electron Microscope, SEM)으로 금 나노입자의 크기를 확인하였다.The present inventors prepared gold nano-particles (Gold-NP) in order to confirm whether they are effective for arthritis. Specifically, it was synthesized using the seed mediated growth method. To prepare spherical gold nanoparticles with a size of 17 nm, 3 ml of citric acid (Citrate, 0.01 g) was added to 100 ml of gold precursor (HAuCl 4 , 0.01 wt%) at 95 ° C. /ml) was added and reacted for 20 minutes. Then, for the growth of additional particles, 10 ml of synthesized 17 nm spherical gold nanoparticles and 0.833 ml of the gold precursor at a concentration of 0.01 g/ml were added to 90 ml of deionized water (DI water). . Thereafter, 1 ml of hydroxylamine hydrochloride was added at a concentration of 0.2 M and reacted for 20 minutes. After that, the size of the gold nanoparticles was confirmed by UV-Vis Absorption and scanning electron microscope (SEM).
그 결과, 도 1에 나타낸 바와 같이, 본 발명의 금 나노입자는 400 내지 700 nm의 파장을 흡수하며(도 1A), SEM 사진 분석을 통해 31.5 ± 3.2 nm의 크기를 가지는 것을 확인하였다(도 1B).As a result, as shown in FIG. 1, it was confirmed that the gold nanoparticles of the present invention absorb wavelengths of 400 to 700 nm (FIG. 1A) and have a size of 31.5 ± 3.2 nm through SEM photo analysis (FIG. 1B). ).
<실시예 1> 류마티스 관절염 동물 모델에서의 금 나노입자의 효과 확인<Example 1> Confirmation of effect of gold nanoparticles in rheumatoid arthritis animal model
본 발명의 금 나노입자의 류마티스 관절염에 대한 효과를 확인하기 위하여, 류마티스 관절염 동물모델을 제작하였다. 구체적으로, 7주령 수컷 DBA 마우스의 꼬리에 경피내 주사를 통에 제 2형 콜라겐(Type 2 collagen)을 4 mg/ml의 농도가 되도록 0.1 N의 아세트산에 녹이고, 동량의 Complete Freud's 애주번트(CFA, Chondrex)와 함께 1차 주입하였다. 그 후 2주 뒤 동일한 방법으로, 제 2형 콜라겐 및 imcomplete Freud's 애주번트 (IFA, Chondrex)를 주입하여 류마티스 관절염을 유도하였다. 그 후 상기 제조예 1의 금 나노입자를 10 mg/kg의 농도로 증류수에 희석하여 주 2회 복강투여 하였다(Gold-NP 군). 그 후 주 2회 동안 관절염 지수(arthritis score) 및 유병율(incidence)을 평가하였다. 대조군으로는, 류마티스 관절염을 유도하고, 생리 식염수를 주입한 Vehicle 군을 이용하였으며, 관절염 평가에 따른 점수와 기준은 다음과 같다.In order to confirm the effect of the gold nanoparticles of the present invention on rheumatoid arthritis, a rheumatoid arthritis animal model was prepared. Specifically, through intradermal injection into the tail of 7-week-old male DBA mice, type 2 collagen was dissolved in 0.1 N acetic acid to a concentration of 4 mg/ml, and the same amount of Complete Freud's adjuvant (CFA , Chondrex) was first injected. Two weeks later, rheumatoid arthritis was induced by injecting type 2 collagen and imcomplete Freud's adjuvant (IFA, Chondrex) in the same manner. Thereafter, the gold nanoparticles of Preparation Example 1 were diluted in distilled water at a concentration of 10 mg/kg and intraperitoneally administered twice a week (Gold-NP group). Then, the arthritis score and incidence were evaluated twice a week. As a control group, a vehicle group in which rheumatoid arthritis was induced and physiological saline was injected was used, and the scores and criteria according to the arthritis evaluation are as follows.
0점 : 부족이나 종창이 없다.0 point: There is no deficiency or swelling.
1점 : 발 또는 발목관절에 국한된 경한 부종과 발적1 point: Mild swelling and redness localized to the foot or ankle joint
2점 : 발목관절에서 족근골(metatarsal)에 걸친 경한 부종과 발적2 points: Mild swelling and redness from the ankle joint to the metatarsal
3점 : 발목관절에서 족근골에 걸친 중등도의 부종과 발적3 points: Moderate swelling and redness from the ankle joint to the tarsal bone
4점 : 발목에서 다리 전체에 걸쳐 부종과 발적4 points: swelling and redness from the ankle to the entire leg
그 결과, Vehicle군과 비교하여, Gold-NP 군에서는 관절염 지수(도 2A) 및 유병율(도 2B)이 유의적으로 감소하는 것을 확인하여, 본 발명의 금 나노입자가 류마티스 관절염의 진행을 억제시키는 것을 확인하였다.As a result, compared to the Vehicle group, it was confirmed that the arthritis index (Fig. 2A) and prevalence (Fig. 2B) were significantly reduced in the Gold-NP group, indicating that the gold nanoparticles of the present invention inhibit the progression of rheumatoid arthritis. confirmed that
<실시예 2> 금 나노입자의 관절 보호 효과 확인<Example 2> Confirmation of joint protection effect of gold nanoparticles
상기 실시예 1의 각 군의 마우스를 실험 종료 시점에 인도적으로 희생하고, 관절 조직을 분리하여, 고정시켰다. 그 후 관절 조직을 절편으로 제작하고, 헤막토실린&에오신(hematoxylin&eosin, H&E) 염색과, 사프라닌 O(safranine O)염색으로 관절 조직의 손상 정도를 염증 지수(inflammation score), 뼈 손상(bone damage) 및 연골 손상(cartilage damage) 지수로 평가하였다.The mice of each group of Example 1 were humanely sacrificed at the end of the experiment, and joint tissues were separated and fixed. After that, the joint tissue was prepared as a section, and the degree of damage to the joint tissue was evaluated by hematoxylin & eosin (H&E) staining and safranine O staining. Inflammation score, bone damage (bone damage) damage) and cartilage damage index.
그 결과 도 3에 나타낸 바와 같이 Vehicle 군과 비교하여, Gold-NP 군에서는 염증 지수(inflammation score), 뼈 손상(bone damage) 및 연골 손상(cartilage damage) 지수가 유의적으로 감소한 것을 확인하였다.As a result, as shown in FIG. 3, it was confirmed that, compared to the Vehicle group, the inflammation score, bone damage, and cartilage damage scores were significantly reduced in the Gold-NP group.
<실시예 3> 금 나노입자의 미토콘드리아 기능 향상 확인<Example 3> Confirmation of mitochondrial function improvement of gold nanoparticles
<3-1> ATP 양 및 ATP 합성능 향상 확인 <3-1> Confirmation of ATP amount and ATP synthesis ability improvement
류마티스 관절염 모델에서는 미토콘드리아의 기능이 저하된 것으로 보고되어 있기에, 본 발명의 금 나노입자가 류마티스 관절염에서 미토콘드리아의 기능을 향상시키는 것을 확인하고자 하였다. 구체적으로, 상기 실시예 2에서 희생된 마우스로부터, 비장을 적출하고, 비장세포에서 금 나노입자의 미토콘드리아 기능향상 평가를 위하여, ATP 양(contents), ATP 합성능(ATP synthesis)을 확인하였다. 분리한 비장세포의 금 나노파티클을 24시간 반응시킨 후, ATP 측정 실험은 퍼킨 엘머사의 ATP Lite Luminescence Assay 키트를 사용해 진행되었다. ATP 합성능의 경우 세포에 ADP 1mM을 자극하여 45분간 반응시킨 뒤, 키트를 이용하여 ATP 양을 측정하였다.Since mitochondrial function has been reported to be reduced in the rheumatoid arthritis model, it was confirmed that the gold nanoparticles of the present invention improve mitochondrial function in rheumatoid arthritis. Specifically, the spleen was removed from the mouse sacrificed in Example 2, and ATP contents and ATP synthesis were confirmed in order to evaluate mitochondrial function improvement of the gold nanoparticles in the splenocytes. After reacting the gold nanoparticles of the isolated splenocytes for 24 hours, the ATP measurement experiment was conducted using the Perkin Elmer ATP Lite Luminescence Assay kit. In the case of ATP synthesis ability, the cells were stimulated with 1 mM ADP and reacted for 45 minutes, and then the amount of ATP was measured using a kit.
그 결과, 도 4에 나타낸 바와 같이, Vehicle 군과 비교하여, Gold-NP 군에서는, 비장세포에서 ATP 양 및 ATP 합성이 증가하는 것을 확인하여, 미토콘드리아의 기능이 향상된 것을 확인하였다.As a result, as shown in FIG. 4 , compared to the Vehicle group, in the Gold-NP group, it was confirmed that the amount of ATP and the synthesis of ATP increased in the splenocytes, indicating that mitochondrial function was improved.
<3-2> 미토콘드리아 호흡양 증가 확인<3-2> Confirmation of increased mitochondrial respiration
상기 실시예 2에서 희생된 마우스로부터, 비장을 적출하고, 비장세포에서 금 나노입자의 미토콘드리아 기능향상 평가를 위하여, OCR assay를 이용하여 미토콘드리아의 호흡양을 평가하였다. OCR assay는 XF seahorse 장비를 이용하여서 측정되었으며, 희생된 마우스의 비장세포를 1x10^6 cell를 OCR plate에 넣고, 미토콘드리아 전자전달계 억제제 (Oligomycin 7mM, FCCP 3mM, Rotenone 10uM, Antimycin-A 10uM)를 OCR plate에 넣는다. 장비 사용은 XF seahorse 프로그램을 통해 진행되었다. The spleen was removed from the mouse sacrificed in Example 2, and mitochondrial respiration was evaluated using OCR assay in order to evaluate mitochondrial function improvement of gold nanoparticles in spleen cells. The OCR assay was measured using the XF seahorse equipment, 1x10^6 cells of splenocytes from sacrificed mice were put into an OCR plate, and mitochondrial electron transport inhibitors (Oligomycin 7mM, FCCP 3mM, Rotenone 10uM, Antimycin-A 10uM) were applied to OCR. put on plate Equipment use was conducted through the XF seahorse program.
그 결과, 도 5에 나타낸 바와 같이, Vehicle 군과 비교하여, Gold-NP 군에서는, 비장세포에서 미토콘드리아의 호흡양이 증가하는 것을 확인하여, 미토콘드리아의 기능이 향상된 것을 확인하였다.As a result, as shown in FIG. 5 , compared to the Vehicle group, in the Gold-NP group, it was confirmed that the amount of mitochondrial respiration in spleen cells was increased, and mitochondrial function was improved.
<실시예 4> 금 나노입자의 면역세포 발현 조절 확인<Example 4> Confirmation of regulation of immune cell expression by gold nanoparticles
본 발명의 금 나노입자가 류마티스 관절염의 주요 병인 세포인 Th17 세포의 발현을 억제하는지 확인하고자, 상기 실시예 2의 희생된 마우스로부터, 비장을 수득하고, 비장 세포에서 IL-17 양성 세포를 유세포 분석으로 분석하였다.In order to confirm whether the gold nanoparticles of the present invention inhibit the expression of Th17 cells, which are the main etiologic cells of rheumatoid arthritis, spleens were obtained from the sacrificed mice of Example 2, and IL-17 positive cells in the spleen cells were analyzed by flow cytometry analyzed.
그 결과, Vehicle 군과 비교하여, Gold-NP 군에서는 Th17 세포의 발현이 유의적으로 감소한 것을 확인하였다(도 6).As a result, it was confirmed that the expression of Th17 cells was significantly decreased in the Gold-NP group compared to the Vehicle group (FIG. 6).
<실시예 5> 금 나노입자의 염증성 사이토카인 억제 확인<Example 5> Confirmation of suppression of inflammatory cytokines by gold nanoparticles
상기 실시예 2에서 수득된 장조직을 파라핀 블록으로 제작한 후 절단하여, 절편을 제작하고, 염증성 사이토카인인 IL-1β(interleukin 1β), IL-17(interleukin 17), IL-6(interleukin 6) 및 TNF-α(tumor necrosis factor-α)의 발현을 면역조직화학염색을 통해 확인하였다.After preparing the intestinal tissue obtained in Example 2 as a paraffin block, cutting it to prepare a section, inflammatory cytokines IL-1β (interleukin 1β), IL-17 (interleukin 17), IL-6 (interleukin 6) ) and expression of TNF-α (tumor necrosis factor-α) was confirmed through immunohistochemical staining.
그 결과, 도 7에 나타낸 바와 같이, Vehicle군과 비교하여, Gold-NP 군에서는 염증성 사이토카인인 IL-1β, IL-17, IL-6 및 TNF-α의 발현이 유의적으로 감소한 것을 확인하였다.As a result, as shown in FIG. 7, it was confirmed that the expression of inflammatory cytokines IL-1β, IL-17, IL-6, and TNF-α was significantly decreased in the Gold-NP group compared to the Vehicle group. .
<실시예 6> Citrulinet vimentin specific IgG 발현 억제 확인<Example 6> Confirmation of suppression of Citrulinet vimentin specific IgG expression
류마티스 관절염 모델에서 증가하는 비정상적인 비멘틴인 citrulinet vimentin specific IgG를 본 발명의 금 나노입자가 억제할 수 있는지 확인하고자 하였다. 구체적으로 상기 실시예 2에서 희생한 마우스의 전혈을 수득하고, 수득된 전혈로부터 혈청 분석을 통해, citrulinet vimentin specific IgG의 발현을 확인하였다. ELISA 플레이트에 Vimentin 펩타이드 5ug을 2시간 코팅하고, 마우스의 세럼을 넣어주었다. 그 이후 IgG HRP를 넣어 2시간 반응 시킨 후, 발색시켜 450nm의 흡광 파장에서 측정되었다.It was intended to confirm whether the gold nanoparticles of the present invention can inhibit citrulinet vimentin specific IgG, an abnormal vimentin that increases in a rheumatoid arthritis model. Specifically, whole blood of the mouse sacrificed in Example 2 was obtained, and the expression of citrulinet vimentin specific IgG was confirmed through serum analysis from the obtained whole blood. An ELISA plate was coated with 5ug of Vimentin peptide for 2 hours, and mouse serum was added thereto. After that, IgG HRP was added and reacted for 2 hours, and color development was measured at an absorption wavelength of 450 nm.
그 결과, 도 8에 나타낸 바와 같이, Vehicle 군과 비교하여, Gold-NP 군에서는 vimentin specific IgG의 발현은 유의미한 차이를 나타내지 않았으나, citrulinet vimentin specific IgG의 발현이 유의적으로 감소한 것을 확인하여, 본 발명의 금 나노입자가, 총 비멘틴의 발현을 저하시키지 않으면서도, 류마티스 관절염에서의 비정상적인 비멘틴의 발현을 조절하는 것을 확인하였다.As a result, as shown in FIG. 8, compared to the Vehicle group, the Gold-NP group did not show a significant difference in the expression of vimentin specific IgG, but it was confirmed that the expression of citrulinet vimentin specific IgG was significantly reduced. It was confirmed that the gold nanoparticles of , without reducing the expression of total vimentin, regulate the expression of abnormal vimentin in rheumatoid arthritis.
따라서, 본 발명의 금 나노입자는 류마티스 관절염이 유도된 동물모델에서, 관절염 지수 및 유병률을 감소시키고, 관절 조직을 보호하는 것을 확인하였다. 또한, 류마티스 관절염 모델에서 감소한 것으로 알려진 미토콘드리아의 활성을 증가시키며, Th17 세포의 발현을 억제시키는 것을 확인하였다. 또한, 염증성 사이토카인인 IL-1β, IL-17, IL-6 및 TNF-α의 양을 감소시키고, 혈청 내 citrulinet vimentin specific IgG의 양을 감소시키는 것을 확인하여, 관절염의 치료 효과를 확인하였다.Therefore, it was confirmed that the gold nanoparticles of the present invention reduce the index and prevalence of arthritis and protect joint tissues in an animal model in which rheumatoid arthritis is induced. In addition, it was confirmed that mitochondrial activity, which is known to be decreased in the rheumatoid arthritis model, was increased, and expression of Th17 cells was suppressed. In addition, it was confirmed that the amounts of inflammatory cytokines IL-1β, IL-17, IL-6, and TNF-α were reduced, and the amount of citrulinet vimentin specific IgG in serum was reduced, thereby confirming the therapeutic effect of arthritis.
Claims (13)
상기 금 나노입자는 20 내지 40 nm의 입자 크기를 갖는 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 1,
The gold nanoparticles having a particle size of 20 to 40 nm, a pharmaceutical composition for preventing or treating arthritis.
상기 조성물은 관절염 지수(arthritis score) 및 유병율(indicence)를 감소시키는 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 1,
The composition is to reduce the arthritis index (arthritis score) and prevalence (indicence), a pharmaceutical composition for preventing or treating arthritis.
상기 조성물은, 미토콘드리아의 기능을 증가시키는 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 1,
The composition, to increase the function of mitochondria, a pharmaceutical composition for the prevention or treatment of arthritis.
상기 미토콘드리아의 기능 증가는, ATP 양(ATP contents)을 증가시키는 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 4,
The increase in mitochondrial function is to increase the amount of ATP (ATP contents), a pharmaceutical composition for preventing or treating arthritis.
상기 미토콘드리아 기능 증가는, ATP 합성능(ATP synthesis)을 증가시키는 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 4,
The increase in mitochondrial function is to increase ATP synthesis, a pharmaceutical composition for preventing or treating arthritis.
상기 미토콘드리아 기능 증가는, 미토콘드리아의 호흡양을 증가시키는 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 4,
The increase in mitochondrial function, to increase the amount of respiration of mitochondria, a pharmaceutical composition for preventing or treating arthritis.
상기 조성물은, Th17 세포의 발현을 억제시키는 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 1,
The composition inhibits the expression of Th17 cells, a pharmaceutical composition for preventing or treating arthritis.
상기 조성물은, 염증성 사이토카인의 양을 감소시키는 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 1,
The composition is to reduce the amount of inflammatory cytokines, a pharmaceutical composition for the prevention or treatment of arthritis.
상기 염증성 사이토카인은 IL-1β(interleukin 1 beta), IL-17(interleukin 17), IL-6(interleukin 6) 및 TNF-α(tumor necrosis factor-α)로 이루어진 군에서 선택된 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 9,
The inflammatory cytokine is one selected from the group consisting of interleukin 1 beta (IL-1β), interleukin 17 (IL-17), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) of arthritis A pharmaceutical composition for prevention or treatment.
상기 조성물은, 혈청 내 citrulinet vimentin specific IgG의 양을 감소시키는 것인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 1,
Wherein the composition reduces the amount of citrulinet vimentin specific IgG in serum, a pharmaceutical composition for preventing or treating arthritis.
상기 관절염은, 류마티스 관절염 (Rheumatoid Arthritis) 또는 골관절염(osteoarthritis)인, 관절염의 예방 또는 치료용 약학적 조성물.According to claim 1,
The arthritis is, rheumatoid arthritis (Rheumatoid Arthritis) or osteoarthritis (osteoarthritis), a pharmaceutical composition for the prevention or treatment of arthritis.
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