KR101935497B1 - Anti-cancer drug Effective for Multidrug resistant cancer cells - Google Patents

Anti-cancer drug Effective for Multidrug resistant cancer cells Download PDF

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KR101935497B1
KR101935497B1 KR1020160175777A KR20160175777A KR101935497B1 KR 101935497 B1 KR101935497 B1 KR 101935497B1 KR 1020160175777 A KR1020160175777 A KR 1020160175777A KR 20160175777 A KR20160175777 A KR 20160175777A KR 101935497 B1 KR101935497 B1 KR 101935497B1
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dobutamine
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한희동
노주원
박영민
김가희
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건국대학교 글로컬산학협력단
동국대학교 산학협력단
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    • A61K9/51—Nanocapsules; Nanoparticles
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    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A61K47/6937—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol the polymer being PLGA, PLA or polyglycolic acid

Abstract

본 발명은 도부타민을 탑재한 PLGA 나노입자 및 이를 포함하는 암 예방 또는 치료용 조성물에 관한 것이다. 본 발명에 따른 도부타민을 탑재한 PLGA 나노입자는 나노에멀젼 형태로서 수성 용매에 대한 용해성 및 분산성을 현저히 개선시키며, 암세포에 선택적인 전달효율이 우수하다. 또한, 심혈관 치료제로 사용하고 있는 도부타민의 신규 적용증을 확대함과 동시에, 뚜렷한 치료방법이 부재한 항암화학제 내성 난치암에 대한 신규 치료제로 유용하게 사용될 수 있다. The present invention relates to a PLGA nanoparticle loaded with dobutamine and a composition for preventing or treating cancer comprising the same. The PLGA nanoparticles loaded with dobutamine according to the present invention are in the form of a nano emulsion, which remarkably improves solubility and dispersibility in an aqueous solvent, and is excellent in the selective delivery efficiency to cancer cells. In addition, it can be used as a new therapeutic agent for cancer-resistant intractable cancer which has no distinct treatment method, while expanding the application of dobutamine as a cardiovascular treatment agent.

Description

다중약물내성 암세포에 유용한 항암제 {Anti-cancer drug Effective for Multidrug resistant cancer cells}[0001] The present invention relates to an anticancer drug useful for multiple drug resistant cancer cells.

본 발명은 심혈관치료제로 활용되는 도부타민을 항암치료제로 적용하는 신규방법을 제시하는 것으로서, 난치성 암종에서 항암화학제에 내성을 보이는 다중약물내성 억제용 조성물에 관한 것이다. 자세하게는 암세포로의 전달 효율을 향상시키기 위해 상기 도부타민을 PLGA(Poly(lactic acid-co-glycolic acid))에 탑재한 나노입자의 발명에 관한 것이다. The present invention provides a novel method for applying dobutamine, which is used as a cardiovascular treatment agent, as an anticancer therapeutic agent, and relates to a composition for inhibiting multidrug resistance which shows resistance to chemotherapeutic agents in intractable carcinoma. More specifically, the present invention relates to nanoparticles having the above-mentioned dobutamine loaded on PLGA (poly (lactic acid-co-glycolic acid)) in order to improve the transfer efficiency to cancer cells.

Yes-associated protein (YAP)은 배아발달과 생체 기관의 성장을 조절하는 데 매우 중요한 Hippo pathway의 핵심 분자이다. Hippo pathway는 비교적 최근에 신호전달체계가 밝혀졌으며, 정상적으로는 배아의 발생과 장기의 성장을 적절할 크기에서 멈추게 하는 역할을 하나, 성인에서는 생리적 작용이 비교적 미미한 것으로 알려져 있으며, 반면에 간암, 위암, 식도암, 난소암 등 여러 가지 악성종양에서 비정상적인 발현이 관찰되었고, 전이, 재발, 치료 저항성 등의 불량한 예후와도 관련이 있음이 보고되었다. 또한 실험실적으로 YAP의 발현을 억제할 경우 종양세포의 성장이 억제됨이 여러 차례 보고되었으며, 이로 인해 최근 YAP 발현억제가 분자생물학적 치료법의 주목받는 목표물이 되고 있다. Yes-associated protein (YAP) is a key molecule in the Hippo pathway, which is crucial for controlling embryonic development and organ growth. The Hippo pathway has been shown to have a relatively recent signal transduction system and normally plays a role in stopping embryonic development and organ growth at an appropriate size, but it is known that physiological actions are relatively minor in adults, whereas liver cancer, stomach cancer, , Ovarian cancer and other malignant tumors, and it was also reported to be associated with poor prognosis such as metastasis, recurrence, and resistance to therapy. In addition, it has been reported several times that the inhibition of YAP expression inhibits the growth of tumor cells. Thus, recent inhibition of YAP expression has become a target of molecular biologic therapy.

도부타민은 심부전 치료제로서 일반적으로 사용되고 있는 화합물 중에 하나이다. 그러나 본 발명자들은 도부타민이 YAP 유전자를 효과적으로 억제한다는 사실을 알아냈고, 이를 이용하여 도부타민이 암의 치료, 특히 다중약물내성 암,에 효과가 있음을 알아내었다. 본 발명자들은 도부타민을 항암조직으로 효율적으로 전달 하기 위하여 나노입자 시스템을 도입하였다. 이때 수용성 도부타민의 최적 탑재 조건을 평가하였으며, 상기의 조건을 바탕으로 만들어진 PLGA나노입자를 마우스를 대상으로 투여하여, PLGA나노입자의 항암효능을 평가하였다. Dobutamine is one of the compounds commonly used as a therapeutic agent for heart failure. However, the present inventors have found that dobutamine effectively inhibits the YAP gene, and has found that dobutamine is effective in the treatment of cancer, in particular, multiple drug resistant cancers. The present inventors have introduced a nanoparticle system in order to efficiently transfer dobutamine to an anti-cancer tissue. At this time, optimal loading conditions of water-soluble dobutamine were evaluated, and PLGA nanoparticles prepared on the basis of the above conditions were administered to mice to evaluate the anticancer efficacy of the PLGA nanoparticles.

PLGA 고분자는 생체친화성이 좋으며, 체내에서 생분해되는 특성이 있다. 또한, PLGA 고분자는 미국 FDA의 허가를 득한 생체친화적 고분자로서 체내주입에 대하여 독성이 없다. PLGA 고분자로 제형을 제조 시에, 고분자의 말단기에 리간드등의 생접합이 유리하며, 리간드를 생접합 시킬 경우, 표적하는 암세포에서 특이적으로 발현하는 리셉터에 대한 결합효율을 증가시켜 표적화 약물 전달을 가능하게 한다. PLGA polymers have good biocompatibility and are biodegradable in the body. In addition, the PLGA polymer is a biocompatible polymer approved by the US FDA and is not toxic to the body. When preparing a formulation with a PLGA polymer, the bioadhesion of a ligand or the like at the terminal end of the polymer is advantageous, and when the ligand is bioadhesed, the binding efficiency to the receptor specifically expressed in the target cancer cells is increased, .

본 발명에서는 CD44의 리간드인 히알루론 산을 PLGA 나노입자 표면에 생접합 시켜 도부타민이 탑재된 PLGA 나노입자의 암세포 선택적인 전달 효율을 증가시켰다.In the present invention, hyaluronic acid, which is a ligand of CD44, is bonded to the surface of PLGA nanoparticles to increase the cancer cell selective delivery efficiency of dobutamine-loaded PLGA nanoparticles.

한편, 보통 '종양(tumor)'은 신체 조직의 자율적인 과잉 성장에 의해 비정상적으로 자라난 덩어리를 의미하며, 양성종양(benign tumor)과 악성종양(malignant tumor)으로 구분할 수 있다. 양성종양이 비교적 성장 속도가 느리고 전이(metastasis; 종양이 원래 발생한 곳에서 멀리 떨어진 곳으로 이동함)되지 않는 것에 반해 악성종양은 주위 조직에 침윤하면서 빠르게 성장하고 신체 각 부위에 확산되거나 전이되어 생명을 위협하게 된다. 악성종양은 암과 동일한 의미로 생각할 수 있다. On the other hand, 'tumor' usually refers to a mass that grows abnormally due to autonomous overgrowth of body tissue, and can be divided into benign tumor and malignant tumor. While benign tumors are relatively slow to grow and do not metastasize (move away from where the tumor originally originated), malignant tumors grow rapidly, infiltrating the surrounding tissues, spread or spread to each part of the body, Threatening. Malignant tumors can be thought of in the same sense as cancer.

본 발명자들은 상기와 같은 요구를 충족시키기 위하여 연구를 거듭한 결과 도부타민이 탑재된 나노입자 주사제형을 개발하였고, 이의 항암화학제에 내성을 보이는 난치성 암종에서 현저한 암치료 효과를 확인함으로써 본 발명을 완성하였다.The inventors of the present invention have conducted research to satisfy the above requirements and have developed a nano-particle injectable drug form with dobutamine, and confirmed the remarkable effect of cancer treatment in intractable cancer resistant to the chemotherapeutic agent of the present invention, Completed.

본 발명의 목적은 심혈관 치료제인 도부타민을 적용하여 신규 항암치료제를 개발하는 것으로서 뚜렷한 치료방법이 없는 항암화학제 내성 난치암의 치료제 개발에 목적이 있다. 상기 도부타민을 종양조직으로 효율적으로 전달하기 위하여 나노입자에 탑재하였으며, 나노입자의 표면에는 히알루론산을 결합하여 종양조직으로 선택적으로 전달이 가능하게 하였다.It is an object of the present invention to develop a novel chemotherapeutic agent by applying dobutamine, a cardiovascular therapeutic agent, and to develop a therapeutic agent for chemotherapy-resistant intractable cancer that has no obvious treatment method. In order to efficiently transfer the dobutamine to the tumor tissue, the nanoparticles were mounted on the nanoparticles, and hyaluronic acid was bonded to the surface of the nanoparticles to enable selective delivery to the tumor tissue.

상기와 같은 과제를 해결하기 위하여, 본 발명은 화학식 1로 표시되는 도부타민 및 고분자를 포함하는 나노입자를 제공할 수 있다.In order to solve the above-mentioned problems, the present invention provides nanoparticles containing dobutamine and a polymer represented by the general formula (1).

[화학식 1][Chemical Formula 1]

Figure 112016125739356-pat00001
Figure 112016125739356-pat00001

상기 도부타민은 수용성 이다. The dobutamine is water-soluble.

상기 고분자는 리에틸렌글리콜(polyethyleneglycol, PEG), 폴리에틸렌옥사이드(poly(ethylene oxide), 폴리프로필렌옥사이드(poly(propylene oxide), 엔-옥틸트리에틸렌글라이콜에테르(n-octyltriethylene glycol ether, 8E3) 및 PLGA(Poly(lactic acid-co-glycolic acid))으로 이루어진 군에서 선택되는 어느 하나 이상을 포함할 수 있다. The polymer may be selected from the group consisting of polyethyleneglycol (PEG), poly (ethylene oxide), poly (propylene oxide), n-octyltriethylene glycol ether (8E3) And poly (lactic acid-co-glycolic acid) (PLGA).

본 발명은 또한, 상기 나노입자의 표면에 히알루론산을 결합시킨 나노입자 복합체를 제공 할 수 있다. The present invention can also provide a nanoparticle composite in which hyaluronic acid is bound to the surface of the nanoparticle.

본 발명은 또한, 상기 나노입자 또는 나노입자 복합체를 유효성분으로 포함하는 함암제에 대한 다중약물내성 억제용 조성물을 제공할 수 있다. The present invention can also provide a composition for inhibiting multiple drug resistance to a cancer drug comprising the nanoparticle or nanoparticle complex as an active ingredient.

상기 나노입자 또는 나노입자 복합체는 정제, 과립제, 환제, 캅셀제, 액제, 주사제, 연고제, 좌제 및 산제로 구성된 군으로부터 선택되는 하나 이상의 제형으로 제형화될 수 있다. The nanoparticle or nanoparticle complex may be formulated into one or more formulations selected from the group consisting of tablets, granules, pills, capsules, solutions, injections, ointments, suppositories and powders.

상기 나노입자 또는 나노입자 복합체는 일반적인 암세포 및 다중약물내성 암세포에서 세포독성을 나타낼 수 있다. The nanoparticle or nanoparticle complex may exhibit cytotoxicity in common cancer cells and multiple drug resistant cancer cells.

상기 다중약물내성 암세포는 항암제 구조에 상관없이 비 특이적인 내성을 획득한 암세포일 수 있다. The multiple drug resistant cancer cells may be cancer cells that have acquired nonspecific resistance regardless of the structure of the cancer drug.

상기 암세포는 대장암(colon cancer), 방광암(bladder cancer), 난소암(ovarian cancer), 위암(gastric cancer), 폐암(lung cancer), 전립선암(prostate cancer), 췌장암(pancreatic cancer) 및 대장직장암(colorectal cancer)으로 구성된 군으로부터 선택되는 하나 이상의 것일 수 있다. The cancer cells may be selected from the group consisting of colon cancer, bladder cancer, ovarian cancer, gastric cancer, lung cancer, prostate cancer, pancreatic cancer, and colorectal cancer.

본 발명은 또한, 하기의 단계를 포함하는 나노 입자의 제조방법을 제공할 수 있다. The present invention can also provide a method for producing nanoparticles comprising the following steps.

i) 도부타민 및 고분자를 균일하게 혼합하여 1차 에멀젼을 형성하는 단계; 및 i) uniformly mixing dobutamine and a polymer to form a primary emulsion; And

ii) 상기 1차 에멀젼을 양친매성 고분자와 혼합하여 2차 에멀젼을 형성하는 단계;ii) mixing the primary emulsion with an amphipathic polymer to form a secondary emulsion;

상기 도부타민은 수용성 일 수 있다. The dobutamine may be water-soluble.

상기 고분자는 폴리에틸렌글리콜(polyethyleneglycol, PEG), 폴리에틸렌옥사이드(poly(ethylene oxide), 폴리프로필렌옥사이드(poly(propylene oxide), 엔-옥틸트리에틸렌글라이콜에테르(n-octyltriethylene glycol ether, 8E3) 및 PLGA(Poly(lactic acid-co-glycolic acid))으로 이루어진 군으로부터 선택되는 어느 하나 이상을 포함할 수 있다 .The polymer may be selected from the group consisting of polyethyleneglycol (PEG), poly (ethylene oxide), poly (propylene oxide), n-octyltriethylene glycol ether (8E3) And poly (lactic acid-co-glycolic acid) (PLGA).

상기 고분자는 유기상용매에 용해되어 있을 수있다. The polymer may be dissolved in an organic phase solvent.

상기 양친매성 고분자는 소듐 콜레이트(sodium cholate), 소듐 디옥시콜레이트(sodium deoxycholate), Span 20(Sorbitan Monolaurate), Span 60(Sorbitan Monostearate), Span 80(Sorbitan Monooleate), Tween 20(Polyoxyethylene(20) Sorbitan Monolaurate), Tween 60(Polyoxyethylene(20) Sorbitan Monostearte), Tween 80(Polyoxyethylene(20) Sorbitan Monolaurate) 및 DPG(dipotassium glycyrrhizinate)으로 이루어진 군으로부터 선택되는 어느 하나 이상을 포함할 수 있다. The amphipathic polymer may be selected from the group consisting of sodium cholate, sodium deoxycholate, Span 20 (Sorbitan Monolaurate), Span 60 (Sorbitan Monostearate), Span 80 (Sorbitan Monooleate), Tween 20 (Polyoxyethylene Monolaurate, Tween 60, Polyoxyethylene (20) Sorbitan Monostearate, Tween 80 (Polyoxyethylene (20) Sorbitan Monolaurate) and DPG (dipotassium glycyrrhizinate).

상기 ii)단계의 나노분자의 표면에 히알루론산을 결합시키는 단계를 추가할 수 있다.The step of binding hyaluronic acid to the surface of the nanomolecule of step ii) may be added.

본 발명에 따른 도부타민 나노입자는 도부타민의 전신 확산을 방지하고, 암세포로의 전달 효율을 향상시켜 암 치료에 유용하게 사용될 수 있으며, 나노입자의 표면에는 히알루론산을 결합하여 종양조직으로 선택적으로 전달이 가능하게 한다. The dobutamine nanoparticles according to the present invention can prevent the systemic diffusion of dobutamine and improve the efficiency of delivery to cancer cells, and thus can be usefully used for cancer treatment. The surface of nanoparticles is bound to hyaluronic acid, To be delivered.

도 1은 본 발명에서 개발된 도부타민이 탑재된 나노입자의 물리적인 특성을 나타낸다. A는 나노입자의 크기, B는 나노입자에 탑재된 도부타민의 양, C는 나노입자의 표면전하, 그리고 D는 나노입자의 형태를 나타낸다.
도 2는 PLGA 나노입자의 표면에 히알루론산을 결합시켜 종양세포 표면에서 발현되는 CD44 수용체에 선택적인 결합을 나타낸다. A는 난소암세포주 (A2780)으로서 CD44 수용체의 발현이 적은 negative expression을 나타낸다. B는 난소암세포주 (HeyA8)으로서 CD44 수용체의 발현이 높은 positive expression을 나타낸다. C는 CD44 negative cell line (A2780)에서 PLGA 나노입자의 결합능력을 나타낸다. D는 CD44 positive cell line (HeyA8)에 대해서 PLGA 나노입자의 선택적인 결합능력을 나타낸다.
도 3은 항암화학제 민감성 (HeyA8)과 항암화학제 내성 (HeyA8-MDR, MDR; multi-drug resistance) 세포에 대해서 도부타민 농도에 따른 종양세포의 독성을 나타낸다.
도 4는 항암화학제 민감섬 (HeyA8)과 항암화학제 내성 (HeyA8-MDR, MDR; multi-drug resistance) 세포에 대해서 도부타민 농도에 따른 종양세포내의 YAP 유전자 억제를 나타낸다.
도 5는 도부타민이 탑재된 PLGA 나노입자를 주사 후에 항암치료 효능을 나타낸 도이다. IP는 복강주사, IV는 정맥주사를 나타내고, A는항암화학제 민감성 (HeyA8)의 항암치료 효능을 나타낸 것이고, B는 항암화학제 내성 (HeyA8-MDR, MDR; multi-drug resistance)의 항암치료 효능을 나타낸 것이다. Figure 1 shows the physical properties of the nanoparticles loaded with dobutamine developed in the present invention. A is the size of the nanoparticle, B is the amount of dobutamine loaded on the nanoparticle, C is the surface charge of the nanoparticle, and D is the shape of the nanoparticle.
FIG. 2 shows binding of hyaluronic acid to the surface of PLGA nanoparticles to bind selectively to the CD44 receptor expressed on the surface of tumor cells. A is an ovarian cancer cell line (A2780), which shows a negative expression with low expression of the CD44 receptor. B is an ovarian cancer cell line (HeyA8) and expresses positive expression of CD44 receptor. C represents the binding capacity of PLGA nanoparticles in the CD44 negative cell line (A2780). D shows the selective binding capacity of PLGA nanoparticles for the CD44 positive cell line (HeyA8).
FIG. 3 shows tumor cell toxicity according to dobutamine concentration on HeyA8 and HeyA8-MDR (multi-drug resistance) cells.
FIG. 4 shows inhibition of YAP gene in tumor cells according to dobutamine concentration on HeyA8 and HeyA8-MDR (multi-drug resistance) cells.
Fig. 5 is a graph showing the anticancer treatment efficacy after injection of dobutamine-loaded PLGA nanoparticles. IP represents intraperitoneal injection, IV represents intravenous injection, A represents the chemotherapeutic efficacy of HeyA8, B represents the chemotherapeutic agent of HeyA8-MDR, multi-drug resistance Efficacy.

본 발명은 화학식 1로 표시되는 도부타민 고분자를 포함하는 나노입자를 제공한다. The present invention provides nanoparticles comprising a dobutamine polymer represented by the general formula (1).

[화학식 1][Chemical Formula 1]

Figure 112016125739356-pat00002
Figure 112016125739356-pat00002

상기 도부타민은 심장박동의 출력을 단기적으로 증가시키기 위하여 쓰는 교감 신경 흥분제로 심부전으로 인한 충격의 응급 치료시에 쓰이는 약물제제로서, 무색 내지 미황색의 투명한 액이든 무색 투명한 앰플 주사제이다. 본 발명에서 사용하는 도부타민은 수용성 일 수 있다. The dobutamine is a sympathomimetic stimulant used to increase the output of the heartbeat in the short term. It is a drug preparation used in the emergency treatment of the shock caused by heart failure. It is a colorless transparent ampule injectable solution, which is a colorless to light yellow transparent solution. The dobutamine used in the present invention may be water-soluble.

상기 고분자는 폴리에틸렌글리콜(polyethyleneglycol, PEG), 폴리에틸렌옥사이드(poly(ethylene oxide), 폴리프로필렌옥사이드(poly(propylene oxide), 엔-옥틸트리에틸렌글라이콜에테르(n-octyltriethylene glycol ether, 8E3) 및 PLGA(Poly(lactic acid-co-glycolic acid))으로 이루어진 군에서 선택되는 어느 하나 이상일 수 있으며, 가장 바람직하게는 락타이드와 글라이콜라이드의 단량체의 공중합체로 구성된 고분자인, PLGA(Poly(lactic acid-co-glycolic acid))일 수 있다. The polymer may be selected from the group consisting of polyethyleneglycol (PEG), poly (ethylene oxide), poly (propylene oxide), n-octyltriethylene glycol ether (8E3) PLGA (poly (lactic acid-co-glycolic acid)), which is a polymer composed of a copolymer of lactide and glycolide monomers, acid-co-glycolic acid).

상기 도부타민 및 고분자를 포함하는 나노입자에 히알루론산을 결합시킨 나노입자 복합체를 제공할 수 있다. And nanoparticle complexes in which hyaluronic acid is bound to nanoparticles containing dobutamine and polymers can be provided.

본 발명의 나노 복합체는 계면활성제와 같은 양친매성 고분자를 이용하여 나노-유화 약물 전달 시스템(nanoemulsifying drug delivery system(NEDDS))의 방법으로 제조할 수 있으며, 상기 양친매성 고분자는 소듐 콜레이트(sodium cholate), 소듐 디옥시콜레이트(sodium deoxycholate), Span 20(Sorbitan Monolaurate), Span 60(Sorbitan Monostearate), Span 80(Sorbitan Monooleate), Tween 20(Polyoxyethylene(20) Sorbitan Monolaurate), Tween 60(Polyoxyethylene(20) Sorbitan Monostearte), Tween 80(Polyoxyethylene(20) Sorbitan Monolaurate) 또는 DPG(dipotassium glycyrrhizinate)일 수 있으며, 바람직하게는 PVA (Polyvinyl alcohol)이다.The nanocomposite of the present invention can be prepared by a method of a nanoemulsifying drug delivery system (NEDDS) using an amphipathic polymer such as a surfactant, and the amphipathic polymer is sodium cholate, , Sodium deoxycholate, Span 20 (Sorbitan Monolaurate), Span 60 (Sorbitan Monostearate), Span 80 (Sorbitan Monooleate), Tween 20 (Polyoxyethylene (20) Sorbitan Monolaurate), Tween 60 (Polyoxyethylene Monostearte), Tween 80 (Polyoxyethylene (20) Sorbitan Monolaurate) or DPG (dipotassium glycyrrhizinate), preferably PVA (Polyvinyl alcohol).

본 발명은 상기 나노 입자 또는 나노 복합체를 유효성분으로 포함하는 함암제에 대한 다중약물내성 억제용 조성물을 제공할 수 있다. The present invention can provide a composition for inhibiting multiple drug resistance to a cancer drug comprising the nanoparticle or nanocomposite as an active ingredient.

상기 나노입자 또는 나노입자 복합체는 정제, 과립제, 환제, 캅셀제, 액제, 주사제, 연고제, 좌제 및 산제로 구성된 군으로부터 선택되는 하나 이상의 제형으로 제형화 될 수 있으며, 가장 바람직하게는 주사제형일 수 있다. The nanoparticle or nanoparticle complex may be formulated into one or more formulations selected from the group consisting of tablets, granules, pills, capsules, solutions, injections, ointments, suppositories and powders, most preferably in the form of injections.

상기 나노입자 또는 나노입자 복합체는 일반적인 암세포 및 다중약물내성 암세포에서 세포독성을 나타낼 수 있다. The nanoparticle or nanoparticle complex may exhibit cytotoxicity in common cancer cells and multiple drug resistant cancer cells.

본 발명의 나노 입자 또는 나노 복합체는 YAP의 비활성화를 유도하고, 이에 따라 YAP의 비활성화됨에 따라 각종 종양형성 유전자를 촉진시키는 현상을 감소시키는 효과를 나타낼 수 있다.The nanoparticles or nanocomposites of the present invention can induce inactivation of YAP and thus reduce the phenomenon of promoting various tumorigenic genes as YAP is inactivated.

상기 다중약물내성 암세포는 항암제 구조에 상관없이 비 특이적인 내성을 획득한 암세포인 것일 수 있다. The multi-drug resistant cancer cell may be a cancer cell that acquires non-specific resistance regardless of the structure of the anti-cancer drug.

상기 암세포는 대장암(colon cancer), 방광암(bladder cancer), 난소암(ovarian cancer), 위암(gastric cancer), 폐암(lung cancer), 전립선암(prostate cancer), 췌장암(pancreatic cancer) 및 대장직장암(colorectal cancer)으로 구성된 군으로부터 선택되는 하나 이상의 것일 수 있으며, 가장 바람직하게는 난소암 일 수 있다. The cancer cells may be selected from the group consisting of colon cancer, bladder cancer, ovarian cancer, gastric cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, and most preferably an ovarian cancer.

본 발명의 조성물은 암의 예방 및 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers for the prevention and treatment of cancer.

본 발명은 하기 단계를 포함하는 나노입자의 제조방법을 제공할수 있다. The present invention can provide a method for producing nanoparticles comprising the following steps.

i) 도부타민 및 고분자를 균일하게 혼합하여 1차 에멀젼을 형성하는 단계; 및 i) uniformly mixing dobutamine and a polymer to form a primary emulsion; And

ii) 상기 1차 에멀젼을 양친매성 고분자와 혼합하여 2차 에멀젼을 형성하는 단계; ii) mixing the primary emulsion with an amphipathic polymer to form a secondary emulsion;

상기 도부타민은 수용성이다.  The dobutamine is water-soluble.

상기 고분자는 폴리에틸렌글리콜(polyethyleneglycol, PEG), 폴리에틸렌옥사이드(poly(ethylene oxide), 폴리프로필렌옥사이드(poly(propylene oxide), 엔-옥틸트리에틸렌글라이콜에테르(n-octyltriethylene glycol ether, 8E3) 및 PLGA(Poly(lactic acid-co-glycolic acid))으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있으며, 가장 바람직하게는 락타이드와 글라이콜라이드의 단량체의 공중합체로 구성된 고분자인, PLGA(Poly(lactic acid-co-glycolic acid))일 수 있다.  The polymer may be selected from the group consisting of polyethyleneglycol (PEG), poly (ethylene oxide), poly (propylene oxide), n-octyltriethylene glycol ether (8E3) PLGA (poly (lactic acid-co-glycolic acid)), which is a polymer composed of a copolymer of lactide and glycolide monomers, acid-co-glycolic acid).

상기 고분자는 유기상용매에 용해되어 있을 수 있으며, 상기 유기상용매는 클로로포름일 수 있다. The polymer may be dissolved in an organic phase solvent, and the organic phase solvent may be chloroform.

본 발명의 나노 복합체는 계면활성제와 같은 양친매성 고분자를 이용하여 나노-유화 약물 전달 시스템(nanoemulsifying drug delivery system(NEDDS))의 방법으로 제조할 수 있으며, 상기 양친매성 고분자는 소듐 콜레이트(sodium cholate), 소듐 디옥시콜레이트(sodium deoxycholate), Span 20(Sorbitan Monolaurate), Span 60(Sorbitan Monostearate), Span 80(Sorbitan Monooleate), Tween 20(Polyoxyethylene(20) Sorbitan Monolaurate), Tween 60(Polyoxyethylene(20) Sorbitan Monostearte), Tween 80(Polyoxyethylene(20) Sorbitan Monolaurate) 또는 DPG(dipotassium glycyrrhizinate)일 수 있으며, 바람직하게는 PVA (Polyvinyl alcohol)이다.The nanocomposite of the present invention can be prepared by a method of a nanoemulsifying drug delivery system (NEDDS) using an amphipathic polymer such as a surfactant, and the amphipathic polymer is sodium cholate, , Sodium deoxycholate, Span 20 (Sorbitan Monolaurate), Span 60 (Sorbitan Monostearate), Span 80 (Sorbitan Monooleate), Tween 20 (Polyoxyethylene (20) Sorbitan Monolaurate), Tween 60 (Polyoxyethylene Monostearte), Tween 80 (Polyoxyethylene (20) Sorbitan Monolaurate) or DPG (dipotassium glycyrrhizinate), preferably PVA (Polyvinyl alcohol).

본 발명은 상기 ii)단계의 나노분자의 표면에 히알루론산을 결합시키는 단계를 추가할 수 있다. The present invention may further comprise the step of binding hyaluronic acid to the surface of the nanomolecule of step ii).

이하, 본 발명을 실시예 및 실험예에 의하여 더욱 상세하게 설명한다. 단, 하기 실시예 및 실험 예들은 본 발명을 더욱 쉽게 이해할 수 있도록 예시하는 것으로 본 발명의 내용이 실시 예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following examples and experimental examples are provided to illustrate the present invention more easily, and the present invention is not limited to the examples.

실시예Example 1.  One. 도부타민Dobutamine 나노입자의 제조 Manufacture of nanoparticles

도부타민 나노입자를 제조하기 위하여, W/O/W의 2차 에멀젼 방법으로 제작되며 유기용매를 증발시켜 나노입자를 제조한다. 첫 번째 물상인 도부타민 용액 (50mg/ml, 5%)을 PLGA (50 : 50, 2.5 mg/ml, Sigma Aldrich)가 용해되어 있는 클로로포름 (>99.5 %, 2ml, Bio basic) 유기용매상과 섞어 초음파분쇄기 (Time : 30 sec, purse on : 5 sec, purse off : 3 sec, AMP : 20%) 를 이용하여 물상과 유기 용매상을 균일하게 섞어 1차 에멀젼을 형성한다. 형성된 1차 에멀젼(W/O)을 히알루론산 (10 mg/ml, TOKYO CHEMICAL INDUSTRY)이 용해되어 있는 폴리비닐알콜 (PVA_hyaluronic acid) 1% 수용액에 섞어 초음파 분쇄기를 이용해 2차 에멀젼을 제조한다. 형성된 2차 에멀젼을 증발기를 이용하여 클로로포름을 증발시킨다. 증발 후 남은 나노입자를 원심분리기를 이용하여 모으고 이를 물로 2번 세척하여 준다. 그 후 남은 pellet을 수용액에 섞어서 이용한다.To prepare dobutamine nanoparticles, a second emulsion method of W / O / W is used and the organic solvent is evaporated to prepare nanoparticles. The first isobutamin solution (50 mg / ml, 5%) was mixed with chloroform (> 99.5%, 2 ml, Bio basic) organic solvent phase in which PLGA (50:50, 2.5 mg / ml, Sigma Aldrich) The primary emulsion is formed by homogeneously mixing the water phase and the organic solvent phase using an ultrasonic mill (Time: 30 sec, purge on: 5 sec, purse off: 3 sec, AMP: 20%). The primary emulsion (W / O) formed is mixed with 1% aqueous solution of polyvinyl alcohol (PVA_hyaluronic acid) in which hyaluronic acid (10 mg / ml, TOKYO CHEMICAL INDUSTRY) is dissolved to prepare a secondary emulsion using an ultrasonic grinder. The formed secondary emulsion is evaporated with chloroform using an evaporator. The remaining nanoparticles after evaporation are collected using a centrifuge and washed twice with water. The remaining pellets are then mixed with the aqueous solution.

실험예Experimental Example 1.  One. 도부타민Dobutamine 나노입자의 물리적 특성 Physical properties of nanoparticles

상기 실시예 1에서 제조한 도부타민 나노입자의 크기를 광산란장치를 이용하여 측정하였으며, 그 결과를 도 1A에 나타내었다. 도 1A에 나타낸 바와 같이, 도부타민 나노입자의 크기는 250nm임을 확인하였다. 또한, 나노입자에 담지된 도부타민의 적재효율(loading efficiency)을 UV 분광 광도계를 이용하여 280 nm의 흡광 파장에서 측정하고 이를 도 1B에 나타내었다.The size of the dobutamine nanoparticles prepared in Example 1 was measured using a light scattering apparatus, and the results are shown in FIG. 1A. As shown in Fig. 1A, it was confirmed that the size of the dobutamine nanoparticles was 250 nm. The loading efficiency of dobutamine loaded on the nanoparticles was measured at a wavelength of 280 nm using a UV spectrophotometer and is shown in Fig. 1B.

실험예Experimental Example 2.  2. 도부타민Dobutamine 나노입자의  Of nanoparticles 세포내Intracellular 전달효율 Transfer efficiency

PLGA 나노입자의 표면에 히알루론산을 결합시켜 종양세포 표면에서 발현되는 CD44 수용체에 선택적인 결합을 나타내는 도이다. 도 2A는 난소암세포주 (A2780)으로서 CD44 수용체의 발현이 적은 negative expression을 나타낸다. 도 2B는 난소암세포주 (HeyA8)으로서 CD44 수용체의 발현이 높은 positive expression을 나타낸다. 도 2C는 CD44 negative cell line (A2780)에서 PLGA 나노입자의 결합능력을 나타낸다. 도 2D는 CD44 positive cell line (HeyA8)에 대해서 PLGA 나노입자의 선택적인 결합능력을 나타낸다. 유세포 분석기와 공초점 레이저 분석기를 통하여 측정하여 CD44 양성 발현 세포에서 히알루론산이 결합되어 있는 PLGA 나노입자의 세포내로의 높은 전달력을 확인한 결과를 도 2에 나타내었다.  FIG. 5 shows binding of hyaluronic acid to the surface of PLGA nanoparticles to bind selectively to the CD44 receptor expressed on the surface of tumor cells. Fig. 2A shows a negative expression with low expression of CD44 receptor as ovarian cancer cell line (A2780). Fig. 2B shows a positive expression of a high expression of the CD44 receptor as an ovarian cancer cell line (HeyA8). Figure 2C shows the binding ability of PLGA nanoparticles in the CD44 negative cell line (A2780). 2D shows the selective binding capacity of PLGA nanoparticles for the CD44 positive cell line (HeyA8). The results are shown in FIG. 2. The results are shown in FIG. 2. The results are shown in FIG. 2. FIG. 2 shows the results of confirming the high transfer of hyaluronic acid-bound PLGA nanoparticles into the cells in CD44-positive expressing cells by measurement using flow cytometry analyzer and confocal laser analyzer.

실험예Experimental Example 3.  3. 도부타민의Dobutamine 세포 독성 확인 Cytotoxicity check

본 발명의 도부타민이 암세포의 생존에 미치는 영향을 확인하기 위하여 도부타민을 인간 난소암 세포주인 HeyA8, HeyA8-MDR에 각각 10 μM, 20 μM, 30 μM 및 100 μM씩 처리하고, 24 시간마다 MTT 분석을 통하여 세포 독성을 측정하였으며, 그 결과를 도 3에 나타내었다. 도 3에 나타낸 바와 같이, 도부타민의 농도가 증가할수록 세포 독성이 증가하며, 항암 효과가 높아지는 경향을 확인하였다. In order to confirm the effect of the dobutamine of the present invention on the survival of cancer cells, dobutamine was treated at 10 μM, 20 μM, 30 μM and 100 μM for human ovarian cancer cell lines HeyA8 and HeyA8-MDR, respectively, The cytotoxicity was measured through analysis, and the results are shown in FIG. As shown in Fig. 3, as the concentration of dobutamine increases, the cytotoxicity increases and the anticancer effect tends to be enhanced.

실험예Experimental Example 4. 종양세포에서  4. In tumor cells 도부타민의Dobutamine YAP발현YAP expression 억제 확인 Check for inhibition

종양세포에서 도부타민의 YAP의 활성을 조절하는지 알아보기 위해, 세포를 nucleus 및 cytosol로 분리한 뒤 각각 웨스턴 블랏을 실행하였다. 그 결과, 종양세포주인 HeyA8, HeyA8-MDR 세포에 도부타민을 처리하면, YAP의 phosphorylation을 유도하고, 이에 의해 핵에서 세포질로의 이동을 촉진하고, 결과적으로 Yap의 비활성화를 유도한다는 것을 확인한 하였다 (도 4). To determine whether YAP activity of dobutamine was modulated in tumor cells, the cells were separated into nucleus and cytosol and then subjected to Western blotting. As a result, it was confirmed that treatment of dobutamine on the tumor cells HeyA8, HeyA8-MDR cells induces phosphorylation of YAP, thereby promoting migration of nuclei to the cytoplasm, resulting in inactivation of Yap 4).

실험예Experimental Example 5.  5. 도부타민Dobutamine 나노입자의 항암 치료 효과 확인 Confirming the effect of nanoparticles on chemotherapy

도부타민의 항암 치료 효과를 확인하기 위하여, 인간 난소암 세포주인 HeyA8과 HeyA8-MDR을 누드마우스에 직접 주사하여 종양모델을 제작하고, 상기 도부타민 200㎍이 탑재되어있는 나노입자를 마우스에 정맥 또는 복강에 주사하였다. 실험 종료 시점은 대조군 마우스가 죽기 직전으로 하였다. 실험 종료 시점에 각각의 마우스의 무게와 종양 조직을 적출하여 무게를 측정하였다. 도 5에 나타낸 바와 같이, 도부타민을 탑재한 PLGA 나노입자가 종양의 크기를 감소시키는 것을 확인하여 치료효과가 있는 것을 확인하였다. 또, 마우스의 체중에 변화가 없는 것을 통해 생체적합한 나노입자라는 것을 확인 할 수 있었다.In order to confirm the antitumor effect of dobutamine, a tumor model was prepared by directly injecting human ovarian cancer cell lines HeyA8 and HeyA8-MDR into nude mice, and nanoparticles loaded with 200 μg of dobutamine were intravenously administered Were injected intraperitoneally. At the end of the experiment, the control mice were immediately before their deaths. At the end of the experiment, the weight and tumor tissue of each mouse were extracted and weighed. As shown in Fig. 5, it was confirmed that the dobutamine-loaded PLGA nanoparticles decrease the size of the tumor, thereby confirming the therapeutic effect. In addition, it was confirmed that the nanoparticles were biocompatible through the mice having no change in body weight.

Claims (15)

삭제delete 삭제delete 삭제delete 삭제delete 하기 화학식 1로 표시되는 도부타민 및 PLGA(Poly(lactic acid-co-glycolic acid))을 포함하는 나노입자 표면에 히알루론산을 결합시킨 나노입자 복합체를 유효성분으로 포함하는 항암제에 대한 다중약물 내성을 가지고 CD 44의 높은 발현을 나타내는 난소암 억제용 주사제 조성물;
Figure 112018075423420-pat00009
.
A multi-drug resistance to an anticancer agent comprising, as an active ingredient, a nanoparticle complex in which hyaluronic acid is bound to the surface of nanoparticles comprising dobutamine and PLGA (poly (lactic acid-co-glycolic acid) An injectable composition for inhibiting ovarian cancer showing high expression of CD44;
Figure 112018075423420-pat00009
.
삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete
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Citations (1)

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Publication number Priority date Publication date Assignee Title
US20070190160A1 (en) * 2003-09-02 2007-08-16 Edward Turos Nanoparticles for drug-delivery

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070190160A1 (en) * 2003-09-02 2007-08-16 Edward Turos Nanoparticles for drug-delivery

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Anticancer Research. 2013. Vol.33, pp.2425-2434.*
World Journal of Gastroenterology. 2014. Vol.20, No.45, pp.17092-17099.*

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