KR102176982B1 - Reactive oxygen-sensitive ferrocene-based nano particles and method for preparing the same - Google Patents

Reactive oxygen-sensitive ferrocene-based nano particles and method for preparing the same Download PDF

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KR102176982B1
KR102176982B1 KR1020180126529A KR20180126529A KR102176982B1 KR 102176982 B1 KR102176982 B1 KR 102176982B1 KR 1020180126529 A KR1020180126529 A KR 1020180126529A KR 20180126529 A KR20180126529 A KR 20180126529A KR 102176982 B1 KR102176982 B1 KR 102176982B1
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methacrylate
ferrocene
reactive oxygen
based nanoparticles
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KR20190054919A (en
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성대경
최원일
나윤희
이진실
우지섭
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한국세라믹기술원
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F216/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical
    • C08F216/36—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical by a ketonic radical
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    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
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Abstract

본 발명은 활성산소 민감성 페로센 기반 나노입자 및 이의 제조방법에 관한 것이다. 보다 구체적으로, 본 발명은 페로센 함유 고분자가 자가-조립하여 형성된 페로센 기반 나노입자 및 이의 제조방법에 관한 것이다.
The present invention relates to reactive oxygen-sensitive ferrocene-based nanoparticles and a method for preparing the same. More specifically, the present invention relates to ferrocene-based nanoparticles formed by self-assembly of ferrocene-containing polymers and a method for preparing the same.

Description

활성산소 민감성 페로센 기반 나노입자 및 이의 제조방법{REACTIVE OXYGEN-SENSITIVE FERROCENE-BASED NANO PARTICLES AND METHOD FOR PREPARING THE SAME} Reactive oxygen-sensitive ferrocene-based nanoparticles and their manufacturing method {REACTIVE OXYGEN-SENSITIVE FERROCENE-BASED NANO PARTICLES AND METHOD FOR PREPARING THE SAME}

본 발명은 활성산소 민감성 페로센 기반 나노입자 및 이의 제조방법에 관한 것이다. 보다 구체적으로, 본 발명은 페로센 기반 고분자가 자가-조립하여 형성된 활성산소 민감성 페로센 기반 나노입자 및 이의 제조방법에 관한 것이다.The present invention relates to reactive oxygen-sensitive ferrocene-based nanoparticles and a method for preparing the same. More specifically, the present invention relates to an active oxygen-sensitive ferrocene-based nanoparticle formed by self-assembly of a ferrocene-based polymer and a method for preparing the same.

현재까지 조직공학에서는 다양한 생분해성 고분자가 개발되어 광범위하게 이용되었다. 생분해성 고분자는 적합한 물리화학적, 생물학적, 기계적인 특성을 가지고 있으며, 조직공학에 이용된 고분자는 크게 천연 고분자와 합성 고분자로 나눌 수 있다. 천연 고분자에는 콜라겐, 히알루론산, 알지네이트, 젤라틴, 잔탄검, 케라틴, 소장 점막하조직(small intestinal submucosa)등이 포함되며, 이들은 우수한 생체 적합성과 이식 후 낮은 면역 반응을 가지고 있다. 그러나, 천연 고분자는 개별적으로 쓰일 경우 충분한 기계적 특성을 가지고 있지 못한 단점이 있다.Until now, in tissue engineering, various biodegradable polymers have been developed and widely used. Biodegradable polymers have suitable physicochemical, biological and mechanical properties, and polymers used in tissue engineering can be largely divided into natural polymers and synthetic polymers. Natural polymers include collagen, hyaluronic acid, alginate, gelatin, xanthan gum, keratin, and small intestinal submucosa, which have excellent biocompatibility and low immune response after transplantation. However, natural polymers have a disadvantage in that they do not have sufficient mechanical properties when used individually.

합성 고분자에는 PLA(poly(lactic acid)), PGA(poly(glycolic acid)), PLGA(poly(lactic-co-glycolic acid)), PCL(poly(e-caprolactone))등이 포함되며, 주로 소수성 폴리에스테르이다. 그 중 α-하이드록시산 계열인 폴리글리콜라이드(PGA), 폴리락타이드(PLA) 및 그들의 공중합체인 PLGA는 미국 FDA의 승인을 받은 합성 고분자로서 조직공학적 다공성 지지체, 약물전달체 등의 생체재료로 널리 이용되고 있으며, 높은 생체적합성, 생분해성 및 가공성을 가지고 있다. 하지만 생체 활성물질의 결여와 소수성으로 인해 세포부착에 어려움을 가지며, PLGA의 가수분해 과정 중 생성되는 산 분해물이 조직주변의 pH를 감소시켜 염증을 유발하는 단점이 있다. Synthetic polymers include PLA (poly(lactic acid)), PGA (poly(glycolic acid)), PLGA (poly(lactic-co-glycolic acid)), PCL (poly(e-caprolactone)), etc., mainly hydrophobic It is polyester. Among them, α-hydroxy acid-based polyglycolide (PGA), polylactide (PLA), and their copolymer, PLGA, are synthetic polymers approved by the US FDA and are widely used as biomaterials such as tissue engineering porous scaffolds and drug delivery systems. It is used and has high biocompatibility, biodegradability and processability. However, due to the lack of biologically active substances and hydrophobicity, it is difficult to adhere to cells, and the acid decomposition product generated during the hydrolysis process of PLGA decreases the pH around the tissue, causing inflammation.

한편, 페로센(ferrocene)은 매우 안정한 구조의 무독성 유기금속(organometallic) 복합체로 소수성(hydrophobic) 특성을 가지고 있기 때문에 소수성 결합을 통한 코어 형성이 가능하다. On the other hand, ferrocene is a non-toxic organometallic complex having a very stable structure and has hydrophobic properties, so that a core can be formed through a hydrophobic bond.

본 발명은 활성산소 민감성 페로센 기반 나노입자를 제공하는 것을 목적으로 한다.An object of the present invention is to provide active oxygen-sensitive ferrocene-based nanoparticles.

본 발명은 또한 활성산소 민감성 페로센 기반 나노입자의 제조방법을 제공하는 것을 목적으로 한다. Another object of the present invention is to provide a method for preparing reactive oxygen-sensitive ferrocene-based nanoparticles.

제1구현예에 따르면, According to the first embodiment,

본 발명은 페로센 함유 고분자, 및 상기 페로센 함유 고분자에 결합된 메타크릴레이트(methacrylate, MA)를 포함하는 복합체가 자기-조립(self-assembled)하여 형성된 활성산소 민감성 페로센 기반 나노입자 제공하고자 한다. 본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 도식도를 도 1에 나타내었다.
본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 페로센 함유 고분자는 페로세닐메틸 메타크릴레이트(ferrocenylmethyl methacrylate, FMMA)인 것을 특징으로 한다. The present invention is to provide a ferrocene-sensitive ferrocene-based nanoparticles formed by self-assembly of a ferrocene-containing polymer, and a complex including methacrylate (MA) bound to the ferrocene-containing polymer. Fig. 1 shows a schematic diagram of an active oxygen-sensitive ferrocene-based nanoparticle according to the present invention.
In the reactive oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the ferrocene-containing polymer is ferrocenylmethyl methacrylate (FMMA).

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 활성산소 민감성 페로센 기반 나노입자는 화학식 1로 표시되는 것을 특징으로 한다:In the reactive oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the reactive oxygen-sensitive ferrocene-based nanoparticles are represented by Formula 1:

<화학식 1><Formula 1>

Figure 112018104495736-pat00001
Figure 112018104495736-pat00001

(상기 화학식 1에서, (In Formula 1,

상기 l 및 m은 서로 독립적으로 1 내지 10,000의 정수를 나타낸다.)The l and m each independently represent an integer of 1 to 10,000.)

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 페로센 함유 고분자와 메타크릴레이트의 몰비는 1:1 내지 1:10, 바람직하기는 1:2 내지 1:8인 것을 특징으로 한다. In the active oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the molar ratio of the ferrocene-containing polymer and methacrylate is 1:1 to 1:10, preferably 1:2 to 1:8.

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 페로센 기반 나노입자는 1 nm 내지 5,000 nm의 크기를 갖는 것을 특징으로 한다. 예를 들면, 상기 활성산소 민감성 페로센 기반 나노입자의 크기는 50-1,000 nm, 바람직하기는 50-500 nm, 더욱 바람직하기는 50-300 nm일 수 있다. In the active oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the ferrocene-based nanoparticles are characterized in that they have a size of 1 nm to 5,000 nm. For example, the size of the reactive oxygen-sensitive ferrocene-based nanoparticles may be 50-1,000 nm, preferably 50-500 nm, more preferably 50-300 nm.

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 활성산소 민감성 페로센 기반 나노입자는 운반대상(cargo)을 봉입하고 있는 것을 특징으로 한다. 본 명세서에서 사용된 용어 "봉입"은 운반대상의 포집을 포함하는 넓은 개념으로 사용된다.In the reactive oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the reactive oxygen-sensitive ferrocene-based nanoparticles are characterized in that the carrier is encapsulated. The term "encapsulation" as used herein is used in a broad concept including the collection of objects to be transported.

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 운반대상은 약물인 것을 특징으로 한다. 상기 약물에는 친수성 약물, 소수성 약물, 화학약물 및 바이오 약물이 모두 포함된다. 예를 들면, 상기 약물은 항암제, 항산화제, 항염증증제, 진통제, 항관절염제, 진정제, 항우울증제, 항정신병 약물, 신경안정제, 항불안제, 항혈관신생 억제제, 면역억제제, 항바이러스제, 항생제, 식용억제제, 항히스타민제, 호르몬제, 항혈전제, 이뇨제, 항고혈압제, 심혈관질환 치료제 및 혈관 확장제 등을 포함할 수 있다.In the reactive oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the carrier is characterized in that the drug. The drugs include hydrophilic drugs, hydrophobic drugs, chemical drugs, and bio drugs. For example, the drugs are anticancer agents, antioxidants, anti-inflammatory agents, analgesics, antiarthritis agents, sedatives, antidepressants, antipsychotics, tranquilizers, anti-anxiety agents, antiangiogenic inhibitors, immunosuppressants, antiviral agents, antibiotics, Food inhibitors, antihistamines, hormones, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular disease treatment agents, vasodilators, and the like may be included.

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 페로센 기반 나노입자는 활성산소 또는 산화제에 의하여 와해(disassembled or disruption) 되어 봉입된 운반대상을 주위로 방출시킬 수 있다. 예를 들면, 본 발명에 따른 페로센 기반 나노입자가 항암제를 봉입하는 경우, 상기 나노입자는 종양 조직에 선택적으로 축적될 수 있으므로, 활성산소 또는 산화제에 의하여 나노입자가 와해됨으로써 암조직으로 항암제를 방출할 수 있고, 방출된 항암제에 의하여 암 치료효과를 거둘 수 있다. In the active oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the ferrocene-based nanoparticles may be disassembled or disrupted by active oxygen or an oxidizing agent to release the enclosed transport object to the surroundings. For example, when the ferrocene-based nanoparticles according to the present invention are encapsulated with an anticancer agent, the nanoparticles can be selectively accumulated in the tumor tissue, and thus the nanoparticles are broken down by active oxygen or an oxidizing agent to release the anticancer agent It can be done, and cancer treatment effects can be achieved by the released anticancer drug.

제2구현예에 따르면, According to the second embodiment,

본 발명은 The present invention

(a) 페로세닐메틸 메타크릴레이트(ferrocenylmethyl methacrylate, FMMA)에 메타크릴레이트(methacrylate, MA)를 결합시켜 페노세닐메틸 메타크릴레이트-메타크릴레이트 복합체를 제조하는 단계; (a) combining ferrocenylmethyl methacrylate (FMMA) with methacrylate (MA) to prepare a phenocenylmethyl methacrylate-methacrylate complex;

(b) 상기 페노세닐메틸 메타크릴레이트-메타크릴레이트 복합체를 유기용매에 용해시키는 단계; (b) dissolving the phenocenylmethyl methacrylate-methacrylate complex in an organic solvent;

(c) 상기 유기용매를 제거하여 페노세닐메틸 메타크릴레이트-메타크릴레이트 복합체 필름층을 형성시키는 단계; 및 (c) removing the organic solvent to form a phenocenylmethyl methacrylate-methacrylate composite film layer; And

(d) 상기 필름 층에 친수성 용매를 처리하여 페노세닐메틸 메타크릴레이트-메타크릴레이트 나노입자를 자기-조립(selfassemble)시키는 단계를 포함하는 활성산소 민감성 페로센 기반 나노입자의 제조방법을 제공하고자 한다. (d) treating the film layer with a hydrophilic solvent to provide a method for preparing active oxygen-sensitive ferrocene-based nanoparticles comprising the step of self-assembling phenocenylmethyl methacrylate-methacrylate nanoparticles. .

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 제조방법에 있어서, 상기 활성산소 민감성 페로센 기반 나노입자는 하기의 화학식 1로 표시되는 것을 특징으로 한다:In the method for preparing reactive oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the reactive oxygen-sensitive ferrocene-based nanoparticle is characterized by represented by the following Formula 1:

<화학식 1><Formula 1>

Figure 112018104495736-pat00002
Figure 112018104495736-pat00002

(상기 화학식 1에서, (In Formula 1,

상기 l 및 m은 서로 독립적으로 1 내지 10,000의 정수를 나타낸다.)The l and m each independently represent an integer of 1 to 10,000.)

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 제조방법에 있어서, 상기 페로세닐메틸 메타크릴레이트와 메타크릴레이트의 몰비는 1:1 내지 1:10, 바람직하기는 1:2 내지 1:8인 것을 특징으로 한다. In the method for producing reactive oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the molar ratio of ferrocenylmethyl methacrylate and methacrylate is 1:1 to 1:10, preferably 1:2 to 1:8. It features.

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 제조방법에 있어서, 상기 활성산소 민감성 페로센 기반 나노입자는 1 nm 내지 5,000 nm의 크기를 갖는 것을 특징으로 한다. 예를 들면, 상기 페로센 기반 나노입자의 크기는 50-1,000 nm, 바람직하기는 50-500 nm, 더욱 바람직하기는 50-300 nm일 수 있다. In the method for producing reactive oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the reactive oxygen-sensitive ferrocene-based nanoparticles have a size of 1 nm to 5,000 nm. For example, the size of the ferrocene-based nanoparticles may be 50-1,000 nm, preferably 50-500 nm, more preferably 50-300 nm.

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 제조방법에 있어서, 상기 유기용매는 THF, 크실렌, 톨루엔, 염화 메틸렌, CH3OH, CH3CH2OH, CH3CH2CH2OH, 헥산, 에틸렌글리콜, 디에틸렌글리콜, 트리에틸렌글리콜, 프로필렌글리콜, 부틸렌글리콜, 디에틸렌글리콜 모노메틸 에테르, 디에틸렌글리콜 모노부틸 에테르, 프로필렌글리콜 모노메틸 에테르 또는 DMSO를 포함하나, 이에 한정되는 것은 아니다. In the method for preparing reactive oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the organic solvent is THF, xylene, toluene, methylene chloride, CH 3 OH, CH 3C H 2 OH, CH 3 CH 2 CH 2 OH, hexane, Ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, butylene glycol, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, propylene glycol monomethyl ether, or DMSO, but is not limited thereto.

본 발명에 따른 활성산소 민감성 페로센 기반 나노입자는 산화환원 자극 반응에 의해 적합한 사이즈 변화, 활성 물질 (예를 들면, 항산화, 항암 등) 담지 및 방출이 가능한 원천 소재로 기능성 화장품, 치료용 화장품 및 의약품 등 다양한 플랫폼으로 응용 가능할 것으로 기대된다. The active oxygen-sensitive ferrocene-based nanoparticles according to the present invention are a source material capable of supporting and releasing suitable size changes and active substances (eg, antioxidants, anticancers, etc.) by stimulating redox reactions. Functional cosmetics, therapeutic cosmetics and pharmaceuticals It is expected to be applicable to various platforms such as.

도 1은 본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 제조 과정 및 활성산소 반응에 따른 담지물질 방출에 대한 도식도를 나타낸다.
도 2는 실시예 1에 따른 고분자 라이브러리의 제조방법을 나타낸다.
도 3은 실시예 1에 따라 제조된 고분자 라이브러리의 NMR 측정 결과를 나타낸다.
도 4는 실시예 2에 따라 제조된 고분자 나노입자의 size, PDI 및 zeta potential 측정 결과를 나타낸다.
도 5는 실시예 2에 따라 제조된 고분자 나노입자의 TEM 측정 결과를 나타낸다.
도 6은 실시예 2에 따라 제조된 고분자 나노입자의 4주 동안의 사이즈 변화 값을 나타낸다. 1 shows a schematic diagram of a process for preparing reactive oxygen-sensitive ferrocene-based nanoparticles according to the present invention and release of a supporting material according to reactive oxygen reaction.
2 shows a method of manufacturing a polymer library according to Example 1.
3 shows the NMR measurement results of the polymer library prepared according to Example 1.
Figure 4 shows the results of measuring the size, PDI and zeta potential of the polymer nanoparticles prepared according to Example 2.
5 shows the TEM measurement results of the polymer nanoparticles prepared according to Example 2.
6 shows the size change values for 4 weeks of the polymer nanoparticles prepared according to Example 2.

이하, 발명의 이해를 돕기 위해 다양한 실시예를 제시한다. 하기 실시예는 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 발명의 보호범위가 하기 실시예에 한정되는 것은 아니다. Hereinafter, various embodiments are presented to aid in understanding the invention. The following examples are provided for easier understanding of the invention, and the scope of protection of the invention is not limited to the following examples.

<실시예> <Example>

실시예 1. 고분자 라이브러리 합성Example 1. Polymer library synthesis

0.4 mmol FMMA 기준으로 MA의 비율을 0.5 mmol, 1 mmol, 2 mmol 및 3 mmol로 달리하여 monomer 4개를 칭량하였다 (도 2). 칭량한 monomer을 용매 THF에 넣고(monomer 0.1g 기준 THF 1ml의 비율로) 70 ℃ 의 온도에서 24시간 동안 350 rpm으로 합성한 후, NMR을 통해 확인하였다. 그 결과, 제조된 4개의 고분자 모두 6 전후의 monomer peak이 사라지고 2 앞쪽의 Alkyl Chain 이 형성된 것을 보아 합성이 잘 이루어졌음이 확인되었다 (도 3). 4 monomers were weighed by varying the ratio of MA to 0.5 mmol, 1 mmol, 2 mmol, and 3 mmol based on 0.4 mmol FMMA (FIG. 2). The weighed monomer was put in a solvent THF (at a ratio of 1 ml of THF based on 0.1 g of monomer) and synthesized at a temperature of 70° C. for 24 hours at 350 rpm, and then confirmed by NMR. As a result, it was confirmed that the synthesis was well performed by seeing that the monomer peaks around 6 disappeared and the Alkyl Chain in front of 2 was formed in all of the prepared 4 polymers (FIG. 3).

실시예 2. 고분자 나노입자의 제조Example 2. Preparation of polymer nanoparticles

상기 실시예 1에서 제조된 고분자를 용매 THF에 5mg/ml 의 농도로 희석하고, 고분자 용액을 30G needle을 끼운 syringe 에 담았다. 그 다음, 20ml 의 vial 에 DI.Water 를 5ml 채웠다. 5ml의 DI.water가 담긴 vial을 530rpm의 속도로 strring 하면서 syringe pump를 이용하여 syringe 에 담긴 고분자 용액을 한 방울씩 dropwise 하였다. (syringe pump 가동 속도 : 0.75ml/min) Dropwise가 끝나면 vial 뚜껑을 닫고 5분간 stirring 하여 나노입자를 안정화 시켰다. 5분 후 Vial 뚜껑을 열고 vial 입구에 고무 septa를 끼운 후 18G needle을 2개 꽂아 2시간 동안 vacuum drying 하여 THF를 제거하였다. DI.Water 에서의 농도가 5mg/5ml 인 고분자 나노입자 얻었다. The polymer prepared in Example 1 was diluted in a solvent THF to a concentration of 5 mg/ml, and the polymer solution was put in a syringe fitted with a 30G needle. Then, a 20ml vial was filled with 5ml of DI.Water. While strring a vial containing 5ml of DI.water at a speed of 530rpm, the polymer solution in the syringe was droppedwise by dropwise using a syringe pump. (syringe pump operation speed: 0.75ml/min) After dropwise, the vial lid was closed and stirred for 5 minutes to stabilize the nanoparticles. After 5 minutes, the vial lid was opened, a rubber septa was inserted into the vial inlet, and two 18G needles were inserted, followed by vacuum drying for 2 hours to remove THF. Polymeric nanoparticles having a concentration of 5mg/5ml in DI.Water were obtained.

실시예 3. 고분자 나노입자의 안정성 확인Example 3. Confirmation of stability of polymer nanoparticles

상기 실시예 2에서 제조된 고분자 나노입자의 초기 size, PDI 및 zeta potential을 측정하였다. 그 결과, 고분자의 MA의 비율이 높아질수록 작은 사이즈의 안정적인 입자가 형성되는 것으로 나타났으며, MA의 영향으로 - Charge 값이 점점 커지는 것으로 확인되었다 (도 4). 또한, 상기 고분자 나노입자의 제조 직후 형상을 TEM 으로 확인한 결과, 고분자의 MA의 비율이 높아질수록 초기 사이즈가 작아지는 것으로 확인되었다 (도 5).The initial size, PDI, and zeta potential of the polymer nanoparticles prepared in Example 2 were measured. As a result, it was found that as the ratio of MA of the polymer increased, stable particles of small size were formed, and it was confirmed that the -Charge value gradually increased due to the effect of MA (FIG. 4). In addition, as a result of confirming the shape by TEM immediately after preparation of the polymer nanoparticles, it was confirmed that the initial size decreased as the ratio of MA of the polymer increased (FIG. 5).

한편, 상기 고분자 나노입자를 각각 제조한 후로부터 4주간의 사이즈 변화 값을 측정한 결과, 고분자 Poly-c-0.5는 소수성인 FMMA의 비율이 다른 세 개의 고분자들에 비해 상대적으로 높아 입자의 뭉침 현상이 발생해 사이즈가 점점 커지는 것으로 나타난 반면, 고분자 poly-c-1 ~ poly-c-3 은 4주 동안의 사이즈 변화가 거의 없는 것으로 보아 안정적인 입자임이 확인되었다 (도 6). Meanwhile, as a result of measuring the size change value for 4 weeks after each preparation of the polymer nanoparticles, the polymer Poly-c-0.5 has a relatively high proportion of hydrophobic FMMA compared to the other three polymers, resulting in particle aggregation. While this occurred and appeared to increase in size, the polymers poly-c-1 to poly-c-3 were found to be stable particles as there was little change in size for 4 weeks (FIG. 6).

실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.It looked at around the examples. Those of ordinary skill in the art to which the present invention pertains will be able to understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative point of view rather than a limiting point of view. The scope of the present invention is shown in the claims rather than the above description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (9)

페로세닐메틸 메타크릴레이트(ferrocenylmethyl methacrylate, FMMA), 및 상기 페로세닐메틸 메타크릴레이트에 결합된 메타크릴레이트(methacrylate, MA)를 포함하는 복합체가 자기-조립(self-assembled)하여 형성되고,
상기 페로세닐메틸 메타크릴레이트와 메타크릴레이트의 몰비는 1:2 내지 1:8 인 것을 특징으로 하는 것인 활성산소 민감성 페로센 기반 나노입자.
A complex comprising ferrocenylmethyl methacrylate (FMMA) and methacrylate (MA) bound to the ferrocenylmethyl methacrylate is formed by self-assembled,
The molar ratio of ferrocenylmethyl methacrylate and methacrylate is 1:2 to 1:8, wherein the reactive oxygen-sensitive ferrocene-based nanoparticles, characterized in that.
 제 1 항에 있어서,
상기 활성산소 민감성 페로센 기반 나노입자는 화학식 1로 표시되는 것을 특징으로 하는 것인, 활성산소 민감성 페로센 기반 나노입자.
<화학식 1>
Figure 112020032315819-pat00003

(상기 화학식 1에서,
상기 l 및 m은 서로 독립적으로 1 내지 10,000의 정수를 나타낸다.)
The method of claim 1,
The reactive oxygen-sensitive ferrocene-based nanoparticles are characterized in that represented by Formula 1, reactive oxygen-sensitive ferrocene-based nanoparticles.
<Formula 1>
Figure 112020032315819-pat00003

(In Formula 1,
Each of l and m independently represents an integer of 1 to 10,000.)
 삭제delete 제1항에 있어서,
상기 페로센 기반 나노입자는 1 nm 내지 5,000 nm의 크기를 갖는 것을 특징으로 하는 것인, 활성산소 민감성 페로센 기반 나노입자.
The method of claim 1,
The ferrocene-based nanoparticles are characterized in that having a size of 1 nm to 5,000 nm, reactive oxygen-sensitive ferrocene-based nanoparticles.
 (a) 페로세닐메틸 메타크릴레이트(ferrocenylmethyl methacrylate, FMMA)에 메타크릴레이트(methacrylate, MA)를 결합시켜 페노세닐메틸 메타크릴레이트-메타크릴레이트 복합체를 제조하는 단계;
(b) 상기 페노세닐메틸 메타크릴레이트-메타크릴레이트 복합체를 유기용매에 용해시키는 단계;
(c) 상기 유기용매를 제거하여 페노세닐메틸 메타크릴레이트-메타크릴레이트 복합체 필름층을 형성시키는 단계; 및
(d) 상기 필름 층에 친수성 용매를 처리하여 페노세닐메틸 메타크릴레이트-메타크릴레이트　 나노입자를 자기-조립(selfassemble)시키는 단계를 포함하고,
상기 페로세닐메틸 메타크릴레이트와 메타크릴레이트의 몰비는 1:2 내지 1:8 인 것을 특징으로 하는 것인, 활성산소 민감성 페로센 기반 나노입자의 제조방법.
(a) combining ferrocenylmethyl methacrylate (FMMA) with methacrylate (MA) to prepare a phenocenylmethyl methacrylate-methacrylate complex;
(b) dissolving the phenocenylmethyl methacrylate-methacrylate complex in an organic solvent;
(c) removing the organic solvent to form a phenocenylmethyl methacrylate-methacrylate composite film layer; And
(d) treating the film layer with a hydrophilic solvent to self-assemble phenocenylmethyl methacrylate-methacrylate nanoparticles,
The ferrocenyl methyl methacrylate and the molar ratio of methacrylate is 1: 2 to 1: 8, characterized in that the method of producing reactive oxygen-sensitive ferrocene-based nanoparticles.
 제 5 항에 있어서,
상기 활성산소 민감성 페로센 기반 나노입자는 화학식 1로 표시되는 것을 특징으로 하는 것인, 활성산소 민감성 페로센 기반 나노입자의 제조방법.
<화학식 1>
Figure 112020032315819-pat00004

(상기 화학식 1에서,
상기 l 및 m은 서로 독립적으로 1 내지 10,000의 정수를 나타낸다.)
The method of claim 5,
The reactive oxygen-sensitive ferrocene-based nanoparticles are characterized in that represented by the formula (1), the method for producing reactive oxygen-sensitive ferrocene-based nanoparticles.
<Formula 1>
Figure 112020032315819-pat00004

(In Formula 1,
Each of l and m independently represents an integer of 1 to 10,000.)
 삭제delete 제5항에 있어서,
상기 페로센 기반 나노입자는 1 nm 내지 5,000 nm의 크기를 갖는 것을 특징으로 하는 것인, 활성산소 민감성 페로센 기반 나노입자의 제조방법.
The method of claim 5,
The ferrocene-based nanoparticles are characterized in that having a size of 1 nm to 5,000 nm, the method of producing reactive oxygen-sensitive ferrocene-based nanoparticles.
 제5항에 있어서,
상기 유기용매는 THF, 크실렌, 톨루엔, 염화 메틸렌, CH3OH, CH3CH2OH, CH3CH2CH2OH, 헥산, 에틸렌글리콜, 디에틸렌글리콜, 트리에틸렌글리콜, 프로필렌글리콜, 부틸렌글리콜, 디에틸렌글리콜 모노메틸 에테르, 디에틸렌글리콜 모노부틸 에테르, 프로필렌글리콜 모노메틸 에테르 또는 DMSO인 것을 특징으로 하는 것인, 활성산소 민감성 페로센 기반 나노입자의 제조방법.The method of claim 5,
The organic solvent is THF, xylene, toluene, methylene chloride, CH 3 OH, CH 3 CH 2 OH, CH 3 CH 2 CH 2 OH, hexane, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, butylene glycol , Diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, propylene glycol monomethyl ether or DMSO, characterized in that, reactive oxygen sensitive ferrocene-based nanoparticles manufacturing method.
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