KR20230111688A - Reactive oxygen-sensitive ferrocene-based nanoparticles having improved stability, method for preparing the same and uses thereof - Google Patents
Reactive oxygen-sensitive ferrocene-based nanoparticles having improved stability, method for preparing the same and uses thereof Download PDFInfo
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- KR20230111688A KR20230111688A KR1020220007207A KR20220007207A KR20230111688A KR 20230111688 A KR20230111688 A KR 20230111688A KR 1020220007207 A KR1020220007207 A KR 1020220007207A KR 20220007207 A KR20220007207 A KR 20220007207A KR 20230111688 A KR20230111688 A KR 20230111688A
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- active oxygen
- based nanoparticles
- ferrocene
- sensitive
- nanoparticles
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Abstract
본 발명은 안정성이 향상된 활성산소 민감성 페로센 기반 나노입자, 이의 제조방법 및 이의 용도에 관한 것이다. 보다 구체적으로, 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜 (polyethylene glycol, PEG)을 포함하는 활성산소 민감성 PEG-페로센 기반 나노입자, 자기-조립(self-assemble)에 의한 이의 제조 방법, 및 약물 전달체, 화장료 조성물, 영상화 조성물 및 암 진단 및 치료용 조성물로서의 이의 용도에 관한 것이다. The present invention relates to active oxygen-sensitive ferrocene-based nanoparticles with improved stability, a method for preparing the same, and a use thereof. More specifically, active oxygen-sensitive PEG-ferrocene-based nanoparticles comprising ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol (PEG), a method for producing the same by self-assembly, and its use as a drug delivery vehicle, cosmetic composition, imaging composition, and cancer diagnosis and treatment composition.
Description
본 발명은 안정성이 향상된 활성산소 민감성 페로센 기반 나노입자, 이의 제조방법 및 이의 용도에 관한 것이다. 보다 구체적으로, 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜 (polyethylene glycol, PEG)을 포함하는 활성산소 민감성 PEG-페로센 기반 나노입자, 자기-조립(self-assemble)에 의한 이의 제조 방법, 및 약물 전달체, 화장료 조성물, 영상화 조성물 및 암 진단 및 치료용 조성물로서의 이의 용도에 관한 것이다. The present invention relates to active oxygen-sensitive ferrocene-based nanoparticles with improved stability, a method for preparing the same, and a use thereof. More specifically, active oxygen-sensitive PEG-ferrocene-based nanoparticles comprising ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol (PEG), a method for producing the same by self-assembly, and its use as a drug delivery vehicle, cosmetic composition, imaging composition, and cancer diagnosis and treatment composition.
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, various biodegradable polymers have been developed and widely used in tissue engineering. 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., and are mainly hydrophobic polyesters. 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, and have high biocompatibility, biodegradability, and processability. However, it has difficulties in cell adhesion due to lack of bioactive substances and hydrophobicity, and acid decomposition products generated during the hydrolysis of PLGA reduce the pH around the tissue and cause inflammation.
한편, 페로센(ferrocene)은 매우 안정한 구조의 무독성 유기금속(organometallic) 복합체로 소수성(hydrophobic) 특성을 가지고 있기 때문에 소수성 결합을 통한 코어 형성이 가능하며, 이러한 특성을 바탕으로 본 출원인은 특허 제10-2176982호에서 페로세닐메틸 메타크릴레이트(ferrocenylmethyl methacrylate, FMMA), 및 상기 페로세닐메틸 메타크릴레이트에 결합된 메타크릴레이트(methacrylate, MA)를 포함하는 복합체가 자기-조립(self-assembled)하여 형성된 활성산소 민감성 페로센 기반 나노입자를 개시한바 있다. On the other hand, since ferrocene is a non-toxic organometallic complex with a very stable structure and has hydrophobic properties, it is possible to form a core through hydrophobic bonding. ) has disclosed active oxygen sensitive ferrocene-based nanoparticles formed by self-assembling of complexes including.
본 발명자는 상기 활성산소 민감성 페로센 기반 나노입자의 안정성을 향상시켜 약물전달체로서의 기능을 더욱 향상시키기 위하여 예의 노력한 결과, 상기 활성산소 민감성 페로센 기반 나노입자의 제조시 폴리에틸렌글리콜의 첨가 및 이의 함량을 조절하는 것에 의해 종래 페로센 기반 나노입자에 비하여 활성산소 반응성 및 안정성이 향상될 뿐만 아니라, 생체적합성 및 약물 방출 효능이 우수한 활성산소 민감성 페로센 기반 나노입자가 제조될 수 있음을 확인한 후, 본 발명을 완성하기에 이르렀다. The present inventors have made diligent efforts to improve the stability of the active oxygen-sensitive ferrocene-based nanoparticles to further improve their function as a drug delivery system. As a result, by adding polyethylene glycol and adjusting its content during the preparation of the active oxygen-sensitive ferrocene-based nanoparticles, the present invention was completed after confirming that active oxygen-sensitive ferrocene-based nanoparticles having improved biocompatibility and drug release efficacy as well as improved active oxygen reactivity and stability compared to conventional ferrocene-based nanoparticles could be prepared, and completed the present invention. I came to do it.
또한, 본 발명자들은 상기 활성산소 민감성 페로센 기반 나노입자가 현저히 개선된 항암효과 및 세포 내 흡수율을 나타냄으로써, 암의 진단 (diagnosis)과 치료 (therapy)를 동시에 수행하는 테라그노시스 (theragnosis)로서 사용될 수 있음을 확인하였다. In addition, the present inventors have confirmed that the reactive oxygen-sensitive ferrocene-based nanoparticles can be used as theragnosis, which simultaneously performs cancer diagnosis and therapy, by exhibiting significantly improved anticancer effects and intracellular absorption rates.
본 발명은 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜 (polyethylene glycol, PEG)을 포함하는 복합체가 자기-조립(self-assembled)하여 형성된 활성산소 민감성 페로센 기반 나노입자를 제공하는 것을 목적으로 한다. An object of the present invention is to provide active oxygen sensitive ferrocene-based nanoparticles formed by self-assembling of a complex containing ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA), and polyethylene glycol (PEG).
본 발명은 또한 상기 활성산소 민감성 페로센 기반 나노입자의 제조방법을 제공하는 것을 목적으로 한다. Another object of the present invention is to provide a method for preparing the active oxygen-sensitive ferrocene-based nanoparticles.
본 발명은 또한 상기 활성산소 민감성 페로센 기반 나노입자 및 상기 나노입자에 담지된 소수성 약물을 포함하는 약물 전달체를 제공하는 것을 목적으로 한다.Another object of the present invention is to provide a drug delivery system comprising the active oxygen-sensitive ferrocene-based nanoparticles and a hydrophobic drug loaded on the nanoparticles.
본 발명은 또한 상기 활성산소 민감성 페로센 기반 나노입자 및 상기 나노입자에 담지된 화장료를 포함하는 화장료 조성물를 제공하는 것을 목적으로 한다.Another object of the present invention is to provide a cosmetic composition comprising the active oxygen-sensitive ferrocene-based nanoparticles and a cosmetic material supported on the nanoparticles.
본 발명은 또한 상기 활성산소 민감성 페로센 기반 나노입자 및 상기 나노입자에 담지된 조영제를 포함하는 영상화 조성물를 제공하는 것을 목적으로 한다.Another object of the present invention is to provide an imaging composition comprising the active oxygen-sensitive ferrocene-based nanoparticles and a contrast agent supported on the nanoparticles.
본 발명은 또한 상기 활성산소 민감성 페로센 기반 나노입자 및 상기 나노입자에 담지된 항암제 및 조영제를 포함하는 암 진단 및 치료용 조성물을 제공하는 것을 목적으로 한다. Another object of the present invention is to provide a composition for diagnosing and treating cancer, including the active oxygen-sensitive ferrocene-based nanoparticles and an anticancer agent and a contrast agent loaded on the nanoparticles.
본 발명에 따른 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜 (polyethylene glycol, PEG)을 포함하는 활성산소 민감성 PEG-페로센 기반 나노입자는 종래 페로센 기반 나노입자에 비하여 활성산소 반응성 및 안정성 (실시예 3)이 향상될 뿐만 아니라, 생체적합성 (실험예 3) 및 약물 방출 효능 (실험예 2)이 우수하여 나노 캐리어로서 사용될 수 있다. Active oxygen sensitive PEG-ferrocene-based nanoparticles containing ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol (PEG) according to the present invention have improved active oxygen reactivity and stability (Example 3) compared to conventional ferrocene-based nanoparticles, as well as excellent biocompatibility (Experimental Example 3) and drug release efficacy (Experimental Example 2). can be used as a carrier.
또한, 본 발명에 따른 활성산소 민감성 PEG-페로센 기반 나노입자는 현저히 개선된 항암효과 (실험예 3) 및 세포 내 흡수율 (실험예 4)을 나타냄으로써, 암의 진단(diagnosis)과 치료(therapy)를 동시에 수행하는 테라그노시스(theragnosis)로서 사용될 수 있을 것으로 기대된다. In addition, the active oxygen-sensitive PEG-ferrocene-based nanoparticles according to the present invention exhibit significantly improved anticancer effect (Experimental Example 3) and intracellular absorption rate (Experimental Example 4), thereby diagnosing and treating cancer. It is expected that it can be used as theragnosis that performs therapy at the same time.
도 1은 실시예 2에 따른 PEG-ferrocene 나노 입자의 크기 (a), 분산값 (b) 및 표면전하 (c)를 나타낸다.
도 2는 실시예 3에 따른 PEG-ferrocene 나노 입자의 반응성 평가 결과로서, 1.4% H2O2 처리 후 나노입자의 크기 (a), 분산값 (b) 및 표면전하 (c)를 나타낸다.
도 3은 실시예 3에 따른 PEG-ferrocene 나노 입자의 안정성 평가 결과로서, 동결건조 전과 후 (a), 4주간 3차 증류수 내 보관 후 (b), 5일 동안 PBS 보관 후 (c) 및 72시간 동안 serum-함유 PBS 내 보관 후 (d)의 나노 입자의 크기를 나타낸다.
도 4는 실시예 3에 따른 PEG-ferrocene 나노 입자의 안정성 평가 결과로서, 동결건조 전과 후 (a), 4주간 3차 증류수 내 보관 후 (b), 5일 동안 PBS 보관 후 (c) 및 72시간 동안 serum-함유 PBS 내 보관 후 (d)의 나노 입자의 분산값을 나타낸다.
도 5는 실험예 1에 따른 다양한 양의 PTX 로딩 후 PFNP3의 크기 (a), 분산값 (b) 및 표면전하 (c)를 나타낸다.
도 6은 실험예 1에 따른 다양한 양의 PTX 로딩 후 PFNP3의 동결건조 안정성 평가 결과로서, 동결건조 전과 후 나노입자의 크기 (a) 및 분산값 (b)을 나타낸다.
도 7은 실험예 1에 따른 PXT (2 wt%) 및 NR (0.1 wt%) 로딩 후 PFNP3의 특성 평가 결과로서, PTX,NR@PFNP의 TEM 사진 (scale bar, 50 nm) 및 분산도 (a), PTX,NR@PFNP의 H2O2 처리 후 나노 입자의 크기 (black) 및 표면전하 (red) (b) 및 PTX,NR@PFNP의 PBS 내 5일간 보관 후 나노 입자의 크기 (black) 및 분산값 (red) (c)를 나타낸다.
도 8은 실험예 2에 따른 PTX,NR@PFNP3의 ROS 반응성 PTX 방출 특성을 나타낸다.
도 9는 실험예 3에 따른 PTX,NR@PFNP의 in vitro 세포 독성 및 항암 효능 평가 결과로서, NIH 3T3 세포 내 PFNP3의 세포 독성 결과 (a), PTX,NR@PFNP의 NIH 3T3 및 SCC-7 세포 내 ROS 반응성 항암 효능 결과 (b) 및 NAC, ROS inhibitor 처리 후 PTX,NR@PFNP의 ROS 반응성 항암 효능 결과 (c)를 나타낸다.
도 10은 PTX,NR@PFNP의 SCC-7 세포 내 흡수율 평가 결과로서, 시간 별 SCC-7 세포 내 축적된 PTX,NR@PFNP의 형광 사진 (b) 및 시간 별 세포 내 축적된 나노 입자의 Nile Red의 mean fluorescence intensity (MFI) (b)를 나타낸다.Figure 1 shows the size (a), dispersion value (b) and surface charge (c) of PEG-ferrocene nanoparticles according to Example 2.
2 shows the reactivity evaluation results of PEG-ferrocene nanoparticles according to Example 3, and shows the size (a), dispersion value (b) and surface charge (c) of nanoparticles after treatment with 1.4% H 2 O 2 .
Figure 3 shows the stability evaluation results of PEG-ferrocene nanoparticles according to Example 3, before and after lyophilization (a), after storage in tertiary distilled water for 4 weeks (b), after storage in PBS for 5 days (c) and after storage in serum-containing PBS for 72 hours (d) shows the size of the nanoparticles.
Figure 4 shows the stability evaluation results of PEG-ferrocene nanoparticles according to Example 3, before and after freeze-drying (a), after storage in tertiary distilled water for 4 weeks (b), after storage in PBS for 5 days (c) and after storage in serum-containing PBS for 72 hours (d) shows the dispersion values of the nanoparticles.
5 shows the size (a), dispersion value (b), and surface charge (c) of PFNP3 after loading various amounts of PTX according to Experimental Example 1.
6 is a result of evaluating the freeze-drying stability of PFNP3 after loading various amounts of PTX according to Experimental Example 1, and shows the size (a) and dispersion value (b) of nanoparticles before and after freeze-drying.
7 is a result of characterization of PFNP3 after loading PXT (2 wt%) and NR (0.1 wt%) according to Experimental Example 1, TEM picture (scale bar, 50 nm) and dispersion of PTX, NR@PFNP (a), H 2 O 2 of PTX, NR@PFNP After treatment, size (black) and surface charge (red) of nanoparticles (b) and size of nanoparticles after storage of PTX, NR@PFNP in PBS for 5 days (black) ) and variance values (red) (c).
8 shows the ROS reactive PTX release characteristics of PTX,NR@PFNP3 according to Experimental Example 2.
9 shows the in vitro cytotoxicity and anticancer efficacy evaluation results of PTX,NR@PFNP according to Experimental Example 3, showing the cytotoxicity of PFNP3 in NIH 3T3 cells (a), the ROS-responsive anticancer efficacy of PTX,NR@PFNP in NIH 3T3 and SCC-7 cells (b), and the ROS-responsive anticancer efficacy of PTX,NR@PFNP after treatment with NAC and ROS inhibitors (c).
FIG. 10 shows the results of evaluation of the uptake rate of PTX,NR@PFNP in SCC-7 cells, showing fluorescence images of PTX,NR@PFNP accumulated in SCC-7 cells over time (b) and mean fluorescence intensity (MFI) of Nile Red nanoparticles accumulated in cells over time (MFI) (b).
이하, 발명의 구체적인 구현예에 따른 안정성이 향상된 활성산소 민감성 페로센 기반 나노입자, 이의 제조방법 및 이의 용도에 대하여 상세하게 설명하기로 한다. 다만, 이는 발명의 하나의 예시로서 제시되는 것으로, 이에 의해 발명의 권리범위가 한정되는 것은 아니며, 발명의 권리범위 내에서 구현예에 대한 다양한 변형이 가능함은 당업자에게 자명하다. 본 명세서 전체에서 특별한 언급이 없는 한 "포함" 또는 "함유"라 함은 어떤 구성 요소(또는 구성 성분)를 별다른 제한 없이 포함함을 지칭하며, 다른 구성 요소(또는 구성 성분)의 부가를 제외하는 것으로 해석될 수 없다.Hereinafter, active oxygen-sensitive ferrocene-based nanoparticles with improved stability according to specific embodiments of the present invention, a manufacturing method thereof, and uses thereof will be described in detail. However, this is presented as an example of the invention, whereby the scope of the invention is not limited, and it is obvious to those skilled in the art that various modifications to the embodiments are possible within the scope of the invention. Throughout this specification, unless otherwise specified, "include" or "include" refers to including a certain component (or component) without particular limitation, and excludes the addition of other components (or components). Cannot be interpreted.
제1구현예에 따르면, According to the first embodiment,
본 발명은 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜을 포함하는 활성산소 민감성 페로센 기반 나노입자를 제공하고자 한다. The present invention is to provide active oxygen sensitive ferrocene-based nanoparticles containing ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol.
본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 0.2 내지 1 : 2인 것을 특징으로 한다. 바람직하기는, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 1일 수 있다. In the active oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol is 1: 0.2 to 1: 2. Preferably, the molar ratio of methacrylic acid and polyethylene glycol may be 1:1.
본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 페로세닐메틸 메타크릴레이트를 기준으로 메타크릴산 및 폴리에틸렌글리콜의 몰비는 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 methacrylic acid and polyethylene glycol based on the ferrocenylmethyl methacrylate is characterized in that 1: 2 to 1: 8.
본 발명에 따른 활성산소 민감성 페로센 기반 나노입자에 있어서, 상기 페로세닐메틸 메타크릴레이트, 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2.5 : 2.5인 것을 특징으로 한다. In the active oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the molar ratio of ferrocenylmethyl methacrylate, methacrylic acid and polyethylene glycol is 1:2.5:2.5.
제2구현예에 따르면, According to the second embodiment,
본 발명은 (A) 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜 (polyethylene glycol, PEG)를 결합시켜 FMMA-MA-PEG 복합체를 제조하는 단계;The present invention (A) preparing a FMMA-MA-PEG composite by combining ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol (PEG);
(B) 상기 FMMA-MA-PEG 복합체를 유기용매에 용해시키는 단계;(B) dissolving the FMMA-MA-PEG complex in an organic solvent;
(C) 상기 유기용매를 제거하여 FMMA-MA-PEG 복합체 필름층을 형성시키는 단계; 및(C) forming a FMMA-MA-PEG composite film layer by removing the organic solvent; and
(D) 상기 필름 층에 친수성 용매를 처리하여 FMMA-MA-PEG 나노입자를 자기-조립(self-assemble)시키는 단계를 포함하는 활성산소 민감성 페로센 기반 나노입자의 제조 방법을 제공하고자 한다. (D) treating the film layer with a hydrophilic solvent to self-assemble FMMA-MA-PEG nanoparticles.
본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 제조 방법에 있어서, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 0.2 내지 1 : 2인 것을 특징으로 한다. 바람직하기는, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 1일 수 있다. In the method for producing active oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol is 1: 0.2 to 1: 2. Preferably, the molar ratio of methacrylic acid and polyethylene glycol may be 1:1.
본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 제조 방법에 있어서, 상기 페로세닐메틸 메타크릴레이트를 기준으로 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2 내지 1 : 8인 것을 특징으로 한다. In the method for producing active oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol based on the ferrocenylmethyl methacrylate is 1:2 to 1:8.
본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 제조 방법에 있어서, 상기 페로세닐메틸 메타크릴레이트, 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2.5 : 2.5인 것을 특징으로 한다. In the method for producing active oxygen-sensitive ferrocene-based nanoparticles according to the present invention, the molar ratio of ferrocenylmethyl methacrylate, methacrylic acid and polyethylene glycol is 1:2.5:2.5.
본 발명에 따른 활성산소 민감성 페로센 기반 나노입자의 제조 방법에 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 한다. In the method for producing active oxygen-sensitive ferrocene-based nanoparticles according to the present invention, 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 Characterized in that it is ether or DMSO.
제3구현예에 따르면, According to the third embodiment,
본 발명은 (a) 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜 (polyethylene glycol, PEG)을 포함하는 활성산소 민감성 페로센 기반 나노입자; 및The present invention (a) ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol (polyethylene glycol, PEG) including active oxygen sensitive ferrocene-based nanoparticles; and
(b) 상기 활성산소 민감성 페로센 기반 나노입자에 담지된 소수성 약물을 포함하는 약물 전달체를 제공하고자 한다. (b) It is intended to provide a drug delivery system including a hydrophobic drug loaded on the active oxygen-sensitive ferrocene-based nanoparticles.
본 발명에 따른 약물 전달체에 있어서, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 0.2 내지 1 : 2인 것을 특징으로 한다. 바람직하기는, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 1일 수 있다. In the drug delivery system according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol is 1: 0.2 to 1: 2. Preferably, the molar ratio of methacrylic acid and polyethylene glycol may be 1:1.
본 발명에 따른 약물 전달체에 있어서, 상기 페로세닐메틸 메타크릴레이트를 기준으로 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2 내지 1 : 8인 것을 특징으로 한다. In the drug delivery system according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol based on the ferrocenylmethyl methacrylate is characterized in that 1: 2 to 1: 8.
본 발명에 따른 약물 전달체에 있어서, 상기 페로세닐메틸 메타크릴레이트, 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2.5 : 2.5인 것을 특징으로 한다. In the drug delivery system according to the present invention, the molar ratio of ferrocenylmethyl methacrylate, methacrylic acid and polyethylene glycol is 1:2.5:2.5.
본 발명에 따른 약물 전달체에 있어서, 상기 소수성 약물은 활성산소 민감성 페로센 기반 나노 입자의 중량을 기준으로 1 내지 5 중량%의 양으로 함유된 것을 특징으로 한다. 바람직하기는, 상기 소수성 약물은 활성산소 민감성 페로센 기반 나노 입자의 중량을 기준으로 2 중량%의 양으로 함유될 수 있다. In the drug delivery system according to the present invention, the hydrophobic drug is characterized in that it is contained in an amount of 1 to 5% by weight based on the weight of the active oxygen-sensitive ferrocene-based nanoparticles. Preferably, the hydrophobic drug may be contained in an amount of 2% by weight based on the weight of the active oxygen-sensitive ferrocene-based nanoparticles.
본 발명에 따른 약물 전달체에 있어서, 상기 소수성 약물은 파클리탁셀(paclitaxel), 독소루비신 (doxorubicin), 시스플라틴(cis-platin), 도데탁셀(docetaxel), 타목시펜(tamoxifen), 캄토세신(camtothecin), 아나스테로졸(anasterozole), 카보플라틴(carboplatin), 토포테칸(topotecan), 베로테칸(belotecan), 이리노테칸 (irinotecan), 글리벡(gleevec), 빈크리스틴(vincristine), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐타존(phenyltazone), 메소트렉세이트(methotrexate), 시클로포스파미드 (cyclophosphamide), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 또는 코르티코스테로이드을 포함하는 항암제; 항바이러스제; 스테로이드계 소염제; 항생제; 항진균제; 비타민; 프로스타사이클린; 항대사제; 축동제; 아드레날린 길항제; 항경련제; 항불안제; 정온제; 항우울제; 마취제; 진통제; 동화성 스테로이드제; 면역 억제제 또는 면역 촉진제인 것을 특징으로 한다.In the drug delivery system according to the present invention, the hydrophobic drug is paclitaxel, doxorubicin, cis-platin, dodetaxel, tamoxifen, camtothecin, anasterozole, carboplatin, topotecan, belotecan can, irinotecan, gleevec, vincristine, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenyltazone, methotrexate, cyclophosphamide ), mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone, or corticosteroids; antiviral agents; steroidal anti-inflammatory drugs; Antibiotic; antifungal agents; vitamin; prostacyclin; antimetabolites; mimics; adrenergic antagonists; anticonvulsants; anti-anxiety drugs; calming agent; antidepressants; anesthetic; painkiller; anabolic steroids; Characterized in that it is an immunosuppressant or immune stimulator.
제4구현예에 따르면, According to the fourth embodiment,
(a) 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜 (polyethylene glycol, PEG)을 포함하는 활성산소 민감성 페로센 기반 나노입자; 및(a) active oxygen sensitive ferrocene-based nanoparticles including ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol (PEG); and
(b) 상기 활성산소 민감성 페로센 기반 나노입자에 담지된 화장료를 포함하는 화장료 조성물을 제공하고자 한다. (b) to provide a cosmetic composition comprising a cosmetic supported on the active oxygen-sensitive ferrocene-based nanoparticles.
본 발명에 따른 화장료 조성물에 있어서, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 0.2 내지 1 : 2인 것을 특징으로 한다. 바람직하기는, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 1일 수 있다. In the cosmetic composition according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol is characterized in that 1: 0.2 to 1: 2. Preferably, the molar ratio of methacrylic acid and polyethylene glycol may be 1:1.
본 발명에 따른 화장료 조성물에 있어서, 상기 페로세닐메틸 메타크릴레이트를 기준으로 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2 내지 1 : 8인 것을 특징으로 한다. In the cosmetic composition according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol based on the ferrocenylmethyl methacrylate is characterized in that 1: 2 to 1: 8.
본 발명에 따른 화장료 조성물에 있어서, 상기 페로세닐메틸 메타크릴레이트, 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2.5 : 2.5인 것을 특징으로 한다. In the cosmetic composition according to the present invention, the molar ratio of the ferrocenylmethyl methacrylate, methacrylic acid and polyethylene glycol is characterized in that 1: 2.5: 2.5.
본 발명에 따른 화장료 조성물에 있어서, 상기 화장료는 피부연화제, 방부제, 향수 물질, 항여드름제, 항진균제, 산화방지제, 방취제, 지한제, 항비듬제, 탈색소제, 항지루성제, 염료, 선탠로션, UV 빛 흡수제, 효소 또는 방향 물질을 포함하는 것을 특징으로 한다. In the cosmetic composition according to the present invention, the cosmetic is a skin softener, preservative, perfume material, anti-acne agent, antifungal agent, antioxidant, deodorant, antiperspirant, anti-dandruff agent, depigmentation agent, anti-seborrheic agent, dye, suntan lotion, UV light absorbent, enzyme or fragrance It is characterized by including a substance.
제5구현예에 따르면, According to the fifth embodiment,
(a) 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜 (polyethylene glycol, PEG)을 포함하는 활성산소 민감성 페로센 기반 나노입자; 및(a) active oxygen sensitive ferrocene-based nanoparticles including ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol (PEG); and
(b) 상기 활성산소 민감성 페로센 기반 나노입자에 담지된 조영제를 포함하는 조영제 조성물을 제공하고자 한다. (b) It is intended to provide a contrast agent composition comprising a contrast agent supported on the active oxygen-sensitive ferrocene-based nanoparticles.
본 발명에 따른 조영제 조성물에 있어서, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 0.2 내지 1 : 2인 것을 특징으로 한다. 바람직하기는, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 1일 수 있다. In the contrast medium composition according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol is 1:0.2 to 1:2. Preferably, the molar ratio of methacrylic acid and polyethylene glycol may be 1:1.
본 발명에 따른 조영제 조성물에 있어서, 상기 페로세닐메틸 메타크릴레이트를 기준으로 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2 내지 1 : 8인 것을 특징으로 한다. In the contrast medium composition according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol based on the ferrocenylmethyl methacrylate is characterized in that 1: 2 to 1: 8.
본 발명에 따른 조영제 조성물에 있어서, 상기 페로세닐메틸 메타크릴레이트, 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2.5 : 2.5인 것을 특징으로 한다. In the contrast medium composition according to the present invention, the molar ratio of ferrocenylmethyl methacrylate, methacrylic acid and polyethylene glycol is 1:2.5:2.5.
본 발명에 따른 조영제 조성물에 있어서, 상기 조영제는 활성산소 민감성 페로센 기반 나노 입자의 중량을 기준으로 0.1 내지 0.5 중량%의 양으로 함유된 것을 특징으로 한다. In the contrast medium composition according to the present invention, the contrast medium is characterized in that it is contained in an amount of 0.1 to 0.5% by weight based on the weight of the active oxygen-sensitive ferrocene-based nanoparticles.
본 발명에 따른 조영제 조성물에 있어서, 상기 조영제는 플루오레세인(fluorescein), FITC(fluorescein isothiocyanate), 오레곤 그린(Oregon green) 및 텍사스 레드(Texas red)로 구성된 군으로부터 선택되는 같은 잔틴(Xanthene) 유도체; Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, 인도카르보사이아닌(indocarbocyanine), 로다민(rhodamine), 옥사카르보사이아닌(oxacarbocyanine), 티아카르보사이아닌(thiacarbocyanine) 및 메로사이아닌(merocyanine)로 구성된 군으로부터 선택되는 사이아닌 유도체(cyanien derivatives); 피리딜록사졸(pyrodyloxazole), 니트로벤족사디아졸(nitrobenzoxadiazole), 및 벤족사디아졸(benzoxadiazole)로 구성된 군으로부터 선택되는 옥사디아졸(oxadiazole) 유도체; 나일 레드(Nile red), 나일 오렌지(Nile orange), 및 아크리딘 옐로우(acridine yellow)로 구성된 군으로부터 선택되는 아크리딘 유도체(acridine derivative); 오마린(aumarine), 크리스탈 바이올렌(crystal violet), 및 말라카이트 그린(malachite green)으로 구성된 군으로부터 선택되는 아릴메틴 유도체(arylmethine derivative); 포르핀(porphin), 프탈로사이아닌(phthalocyanine) 및 빌리루빈(bilirubin)로 구성된 군으로부터 선택되는 테트라피롤 유도체(tetrapyrrole derivative); 및 X-SIGHT, Pz 247, DyLight 750, DyLight 800, Alexa Fluor 680, Alexa Fluor 750, IRDye 680, IRDye 800CW, 인도시아닌 그린(indocyanine green) 및 양성이온근적외광 형광체(zwitterionic near-infrared fluorophores)로 구성된 군으로부터 선택되는 근적외광 형광체(NIR fluorophore)로 이루어진 군으로부터 선택되는 하나 또는 그 이상인 적을 특징으로 한다. In the contrast medium composition according to the present invention, the contrast medium is a xanthene derivative selected from the group consisting of fluorescein, fluorescein isothiocyanate (FITC), Oregon green and Texas red; Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, indocarbocyanine, rhodamine, oxacarbocyanine, thiacarbocyanine and merocyanine; oxadiazole derivatives selected from the group consisting of pyrodyloxazole, nitrobenzoxadiazole, and benzoxadiazole; an acridine derivative selected from the group consisting of Nile red, Nile orange, and acridine yellow; an arylmethine derivative selected from the group consisting of aumarine, crystal violet, and malachite green; tetrapyrrole derivatives selected from the group consisting of porphin, phthalocyanine and bilirubin; and X-SIGHT, Pz 247, DyLight 750, DyLight 800, Alexa Fluor 680, Alexa Fluor 750, IRDye 680, IRDye 800CW, indocyanine green, and zwitterionic near-infrared fluorophores. Characterized by one or more enemies selected from the group.
제6구현예에 따르면, According to the sixth embodiment,
(a) 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA) 및 폴리에틸렌글리콜 (polyethylene glycol, PEG)을 포함하는 활성산소 민감성 페로센 기반 나노입자; 및(a) active oxygen sensitive ferrocene-based nanoparticles including ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol (PEG); and
(b) 상기 활성산소 민감성 페로센 기반 나노입자에 담지된 항암제 및 조영제를 포함하는 암 진단 및 치료용 조성물을 제공하고자 한다. (b) It is intended to provide a composition for diagnosing and treating cancer including an anticancer agent and a contrast agent loaded on the active oxygen-sensitive ferrocene-based nanoparticles.
본 발명에 따른 암 진단 및 치료용 조성물에 있어서, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 0.2 내지 1 : 2인 것을 특징으로 한다. 바람직하기는, 상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 1일 수 있다. In the composition for diagnosing and treating cancer according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol is 1: 0.2 to 1: 2. Preferably, the molar ratio of methacrylic acid and polyethylene glycol may be 1:1.
본 발명에 따른 암 진단 및 치료용 조성물에 있어서, 상기 페로세닐메틸 메타크릴레이트를 기준으로 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2 내지 1 : 8인 것을 특징으로 한다. In the cancer diagnosis and treatment composition according to the present invention, the molar ratio of methacrylic acid and polyethylene glycol based on the ferrocenylmethyl methacrylate is characterized in that 1: 2 to 1: 8.
본 발명에 따른 암 진단 및 치료용 조성물에 있어서, 상기 페로세닐메틸 메타크릴레이트, 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2.5 : 2.5인 것을 특징으로 한다. In the composition for diagnosing and treating cancer according to the present invention, the molar ratio of ferrocenylmethyl methacrylate, methacrylic acid and polyethylene glycol is 1:2.5:2.5.
본 발명에 따른 암 진단 및 치료용 조성물에 있어서, 상기 항암제는 활성산소 민감성 페로센 기반 나노 입자의 중량을 기준으로 1 내지 5 중량%의 양으로 함유된 것을 특징으로 한다. In the cancer diagnosis and treatment composition according to the present invention, the anticancer agent is characterized in that it is contained in an amount of 1 to 5% by weight based on the weight of the active oxygen-sensitive ferrocene-based nanoparticles.
본 발명에 따른 암 진단 및 치료용 조성물에 있어서, 상기 항암제는 파클리탁셀(paclitaxel), 독소루비신 (doxorubicin), 시스플라틴(cis-platin), 도데탁셀(docetaxel), 타목시펜(tamoxifen), 캄토세신(camtothecin), 아나스테로졸(anasterozole), 카보플라틴(carboplatin), 토포테칸(topotecan), 베로테칸(belotecan), 이리노테칸 (irinotecan), 글리벡(gleevec), 빈크리스틴(vincristine), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐타존(phenyltazone), 메소트렉세이트(methotrexate), 시클로포스파미드 (cyclophosphamide), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 또는 코르티코스테로이드인 것을 특징으로 한다. In the composition for diagnosing and treating cancer according to the present invention, the anticancer agent is paclitaxel, doxorubicin, cis-platin, docetaxel, tamoxifen, camtothecin, anasterozole, carboplatin, topotecan, and berotecan. otecan, irinotecan, gleevec, vincristine, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenyltazone, methotrexate, cyclophosphamide amide), mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone, or a corticosteroid.
본 발명에 따른 암 진단 및 치료용 조성물에 있어서, 상기 조영제는 활성산소 민감성 페로센 기반 나노 입자의 중량을 기준으로 0.1 내지 0.5 중량%의 양으로 함유된 것을 특징으로 한다. In the cancer diagnosis and treatment composition according to the present invention, the contrast agent is characterized in that it is contained in an amount of 0.1 to 0.5% by weight based on the weight of the active oxygen-sensitive ferrocene-based nanoparticles.
본 발명에 따른 암 진단 및 치료용 조성물에 있어서, 상기 조영제는 플루오레세인(fluorescein), FITC(fluorescein isothiocyanate), 오레곤 그린(Oregon green) 및 텍사스 레드(Texas red)로 구성된 군으로부터 선택되는 같은 잔틴(Xanthene) 유도체; Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, 인도카르보사이아닌(indocarbocyanine), 로다민(rhodamine), 옥사카르보사이아닌(oxacarbocyanine), 티아카르보사이아닌(thiacarbocyanine) 및 메로사이아닌(merocyanine)로 구성된 군으로부터 선택되는 사이아닌 유도체(cyanien derivatives); 피리딜록사졸(pyrodyloxazole), 니트로벤족사디아졸(nitrobenzoxadiazole), 및 벤족사디아졸(benzoxadiazole)로 구성된 군으로부터 선택되는 옥사디아졸(oxadiazole) 유도체; 나일 레드(Nile red), 나일 오렌지(Nile orange), 및 아크리딘 옐로우(acridine yellow)로 구성된 군으로부터 선택되는 아크리딘 유도체(acridine derivative); 오마린(aumarine), 크리스탈 바이올렌(crystal violet), 및 말라카이트 그린(malachite green)으로 구성된 군으로부터 선택되는 아릴메틴 유도체(arylmethine derivative); 포르핀(porphin), 프탈로사이아닌(phthalocyanine) 및 빌리루빈(bilirubin)로 구성된 군으로부터 선택되는 테트라피롤 유도체(tetrapyrrole derivative); 및 X-SIGHT, Pz 247, DyLight 750, DyLight 800, Alexa Fluor 680, Alexa Fluor 750, IRDye 680, IRDye 800CW, 인도시아닌 그린(indocyanine green) 및 양성이온근적외광 형광체(zwitterionic near-infrared fluorophores)로 구성된 군으로부터 선택되는 근적외광 형광체(NIR fluorophore)로 이루어진 군으로부터 선택되는 하나 또는 그 이상인 적을 특징으로 한다. In the composition for diagnosing and treating cancer according to the present invention, the contrast medium is selected from the group consisting of fluorescein, fluorescein isothiocyanate (FITC), Oregon green and Texas red. Xanthene derivatives; Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, indocarbocyanine, rhodamine, oxacarbocyanine, thiacarbocyanine and merocyanine; oxadiazole derivatives selected from the group consisting of pyrodyloxazole, nitrobenzoxadiazole, and benzoxadiazole; an acridine derivative selected from the group consisting of Nile red, Nile orange, and acridine yellow; an arylmethine derivative selected from the group consisting of aumarine, crystal violet, and malachite green; tetrapyrrole derivatives selected from the group consisting of porphin, phthalocyanine and bilirubin; and X-SIGHT, Pz 247, DyLight 750, DyLight 800, Alexa Fluor 680, Alexa Fluor 750, IRDye 680, IRDye 800CW, indocyanine green, and zwitterionic near-infrared fluorophores. Characterized by one or more enemies selected from the group.
이하에서는 본 발명을 실시예에 의하여 더욱 상세히 설명한다. 그러나, 본 발명이 이하의 실시예에 의하여 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail by examples. However, the present invention is not limited by the following examples.
<실시예> <Example>
실시예 1. PEG-ferrocene 고분자의 제조Example 1. Preparation of PEG-ferrocene polymer
단량체로서 페로세닐메틸 메타크릴레이트 (ferrocenylmethyl methacrylate, FMMA), 메타크릴산 (methacrylic acid, MA), 및 폴리에틸렌글리콜 메틸 에테르 메카트릴레이트 (poly(ethylene glycol) methyl ether methacrylate, PEGMA)를 이용하여 3종의 PEG-ferrocene 고분자를 제조하였다. 먼저, FMMA (0.4 mmol)를 2 ml 테트라하이드로퓨란 (THF)에 녹이고, 하기 표 1에 나타낸 몰비에 따라 MA 및 PEGMA를 첨가한 후, 아조비시소부티로니트릴 (AIBN)를 넣고 70℃에서 24시간 magnetic stirring하여 중합시켜 고분자를 제조하였다. 제조된 고분자는 다음 실험을 위하여 사용 전 4℃에서 보관하였다.Three PEG-ferrocene polymers were prepared using ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA), and poly(ethylene glycol) methyl ether methacrylate (PEGMA) as monomers. first, FMMA (0.4 mmol) was dissolved in 2 ml tetrahydrofuran (THF), MA and PEGMA were added according to the molar ratio shown in Table 1, and then azobisisobutyronitrile (AIBN) was added and polymerized by magnetic stirring at 70 ° C. for 24 hours to prepare a polymer. The prepared polymer was stored at 4°C before use for the next experiment.
실시예 2. PEG-ferrocene 나노 입자 (PFNP)의 제조 및 특성 평가Example 2. Preparation and characterization of PEG-ferrocene nanoparticles (PFNP)
상기 실시예 1에서 제조된 각각의 PEG-ferrocene 고분자 용액 (100 mg/ml)을 1ml THF에 농도 5 mg/ml로 희석하였다. 530 rpm에서 magnetic stirring 중인 5 ml 3차 증류수 (DI water, deionized water)에 희석한 고분자 용액을 천천히 한 방울씩 떨어트렸다. 나노 입자의 안정화를 위해 5분간 더 stirring하고 2시간 동안 진공 상태에서 THF를 제거하였다. 이때, 상기 실시예 1에서 제조한 고분자 Poly-PC-1, Poly-PC-2 및 Poly-PC-3를 이용하여 제조된 PEG-페로센 기반 나노입자 (PEG-ferrocene nano particle, PFNP)를 각각 PFNP1, PFNP2 및 PFNP3로 명명하였다. Each PEG-ferrocene polymer solution (100 mg/ml) prepared in Example 1 was diluted to a concentration of 5 mg/ml in 1ml THF. The polymer solution diluted in 5 ml of tertiary distilled water (DI water, deionized water) under magnetic stirring at 530 rpm was slowly dropped drop by drop. To stabilize the nanoparticles, stirring was performed for 5 minutes and THF was removed under vacuum for 2 hours. At this time, PEG-ferrocene nanoparticles (PEG-ferrocene nano particles, PFNP) prepared using the polymers Poly-PC-1, Poly-PC-2 and Poly-PC-3 prepared in Example 1 were respectively PFNP1, PFNP2 and PFNP3.
2-1. 특성 평가2-1. Characteristic evaluation
상기 제조된 PFNP 3종의 크기, 분산값, 표면전하를 DLS (ELSZ-2000, Otsuka, Osaka, Japan)를 이용해 분석하였다. 그 결과, 3종의 PFNP 크기는 모두 약 165 nm 내지 138 nm이었으며, 분산값도 모두 0.3 미만으로 크기가 균일하게 제조된 것으로 확인되었다. 또한, 표면전하의 경우 MA의 몰비율이 적을수록 카복실기의 수가 줄어들어 less negative인 것으로 나타났다 (도 1).The size, dispersion value, and surface charge of the three prepared PFNPs were analyzed using DLS (ELSZ-2000, Otsuka, Osaka, Japan). As a result, the sizes of all three types of PFNPs were about 165 nm to 138 nm, and all dispersion values were less than 0.3, confirming that the sizes were uniformly prepared. In addition, in the case of surface charge, as the molar ratio of MA decreased, the number of carboxyl groups decreased, indicating less negative (FIG. 1).
실시예 3. PEG-ferrocene 나노 입자 (PFNP)의 활성산소 반응성 및 안정성 평가Example 3. Evaluation of active oxygen reactivity and stability of PEG-ferrocene nanoparticles (PFNP)
상기 실시예 2에서 제조된 PFNP 3종의 ROS 반응성을 평가하기 위해 1 ml의 나노 입자 용액 (1 mg/ml)에 50 μl H2O2 (0.4 M)를 첨가하고, Rotatory shaker를 이용해 24시간 동안 반응시키면서 정해진 시간 (0, 2, 4, 8, 24h) 마다 나노 입자의 크기, 분산값 및 표면전하를 DLS를 이용해 분석하였다. 또한, 나노 입자 용액을 3일간 동결건조한 뒤, DI water, 생리식염수 (PBS) 및 소태아혈청 (FBS) 함유 PBS에 농도 1 mg/ml로 재분산시킨 후, 각각 4주, 5일, 및 72시간 동안 37℃, 100 rpm 인큐베이터에 보관하면서 나노 입자의 크기 및 분산값을 분석하여 안정성을 평가하였다. In order to evaluate the ROS reactivity of the three PFNPs prepared in Example 2, 50 μl H 2 O 2 (0.4 M) was added to 1 ml of the nanoparticle solution (1 mg / ml), and the reaction was performed for 24 hours using a rotary shaker. The size, dispersion value, and surface charge of the nanoparticles were analyzed using DLS at predetermined times (0, 2, 4, 8, 24h). In addition, the nanoparticle solution was lyophilized for 3 days, then redispersed in DI water, physiological saline (PBS) and PBS containing fetal bovine serum (FBS) at a concentration of 1 mg / ml, and then 4 weeks, 5 days, and 72 hours. While stored in an incubator at 37 ° C. and 100 rpm, stability was evaluated by analyzing the size and dispersion of nanoparticles.
그 결과, 도 2로부터 알 수 있는 바와 같이 H2O2 처리 후 나노 입자의 크기가 크게 증가하였으며, 페로센이 소수성에서 친수성으로 변하면서 나노 입자가 깨져 부분적 침전이 발생하였다. 이 때 부분적 침전을 ▲으로 표시하였고 완전히 침전되어 크기가 측정이 불가능한 경우 N/D로 표시하였다. PEGMA의 몰 비율이 낮은 PFNP1와 PFNP2의 ROS 반응성은 빨라 H2O2 처리 후 4시간 만에 침전이 발생하였으며, PFNP3의 크기는 8시간 뒤 크게 증가하는 것으로 나타났다. 나노 입자의 분산값 또한 ROS 환경에서 크게 증가하였으며 표면전하는 줄어들어 neutral해진 것으로 확인되었다 (도 2). As a result, as can be seen from FIG. 2, the size of the nanoparticles greatly increased after the H 2 O 2 treatment, and ferrocene was changed from hydrophobic to hydrophilic, and the nanoparticles were broken, resulting in partial precipitation. At this time, partial precipitation was marked with ▲, and complete precipitation and the size of which could not be measured was marked with N/D. The ROS reactivity of PFNP1 and PFNP2 with a low molar ratio of PEGMA was fast, so precipitation occurred in 4 hours after H 2 O 2 treatment, and the size of PFNP3 increased significantly after 8 hours. The dispersion value of nanoparticles also greatly increased in the ROS environment, and it was confirmed that the surface charge decreased and became neutral (Fig. 2).
또한, PEGMA를 포함하지 않는 PFNP1는 동결건조 후 3차 증류수에 재분산한 경우 부분적 침전 (▲)이 발생하였으며 크기 및 분산값이 증가하였지만 PEGMA를 포함하는 PFNP2 및 PFNP3은 동결건조 전후의 크기 및 분산값 변화 없이 안정한 것으로 나타났다. 한편, PFNP1 내지 3를 3차 증류수에서 4주간 보관한 후 크기 및 분산값을 측정한 경우 PFNP3만 그 특성을 유지하였으며, 또한 PBS 및 serum-containing PBS에서도 PFNP3는 안정적으로 존재하는 것으로 확인되었다 (도 3 및 4). 따라서, PFNP3는 반응성 및 안정성이 모두 뛰어난 나노 캐리어로서 이용될 수 있음이 확인되었다. In addition, PFNP1 without PEGMA partially precipitated (▲) when re-dispersed in tertiary distilled water after freeze-drying, and the size and dispersion values increased. However, PFNP2 and PFNP3 containing PEGMA were stable with no change in size and dispersion before and after freeze-drying. On the other hand, when PFNP1 to 3 were stored in tertiary distilled water for 4 weeks and the size and dispersion values were measured, only PFNP3 maintained its properties, and it was confirmed that PFNP3 was stably present in PBS and serum-containing PBS (FIGS. 3 and 4). Accordingly, it was confirmed that PFNP3 can be used as a nanocarrier with excellent reactivity and stability.
<실험예> <Experimental example>
실험예 1. 파클리탁셀 및 나일 레드 담지된 PEG-ferrocene 나노 입자의 제조 및 특성평가Experimental Example 1. Preparation and Characterization of PEG-ferrocene Nanoparticles Supported with Paclitaxel and Nile Red
1-1. 파클리텍셀 담지된 PFNP (PTX@PFNP)의 제조1-1. Preparation of paclitaxel-supported PFNP (PTX@PFNP)
상기 실시예 1에서 제조된 고분자 Poly-PC-3를 THF (1 ml)에 5 mg/ml 농도로 희석시킨 후, PTX를 loading content가 0, 2, 5 및 10 wt%가 되도록 0, 100, 250 및 500 μg 첨가하였다. Rotatory shaking으로 1시간 반응시키고 magnetic stirring 중인 5 mL DI water에 천천히 한 방울씩 떨어트렸다. 5분간 magnetic stirring해 제조된 나노 입자를 안정화시키고 진공상태에서 2시간동안 유기용매를 제거하였다. 그 다음 3일 동안 동결건조시켜 파우더 상태의 PTX 담지된 PFNP3를 제조하고, DLS analysis를 통해 최적화된 PTX 로딩양을 확인하였다. 이때 안정성 평가를 위해 PTX@PFNP를 생리식염수에서 5일간 보관하면서 나노 입자의 크기 및 분산값을 상기 실시예 3과 동일한 방법으로 관찰하였다. After diluting the polymer Poly-PC-3 prepared in Example 1 to a concentration of 5 mg/ml in THF (1 ml), 0, 100, 250, and 500 μg of PTX were added so that the loading content was 0, 2, 5, and 10 wt%. After reacting for 1 hour with rotary shaking, the mixture was slowly added dropwise to 5 mL DI water under magnetic stirring. The prepared nanoparticles were stabilized by magnetic stirring for 5 minutes, and the organic solvent was removed for 2 hours in a vacuum state. Then, PFNP3 loaded with PTX in a powder state was prepared by lyophilization for 3 days, and the optimized PTX loading amount was confirmed through DLS analysis. At this time, while storing PTX@PFNP in physiological saline for 5 days to evaluate stability, the size and dispersion of nanoparticles were observed in the same manner as in Example 3.
1-2. 파클리텍셀 및 나일 레드 담지된 PFNP (PTX,NR@PFNP)의 제조1-2. Preparation of Paclitexel and Nile Red Supported PFNP (PTX,NR@PFNP)
PTX (100 μg), NR (5 μg) 및 Poly-PC-3 (5 mg)를 THF (1 ml)에 녹인 후 5 ml DI water에 한 방울씩 떨어트려 나노 입자를 제조하였다. 이 때 담지되지 않은 PTX와 NR을 Amicon Ultra-15 centrifugal filter (molecular weight cutoff 100 kDa; Merck Millipore, Billerica, MA, USA)를 이용해 spin filtration해서 제거하였다. After dissolving PTX (100 μg), NR (5 μg) and Poly-PC-3 (5 mg) in THF (1 ml), they were added dropwise to 5 ml DI water to prepare nanoparticles. At this time, unsupported PTX and NR were removed by spin filtration using an Amicon Ultra-15 centrifugal filter (molecular weight cutoff 100 kDa; Merck Millipore, Billerica, MA, USA).
1-3 특성 확인1-3 Check Characteristics
담지된 PTX와 NR의 양은 HPLC (Waters 2695, Waters Corp., Milford, MO, USA)와 microplate reader (SpectraMax iD3, Molecular devices, CA, USA)를 이용해 분석하였다. PTX는 C18 column (5 μm, 4.6 x 150 mm, SunFire®C18 colmn, Water, MO, USA)을 장착한 HPLC로 228 nm 파장대에서 유속 1 ml/min의 70% 아세토니트릴와 함께 20분간 분석하였다. NR는 microplate reader를 이용해 형광도 (Ex/Em = 530/635 nm)를 측정해 분석하였다. PTX와 NR의 loading content (LC)와 loading efficiency (LE)를 아래의 식을 이용해 계산하였다:The amount of supported PTX and NR was analyzed using HPLC (Waters 2695, Waters Corp., Milford, MO, USA) and microplate reader (SpectraMax iD3, Molecular devices, CA, USA). PTX was analyzed for 20 minutes with 70% acetonitrile at a flow rate of 1 ml/min in the 228 nm wavelength band with HPLC equipped with a C18 column (5 μm, 4.6 x 150 mm, SunFire®C18 collmn, Water, MO, USA). NR was analyzed by measuring fluorescence (Ex/Em = 530/635 nm) using a microplate reader. The loading content (LC) and loading efficiency (LE) of PTX and NR were calculated using the equation below:
PTX,NR@PFNP의 물리화학적 특성은 DLS와 transmission electron microscopy (TEM; JEM-2100Plus HR, JEOL, Tokyo, Japan)을 이용해 분석하였다. 또한, 실시예 3과 마찬가지의 방법으로 PTX와 NR 담지 후 나노 입자의 ROS 반응성 및 안정성을 평가하였다. 이 때 안정성 평가를 위해 PTX,NR@PFNP를 생리식염수에서 5일간 보관하면서 나노 입자의 크기 및 분산값을 관찰하였다. The physicochemical properties of PTX,NR@PFNP were analyzed using DLS and transmission electron microscopy (TEM; JEM-2100Plus HR, JEOL, Tokyo, Japan). In addition, in the same manner as in Example 3, the ROS reactivity and stability of the nanoparticles after carrying PTX and NR were evaluated. At this time, the size and dispersion of nanoparticles were observed while storing PTX,NR@PFNP in physiological saline for 5 days to evaluate stability.
그 결과, PTX를 5 wt%까지 로딩하는 경우 나노 입자의 크기, 분산값 및 표면 전하의 변화가 나타나지 않았으나, 10 wt%의 PTX를 로딩하는 경우 나노 입자의 크기 및 분산값이 크게 증가하는 것으로 나타났다 (도 5). PTX를 로딩한 나노 입자를 동결건조 후 3차 증류수에 다시 분산했을 때 5 wt% 및 10 wt% PTX를 로딩한 나노 입자는 크기가 불안정하였으며 또한 분산값이 커지는 것으로 나타났다. 따라서, PFNP3에 최적화된 PTX 로딩량은 2 wt%인 것으로 확인되었다 (도 6). 또한, 2 wt%의 PTX 및 0.1 wt%의 NR를 모두 PFNP3에 성공적으로 담지된 것으로 나타났으며, 산화제가 없는 PBS 내에서도 크기 및 분산값 변화 없이 5일 동안 안정하게 존재할 수 있음이 확인되었다 (도 7).As a result, when the PTX was loaded up to 5 wt%, the nanoparticle size, dispersion value, and surface charge did not change, but when the PTX concentration was 10 wt%, the nanoparticle size and dispersion value significantly increased (FIG. 5). When the PTX-loaded nanoparticles were lyophilized and then dispersed again in tertiary distilled water, the nanoparticles loaded with 5 wt% and 10 wt% PTX were unstable in size and showed an increase in dispersion value. Therefore, it was confirmed that the PTX loading amount optimized for PFNP3 was 2 wt% (FIG. 6). In addition, it was found that both 2 wt% of PTX and 0.1 wt% of NR were successfully loaded on PFNP3, and it was confirmed that they could exist stably for 5 days without change in size and dispersion value even in PBS without an oxidizing agent (FIG. 7).
실험예 2. PTX,NR@PFNP의 ROS 반응성 약물 방출 시험Experimental Example 2. ROS reactive drug release test of PTX,NR@PFNP
상기 제조된 PTX,NR@PFNP3을 Float-A-Lyzer G2 dialysis device (MWCO = 100kDa, Spectrapro/Pro dialysis membrance, Repligen, Massachsetts, USA)에 넣고, 10 ml PBS 또는 PBS 내 0.4 M H2O2에 넣고 37℃, 100 rpm 인큐베이터에서 24시간 동안 보관하였다. 정해진 시간 (20 min, 2, 4, 6, 8, 24h)마다 release medium을 모으고 새 release buffer로 교체하였다. 그 다음 release medium 내 방출된 PTX의 농도를 앞서 설명한 조건으로 HPLC를 이용해 분석하였다.The prepared PTX,NR@PFNP3 was placed in a Float-A-Lyzer G2 dialysis device (MWCO = 100 kDa, Spectrapro/Pro dialysis membrance, Repligen, Massachsetts, USA), added to 10 ml PBS or 0.4 MH 2 O 2 in PBS, and stored in an incubator at 37°C and 100 rpm for 24 hours. The release medium was collected and replaced with a new release buffer at predetermined times (20 min, 2, 4, 6, 8, 24 h). Then, the concentration of PTX released in the release medium was analyzed using HPLC under the conditions described above.
그 결과, 본 발명에 따른 PTX,NR@PFNP3는 24시간 후 30% PTX만이 방출되었으며, ROS 환경하에 약 2.5배 높은 양의 PTX를 방출하는 것으로 확인되었다. 따라서, 이를 통해 PTX,NR@PFNP가 ROS가 높은 질병 부위에 특정적으로 약물을 전달할 수 있는 플랫폼이 될 수 있음이 입증되었다 (도 8).As a result, it was confirmed that PTX,NR@PFNP3 according to the present invention released only 30% PTX after 24 hours, and released about 2.5 times higher amount of PTX under the ROS environment. Therefore, it was demonstrated that PTX,NR@PFNP can be a platform that can deliver drugs specifically to disease sites with high ROS (FIG. 8).
실험예 3. PTX,NR@PFNP의 in vitro 세포 독성 및 항암 효능 평가Experimental Example 3. Evaluation of in vitro cytotoxicity and anticancer efficacy of PTX,NR@PFNP
3-1. 실험 방법3-1. Experiment method
10% FBS와 1% Antibiotic-Antimycotic (AA)를 넣은 Dulbecco's modified Eagle's Medium (DMEM)에서 배양한 NIH 3T3 세포를 이용하여 PTX,NR@PFNP의 in vitro 세포독성을 평가하였다. 먼저 96-well plate에 NIH 3T3를 10,000 cells/well씩 분주하고 37℃, 5% CO2 인큐베이터에서 12시간 배양한 후, PFNP3 (0-200 μg/ml)를 24시간 동안 처리하였다. 세포 생존율을 분석하기 위해 Cell Counting Kit-8 (CCK-8) 용액 (Dojindo Laboratories, Kumamoto, Japan)을 처리 후 microplate reader를 이용해 파장대 450 nm에서 흡광도를 측정하였다.The in vitro cytotoxicity of PTX and NR@PFNP was evaluated using NIH 3T3 cells cultured in Dulbecco's modified Eagle's Medium (DMEM) supplemented with 10% FBS and 1% Antibiotic-Antimycotic (AA). First, 10,000 cells/well of NIH 3T3 was dispensed into a 96-well plate, cultured for 12 hours in a 37°C, 5% CO 2 incubator, and treated with PFNP3 (0-200 μg/ml) for 24 hours. In order to analyze cell viability, after treatment with Cell Counting Kit-8 (CCK-8) solution (Dojindo Laboratories, Kumamoto, Japan), absorbance was measured at a wavelength of 450 nm using a microplate reader.
10% FBS와 1% AA를 넣은 RPMI 1640에서 배양한 SCC-7 세포를 이용해 PTX,NR@PFNP의 in vitro 항암 효능을 평가하였다. 5,000개의 SCC-7 세포를 96-well plate의 각 well에 분주하고 12시간 배양하였다. 그 다음, PFNP (200 μg/ml), PTX (4 μg/ml), 그리고 PTX,NR@PFNP를 24시간 처리하고 CCK-8을 처리해 세포 생존율을 분석하였다. 이 때 ROS 반응 항암 효능 평가를 위하여 ROS level이 낮은 NIH 3T3 내에서 PTX와 PTX,NR@PFNP의 in vitro 항암 효능도 위와 동일한 방법으로 평가하였다. 두 세포, NIH 3T3와 SCC-7의 ROS level은 H2CDFDA (10 μM)을 90분간 처리하고 microplate reader로 ROS 반응 형광도 (Ex/Em = 485/535 nm)를 측정해 분석하였다. 더 나아가 ROS 억제제인 N-acetyl-L-cysteine (NAC)를 SCC-7 세포 내에 처리해 ROS level을 조절하여 PTX,NR@PFNP의 ROS 반응 항암 효능을 평가하였다. 이 때 NAC의 농도는 40 mM이었다.The in vitro anticancer efficacy of PTX,NR@PFNP was evaluated using SCC-7 cells cultured in RPMI 1640 containing 10% FBS and 1% AA. 5,000 SCC-7 cells were dispensed into each well of a 96-well plate and cultured for 12 hours. Then, PFNP (200 μg/ml), PTX (4 μg/ml), and PTX,NR@PFNP were treated for 24 hours, followed by CCK-8, and cell viability was analyzed. At this time, in order to evaluate ROS-responsive anti-cancer efficacy, the in vitro anti-cancer efficacy of PTX, PTX,NR@PFNP in NIH 3T3 with low ROS level was also evaluated in the same manner as above. The ROS level of two cells, NIH 3T3 and SCC-7, was analyzed by treating H 2 CDFDA (10 μM) for 90 minutes and measuring ROS fluorescence (Ex/Em = 485/535 nm) with a microplate reader. Furthermore, N-acetyl-L-cysteine (NAC), a ROS inhibitor, was treated in SCC-7 cells to control the ROS level, and the ROS-responsive anticancer efficacy of PTX,NR@PFNP was evaluated. At this time, the concentration of NAC was 40 mM.
3-2. 세포독성 및 항암 효능 평가3-2. Evaluation of cytotoxicity and anticancer efficacy
세포독성과 관련하여 PTX,NR@PFNP3를 200 μg/ml까지 NIH 3T3에 처리한 경우에도 90% 이상의 세포생존율을 나타내는 것으로 나타났다. 하였다 (도 10a). PTX,NR@PFNP3의 NIH 3T3 및 SCC-7 내에서의 항암 효능과 관련하여, PTX,NR@PFNP3를 처리한 경우 ROS level에 따라 ROS가 풍부한 SCC-7 세포 내에서 PTX,NR@PFNP의 항암효능이 SCC-7 세포 내에서의 항암효능 보다 현저히 우수한 것으로 확인되었다 (도 10b). 한편, ROS 억제제인 NAC를 SCC-7 세포 내 처리 여부에 따른 PTX,NR@PFNP의 ROS 반응성 항암효능의 경우 ROS level과 상관없이 PTX를 처리한 경우와 비슷한 수준의 세포 독성을 나타내는 것으로 확인되었다 (도 10c). 즉, 본 발명에 따른 PTX,NR@PFNP의 효능이 ROS에 의해 결정되는 것임이 입증되었다. Regarding cytotoxicity, even when PTX,NR@PFNP3 was treated with NIH 3T3 up to 200 μg/ml, cell viability was shown to be over 90%. (Fig. 10a). Regarding the anticancer efficacy of PTX,NR@PFNP3 in NIH 3T3 and SCC-7, when PTX,NR@PFNP3 was treated, the anticancer efficacy of PTX,NR@PFNP in ROS-rich SCC-7 cells was significantly superior to that in SCC-7 cells according to the ROS level (FIG. 10b). On the other hand, in the case of ROS-responsive anti-cancer efficacy of PTX,NR@PFNP depending on whether or not NAC, a ROS inhibitor, was treated in SCC-7 cells, it was confirmed that the cytotoxicity was similar to that of the case where PTX was treated regardless of the ROS level (FIG. 10c). That is, it was proved that the efficacy of PTX,NR@PFNP according to the present invention is determined by ROS.
실험예 4. PTX,NR@PFNP의 in vitro 세포 내 흡수율 평가Experimental Example 4. Evaluation of in vitro cell uptake of PTX, NR@PFNP
PTX,NR@PFNP의 in vitro 세포 내 흡수는 NR의 형광을 이용하여 관찰하였다. 먼저 SCC-7 (100,000 cells/well)을 12-well plate에 12시간 배양하고 NR 농도가 0.05 μg/ml인 PTX,NR@PFNP를 4, 8, 24시간 동안 처리하였다. 정해진 시간마다 PBS washing 후 세포의 형광 사진을 형광 현미경 (FLEXACAM C1, Leica Microsystemes, Wetzlar, Germany)을 이용해 찍었다. 또한 Image J software 1.8.0 (NIH, Bethesda, MD, USA)를 이용해 세포 내 축적된 나노 입자의 mean fluorescence intensity (MFI)를 측정하였다. In vitro cellular uptake of PTX,NR@PFNP was observed using NR fluorescence. First, SCC-7 (100,000 cells/well) was cultured in a 12-well plate for 12 hours, and PTX,NR@PFNP with NR concentration of 0.05 μg/ml was treated for 4, 8, and 24 hours. After PBS washing at predetermined times, fluorescence pictures of the cells were taken using a fluorescence microscope (FLEXACAM C1, Leica Microsystemes, Wetzlar, Germany). In addition, the mean fluorescence intensity (MFI) of nanoparticles accumulated in cells was measured using Image J software 1.8.0 (NIH, Bethesda, MD, USA).
그 결과, PTX,NR@PFNP가 처리된 시간에 따라 세포 내 축적된 입자의 형광 세기가 증가하였으며, 또한 세포 내 축적된 Nile Red의 mean fluorescence intensity 또한 PTX,NR@PFNP가 처리 시간에 따라 증가하는 것으로 나타났다. 따라서, 세포내 이입을 통해 흡수되는 나노 입자의 특성으로 인해, 본 발명에 따른 PTX,NR@PFNP가 PTX에 비해 보다 강한 항암 효능을 가질 수 있음이 입증되었다 (도 10).As a result, the fluorescence intensity of the particles accumulated in the cells increased with the treatment time of PTX,NR@PFNP, and the mean fluorescence intensity of Nile Red accumulated in the cells also increased with the treatment time of PTX,NR@PFNP. Therefore, it was demonstrated that PTX,NR@PFNP according to the present invention can have stronger anticancer efficacy than PTX due to the characteristics of nanoparticles absorbed through endocytosis (FIG. 10).
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시태양일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.Having described specific parts of the present invention in detail above, it will be clear to those skilled in the art that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (12)
Active oxygen sensitive ferrocene-based nanoparticles containing ferrocenylmethyl methacrylate (FMMA), methacrylic acid (MA) and polyethylene glycol (PEG).
상기 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 0.2 내지 1 : 2인 것을 특징으로 하는 것인, 활성산소 민감성 페로센 기반 나노입자.
According to claim 1,
The molar ratio of methacrylic acid and polyethylene glycol is 1: 0.2 to 1: 2, characterized in that, active oxygen-sensitive ferrocene-based nanoparticles.
상기 페로세닐메틸 메타크릴레이트를 기준으로 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2 내지 1 : 8인 것을 특징으로 하는 것인, 활성산소 민감성 페로센 기반 나노입자.
According to claim 1,
Based on the ferrocenylmethyl methacrylate, the molar ratio of methacrylic acid and polyethylene glycol is 1: 2 to 1: 8, characterized in that, active oxygen-sensitive ferrocene-based nanoparticles.
상기 페로세닐메틸 메타크릴레이트, 메타크릴산 및 폴리에틸렌글리콜의 몰비는 1 : 2.5 : 2.5인 것을 특징으로 하는 것인, 활성산소 민감성 페로센 기반 나노입자.
According to claim 1,
The molar ratio of ferrocenylmethyl methacrylate, methacrylic acid and polyethylene glycol is 1: 2.5: characterized in that 2.5, active oxygen sensitive ferrocene-based nanoparticles.
A drug delivery system comprising the active oxygen-sensitive ferrocene-based nanoparticles according to any one of claims 1 to 4, and a hydrophobic drug loaded on the active oxygen-sensitive ferrocene-based nanoparticles.
상기 소수성 약물은 활성산소 민감성 페로센 기반 나노 입자의 중량을 기준으로 1 내지 5 중량%의 양으로 함유된 것을 특징으로 하는 것인, 약물 전달체.
According to claim 5,
The hydrophobic drug is characterized in that contained in an amount of 1 to 5% by weight based on the weight of the active oxygen-sensitive ferrocene-based nanoparticles, drug delivery system.
상기 소수성 약물은 파클리탁셀(paclitaxel), 독소루비신 (doxorubicin), 시스플라틴(cis-platin), 도데탁셀(docetaxel), 타목시펜(tamoxifen), 캄토세신(camtothecin), 아나스테로졸(anasterozole), 카보플라틴(carboplatin), 토포테칸(topotecan), 베로테칸(belotecan), 이리노테칸 (irinotecan), 글리벡(gleevec), 빈크리스틴(vincristine), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐타존(phenyltazone), 메소트렉세이트(methotrexate), 시클로포스파미드 (cyclophosphamide), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 또는 코르티코스테로이드을 포함하는 항암제; 항바이러스제; 스테로이드계 소염제; 항생제; 항진균제; 비타민; 프로스타사이클린; 항대사제; 축동제; 아드레날린 길항제; 항경련제; 항불안제; 정온제; 항우울제; 마취제; 진통제; 동화성 스테로이드제; 면역 억제제 또는 면역 촉진제인 것을 특징으로 하는 것인, 약물 전달체.
According to claim 5,
The hydrophobic drugs include paclitaxel, doxorubicin, cis-platin, docetaxel, tamoxifen, camtothecin, anasterozole, carboplatin, topotecan, berotecan, irinotecan (iri notecan, gleevec, vincristine, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenyltazone, methotrexate, cyclophosphamide, mechlorethamine ethamine), dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone, or corticosteroids; antiviral agents; steroidal anti-inflammatory drugs; Antibiotic; antifungal agents; vitamin; prostacyclin; antimetabolites; mimics; adrenergic antagonists; anticonvulsants; anti-anxiety drugs; calming agent; antidepressants; anesthetic; painkiller; anabolic steroids; A drug delivery system characterized in that it is an immunosuppressant or immunostimulant.
A composition for diagnosing and treating cancer, comprising the active oxygen-sensitive ferrocene-based nanoparticles according to any one of claims 1 to 4, and an anticancer agent and a contrast agent loaded on the active oxygen-sensitive ferrocene-based nanoparticles.
상기 항암제는 활성산소 민감성 페로센 기반 나노 입자의 중량을 기준으로 1 내지 5 중량%의 양으로 함유된 것을 특징으로 하는 것인, 암 진단 및 치료용 조성물.
According to claim 8,
The anticancer agent is characterized in that it is contained in an amount of 1 to 5% by weight based on the weight of the active oxygen-sensitive ferrocene-based nanoparticles, cancer diagnosis and treatment composition.
상기 항암제는 파클리탁셀(paclitaxel), 독소루비신 (doxorubicin), 시스플라틴(cis-platin), 도데탁셀(docetaxel), 타목시펜(tamoxifen), 캄토세신(camtothecin), 아나스테로졸(anasterozole), 카보플라틴(carboplatin), 토포테칸(topotecan), 베로테칸(belotecan), 이리노테칸 (irinotecan), 글리벡(gleevec), 빈크리스틴(vincristine), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐타존(phenyltazone), 메소트렉세이트(methotrexate), 시클로포스파미드 (cyclophosphamide), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 또는 코르티코스테로이드인 것을 특징으로 하는 것인, 암 진단 및 치료용 조성물.
According to claim 8,
The anticancer agent is paclitaxel, doxorubicin, cis-platin, docetaxel, tamoxifen, camtothecin, anasterozole, carboplatin, topotecan, berotecan, irinotecan ), gleevec, vincristine, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenyltazone, methotrexate, cyclophosphamide, mechlorethamine ), dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone, or corticosteroid, characterized in that, cancer diagnosis and treatment composition.
상기 조영제는 활성산소 민감성 페로센 기반 나노 입자의 중량을 기준으로 0.1 내지 0.5 중량%의 양으로 함유된 것을 특징으로 하는 것인, 암 진단 및 치료용 조성물.
According to claim 8,
The contrast medium is characterized in that contained in an amount of 0.1 to 0.5% by weight based on the weight of the active oxygen-sensitive ferrocene-based nanoparticles, cancer diagnosis and treatment composition.
상기 조영제는 플루오레세인(fluorescein), FITC(fluorescein isothiocyanate), 오레곤 그린(Oregon green) 및 텍사스 레드(Texas red)로 구성된 군으로부터 선택되는 같은 잔틴(Xanthene) 유도체; Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, 인도카르보사이아닌(indocarbocyanine), 로다민(rhodamine), 옥사카르보사이아닌(oxacarbocyanine), 티아카르보사이아닌(thiacarbocyanine) 및 메로사이아닌(merocyanine)로 구성된 군으로부터 선택되는 사이아닌 유도체(cyanien derivatives); 피리딜록사졸(pyrodyloxazole), 니트로벤족사디아졸(nitrobenzoxadiazole), 및 벤족사디아졸(benzoxadiazole)로 구성된 군으로부터 선택되는 옥사디아졸(oxadiazole) 유도체; 나일 레드(Nile red), 나일 오렌지(Nile orange), 및 아크리딘 옐로우(acridine yellow)로 구성된 군으로부터 선택되는 아크리딘 유도체(acridine derivative); 오마린(aumarine), 크리스탈 바이올렌(crystal violet), 및 말라카이트 그린(malachite green)으로 구성된 군으로부터 선택되는 아릴메틴 유도체(arylmethine derivative); 포르핀(porphin), 프탈로사이아닌(phthalocyanine) 및 빌리루빈(bilirubin)로 구성된 군으로부터 선택되는 테트라피롤 유도체(tetrapyrrole derivative); 및 X-SIGHT, Pz 247, DyLight 750, DyLight 800, Alexa Fluor 680, Alexa Fluor 750, IRDye 680, IRDye 800CW, 인도시아닌 그린(indocyanine green) 및 양성이온근적외광 형광체(zwitterionic near-infrared fluorophores)로 구성된 군으로부터 선택되는 근적외광 형광체(NIR fluorophore)로 이루어진 군으로부터 선택되는 하나 또는 그 이상인 적을 특징으로 하는 것인, 암 진단 및 치료용 조성물. According to claim 8,
The contrast medium is a xanthene derivative selected from the group consisting of fluorescein, fluorescein isothiocyanate (FITC), Oregon green and Texas red; Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, indocarbocyanine, rhodamine, oxacarbocyanine, thiacarbocyanine and merocyanine; oxadiazole derivatives selected from the group consisting of pyrodyloxazole, nitrobenzoxadiazole, and benzoxadiazole; an acridine derivative selected from the group consisting of Nile red, Nile orange, and acridine yellow; an arylmethine derivative selected from the group consisting of aumarine, crystal violet, and malachite green; tetrapyrrole derivatives selected from the group consisting of porphin, phthalocyanine and bilirubin; and X-SIGHT, Pz 247, DyLight 750, DyLight 800, Alexa Fluor 680, Alexa Fluor 750, IRDye 680, IRDye 800CW, indocyanine green, and zwitterionic near-infrared fluorophores. A composition for diagnosing and treating cancer, characterized in that one or more enemies selected from the group.
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