KR102641217B1 - Albumin nanoparticles coated with anticancer agent and producing method thereof - Google Patents
Albumin nanoparticles coated with anticancer agent and producing method thereof Download PDFInfo
- Publication number
- KR102641217B1 KR102641217B1 KR1020190173640A KR20190173640A KR102641217B1 KR 102641217 B1 KR102641217 B1 KR 102641217B1 KR 1020190173640 A KR1020190173640 A KR 1020190173640A KR 20190173640 A KR20190173640 A KR 20190173640A KR 102641217 B1 KR102641217 B1 KR 102641217B1
- Authority
- KR
- South Korea
- Prior art keywords
- albumin
- anticancer agent
- nanoparticles
- reduced
- coated
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
본 발명은 본 발명은 항암제가 코팅된 알부민 나노입자 및 이의 제조방법 등에 관한 것으로, 본 발명의 나노입자는 약물 방출 안정성이 우수할 뿐만 아니라 항암제의 코팅률 및 항암제의 효능을 극대화시킬 수 있기 때문에 다양한 항암제에 폭넓게 적용이 가능할 것으로 기대된다.The present invention relates to albumin nanoparticles coated with an anticancer agent and a method for manufacturing the same. The nanoparticles of the present invention not only have excellent drug release stability, but can also maximize the coating rate and efficacy of the anticancer agent, so they can be used in various ways. It is expected that it can be widely applied to anticancer drugs.
Description
본 발명은 항암제가 코팅된 알부민 나노입자 및 이의 제조방법 등에 관한 것이다. The present invention relates to albumin nanoparticles coated with anticancer agents and methods for producing the same.
약학 분야의 눈부신 발달로 여러 종류의 고성능 신약들이 활발히 개발되고 있으나, 치료하고자 하는 질환의 생리적 조건에 최적화된 전달이 어렵기 때문에 임상에서의 사용에 있어서 많은 제한을 받고 있다. 특히 항암제 전달의 경우에는 선택성 및 지속성의 결여로 인하여 고농도의 약물 투여가 요구되며, 이로 인하여 심각한 부작용들이 발생하고 있는 실정이다. 따라서, 이러한 항암제의 부작용을 최소화하기 위하여 새로운 항암제 제형에 대하여 많은 연구가 진행되어 왔으며, 1980년대 중반에 나노 입자가 고형암 주위에 쉽게 축적될 수 있다는 EPR(enhanced permeation and retention) 효과가 발표되면서 다양한 형태의 나노 입자가 약물 전달 시스템(drug delivery system; DDS)으로서 항암제 전달에 사용되기 시작하였다. 이러한 나노 입자는 작은 크기에 비하여 상대적으로 부피 비율이 크기 때문에 많은 양의 약물을 포함하여 전달할 수 있으며, 암 조직에 형성된 혈관 상피세포 특성 상 간극이 넓기 때문에 암 조직에 선택적으로 침투될 수 있을 뿐만 아니라, 암 조직 주변에는 림프 조직의 발달이 느리기 때문에 침투된 나노 입자가 장기간 배출되지 않고 암 조직 내부에 축적된다는 장점을 가지고 있다. 그러나 이러한 나노 입자도 혈액순환 중의 불안정성, 나노 입자 자체의 독성 등과 같은 문제점을 가지고 있기 때문에 이러한 문제점을 해결할 수 있는 약물 전달 시스템의 개발이 필요한 실정이다.Due to remarkable developments in the pharmaceutical field, various types of high-performance new drugs are being actively developed, but their clinical use is severely limited due to the difficulty in delivering them optimally for the physiological conditions of the disease being treated. In particular, in the case of anticancer drug delivery, high drug concentration is required due to lack of selectivity and persistence, which causes serious side effects. Therefore, in order to minimize the side effects of these anticancer drugs, much research has been conducted on new anticancer drug formulations, and in the mid-1980s, with the announcement of the EPR (enhanced permeation and retention) effect that nanoparticles can easily accumulate around solid tumors, various types of Nanoparticles have begun to be used to deliver anticancer drugs as a drug delivery system (DDS). Since these nanoparticles have a relatively large volume ratio compared to their small size, they can contain and deliver a large amount of drug, and because the gaps are wide due to the nature of the vascular epithelial cells formed in cancer tissue, they can also selectively penetrate cancer tissue. , because the development of lymphoid tissue around cancer tissue is slow, the infiltrated nanoparticles have the advantage of accumulating inside the cancer tissue without being discharged for a long period of time. However, since these nanoparticles also have problems such as instability during blood circulation and toxicity of the nanoparticles themselves, there is a need to develop a drug delivery system that can solve these problems.
한편, 알부민(albumin)은 혈장의 60%를 차지하고 있는 생체 유래 단백질로서 생체 적합성이 뛰어나 화상, 신증후군 등으로 인한 알부민의 상실 및 간경변증 등에 의한 알부민 합성 저하에 의한 저알부민혈증 등의 치료제로 사용되고 있을 뿐만 아니라, 단백질, 효소 등을 포함하는 제제의 안정제 또는 제형을 유지하기 위한 동결건조보조제 등으로 널리 사용되고 있다. 물이나 염용액에 대해 높은 용해도를 가지고 있고, 체내에서 무해한 물질로 분해 및 대사되기 때문에 면역반응을 유도하지 않는 것으로 알려져 있으며, 의료, 제약, 제제, 생명과학 분야에 폭넓게 사용되어 9.2%의 연평균성장률을 보일 정도로 그 사용 범위가 증가되고 있는 추세이다. 특히 최근 주목받고 있는 바이오 분야인 단백질 제제나 백신 제제, 그리고 알부민을 이용한 약물 전달 시스템에 대한 연구가 활발히 진행되고 있다. 하지만 기존의 방법으로 제조된 알부민 나노입자는 표면에는 글루타알데히드가 가교결합제로 사용될 뿐만 아니라, 잔존 알데히드에 의해 표면에 약물을 적재하는 것에 화학 결합을 유도함에 따라 약물의 방출이 용이하지 않은 한계를 나타내고 있다.Meanwhile, albumin is a biologically derived protein that accounts for 60% of plasma and has excellent biocompatibility, so it may be used as a treatment for hypoalbuminemia caused by loss of albumin due to burns, nephrotic syndrome, etc. and decreased albumin synthesis due to cirrhosis. In addition, it is widely used as a stabilizer for preparations containing proteins, enzymes, etc., or as a freeze-drying aid to maintain the formulation. It has high solubility in water or salt solutions, and is known not to induce an immune response because it is decomposed and metabolized into harmless substances in the body. It is widely used in the medical, pharmaceutical, pharmaceutical, and life science fields, with an average annual growth rate of 9.2%. The scope of its use is increasing to the extent that it appears. In particular, research is being actively conducted on protein preparations, vaccine preparations, and drug delivery systems using albumin, which are fields of biotechnology that have recently been attracting attention. However, albumin nanoparticles manufactured by conventional methods not only use glutaraldehyde as a cross-linking agent on the surface, but also have a limitation in that drug release is not easy as the residual aldehyde induces a chemical bond to load the drug on the surface. It is showing.
따라서, 본 발명자들은 이러한 장점을 가지는 알부민을 이용하여 항암제의 알부민 입자 코팅 시 발생하는 낮은 탑재율(loading efficiency)을 향상시키는 동시에, 약물을 효과적으로 전부 방출할 수 있는 기술을 개발할 뿐만 아니라, 약물 전달 시스템으로 대량 생산하기 위한 최적의 제조방법을 개발하고자 예의 연구한 결과 본 발명을 완성하였다.Therefore, the present inventors used albumin, which has these advantages, to improve the low loading efficiency that occurs when coating albumin particles of anticancer drugs, and at the same time develop a technology that can effectively release all of the drug, as well as use it as a drug delivery system. As a result of intensive research to develop an optimal manufacturing method for mass production, the present invention was completed.
본 발명은 상기와 같은 종래 기술상의 문제점을 해결하기 위해 안출된 것으로, 항암제가 표면에 코팅된 환원된 알부민 나노입자 및 그 제조방법 또는 이를 포함하는 조성물을 제공하는 것을 그 목적으로 한다.The present invention was made to solve the problems in the prior art as described above, and its purpose is to provide reduced albumin nanoparticles coated with an anticancer agent on the surface, a method for producing the same, or a composition containing the same.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.
본 발명은 항암제가 표면에 코팅된 환원된 알부민 나노입자를 제공한다.The present invention provides reduced albumin nanoparticles coated on the surface with an anticancer agent.
또한, 본 발명은 항암제의 전달체용 환원된 알부민 나노입자를 제공한다.Additionally, the present invention provides reduced albumin nanoparticles for use as a carrier for anticancer drugs.
본 발명의 일 실시예에서, 상기 환원된 알부민 나노입자는 입자 표면의 카르복실기와 알데히드가 알코올로 환원된 것을 특징으로 하는 것일 수 있으나, 이에 제한되지 않는다.In one embodiment of the present invention, the reduced albumin nanoparticle may be characterized in that the carboxyl group and aldehyde on the particle surface are reduced to alcohol, but is not limited thereto.
본 발명의 다른 실시예에서, 상기 나노입자의 크기는 직경이 50 내지 500 nm일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the size of the nanoparticles may be 50 to 500 nm in diameter, but is not limited thereto.
본 발명의 또 다른 실시예에서, 상기 환원된 알부민 나노입자와 항암제는 1 : 2 내지 1 : 13 질량비(w/w %)로 혼합되어 코팅된 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the reduced albumin nanoparticles and the anticancer agent may be mixed and coated at a mass ratio (w/w %) of 1:2 to 1:13, but is not limited thereto.
본 발명의 또 다른 실시예에서, 상기 환원된 알부민 나노입자는 0.1 내지 15 mg/mL의 농도로 항암제와 혼합되는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the reduced albumin nanoparticles may be mixed with an anticancer agent at a concentration of 0.1 to 15 mg/mL, but are not limited thereto.
본 발명의 또 다른 실시예에서, 상기 항암제는 독소루비신, 파클리탁셀, 도세탁셀, 시스플라틴, 글리벡, 5-플루오로우라실(5-FU), 타목시펜, 카보플라틴, 토포테칸, 벨로테칸, 이마티닙, 이리노테칸, 플록수리딘, 비노렐빈, 젬시타빈, 류프로리드, 플루타미드, 졸레드로네이트, 메토트렉세이트, 캄토테신, 빈크리스틴, 히드록시우레아, 스트렙토조신, 발루비신, 레티노익산, 메클로레타민, 클로람부실, 부술판, 독시플루리딘, 빈블라스틴, 마이토마이신, 프레드니손, 아피니토, 및 미토산트론으로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the anticancer agent is doxorubicin, paclitaxel, docetaxel, cisplatin, Gleevec, 5-fluorouracil (5-FU), tamoxifen, carboplatin, topotecan, belotecan, imatinib, irinotecan, and floc. Suridin, vinorelbine, gemcitabine, leuprolide, flutamide, zoledronate, methotrexate, camptothecin, vincristine, hydroxyurea, streptozocin, valrubicin, retinoic acid, mechlorethamine, chloram. It may be one or more selected from the group consisting of busil, busulfan, doxifluridine, vinblastine, mitomycin, prednisone, afinitor, and mitoxantrone, but is not limited thereto.
본 발명의 또 다른 실시예에서, 상기 항암제가 코팅된 환원된 알부민 나노입자는 약물 방출 안정성이 향상된 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the reduced albumin nanoparticles coated with the anticancer agent may have improved drug release stability, but are not limited thereto.
본 발명의 또 다른 실시예에서, 상기 항암제가 코팅된 환원된 알부민 나노입자는 50% 내지 100% 의 항암제 코팅률을 갖는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the reduced albumin nanoparticles coated with the anticancer agent may have an anticancer agent coating rate of 50% to 100%, but are not limited thereto.
또한, 본 발명은 (i) 알부민 입자를 환원제와 반응시켜 환원 알부민 입자를 제조하는 단계; 및 (ii) 상기 환원 알부민 입자에 항암제를 첨가하고 반응시켜 항암제를 알부민 입자에 코팅하는 단계를 포함하는, 항암제가 코팅된 알부민 입자의 제조방법으로서, 상기 (ii) 단계의 환원 알부민 입자와 항암제의 혼합 비율은 1 : 2 내지 1 : 13 질량비(w/w %)인 것을 특징으로 하는, 제조방법을 제공한다.In addition, the present invention includes the steps of (i) reacting albumin particles with a reducing agent to produce reduced albumin particles; And (ii) a method for producing albumin particles coated with an anticancer agent, comprising the step of adding an anticancer agent to the reduced albumin particles and reacting to coat the anticancer agent onto the albumin particles, wherein the reduced albumin particles of step (ii) and the anticancer agent are A manufacturing method is provided, characterized in that the mixing ratio is 1:2 to 1:13 mass ratio (w/w %).
본 발명의 일 구현예에서, 상기 (ii) 단계의 환원 알부민 입자는 0.1 내지 15 mg/mL의 농도로 첨가되는 것일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the reduced albumin particles in step (ii) may be added at a concentration of 0.1 to 15 mg/mL, but are not limited thereto.
본 발명의 다른 구현예에서, 상기 (ii) 단계의 상기 항암제를 알부민 입자에 코팅하는 단계는 pH 5 내지 10 의 조건에서 수행되는 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the step (ii) of coating the anticancer agent on albumin particles may be performed under conditions of pH 5 to 10, but is not limited thereto.
본 발명의 또 다른 구현예에서, 상기 환원제는 수소화 붕소 나트륨(sodium borohydride), 나트륨시아노보로하이드리드(sodium cyanoborohydride), 수소화 알루미늄 리튬(lithium aluminium hydride), 리튬 트리에틸보로하이드라이드(Lithium triethylborohydride), 수소화 붕소 리튬(Lithium borohydride), 수소화 붕소 마그네슘(Magnesium borohydride), 수소화 붕소 알루미늄(Aluminum borohydride), 및 수소화 붕소 칼슘(Calcium borohydride)으로 이루어진 군으로부터 선택된 하나 이상인 것일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the reducing agent is sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and lithium triethylborohydride. ), lithium borohydride, magnesium borohydride, aluminum borohydride, and calcium borohydride, but is not limited thereto. .
또한, 본 발명은 항암제 및 환원된 알부민을 포함하는 나노입자를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising nanoparticles containing an anticancer agent and reduced albumin as active ingredients.
본 발명의 일 구현예에서, 상기 항암제 및 환원된 알부민을 포함하는 나노입자는 항암제가 표면에 코팅된 환원된 알부민 나노입자의 형태일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the nanoparticles containing the anticancer agent and reduced albumin may be in the form of reduced albumin nanoparticles with the anticancer agent coated on the surface, but are not limited thereto.
또한, 본 발명은 항암제가 표면에 코팅된 환원된 알부민 나노입자를 개체에 투여하는 단계를 포함하는 암 치료 방법을 제공한다.Additionally, the present invention provides a cancer treatment method comprising administering reduced albumin nanoparticles coated on the surface with an anticancer agent to a subject.
또한, 본 발명은 항암제가 표면에 코팅된 환원된 알부민 나노입자의 암 예방 또는 치료 용도를 제공한다.Additionally, the present invention provides a use for cancer prevention or treatment of reduced albumin nanoparticles coated on the surface with an anticancer agent.
또한, 본 발명은 항암제가 표면에 코팅된 환원된 알부민 나노입자의 암 치료제를 생산하기 위한 용도를 제공한다.In addition, the present invention provides the use of reduced albumin nanoparticles coated on the surface with an anticancer agent for producing a cancer treatment agent.
또한, 본 발명은 항암제가 표면에 코팅된 알부민 나노입자로서, 상기 알부민 나노입자와 항암제는 1 : 2 내지 1 : 10의 질량비(w/w %)로 혼합되어 코팅된 것을 특징으로 하는, 나노입자를 제공한다. 상기 알부민 나노입자는 비환원 알부민 나노입자일 수 있다.In addition, the present invention relates to albumin nanoparticles coated on the surface with an anticancer agent, wherein the albumin nanoparticles and the anticancer agent are mixed and coated at a mass ratio (w/w%) of 1:2 to 1:10. provides. The albumin nanoparticles may be non-reduced albumin nanoparticles.
또한, 본 발명은 알부민 나노입자에 항암제를 첨가하고 반응시켜 항암제를 알부민 입자에 코팅하는 단계를 포함하는, 항암제가 코팅된 알부민 입자의 제조방법으로서, 알부민 입자와 항암제의 혼합 비율은 1 : 2 내지 1 : 10의 질량비(w/w %)인 것을 특징으로 하는, 제조방법을 제공한다.In addition, the present invention is a method for producing albumin particles coated with an anticancer agent, comprising the step of adding an anticancer agent to albumin nanoparticles and reacting to coat the anticancer agent on the albumin particles, wherein the mixing ratio of the albumin particles and the anticancer agent is 1:2 to 1:2. A manufacturing method is provided, characterized in that the mass ratio (w/w %) is 1:10.
또한, 본 발명은 상기 항암제가 표면에 코팅된 알부민 나노입자를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer containing albumin nanoparticles coated on the surface with the anticancer agent as an active ingredient.
또한, 본 발명은 항암제가 표면에 코팅된 알부민 나노입자를 개체에 투여하는 단계를 포함하는 암 치료 방법을 제공한다.Additionally, the present invention provides a cancer treatment method comprising administering albumin nanoparticles coated on the surface with an anticancer agent to a subject.
또한, 본 발명은 항암제가 표면에 코팅된 알부민 나노입자의 암 예방 또는 치료 용도를 제공한다.Additionally, the present invention provides a use for cancer prevention or treatment of albumin nanoparticles coated on the surface with an anticancer agent.
또한, 본 발명은 항암제가 표면에 코팅된 알부민 나노입자의 암 치료제를 생산하기 위한 용도를 제공한다.Additionally, the present invention provides the use of albumin nanoparticles coated with an anticancer agent on the surface to produce a cancer treatment agent.
본 발명에 따른 항암제가 표면에 코팅된 환원된 알부민 나노입자는 항암제의 코팅률 및 항암제의 효능을 극대화시킬 수 있을 뿐만 아니라, 초음파와 같은 외부 자극이나 낮은 pH에서만 선택적인 방출이 가능하기 때문에 암 특이적으로 약물이 방출되도록 조절할 수 있다. 따라서, 상기 나노입자는 기존 약물 전달 시스템의 단점을 개선하는 동시에 부작용을 감소시킬 수 있고, 대량생산이 가능하여 저렴하게 약물의 제공이 가능하기 때문에 다양한 항암제에 적용이 가능할 것으로 기대된다.The reduced albumin nanoparticles coated with the anticancer agent according to the present invention not only maximize the coating rate and efficacy of the anticancer agent, but also enable selective release only at low pH or external stimuli such as ultrasound, making them specific for cancer. It is possible to control drug release appropriately. Therefore, the nanoparticles are expected to be applicable to various anticancer drugs because they can improve the shortcomings of existing drug delivery systems while reducing side effects, and can be mass-produced to provide drugs at low cost.
도 1은 본 발명의 일 실시예에 따른 알부민 나노입자(Alb-NPs)와 환원된 알부민 나노입자(rAlb-NPs)의 (a) 크기분포 및 (b) 제타전위를 나타낸 도면이다.
도 2는 본 발명의 일 실시예에 따른 Alb-NPs의 환원 여부를 확인하기 위하여 Alb-NPs 및 rAlb-NPs의 톨렌스 시약 반응 결과를 나타낸 도면이다.
도 3은 본 발명의 일 실시예에 따른 pH 5.5(파란색), pH 6.4 또는 pH 6.5(빨간색) 및 pH 7.4(검정색)에서 알부민과 독소루비신의 반응시간별 시간에 따른 독소루비신 방출량을 나타낸 도면이다.
도 4는 본 발명의 일 실시예에 따라 sDOX 및 rDOX의 안정성을 확인하기 위하여 (좌측) 크기 분포 및 (우측) 방출 효율을 나타낸 도면이다.
도 5는 본 발명이 일 실시예에 따른 Free 독소루비신(free DOX, 알부민 나노입자 미결합), 독소루비신이 코팅된 알부민 나노입자(sDOX 30 min), 및 독소루비신이 코팅된 환원된 알부민 나노입자(rDOX 24h)의 항암 효과를 나타낸 도면이다.Figure 1 is a diagram showing (a) size distribution and (b) zeta potential of albumin nanoparticles (Alb-NPs) and reduced albumin nanoparticles (rAlb-NPs) according to an embodiment of the present invention.
Figure 2 is a diagram showing the results of Tollens reagent reaction of Alb-NPs and rAlb-NPs to confirm whether Alb-NPs are reduced according to an embodiment of the present invention.
Figure 3 is a diagram showing the amount of doxorubicin released over time for each reaction time of albumin and doxorubicin at pH 5.5 (blue), pH 6.4, or pH 6.5 (red) and pH 7.4 (black) according to an embodiment of the present invention.
Figure 4 is a diagram showing (left) size distribution and (right) release efficiency to confirm the stability of sDOX and rDOX according to an embodiment of the present invention.
Figure 5 shows free doxorubicin (free DOX, unbound albumin nanoparticles), doxorubicin-coated albumin nanoparticles (sDOX 30 min), and doxorubicin-coated reduced albumin nanoparticles (rDOX 24h) according to an embodiment of the present invention. ) This is a diagram showing the anti-cancer effect.
본 발명의 항암제가 표면에 코팅된 환원된 알부민 나노입자는 항암제와 알부민 입자의 혼합 비율, 알부민 입자의 농도, 제조 시 pH 등을 다양하게 조합하여 항암제의 코팅률 및 항암제의 효능을 극대화시킬 수 있는 조건을 확인함으로써 완성되었으므로, 다양한 항암제를 적용하여 다양한 암 치료제에 효과적으로 적용이 가능할 것으로 기대된다.The reduced albumin nanoparticles with the anticancer agent coated on the surface of the present invention can maximize the coating rate of the anticancer agent and the efficacy of the anticancer agent by variously combining the mixing ratio of the anticancer agent and albumin particles, the concentration of the albumin particles, and the pH during production. Since it was completed by confirming the conditions, it is expected that it can be effectively applied to various cancer treatments by applying various anticancer drugs.
이에, 본 발명은 항암제가 표면에 코팅된 환원된 알부민 나노입자를 제공한다.Accordingly, the present invention provides reduced albumin nanoparticles coated on the surface with an anticancer agent.
또한, 항암제가 표면에 코팅된 알부민 나노입자로서, 상기 알부민 나노입자와 항암제는 1 : 2 내지 1 : 10의 질량비(w/w %)로 혼합되어 코팅된 것을 특징으로 하는, 나노입자를 제공한다. 상기 알부민 나노입자는 비환원 알부민 나노입자일 수 있으나, 이에 제한되는 것은 아니다.In addition, it provides albumin nanoparticles coated with an anticancer agent on the surface, wherein the albumin nanoparticles and the anticancer agent are mixed and coated at a mass ratio (w/w%) of 1:2 to 1:10. . The albumin nanoparticles may be non-reduced albumin nanoparticles, but are not limited thereto.
본 명세서에 있어서, “알부민”이란 혈청 알부민으로, 포유동물의 혈청 알부민일 수 있으며, 바람직하게는 사람의 혈청 알부민으로서, 분자량이 66,462이고, 분자의 장축이 8 nm이고 단축이 6 nm이며, 등전점 (isoelectric point, IEP)이 4.8인 단백질이다. 또한 혈장단백질의 50% (4 g/dl)를 구성하고 있으며, 단일 폴리펩타이드 체인으로 구성되어 있다.In this specification, “albumin” refers to serum albumin, which may be mammalian serum albumin, preferably human serum albumin, with a molecular weight of 66,462, a long axis of the molecule of 8 nm and a short axis of 6 nm, and an isoelectric point. It is a protein with an isoelectric point (IEP) of 4.8. It also makes up 50% (4 g/dl) of plasma proteins and is composed of a single polypeptide chain.
본 발명에 있어서, 상기 알부민은 바람직하게는 소혈청 알부민, 인간혈청 알부민 또는 이의 단편이나, 알코올에 의하여 자기 집합체(self-aggregation)를 형성하여 나노 크기의 입자를 형성할 수 있는 종류라면 이에 제한되지 않는다. 상기 알코올(alcohol)은 일반식으로 ROH(R=알킬기)로 나타내며, 탄화수소의 수소 원자가 하이드록시기(-OH)로 치환된 화합물의 총칭으로서, 바람직하게는 메탄올, 에탄올, 프로판올, 부탄올 등이며, 더욱 바람직하게는 에탄올이나 알부민의 자기 집합체 형성을 도와줄 수 있는 알코올 종류라면 이에 제한되지 않는다.In the present invention, the albumin is preferably bovine serum albumin, human serum albumin, or fragments thereof, but is not limited thereto as long as it is a type that can form nano-sized particles by self-aggregation with alcohol. No. The alcohol is generally represented by ROH (R = alkyl group), and is a general term for compounds in which the hydrogen atom of a hydrocarbon is replaced with a hydroxy group (-OH), preferably methanol, ethanol, propanol, butanol, etc., More preferably, it is not limited to ethanol or any type of alcohol that can help form self-aggregates of albumin.
본 발명에 있어서, “알부민 입자”는 비환원 알부민 입자 또는 환원 알부민입자를 포함하는 의미로 사용되거나, 비환원 알부민 입자만을 의미하는 것으로 사용될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, “albumin particles” may be used to mean non-reduced albumin particles or reduced albumin particles, or may be used to mean only non-reduced albumin particles, but are not limited thereto.
본 발명에 있어서, “환원형 알부민”, “환원 알부민 입자” 또는 “환원 알부민 나노입자”는 알부민의 알데히드기(-RCHO) 및 카르복실기(-RCOOH)를 알코올기(-ROH) 또는 티올기(-RSH)로 환원한 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, “reduced albumin”, “reduced albumin particles” or “reduced albumin nanoparticles” refer to the aldehyde group (-RCHO) and carboxyl group (-RCOOH) of albumin being replaced with an alcohol group (-ROH) or a thiol group (-RSH). ), but is not limited to this.
본 발명에 있어서, “알부민 입자”, “비환원 알부민 입자” 또는 “환원 알부민 입자”는 바람직하게는 직경이 50 내지 500 nm일 수 있으며, 더욱 바람직하게는 100 내지 400 nm일 수 있으며, 더욱 바람직하게는 100 내지 200 nm이나, 이에 제한되지 않는다.In the present invention, the “albumin particles”, “non-reduced albumin particles” or “reduced albumin particles” may preferably have a diameter of 50 to 500 nm, more preferably 100 to 400 nm, and even more preferably Typically, it is 100 to 200 nm, but is not limited thereto.
본 발명에 있어서, 알부민 입자는 a) 알부민을 물에 용해시킨 후 알코올을 적하하여 자기 집합체(self-aggregation)를 형성하여 알부민 입자를 제조하는 단계;를 포함하는 제조방법에 의해 제조된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the albumin particles may be manufactured by a production method including the step of dissolving albumin in water and then dropping alcohol to form self-aggregation to produce albumin particles. , but is not limited to this.
본 발명에 있어서, “자기 집합체(self-aggregates)”는 외부의 힘에 의해 집합되지 않고, 물질이 포함하고 있는 고유의 분자간 인력 또는 척력에 의해 집합체를 형성하는 물질을 의미할 수 있다.In the present invention, “self-aggregates” may refer to materials that are not aggregated by external forces but form aggregates by the inherent intermolecular attraction or repulsion contained in the material.
본 발명에 있어서, 환원 알부민 입자 또는 비환원 알부민 입자와 항암제의 혼합 비율은 바람직하게는 1 : 2 내지 1 : 13 질량비(w/w %)일 수 있으며, 더욱 바람직하게는 1 : 2 내지 1 : 10.5, 1 : 2.5 내지 1 : 10.5, 1 : 2.5 내지 1 : 5, 1: 2 내지 1 : 4, 1 : 2.5 내지 1 : 4.5, 1 : 2.5 내지 1 : 4, 1 : 2.5 내지 1 : 3, 1 : 1 : 5 내지 1 : 10.5, 1 : 5.5 내지 1 : 10.5, 1 : 6 내지 1 : 10.5, 1 : 6.5 내지 1 : 10.5, 1 : 7 내지 1 : 10.5, 1 : 7.5 내지 1 : 10.5, 1 : 8 내지 1 : 10.5, 1 : 8.5 내지 1 : 10.5, 1 : 9 내지 1 : 10.5, 또는 1 : 9.5 내지 1 : 10.5 질량비(w/w %)일 수 있으나 항암제가 효율적으로 알부민 입자에 코팅될 수 있는 비율이라면 이에 제한되지 않는다. In the present invention, the mixing ratio of reduced or non-reduced albumin particles and the anticancer agent is preferably 1:2 to 1:13 mass ratio (w/w %), more preferably 1:2 to 1:1. 10.5, 1:2.5 to 1:10.5, 1:2.5 to 1:5, 1:2 to 1:4, 1:2.5 to 1:4.5, 1:2.5 to 1:4, 1:2.5 to 1:3, 1:1:5 to 1:10.5, 1:5.5 to 1:10.5, 1:6 to 1:10.5, 1:6.5 to 1:10.5, 1:7 to 1:10.5, 1:7.5 to 1:10.5, The mass ratio (w/w %) may be 1:8 to 1:10.5, 1:8.5 to 1:10.5, 1:9 to 1:10.5, or 1:9.5 to 1:10.5, but the anticancer agent is efficiently coated on the albumin particles. There is no limitation to this ratio as long as it can be achieved.
본 발명에 있어서, 비환원 알부민 입자와 항암제의 혼합 비율은 예를 들어, 1 : 2 내지 1 : 10, 1 : 2 내지 1 : 4, 1 : 2.5 내지 1 : 3.5 또는 1 : 3 의 질량비(w/w %)일 수 있으나, 이에 제한되지 않는다.In the present invention, the mixing ratio of the non-reduced albumin particles and the anticancer agent is, for example, a mass ratio (w) of 1:2 to 1:10, 1:2 to 1:4, 1:2.5 to 1:3.5 or 1:3. /w %), but is not limited thereto.
본 발명에 있어서, 상기 비환원 알부민 나노입자 또는 환원된 알부민 나노입자는 0.1 내지 15 mg/mL의 농도로 항암제와 혼합될 수 있으며, 바람직하게는 1 내지 14 mg/mL, 2 내지 11 mg/mL, 2.5 내지 14 mg/mL, 2.5 내지 13 mg/mL, 2.5 내지 12 mg/mL, 2.5 내지 11 mg/mL, 또는 2.5 내지 10.5 mg/mL의 농도로 혼합될 수 있으며, 더욱 바람직하게는 8 내지 12 mg/mL, 9 내지 11 mg/mL, 또는 9.5 내지 10.5 mg/mL의 농도로 혼합될 수 있으나, 항암제가 효율적으로 알부민 입자에 코팅될 수 있는 비율이라면 이에 제한되지 않는다.In the present invention, the non-reduced albumin nanoparticles or reduced albumin nanoparticles can be mixed with the anticancer agent at a concentration of 0.1 to 15 mg/mL, preferably 1 to 14 mg/mL, 2 to 11 mg/mL. , 2.5 to 14 mg/mL, 2.5 to 13 mg/mL, 2.5 to 12 mg/mL, 2.5 to 11 mg/mL, or 2.5 to 10.5 mg/mL, and more preferably 8 to 10.5 mg/mL. It can be mixed at a concentration of 12 mg/mL, 9 to 11 mg/mL, or 9.5 to 10.5 mg/mL, but is not limited thereto as long as the ratio allows the anticancer agent to be efficiently coated on the albumin particles.
본 발명에 있어서, 상기 항암제를 알부민 입자에 코팅하는 단계는 pH 5 내지 10 의 조건에서 항암제를 코팅할 수 있으나, 항암제가 알부민에 코팅되며, 항암제의 효능에 영향을 미치지 않는 pH라면 이에 제한되지 않는다. 상기 pH는 이에 제한되는 것은 아니나, 5 내지 10, 5.5 내지 9.5, 6 내지 9, 6.5 내지 9, 6.5 내지 8, 또는 6.5 내지 7.5일 수 있다.In the present invention, the step of coating the anticancer agent onto albumin particles may be performed under conditions of pH 5 to 10, but the anticancer agent is coated on albumin and the pH is not limited thereto as long as it does not affect the efficacy of the anticancer agent. . The pH is not limited thereto, but may be 5 to 10, 5.5 to 9.5, 6 to 9, 6.5 to 9, 6.5 to 8, or 6.5 to 7.5.
본 발명에 있어서, 상기 항암제가 코팅된 나노입자의 크기는 바람직하게는 직경이 50 내지 500 nm일 수 있으며, 더욱 바람직하게는 100 내지 400 nm일 수 있으며, 더욱 바람직하게는 100 내지 200 nm이나, 암 조직 특이적으로 효율적으로 침입할 수 있는 크기라면 이에 제한되지 않는다.In the present invention, the size of the nanoparticles coated with the anticancer agent may preferably be 50 to 500 nm in diameter, more preferably 100 to 400 nm, and even more preferably 100 to 200 nm. It is not limited to this as long as it is a size that can efficiently invade cancer tissue specifically.
본 발명에 있어서, 상기 항암제는 바람직하게는 독소루비신, 파클리탁셀, 도세탁셀, 시스플라틴, 글리벡, 5-플루오로우라실(5-FU), 타목시펜, 카보플라틴, 토포테칸, 벨로테칸, 이마티닙, 이리노테칸, 플록수리딘, 비노렐빈, 젬시타빈, 류프로리드, 플루타미드, 졸레드로네이트, 메토트렉세이트, 캄토테신, 빈크리스틴, 히드록시우레아, 스트렙토조신, 발루비신, 레티노익산, 메클로레타민, 클로람부실, 부술판, 독시플루리딘, 빈블라스틴, 마이토마이신, 프레드니손, 아피니토, 미토산트론 등일 수 있으나, 본 발명의 알부민 입자에 코팅될 수 있다고 알려져 있는 항암제라면 이에 제한되지 않는다.In the present invention, the anticancer agent is preferably doxorubicin, paclitaxel, docetaxel, cisplatin, Gleevec, 5-fluorouracil (5-FU), tamoxifen, carboplatin, topotecan, belotecan, imatinib, irinotecan, and flocsuri. Dean, vinorelbine, gemcitabine, leuprolide, flutamide, zoledronate, methotrexate, camptothecin, vincristine, hydroxyurea, streptozocin, valrubicin, retinoic acid, mechlorethamine, chlorambucil. , busulfan, doxyfluridine, vinblastine, mitomycin, prednisone, afinitor, mitoxantrone, etc., but are not limited thereto as long as it is an anticancer agent known to be coated on the albumin particles of the present invention.
본 발명에 있어서, 상기 항암제를 알부민 입자에 코팅하는 단계는 바람직하게는 알부민 입자의 관능기(functional group)와 항암제가 상호작용을 하거나 항암제가 알부민 입자 사이로 들어가서 포함되거나, 단순히 표면에 코팅되는 것이나 일반적으로 알려져 있는 나노 입자에 항암제가 포함되는 방법이라면 이에 제한되지 않는다. 상기 상호작용은 바람직하게는 전하(charge)에 의한 전하 상호작용(charge interaction), 알부민의 소수성(hydrophobic) 부위에 의한 소수성 상호작용(hydrophobic interaction), 물리적 흡착(physical absorption; physisorption) 등일 수 있으나, 알부민 입자의 관능기에 의한 상호작용이라면 이에 제한되지 않는다.In the present invention, the step of coating the anticancer agent on the albumin particles is preferably performed by interacting with the functional group of the albumin particles and the anticancer agent, or by entering the anticancer agent between the albumin particles, or by simply coating the surface. The method is not limited to this as long as it includes an anti-cancer agent in known nanoparticles. The interaction may preferably be charge interaction due to charge, hydrophobic interaction due to the hydrophobic portion of albumin, physical absorption (physisorption), etc., The interaction is not limited to this as long as it is an interaction due to the functional group of the albumin particle.
본 발명에 있어서, 상기 환원제는 수소화 붕소 나트륨(sodium borohydride), 나트륨시아노보로하이드리드(sodium cyanoborohydride), 수소화 알루미늄 리튬(lithium aluminium hydride), 리튬 트리에틸보로하이드라이드(Lithium triethylborohydride), 수소화 붕소 리튬(Lithium borohydride), 수소화 붕소 마그네슘(Magnesium borohydride), 수소화 붕소 알루미늄(Aluminum borohydride), 및 수소화 붕소 칼슘(Calcium borohydride)으로 이루어진 군으로부터 선택된 하나 이상일 수 있으며, 알데히드 또는 카르복실기를 알코올기로 환원시킬 수 있는 물질이라면 이에 제한되지 않는다.In the present invention, the reducing agent is sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, lithium triethylborohydride, and boron hydride. It may be one or more selected from the group consisting of lithium borohydride, magnesium borohydride, aluminum borohydride, and calcium borohydride, and can reduce an aldehyde or carboxyl group to an alcohol group. If it is a substance, it is not limited to this.
본 발명에 있어서, 안정성이란 항암제의 방출을 조절함으로써 타겟 암세포까지 항암제가 안정적으로 도달할 수 있도록 하는 것을 말하며, 바람직하게는 약물 방출 안정성을 의미하나, 이에 제한되는 것은 아니다.In the present invention, stability refers to allowing the anticancer drug to stably reach the target cancer cells by controlling the release of the anticancer drug, and preferably refers to drug release stability, but is not limited thereto.
본 발명자들은 비환원 알부민 입자를 환원시킴으로써 표면의 알데히드 또는 카르복실기를 알코올기로 환원하였으며, 알코올기가 타겟 외의 물질과의 화학적 결합되는 것을 방지할 뿐만 아니라, 항암제가 알부민 입자와 화학결합하는 것을 방지함으로써 항암제가 코팅된 알부민 입자가 타겟 암 세포 또는 조직까지 안정적으로 도달할 수 있음을 확인하였다.The present inventors reduced the aldehyde or carboxyl group on the surface to an alcohol group by reducing the non-reduced albumin particles, and not only prevented the alcohol group from chemically bonding with substances other than the target, but also prevented the anticancer agent from chemically bonding with the albumin particles, thereby preventing the anticancer agent from chemically bonding with the albumin particle. It was confirmed that the coated albumin particles could stably reach the target cancer cells or tissues.
본 발명에 있어서, 용어 “코팅률”은 적재율과 혼용될 수 있다. 본 발명에 있어서, 상기 항암제가 코팅된 알부민 입자는 50 % 내지 100%, 60% 내지 100%. 65% 내지 100%. 70% 내지 100%. 75% 내지 100%. 76% 내지 100%. 77% 내지 100%. 80% 내지 100%. 85% 내지 100%. 87% 내지 100%. 88% 내지 100%. 90% 내지 100%. 또는 95% 내지 100%의 항암제 코팅률을 갖는 것일 수 있으나, 이에 제한되는 것은 아니다. 상기 항암제 코팅률은 첨가한 항암제의 양에 대한 코팅률을 의미할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the term “coating rate” may be used interchangeably with loading rate. In the present invention, the albumin particles coated with the anticancer agent are 50% to 100%, 60% to 100%. 65% to 100%. 70% to 100%. 75% to 100%. 76% to 100%. 77% to 100%. 80% to 100%. 85% to 100%. 87% to 100%. 88% to 100%. 90% to 100%. Alternatively, it may have an anticancer agent coating rate of 95% to 100%, but is not limited thereto. The anticancer agent coating rate may refer to the coating rate relative to the amount of anticancer agent added, but is not limited thereto.
또한, 본 발명은 항암제 및 환원된 알부민을 포함하는 나노입자를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising nanoparticles containing an anticancer agent and reduced albumin as active ingredients.
또한, 본 발명은 항암제가 표면에 코팅된 알부민 나노입자를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer containing albumin nanoparticles coated on the surface with an anticancer agent as an active ingredient.
상기 항암제 및 환원된 알부민을 포함하는 나노입자는 항암제가 표면에 코팅된 환원된 알부민 나노입자일 수 있으나, 이에 제한되는 것은 아니다.The nanoparticles containing the anticancer agent and reduced albumin may be reduced albumin nanoparticles with the anticancer agent coated on the surface, but are not limited thereto.
본 발명에 있어서, 상기 항암제 및 환원된 알부민을 포함하는 나노입자는 항암제가 알부민 나노입자의 표면에 코팅된 것일 수 있으며, 구체적으로 항암제의 코팅률이 향상된 것을 특징으로 하며, 바람직하게는 제조 시 첨가된 항암제의 70 % 이상이 코팅되는 것이며, 더욱 바람직하게는 80 % 이상이 코팅되는 것을 특징으로 하나, 기존의 제조방법과 비교하여 코팅률이 향상되었다면 이에 제한되지 않는다.In the present invention, the nanoparticles containing the anticancer agent and reduced albumin may have the anticancer agent coated on the surface of the albumin nanoparticle, and are specifically characterized by an improved coating rate of the anticancer agent, and are preferably added during production. More than 70% of the anticancer agent is coated, and more preferably, more than 80% is coated, but this is not limited if the coating rate is improved compared to the existing manufacturing method.
본 발명에 있어서, “암(cancer)”이란 비정상적으로 증식될 수 있는 미분화 세포로 구성되어 있는 덩어리를 총칭하며, 일반적으로 종양(tumor)이라고도 지칭된다. 상기 종양은 양성종양(benign tumor)과 악성종양(malignant tumor)으로 구분되며, 양성 종양은 비교적 성장 속도가 느리고, 전이(metastasis)되지 않는 반면, 악성종양은 주위 조직에의 침윤 속도가 빠르고 신체 각 부위에 빠르게 확산되거나 전이되기 때문에 일반적으로 악성종양을 암이라 지칭하며, 바람직하게는 대장암, 직장암, 결장암, 갑상선암, 구강암, 인두암, 후두암, 자궁경부암, 뇌암, 폐암, 난소암, 방광암, 신장암, 간암, 췌장암, 전립선암, 피부암, 혀암, 유방암, 자궁암, 위암, 골암, 혈액암 등일 수 있으나, 본 발명의 항암제에 의하여 치료될 수 있는 암의 종류라면 이에 제한되지 않는다. In the present invention, “cancer” refers collectively to a mass composed of undifferentiated cells that can proliferate abnormally, and is also commonly referred to as a tumor. The above tumors are divided into benign tumors and malignant tumors. While benign tumors have a relatively slow growth rate and do not metastasize, malignant tumors have a rapid rate of invasion into surrounding tissues and are common throughout the body. Malignant tumors are generally referred to as cancer because they rapidly spread or metastasize to areas, and are preferably colon cancer, rectal cancer, colon cancer, thyroid cancer, oral cancer, pharynx cancer, larynx cancer, cervix cancer, brain cancer, lung cancer, ovarian cancer, bladder cancer, and kidney cancer. It may be cancer, liver cancer, pancreatic cancer, prostate cancer, skin cancer, tongue cancer, breast cancer, uterine cancer, stomach cancer, bone cancer, blood cancer, etc., but the type of cancer that can be treated by the anticancer agent of the present invention is not limited thereto.
본 발명에 있어서, “항암제(anticancer agent)”란 상기 악성종양의 치료를 위하여 사용되는 모든 화합물을 총칭하는 의미로서, 그 작용 기작에는 알킬화제, 대사길항물질, 항종양성 항생물질, 알칼로이드, 호르몬류, 면역요법제, 방사성동위원소, 인터페론 등이 있으며, 바람직하게는 독소루비신, 파클리탁셀, 도세탁셀, 시스플라틴, 글리벡, 5-플루오로우라실(5-FU), 타목시펜, 카보플라틴, 토포테칸, 벨로테칸, 이마티닙, 이리노테칸, 플록수리딘, 비노렐빈, 젬시타빈, 류프로리드, 플루타미드, 졸레드로네이트, 메토트렉세이트, 캄토테신, 빈크리스틴, 히드록시우레아, 스트렙토조신, 발루비신, 레티노익산, 메클로레타민, 클로람부실, 부술판, 독시플루리딘, 빈블라스틴, 마이토마이신, 프레드니손, 아피니토, 미토산트 등이나, 본 발명의 알부민 입자에 결합할 수 있는 종류라면 이에 제한되지 않는다.In the present invention, “anticancer agent” refers to a general term for all compounds used for the treatment of malignant tumors, and its mechanism of action includes alkylating agents, antimetabolites, antitumor antibiotics, alkaloids, hormones, Immunotherapeutics, radioisotopes, interferons, etc., preferably doxorubicin, paclitaxel, docetaxel, cisplatin, Gleevec, 5-fluorouracil (5-FU), tamoxifen, carboplatin, topotecan, belotecan, and imatinib. , irinotecan, floxuridine, vinorelbine, gemcitabine, leuprolide, flutamide, zoledronate, methotrexate, camptothecin, vincristine, hydroxyurea, streptozocin, valrubicin, retinoic acid, mechloreta. Min, chlorambucil, busulfan, doxyfluridine, vinblastine, mitomycin, prednisone, afinitor, mitoxant, etc., but are not limited thereto as long as they are types that can bind to the albumin particles of the present invention.
본 발명에 있어서, “예방(prevention)”이란 본 발명에 따른 항암제가 코팅된 알부민 입자의 투여에 의해 암 등의 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.In the present invention, “prevention” refers to all actions that suppress or delay the onset of diseases such as cancer by administering albumin particles coated with an anticancer agent according to the present invention.
본 발명에 있어서, "치료(treatment)"란 본 발명에 따른 항암제가 코팅된 알부민 입자의 투여에 의해 암 등의 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다. In the present invention, “treatment” refers to any action in which symptoms of a disease, such as cancer, are improved or beneficially changed by administration of albumin particles coated with an anticancer agent according to the present invention.
본 발명에 있어서, “개체(individual)”란 본 발명의 조성물이 투여될 수 있는 대상을 말하며, 그 대상에는 제한이 없다. In the present invention, “individual” refers to a subject to whom the composition of the present invention can be administered, and there is no limitation to the subject.
본 발명에 있어서, “약학적 조성물(pharmaceutical composition)”이란 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학적 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. 상기 약학적 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학적 조성물은 약제적으로 허용가능한 담체를 포함할 수 있다. 약제학적으로 허용되는 담체는 경구투여시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약제학적 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형할 수 있다.In the present invention, “pharmaceutical composition” may be characterized as being in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage, and the pharmaceutical composition may be characterized as being intended for human subjects. You can. The pharmaceutical composition is not limited to these, but can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods. . The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavorings, etc. for oral administration. For injections, buffers, preservatives, and analgesics can be used. Topics, solubilizers, isotonic agents, stabilizers, etc. can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives, etc. can be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing it with a pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be manufactured in the form of unit dosage ampoules or multiple dosage forms. there is. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained-release preparation, etc.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Meanwhile, examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.
본 발명에 따른 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. 본원에 사용된 용어 "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.The route of administration of the pharmaceutical composition according to the present invention is not limited to these, but is oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, and topical. , sublingual or rectal. Oral or parenteral administration is preferred. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention can also be administered in the form of a suppository for rectal administration.
본 발명의 약학적 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여시간, 투여경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학적 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.The pharmaceutical composition of the present invention may vary depending on several factors, including the activity of the specific compound used, age, body weight, general health, gender, diet, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. It can vary in various ways, and the dosage of the pharmaceutical composition varies depending on the patient's condition, weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person skilled in the art, and is 0.0001 to 50 mg/day. It can be administered in kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered several times. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
본 발명에서 사용되는 용어는 본 발명에서의 기능을 고려하면서 가능한 현재 널리 사용되는 일반적인 용어들을 선택하였으나, 이는 당 분야에 종사하는 기술자의 의도 또는 판례, 새로운 기술의 출현 등에 따라 달라질 수 있다. 또한, 특정한 경우는 출원인이 임의로 선정한 용어도 있으며, 이 경우 해당되는 발명의 설명 부분에서 상세히 그 의미를 기재할 것이다. 따라서 본 발명에서 사용되는 용어는 단순한 용어의 명칭이 아닌, 그 용어가 가지는 의미와 본 발명의 전반에 걸친 내용을 토대로 정의되어야 한다.The terms used in the present invention are general terms that are currently widely used as much as possible while considering the function in the present invention, but this may vary depending on the intention or precedent of a person working in the art, the emergence of new technology, etc. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, rather than simply the name of the term.
본 발명의 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다. 본 발명의 명세서 전체에서 사용되는 정도의 용어 "약", "실질적으로" 등은 언급된 의미에 고유한 제조 및 물질 허용오차가 제시될 때 그 수치에서 또는 그 수치에 근접한 의미로 사용되고, 본 발명의 이해를 돕기 위해 정확하거나 절대적인 수치가 언급된 개시 내용을 비양심적인 침해자가 부당하게 이용하는 것을 방지하기 위해 사용된다. Throughout the specification of the present invention, when a part is said to “include” a certain component, this means that it may further include other components rather than excluding other components unless specifically stated to the contrary. The terms "about", "substantially", etc. used throughout the specification of the present invention are used to mean at or close to that value when manufacturing and material tolerances inherent in the stated meaning are presented, and the present invention Precise or absolute figures are used to aid understanding and to prevent unscrupulous infringers from taking unfair advantage of the disclosure.
본 발명의 명세서 전체에서, 마쿠시 형식의 표현에 포함된 "이들의 조합"의 용어는 마쿠시 형식의 표현에 기재된 구성 요소들로 이루어진 군에서 선택되는 하나 이상의 혼합 또는 조합을 의미하는 것으로서, 상기 구성 요소들로 이루어진 군에서 선택되는 하나 이상을 포함하는 것을 의미한다.Throughout the specification of the present invention, the term "combination thereof" included in the Markushi format expression means a mixture or combination of one or more selected from the group consisting of the components described in the Markushi format expression, It means containing one or more selected from the group consisting of constituent elements.
이하, 본 발명의 이해를 돕기 위하여 하기 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, the following examples are presented to aid understanding of the present invention. However, the following examples are provided only to make the present invention easier to understand, and the content of the present invention is not limited by the following examples.
실시예Example
실시예 1. 재료 준비Example 1. Material preparation
인간 혈청 알부민 (HSA)은 Sigma-Aldrich에서 구입하였으며, 글루타르알데히드 (25%, GTA)는 Sigma Aldrich로부터 구입하였고, 수소화 붕소 나트륨은 Sigma Aldrich로부터 구입하였고, 독소루비신은 보령제약에서 구매하였다.Human serum albumin (HSA) was purchased from Sigma-Aldrich, glutaraldehyde (25%, GTA) was purchased from Sigma Aldrich, sodium borohydride was purchased from Sigma Aldrich, and doxorubicin was purchased from Boryung Pharmaceutical.
실시예 2: 항암제가 코팅된 알부민 입자/환원 알부민 입자의 제조Example 2: Preparation of albumin particles/reduced albumin particles coated with anticancer agent
2.1. 알부민 입자 (Alb-NPs))의 제조2.1. Preparation of albumin particles (Alb-NPs)
항암제가 코팅된 알부민 입자 (alb-NPs)를 제조하기 위하여, 일차적으로 알부민 입자를 제조하였다. 알부민 입자의 제조를 위하여 인간 혈청 알부민 (human serum albumin, Sigma-Aldrich) 1 g을 34 mL의 증류수에 첨가하여 용해시킨 후에 1 M의 수산화나트륨 (sodium hydroxide) 용액 20 μL를 첨가하여 pH를 조정하였다. 이 후, 알부민의 응집을 유도하기 위하여 에탄올을 소량씩 첨가하였으며, 3 내지 6 mL을 첨가하였을 때 혼합액이 혼탁해짐을 관찰하였다. 혼합액이 혼탁해질 때 용액을 교반하며 그리고 가교제로 8 % 글루타알데하이드 (glutaraldehyde, Sigma-Aldrich) 용액을 80 내지 1,000 μL 첨가한 후에 24 시간 동안 교반하며 반응시켰다. 반응이 완료된 용액은 18,000 rpm으로 4 ℃에서 15 분간 원심분리하였고, 상층액을 제거하여 제조된 알부민 입자 침전물(pellet)을 획득하였다. 침전물은 다시 증류수를 이용하여 분산시킨 후에 3,000 rpm으로 4 ℃에서 5 분간 원심분리하여 상층액에 포함되어 있는 나노 크기의 알부민 입자를 획득하였다. 획득된 알부민 입자는 투과전자현미경 (transmission electron microscope, JEOL, JEM-2100F with probe CS corrected)을 이용하여 크기를 분석하였다. 그 결과를 표 1에 나타내었다.To prepare albumin particles (alb-NPs) coated with anticancer drugs, albumin particles were first prepared. To prepare albumin particles, 1 g of human serum albumin (Sigma-Aldrich) was dissolved in 34 mL of distilled water, and then 20 μL of 1 M sodium hydroxide solution was added to adjust the pH. . Afterwards, ethanol was added in small amounts to induce aggregation of albumin, and it was observed that the mixed solution became cloudy when 3 to 6 mL was added. When the mixture became cloudy, the solution was stirred, and 80 to 1,000 μL of 8% glutaraldehyde (Sigma-Aldrich) solution was added as a cross-linking agent, followed by stirring and reaction for 24 hours. After the reaction was completed, the solution was centrifuged at 18,000 rpm at 4°C for 15 minutes, and the supernatant was removed to obtain a precipitate of albumin particles. The precipitate was dispersed again using distilled water and then centrifuged at 3,000 rpm at 4°C for 5 minutes to obtain nano-sized albumin particles contained in the supernatant. The size of the obtained albumin particles was analyzed using a transmission electron microscope (JEOL, JEM-2100F with probe CS corrected). The results are shown in Table 1.
2-2. 환원 알부민 나노입자(rAlb-NPs)의 제조2-2. Preparation of reduced albumin nanoparticles (rAlb-NPs)
합성된 알부민 나노입자 (Alb-NPs)를 이용하여 환원제와의 반응을 시켜 환원 알부민 나노입자 (rAlb-NPs) 합성을 진행하였으며, 이때 상기 환원제로 인해 생성되는 환원 알부민 나노입자 (rAlb-NPs)의 물성을 비교하였다. Reduced albumin nanoparticles (rAlb-NPs) were synthesized by reacting the synthesized albumin nanoparticles (Alb-NPs) with a reducing agent. At this time, the reduced albumin nanoparticles (rAlb-NPs) produced by the reducing agent were synthesized. Physical properties were compared.
이를 위해, 알부민 나노입자 (Alb-NPs) 100 mg을 에탄올에 분산시킨 후, NaBH4 (Sodium borohydride), 또는 NaBH3CN (sodium cyanoborohydride)를 100 μl 를 분산되어 있는 입자와 24시간 반응시켰다. 그리고나서, 증류수와 pH meter를 이용하여 pH 7~8.5 로 수소 이온 농도를 맞춰준 후, 원심분리기 (20,000 rpm/15min)를 이용하여 환원 알부민 나노입자 (rAlb-NPs)를 분리하여 PBS 버퍼에 분산시킴으로써 환원 알부민 나노입자 (rAlb-NPs)를 제조하였다.For this purpose, 100 mg of albumin nanoparticles (Alb-NPs) were dispersed in ethanol and then dissolved in NaBH 4 100 μl of (sodium borohydride), or NaBH 3 CN (sodium cyanoborohydride) was reacted with the dispersed particles for 24 hours. Then, adjust the hydrogen ion concentration to pH 7~8.5 using distilled water and a pH meter, then separate the reduced albumin nanoparticles (rAlb-NPs) using a centrifuge (20,000 rpm/15min) and disperse them in the PBS buffer. Reduced albumin nanoparticles (rAlb-NPs) were prepared by doing this.
상기 방법으로 생성된 환원 알부민 나노입자 (rAlb-NPs)의 크기 분포 및 zeta 전위는 Malvern Zetasizer Nano (Malvern Instrument Ltd., Worcesterchire, U.K.)를 사용하여 측정하였으며, 환원 알부민 나노입자 (rAlb-NPs)를 PBS (pH 7.4)에 50 mg/ml 로 분산시켜 25℃에서 5회 측정하였다. The size distribution and zeta potential of the reduced albumin nanoparticles (rAlb-NPs) produced by the above method were measured using a Malvern Zetasizer Nano (Malvern Instrument Ltd., Worcesterchire, U.K.). It was dispersed at 50 mg/ml in PBS (pH 7.4) and measured five times at 25°C.
그 결과, 표 1 및 도 1에 나타난 바와 같이, 상기 반응으로 제조된 환원 알부민 나노입자의 크기 및 수득율은 큰 차이를 보이지 않았으며, 비환원 입자와 비교하여 환원 알부민 입자의 제타전위 변화만 발생된 것을 확인하였다.As a result, as shown in Table 1 and Figure 1, there was no significant difference in the size and yield of the reduced albumin nanoparticles prepared by the above reaction, and only a change in the zeta potential of the reduced albumin particles occurred compared to the non-reduced particles. confirmed.
실시예 3. 환원된 알부민 나노입자의 환원 여부 비교 검증 Example 3. Comparative verification of reduction of reduced albumin nanoparticles
0.3 M의 질산은 용액을 만들고 0.3 M의 NaOH를 은 침전 (silver precipitation)이 생성될 때까지 떨어뜨렸다. 그 후, 3 M의 암모니아 용액을 넣어서 다시 용매의 색을 투명하게 만들어 톨렌스 시약 (tollens reagent)을 완성하였다. 알부민 나노입자와 환원 알부민 나노입자 각각 10 mg를 같은 농도와 볼륨으로 맞춰준 후, 1 mL의 톨렌스 시약을 넣어주었다. 37 ℃ 이상의 온도로 하루정도의 시간동안 색 변화를 관찰하여 알데히드 생성 유무를 판단하였다.A 0.3 M silver nitrate solution was prepared, and 0.3 M NaOH was added until silver precipitation was formed. Afterwards, a 3 M ammonia solution was added to make the color of the solvent transparent again, completing the Tollens reagent. After adjusting 10 mg each of albumin nanoparticles and reduced albumin nanoparticles to the same concentration and volume, 1 mL of Tollens reagent was added. The presence or absence of aldehyde formation was determined by observing the color change for about a day at a temperature of 37°C or higher.
그 결과, 도 2에 나타난 바와 같이, NaBH4 또는 NaCNH3로 환원된 알부민 나노입자는 은 (Ag)이 석출되는 양상을 나타낸 반면, 비환원된 알부민 나노입자의 경우 갈색으로 변한 용액이 되돌아오지 않는 양상을 나타내었는 바, NaBH4 또는 NaCNH3 처리를 통해 알부민 나노입자가 환원되었음을 확인하였다.As a result, as shown in Figure 2, albumin nanoparticles reduced with NaBH 4 or NaCNH 3 showed silver (Ag) precipitation, whereas in the case of non-reduced albumin nanoparticles, the brown solution did not return. As shown, it was confirmed that albumin nanoparticles were reduced through treatment with NaBH 4 or NaCNH 3 .
실시예 4. 독소루비신(doxorubicin)이 코팅된 알부민 나노입자/환원 알부민 나노입자의 제조Example 4. Preparation of doxorubicin-coated albumin nanoparticles/reduced albumin nanoparticles
독소루비신이 코팅된 알부민 나노입자, 독소루비신이 코팅된 환원 알부민 나노입자의 제조를 위하여, 제조된 알부민 입자에 증류수로 용해시킨 독소루비신을 첨가하였다. 첨가는 독소루비신 : 알부민 입자, 환원 독소루비신 : 알부민 입자의 중량비(w/w %)가 각각 1 : 1, 1 : 2, 또는 1 : 10이 되도록 첨가하였다. 독소루비신이 첨가된 알부민 입자 용액을 1 M의 수산화나트륨 용액을 이용하여 pH가 8.0 내지 8.5가 되도록 조정한 후에 반응 용기를 호일로 감싸 빛을 차단하고 24시간 동안 교반하며 반응시켰다. 반응이 완료된 용액은 18,000 rpm으로 4 ℃에서 15 분간 원심분리한 후에 상층액을 제거하고 침전물을 다시 증류수로 분산시켜 항암제가 코팅된 알부민 입자를 획득하였다. 획득된 항암제가 코팅된 알부민 입자는 자외선-가시광선 분광법 (UV-visible spectrometry, Shimadzu UV-1800) 및 고성능액체크로마토그래피 (Agilent Technologies, 1260 Infinity II)를 이용하여 알부민 입자에 코팅된 항암제의 양을 정량하였다. 그리고 동적 레이저 광 산란법 분석기 (dynamic light scattering spectrophotometer, Malvern, Zetasizer Nano ZS90)로 제타전위를 확인하였다To prepare doxorubicin-coated albumin nanoparticles and doxorubicin-coated reduced albumin nanoparticles, doxorubicin dissolved in distilled water was added to the prepared albumin particles. The addition was done so that the weight ratio (w/w %) of doxorubicin:albumin particles and reduced doxorubicin:albumin particles was 1:1, 1:2, or 1:10, respectively. The pH of the albumin particle solution to which doxorubicin was added was adjusted to 8.0 to 8.5 using a 1 M sodium hydroxide solution, the reaction vessel was wrapped with foil to block light, and the reaction was stirred for 24 hours. After the reaction was completed, the solution was centrifuged at 18,000 rpm at 4°C for 15 minutes, the supernatant was removed, and the precipitate was dispersed again in distilled water to obtain anticancer drug-coated albumin particles. The obtained anticancer drug-coated albumin particles were measured using ultraviolet-visible spectrometry (Shimadzu UV-1800) and high-performance liquid chromatography (Agilent Technologies, 1260 Infinity II) to measure the amount of anticancer drug coated on the albumin particles. Quantified. And the zeta potential was confirmed using a dynamic laser light scattering spectrophotometer (Malvern, Zetasizer Nano ZS90).
(doxorubicin: NP)Ratio (W/W, %)
(doxorubicin: NP)
상기 표 2에 나타난 바와 같이, 알부민 입자의 경우 환원과 비환원에 관계없이 1 : 1 또는 1 : 2 로 혼합한 경우에는 50 % 정도의 적재율을 보여주나, 크기가 증가되어 입자들이 응집되는 것을 확인하였으며 이 경우 체내 투여 시 혈관을 막을 위험성이 증가되는 것을 확인하였다. 그러나, 1 : 10의 비율로 혼합한 경우에는 적재율이 90 % 이상으로 유지하며 입자들이 응집되지 않는 것을 확인하였다.As shown in Table 2 above, in the case of albumin particles, regardless of reduction or non-reduction, when mixed at 1:1 or 1:2, the loading ratio is about 50%, but the size increases, confirming that the particles aggregate. In this case, it was confirmed that the risk of blocking blood vessels increased when administered in the body. However, when mixed at a ratio of 1:10, it was confirmed that the loading ratio was maintained above 90% and the particles did not aggregate.
따라서, 환원 독소루비신 : 알부민 입자의 중량비 (w/w %)가 1 : 10인 경우 알부민 입자가 응집되지 않아 혈관을 막을 위험성이 감소되면서, 가장 적재율이 우수함을 확인하였는 바, 이하에서는 독소루비신과 알부민 입자의 중량비를 1 : 10으로 설정하고 실험을 진행하였다.Therefore, it was confirmed that when the weight ratio (w/w %) of reduced doxorubicin:albumin particles was 1:10, the albumin particles did not aggregate and the risk of blocking blood vessels was reduced, and the loading rate was the best. Hereinafter, doxorubicin and albumin particles The weight ratio was set to 1:10 and the experiment was conducted.
실시예 5. 최적의 알부민 입자/환원 알부민 입자 농도 확인 실험Example 5. Experiment to confirm optimal albumin particle/reduced albumin particle concentration
항암제가 코팅된 알부민 입자 (sDOX) 그리고 환원된 알부민 입자의 제조시 최적의 알부민 입자 농도를 확인하기 위하여, 알부민 입자의 농도(1, 2, 3, 5, 10, 20, 및 30 mg/mL)를 변경하며 항암제가 코팅된 알부민 입자를 제조하였다. 이 때 독소루비신과 알부민 입자의 혼합 비율은 1 : 10으로, pH는 7.0으로 고정하였고, 제조된 알부민 입자의 코팅율을 확인하였다. In order to determine the optimal albumin particle concentration during the production of anticancer drug-coated albumin particles (sDOX) and reduced albumin particles, the albumin particle concentration (1, 2, 3, 5, 10, 20, and 30 mg/mL) Albumin particles coated with anticancer drugs were prepared by changing this. At this time, the mixing ratio of doxorubicin and albumin particles was fixed at 1:10, pH was fixed at 7.0, and the coating rate of the prepared albumin particles was confirmed.
표 3에 나타난 바와 같이, 두 입자의 농도가 5 내지 10 mg/mL의 농도일 때 85 % 이상의 적재율을 나타내는 것을 확인하였으며, 환원된 알부민 입자를 사용하는 경우 보다 적재율이 우수한 것으로 나타났다. As shown in Table 3, it was confirmed that a loading ratio of more than 85% was observed when the concentration of the two particles was 5 to 10 mg/mL, and the loading ratio was found to be superior to that when reduced albumin particles were used.
상기 결과들을 통하여, 항암제가 코팅된 환원 알부민 입자의 제조 시 최적의 조건은 항암제와 알부민 입자의 중량비(w/w %)가 1 : 10이면서, 알부민 나노입자를 5 내지 10 mg/mL으로 첨가 시 항암제의 적재율이 우수한 것을 확인하였다.Based on the above results, the optimal conditions for producing reduced albumin particles coated with anticancer drugs are when the weight ratio (w/w%) of anticancer drugs and albumin particles is 1:10 and albumin nanoparticles are added at 5 to 10 mg/mL. It was confirmed that the loading rate of anticancer drugs was excellent.
실시예Example 6. 6. 독소루비신이Doxorubicin 코팅된 알부민 나노입자 ( Coated albumin nanoparticles ( sDOXsDOX )와 )and 독소루비신이Doxorubicin 코팅된 환원된 알부민 입자 (rDOX)의 pH별 독소루비신 방출 실험 Doxorubicin release experiment at different pH levels from coated reduced albumin particles (rDOX)
항암제가 코팅된 알부민 입자의 pH 변화에 따른 항암제의 방출을 확인하기 위하여, pH에 따른 독소루비신의 방출 정도를 코팅율을 이용하여 확인하였다.In order to confirm the release of anticancer agent according to the pH change of albumin particles coated with anticancer agent, the degree of release of doxorubicin according to pH was confirmed using the coating ratio.
독소루비신이 코팅된 알부민 나노입자 (sDOX)와 독소루비신이 코팅된 환원된 알부민 입자 (rDOX)의 각 pH 5.5, 6.4 (sDOX는 6.5), 7.4에 대한 독소루비신 방출 시험을 실시하였다. 이 때 준비된 시료는 독소루비신을 30분 반응시킨 알부민 나노입자 (sDOX, 30min), 독소루비신을 24시간 반응시킨 알부민 나노입자 (sDOX 24 hour) 그리고 환원된 알부민 나노입자에 독소루비신을 24시간 반응시킨 알부민 나노입자 (rDOX 24 hour)로 진행하였다. 각 시점에서 방출된 독소루비신의 용량은 정밀 분석 기기인 고성능 액체크로마토그래피를 이용하여 정량 분석하였다.Doxorubicin release tests were conducted on doxorubicin-coated albumin nanoparticles (sDOX) and doxorubicin-coated reduced albumin particles (rDOX) at pH 5.5, 6.4 (6.5 for sDOX), and 7.4, respectively. The samples prepared at this time were albumin nanoparticles reacted with doxorubicin for 30 minutes (sDOX, 30min), albumin nanoparticles reacted with doxorubicin for 24 hours (sDOX 24 hour), and albumin nanoparticles reacted with doxorubicin on reduced albumin nanoparticles for 24 hours. (rDOX 24 hour). The amount of doxorubicin released at each time point was quantitatively analyzed using high-performance liquid chromatography, a precision analysis device.
도 3에 나타난 바와 같이, 두 종류의 독소루비신이 코팅된 알부민 나노입자 (sDOX, 30 min 및 24 hour)는 모두 pH 5.5, 6.4, 7.4 모든 농도에서 방출이 25% 미만이었으나, 독소루비신이 코팅된 환원된 알부민 나노입자 (rDOX)는 pH 5.5 에서는 90% 이상의 독소루비신 방출량을 보였으며 pH 7.4에서도 약 50%의 방출량을 나타내었다.As shown in Figure 3, the release of two types of doxorubicin-coated albumin nanoparticles (sDOX, 30 min and 24 hours) was less than 25% at all concentrations of pH 5.5, 6.4, and 7.4, but the doxorubicin-coated reduced Albumin nanoparticles (rDOX) showed a release of more than 90% of doxorubicin at pH 5.5 and about 50% at pH 7.4.
상기 결과를 통하여, 체내의 혈관 등에서는 본 발명의 항암제가 코팅된 환원 알부민 입자가 암과 같은 산성인 상태에서 특이적으로 약물이 방출됨으로써 안정성 있는 약물 전달 시스템으로 사용가능하다는 것을 확인할 수 있었다. 뿐만 아니라, 환원 알부민 입자의 방출량이 더 우수한 것은 표면의 카르복실기 및 알데히드가 알코올로 환원되어, 항암제와 알부민 입자가 화학결합을 통해 방출이 약화되는 것을 방지하기 때문임을 보다 명확히 확인하였다.Through the above results, it was confirmed that the reduced albumin particles coated with the anticancer agent of the present invention can be used as a stable drug delivery system by specifically releasing the drug in acidic conditions such as cancer in blood vessels in the body. In addition, it was more clearly confirmed that the superior emission amount of the reduced albumin particles was because the carboxyl groups and aldehydes on the surface were reduced to alcohol, thereby preventing the emission from being weakened through chemical bonding between the anticancer drug and the albumin particles.
실시예Example 7. 7. 독소루비신이Doxorubicin 코팅된 알부민 나노입자 ( Coated albumin nanoparticles ( sDOXsDOX )와 )and 독소루비신이Doxorubicin 코팅된 환원된 알부민 나노입자 (rDOX)의 안정성 시험 Stability testing of coated reduced albumin nanoparticles (rDOX)
실시예 4의 방법에 따라 제조된 독소루비신이 코팅된 알부민 나노입자 (sDOX)와 독소루비신이 코팅된 환원된 알부민 나노입자 (rDOX)의 안정성을 평가하기 위하여 설정된 시간 마다 입자의 크기 분포, 제타전위, 적재 효율, 및 추출 효율을 정량/정성 평가하였다. 입자 분포는 동적 광산란 (Dynamic light scattering, DLS) 방법으로 분석하였으며, 코팅 및 추출된 독소루비신은 고성능 액체크로마토그래피로 정량/정성 분석을 수행하였다. In order to evaluate the stability of doxorubicin-coated albumin nanoparticles (sDOX) and doxorubicin-coated reduced albumin nanoparticles (rDOX) prepared according to the method of Example 4, particle size distribution, zeta potential, and loading were measured at set times. Efficiency and extraction efficiency were quantitatively/qualitatively evaluated. Particle distribution was analyzed using dynamic light scattering (DLS), and quantitative/qualitative analysis of coated and extracted doxorubicin was performed using high-performance liquid chromatography.
Efficiency (%)Efficiency (%)
그 결과, 표 4 및 도 4에 나타난 바와 같이, 환원 알부민 입자와 비환원 알부민 입자 모두 입자 직경이 100 nm 내지 200 nm로 크기가 증가되지 않고 입자들이 응집되지 않는 것을 확인하였으며, 제타 변위에도 큰 차이가 없는 것을 확인하였다. As a result, as shown in Table 4 and Figure 4, it was confirmed that the particle diameter of both reduced and non-reduced albumin particles did not increase to 100 nm to 200 nm and that the particles did not aggregate, and there was a significant difference in zeta displacement. It was confirmed that there was no .
그러나, 환원 알부민 입자를 사용한 경우 1 내지 60 시간까지 방출 효율이 90 % 이상을 꾸준히 유지한 반면, 비환원 알부민 입자를 사용한 경우 약물 방출 효율이 24시간 뒤 57.3 %로 현저히 감소함을 확인하였다. However, when reduced albumin particles were used, the release efficiency was consistently maintained at over 90% from 1 to 60 hours, whereas when non-reduced albumin particles were used, the drug release efficiency was confirmed to significantly decrease to 57.3% after 24 hours.
즉, 본 발명의 환원된 알부민 입자를 사용한 경우 약물 방출 효율이 장시간 우수하게 유지되는 것을 확인하였는 바, 본 발명의 나노입자의 약물 방출 안정성이 기존의 알부민 입자보다 현저히 우수한 것을 확인할 수 있었다.That is, it was confirmed that the drug release efficiency was maintained excellently for a long time when the reduced albumin particles of the present invention were used, and it was confirmed that the drug release stability of the nanoparticles of the present invention was significantly superior to that of the existing albumin particles.
실시예 8. 독소루비신이 코팅된 알부민 나노입자 (sDOX)와 독소루비신이 코팅된 환원된 알부민 나노입자 (rDOX)의 효력 시험Example 8. Effect test of doxorubicin-coated albumin nanoparticles (sDOX) and doxorubicin-coated reduced albumin nanoparticles (rDOX)
독소루비신이 코팅된 알부민 나노입자 (sDOX)와 독소루비신이 코팅된 환원된 알부민 나노입자 (rDOX)의 효력을 비교 평가하기 위하여 Balb/C 누드 마우스를 이용하여 항암 효능을 평가하였다. 유방암 질병 동물 모델을 제조하기 위하여, MDA-MB-231 세포주를 이용하여 마우스 대퇴부에 5 내지 10 x 106개의 세포를 이식하여 질병동물 모델을 제작하였으며, 종양의 크기가 100 내지 200 mm3의 크기를 나타낼 때에 치료를 시작하였다. 항암제 및 항암제 함유 입자의 투여는 2 mg/kg dose로, 3일 간격으로 총 5회 투여하며, 투여 종료 후, 한 달간 종양 크기를 측정하여 종양 증식 억제 효과를 비교 평가하였다. To compare and evaluate the efficacy of doxorubicin-coated albumin nanoparticles (sDOX) and doxorubicin-coated reduced albumin nanoparticles (rDOX), the anticancer efficacy was evaluated using Balb/C nude mice. To prepare a breast cancer disease animal model, a disease animal model was created by transplanting 5 to 10 x 10 6 cells into the mouse thigh using the MDA-MB-231 cell line, and the tumor size was 100 to 200 mm 3 Treatment was started when it appeared. The anticancer drug and anticancer drug-containing particles were administered at a dose of 2 mg/kg, administered a total of 5 times at 3-day intervals. After the end of administration, the tumor size was measured for one month to compare and evaluate the tumor growth inhibition effect.
투여 군은 독소루비신 단독 투여군 (free DOX), 독소루비신과 알부민 나노입자를 30분 반응시킨 독소루비신 코팅 알부민 나노입자를 투여한 군 (sDOX, 30 min) 환원된 알부민 나노입자와 독소루비신을 24시간동안 반응시킨 독소루비신 코팅 환원된 알부민 나노입자를 투여한 군 (rDOX, 24h)으로 실험을 진행하였다. The administration group was a group administered doxorubicin alone (free DOX), a group administered doxorubicin-coated albumin nanoparticles made by reacting doxorubicin and albumin nanoparticles for 30 minutes (sDOX, 30 min), and doxorubicin administered by reacting reduced albumin nanoparticles and doxorubicin for 24 hours. The experiment was conducted with the group administered coated reduced albumin nanoparticles (rDOX, 24h).
그 결과, 도 5에 나타난 바와 같이, 종양의 증식정도는 독소루비신을 투여한 군과 sDOX를 투여한 군은 유사한 종양 증식 속도를 나타내는 반면에, 독소루비신이 코팅된 환원된 알부민 나노입자의 종양 증식 억제 효능은 위의 두 군보다 향상됨을 확인하였다. As a result, as shown in Figure 5, the degree of tumor proliferation was similar in the group administered doxorubicin and the group administered sDOX, while the tumor growth inhibition effect of the reduced albumin nanoparticles coated with doxorubicin was observed. was confirmed to be improved over the two groups above.
상기 진술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. The description of the present invention stated above is for illustrative purposes, and those skilled in the art can understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. There will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.
Claims (18)
상기 환원된 알부민 나노입자는 입자 표면의 카르복실기와 알데히드가 알코올기 또는 티올기로 환원된 것인, 나노입자.
Reduced albumin nanoparticles with an anticancer agent coated on the surface,
The reduced albumin nanoparticle is a nanoparticle in which the carboxyl group and aldehyde on the particle surface are reduced to an alcohol group or a thiol group.
상기 환원된 알부민 나노입자와 항암제는 1 : 2 내지 1 : 13 질량비(w/w %)로 혼합되어 코팅된 것을 특징으로 하는, 나노입자.
According to paragraph 1,
Nanoparticles, characterized in that the reduced albumin nanoparticles and the anticancer agent are mixed and coated at a mass ratio (w/w %) of 1:2 to 1:13.
상기 환원된 알부민 나노입자는 0.1 내지 15 mg/mL의 농도로 항암제와 혼합되는 것을 특징으로 하는, 나노입자.
According to paragraph 1,
Nanoparticles, characterized in that the reduced albumin nanoparticles are mixed with an anticancer agent at a concentration of 0.1 to 15 mg/mL.
상기 항암제가 표면에 코팅된 환원된 알부민 나노입자의 크기는 직경이 50 내지 500 nm인 것을 특징으로 하는, 나노입자.
According to paragraph 1,
Nanoparticles, characterized in that the size of the reduced albumin nanoparticles coated with the anticancer agent on the surface is 50 to 500 nm in diameter.
상기 항암제는 독소루비신, 파클리탁셀, 도세탁셀, 시스플라틴, 글리벡, 5-플루오로우라실(5-FU), 타목시펜, 카보플라틴, 토포테칸, 벨로테칸, 이마티닙, 이리노테칸, 플록수리딘, 비노렐빈, 젬시타빈, 류프로리드, 플루타미드, 졸레드로네이트, 메토트렉세이트, 캄토테신, 빈크리스틴, 히드록시우레아, 스트렙토조신, 발루비신, 레티노익산, 메클로레타민, 클로람부실, 부술판, 독시플루리딘, 빈블라스틴, 마이토마이신, 프레드니손, 아피니토, 및 미토산트론으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 나노입자.
According to paragraph 1,
The anticancer drugs include doxorubicin, paclitaxel, docetaxel, cisplatin, Gleevec, 5-fluorouracil (5-FU), tamoxifen, carboplatin, topotecan, belotecan, imatinib, irinotecan, floxuridine, vinorelbine, gemcitabine, Leuprolide, flutamide, zoledronate, methotrexate, camptothecin, vincristine, hydroxyurea, streptozocin, valubicin, retinoic acid, mechlorethamine, chlorambucil, busulfan, doxyfluridine Nanoparticles, characterized in that one or more selected from the group consisting of vinblastine, mitomycin, prednisone, afinitor, and mitoxantrone.
상기 나노입자는 약물 방출 안정성이 향상된 것을 특징으로 하는, 나노입자.
According to paragraph 1,
The nanoparticles are characterized by improved drug release stability.
상기 항암제가 코팅된 환원된 알부민 나노입자는 50% 내지 100% 의 항암제 코팅률을 갖는 것을 특징으로 하는, 나노입자.
According to paragraph 1,
The reduced albumin nanoparticles coated with the anticancer agent are characterized in that they have an anticancer agent coating rate of 50% to 100%.
(ii) 상기 환원 알부민 입자에 항암제를 첨가하고 반응시켜 항암제를 알부민 입자에 코팅하는 단계를 포함하는, 항암제가 코팅된 알부민 입자의 제조방법으로서,
상기 (ii) 단계의 환원 알부민 입자와 항암제의 혼합 비율은 1 : 2 내지 1 : 13 질량비(w/w %)인 것을 특징으로 하는, 제조방법.
(i) reacting albumin particles with a reducing agent to produce reduced albumin particles in which carboxyl groups and aldehydes on the surface of the particles are reduced to alcohol groups or thiol groups; and
(ii) A method for producing albumin particles coated with an anticancer agent, comprising the step of adding an anticancer agent to the reduced albumin particles and reacting to coat the anticancer agent onto the albumin particles,
The mixing ratio of the reduced albumin particles and the anticancer agent in step (ii) is 1:2 to 1:13 mass ratio (w/w %).
상기 (ii) 단계의 환원 알부민 입자는 0.1 내지 15 mg/mL의 농도로 첨가되는 것을 특징으로 하는, 제조방법.
According to clause 9,
A production method, characterized in that the reduced albumin particles in step (ii) are added at a concentration of 0.1 to 15 mg/mL.
상기 (ii) 단계의 상기 항암제를 알부민 입자에 코팅하는 단계는 pH 5 내지 10 의 조건에서 수행되는 것을 특징으로 하는, 제조방법.
According to clause 9,
The manufacturing method of step (ii), wherein the step of coating the anticancer agent on albumin particles is performed under conditions of pH 5 to 10.
상기 환원제는 수소화 붕소 나트륨(sodium borohydride), 나트륨시아노보로하이드리드(sodium cyanoborohydride), 수소화 알루미늄 리튬(lithium aluminium hydride), 리튬 트리에틸보로하이드라이드(Lithium triethylborohydride), 수소화 붕소 리튬(Lithium borohydride), 수소화 붕소 마그네슘(Magnesium borohydride), 수소화 붕소 알루미늄(Aluminum borohydride), 및 수소화 붕소 칼슘(Calcium borohydride)으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 제조방법.
According to clause 9,
The reducing agent is sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, lithium triethylborohydride, and lithium borohydride. , a manufacturing method, characterized in that at least one selected from the group consisting of magnesium borohydride, aluminum borohydride, and calcium borohydride.
상기 항암제는 독소루비신, 파클리탁셀, 도세탁셀, 시스플라틴, 글리벡, 5-플루오로우라실(5-FU), 타목시펜, 카보플라틴, 토포테칸, 벨로테칸, 이마티닙, 이리노테칸, 플록수리딘, 비노렐빈, 젬시타빈, 류프로리드, 플루타미드, 졸레드로네이트, 메토트렉세이트, 캄토테신, 빈크리스틴, 히드록시우레아, 스트렙토조신, 발루비신, 레티노익산, 메클로레타민, 클로람부실, 부술판, 독시플루리딘, 빈블라스틴, 마이토마이신, 프레드니손, 아피니토, 및 미토산트론으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는, 제조방법.
According to clause 9,
The anticancer drugs include doxorubicin, paclitaxel, docetaxel, cisplatin, Gleevec, 5-fluorouracil (5-FU), tamoxifen, carboplatin, topotecan, belotecan, imatinib, irinotecan, floxuridine, vinorelbine, gemcitabine, Leuprolide, flutamide, zoledronate, methotrexate, camptothecin, vincristine, hydroxyurea, streptozocin, valubicin, retinoic acid, mechlorethamine, chlorambucil, busulfan, doxyfluridine , vinblastine, mitomycin, prednisone, afinitor, and mitoxantrone, characterized in that at least one selected from the group consisting of mitoxantrone.
상기 항암제가 코팅된 알부민 입자는 50 % 내지 100% 의 항암제 코팅률을 갖는 것을 특징으로 하는, 제조방법.
According to clause 9,
A manufacturing method, wherein the albumin particles coated with the anticancer agent have an anticancer agent coating rate of 50% to 100%.
A pharmaceutical composition for preventing or treating cancer comprising the nanoparticles of claim 1 as an active ingredient.
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