KR20080019507A - A constrast medium comprising nanoparticles formed with amphiphilic polymer binding a near-infrared fluorochrome for diagnosing tumor - Google Patents
A constrast medium comprising nanoparticles formed with amphiphilic polymer binding a near-infrared fluorochrome for diagnosing tumor Download PDFInfo
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- KR20080019507A KR20080019507A KR1020060081977A KR20060081977A KR20080019507A KR 20080019507 A KR20080019507 A KR 20080019507A KR 1020060081977 A KR1020060081977 A KR 1020060081977A KR 20060081977 A KR20060081977 A KR 20060081977A KR 20080019507 A KR20080019507 A KR 20080019507A
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- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S607/00—Surgery: light, thermal, and electrical application
- Y10S607/901—Cancer detection
Abstract
Description
도 1은 본 발명의 암 조직에 표적성을 갖는 양친성 생체 고분자 및 형광체를 갖는 고분자 복합체 (담즙산-키토산-Cy5.5)와 그것을 이용한 나노 입자의 제조 방법을 도시하고 있고,1 shows a polymer composite (cholanic acid-chitosan-Cy5.5) having an amphiphilic biopolymer and a fluorescent substance having targeting properties to the cancer tissue of the present invention and a method for producing nanoparticles using the same.
도 2는 실시예 1에서 제조된 본 발명의 고분자 나노 입자의 광학적 특성을 CCD 이미지(도 2a) 및 형광 스펙트럼(도 2b)을 도시하고 있으며,FIG. 2 shows a CCD image (FIG. 2A) and a fluorescence spectrum (FIG. 2B) of the polymer nanoparticles of the present invention prepared in Example 1,
도 3은 실시예 1에서 제조된 본 발명의 담즙산-키토산-Cy5.5 나노 입자에 대한 전자 투과 현미경 (TEM) 사진이며,3 is an electron transmission microscope (TEM) photograph of the bile acid-chitosan-Cy5.5 nanoparticles of the present invention prepared in Example 1,
도 4는 3-7 mm 크기의 종양을 가진 누드 쥐의 육안 관찰 결과(a) 및 본 발명의 담즙산-키토산-Cy5.5 나노입자를 주입한 경우의 형광 필터를 이용한 근적외선 이미지(b)를 도시하고 있으며,Fig. 4 is a graph showing the result of visual observation (a) of a nude mouse having a tumor of 3-7 mm in size and a near infrared ray image (b) using a fluorescent filter when cholanic acid-chitosan-Ky5.5 nanoparticles of the present invention are injected However,
도 5는 본 발명의 담즙산-키토산-Cy5.5 나노입자에 항암제인 파클리택셀 (paclitaxel)을 봉입하여 종양을 가진 누드 쥐에 주입하였을 때, 주입한 후의 시간에 따른 본 발명의 나노입자가 종양 세포에 축적되는 정도를 영상화한 사진을 도시하고 있으며,FIG. 5 is a graph showing the results obtained when the bile acid-chitosan-Cy5.5 nanoparticles of the present invention were injected into a nude mouse having a tumor by packing an anti-cancer agent paclitaxel, Showing the degree of accumulation in the cells,
도 6은 본 발명의 담즙산-키토산-Cy5.5 나노입자에 항암제인 파클리택셀 (paclitaxel)을 봉입하여 종양을 가진 누드 쥐에 주입하는 경우, 그 시기 및 그 효과를 나타내고(도 6a), 또한 생체내의 암 치료 효과를 영상화한 사진(도 6b)을 도시하고 있다. FIG. 6 shows the timing and effect of injecting paclitaxel, which is an anticancer agent, into nude mice having tumors, in the bile acid-chitosan-Cy5.5 nanoparticles of the present invention (FIG. 6A) (Fig. 6 (b)) that images the effect of cancer treatment in vivo.
본 발명은 근적외선 형광체가 결합된 양친성 고분자 나노 입자를 포함하여 생체 내 암 조직을 비침투적으로 영상화하는 신규한 암 진단용 조영제에 관한 것이다.The present invention relates to a novel cancer diagnostic imaging agent that implements non-invasive imaging of cancer tissue in vivo, including amphiphilic polymer nanoparticles to which near infrared phosphors are bound.
상세하게는 암 조직 주변의 느슨한 신생 혈관의 높은 투과성 때문에 나타나는 EPR (enhanced permeability and retention) 효과에 의해서 암 조직에 선택적으로 축척이 되며, 비침투적 영상을 위해 근적외선 (near-infrared, NR) 투시가 가능한 근적외선 형광체 (Cy5.5)가 화학적 결합되어 있는 생체적합성/생분해성 고분자 및 근적외선 형광체 복합체의 나노입자에 관한 것이다. Specifically, the enhanced permeability and retention (EPR) effect due to the high permeability of loose neovasculature around the cancer tissue selectively scales to cancerous tissue and near-infrared (NR) penetration for non-invasive imaging Biocompatible / biodegradable polymer and near infrared ray fluorescent material composite in which the near-infrared ray fluorescent material (Cy5.5) is chemically bonded.
현재까지 암 진단은 X-ray, 조직 검사, 내시경에 의한 조사, 혈액 검사에 의한 조사 등의 방법에 의하여 주로 진단되었다. 그러나 상기 방법들은 암 조직의 크기가 1cm 이하의 조기 암을 진단하는 것은 통상적으로 불가능하다. 그러므로 암 조직의 크기가 1cm 이하의 작은 암을 영상화하는 기술은 암 치료 및 진단에 있어서 궁극적인 목표이다. 암 조기 진단의 중요성은 크기가 작으며 치료에 의해 영구적 내지는 장기간에 걸쳐 치유가 가능한 진행도의 암을 진단함으로써 치료 가능성을 높이고, 다른 장기로 전이가 되지 않은 상태에서 암을 외과적 수술이나 적절한 치료제로 비교적 조기에 치료가 가능하도록 하기 때문에 아주 중요하다. Until now, cancer diagnosis was mainly diagnosed by X-ray, histological examination, endoscopic examination, blood test. However, these methods are generally impossible to diagnose early cancers with cancer tissue sizes of less than 1 cm. Therefore, the technique of imaging small cancers of cancer size less than 1 cm is the ultimate goal in cancer treatment and diagnosis. The importance of early detection of cancer is small, and it is possible to improve the possibility of treatment by diagnosing progressive cancer which can be healed by permanent or long-term treatment by treatment. In case of not metastasizing to other organs, This is very important because it allows treatment to be performed relatively early.
현재까지 암 조기 진단을 위한 신규 조영제의 개발은 대부분 양전자 방출 단층 촬영 (position emission tomography : PET), 단일 광자 방출 단층 촬영 (single photon emission computed tomography : SPECT) 과 컴퓨터 단층 촬영 (computed tomography : CT)에 집중되어 있으며, 이는 현재 국내 병원의 방상선 관련 연구자 대부분이 PET/CT 또는 PET/SPECT에 관한 연구를 진행하고 있기 때문이다. 그러나 임상적으로 가장 많은 활용이 되고 있는 PET/CT 또는 PET/SPECT 영상 장비는 1cm 이하의 작은 암을 진단하는데 상당한 어려움이 있다.Up to now, the development of a new contrast agent for the early detection of cancer has been reported in most cases by positron emission tomography (PET), single photon emission computed tomography (SPECT) and computerized tomography This is because most of the researchers involved in radiation therapy in domestic hospitals are currently conducting research on PET / CT or PET / SPECT. However, PET / CT or PET / SPECT imaging equipment, which is the most widely used clinically, has considerable difficulties in diagnosing small cancers smaller than 1 cm.
최근에 암 조기 진단에서 광학 분자 영상 기술이 중요해졌다. 특히, 근적외선 파장 (650nm-900nm)의 스펙트럼 범위 내에서 흡수 및 형광 최대치를 갖고, 수 용해도가 높고 생체 적합성이 우수한 근적외선 형광체의 개발에 의해서, 생체 내 흡수가 최소화되고, 근적외선 투시에서 조직 내로 몇 센티미터를 통과할 수 있기 때문에, 다양한 광학 분자 영상 장치, 즉 형광내시경, CCD 카메라, 형광 단층 촬영 (fluorescence-medicated tomography; FMT)으로 암 조직의 영상이 가능하다.Recently, optical molecular imaging technology became important in early diagnosis of cancer. Particularly, by the development of a near infrared ray fluorescent substance having a maximum absorption and fluorescence within the spectral range of the near infrared ray wavelength (650 nm-900 nm), high water solubility and excellent biocompatibility, in vivo absorption is minimized, Imaging of cancerous tissue is possible with a variety of optical molecular imaging devices, such as fluorescent endoscopes, CCD cameras, and fluorescence-mediated tomography (FMT).
광학 분자 영상 기술을 이용한 암 조기 진단 기술은 암 조직에 표적성을 갖는 바이오마커, 항체 등에 근적외선 형광체를 화학적으로 결합시켜, 다양한 광학 분자 영상 장치로 암을 진단하는 방법이다. 한편, 암 조직에 과발현된 특정 단백질 분해 효소에 소광 효과 (quenching effect) 상태에서 고분자-Cy5.5 복합체가 분해 되어 선택적 근적외선 형광을 나타내는 신규 조영제를 이용하여 영상화하였다. (Nat Biotechnol. 1999. 17. 375-378). 상기의 방법은 암 조직의 표적성 및 암 조직에 과발현된 단백질 분해 효소의 절대량에 의존한 형광 세기를 나타낸다. 현재까지 근적외선 투시에 의한 암 조직 영상법은 기존의 PET/CT 또는 PET/SPECT 진단기술과 비교하여, 방사선 동위원소의 불필요성, 고해상도의 영상, 저렴한 비용 등의 장점을 가지고 있다. Early detection technology using optical molecular imaging technology chemically binds near-infrared phosphors to biomarkers and antibodies that have markers on cancer tissues and diagnoses cancer with various optical molecular imaging devices. On the other hand, polymer-Cy5.5 complex was degraded in a quenching effect on a specific protease overexpressed in cancer tissues and imaged using a new contrast agent exhibiting selective near-infrared fluorescence. (Nat Biotechnol, 1999. 17. 375-378). The above method shows the fluorescence intensity depending on the marking of cancer tissue and the absolute amount of proteolytic enzyme overexpressed in cancer tissue. To date, cancer tissue imaging by NIR has advantages such as radiation isotope redundancy, high-resolution imaging, and low cost compared to conventional PET / CT or PET / SPECT diagnostic techniques.
그러나 암의 조기 진단을 위한 가장 효율적인 방법은 암 조직에 선택적으로 근적외선 투시가 가능한 근적외선 형광체를 많이 전달하여, 작은 암 조직에서 높은 형광 세기를 나타내는 방법이 요구되어 진다. However, the most effective method for early diagnosis of cancer is to transmit a near infrared ray fluorescent substance capable of selectively near-infrared radiation to cancer tissue, and a method of exhibiting high fluorescence intensity in small cancer tissues is required.
이에 본 발명자들은 암 조직의 신생 혈관의 높은 투과율에 의해서 암 조직에 선택적으로 축척이 되는 고분자에 근적외선 투시가 가능한 근적외선 형광체를 화학적으로 결합하여 암 조기진단을 위한 고분자 나노입자형 신규 조영제를 개발함으로써 본 발명을 완성하였다. Accordingly, the present inventors have developed a novel polymer nanoparticle-type contrast agent for early diagnosis of cancer by chemically bonding a near infrared ray fluorescent substance capable of near-infrared ray penetration to a polymer selectively scaled to cancer tissue by high transmittance of cancer blood vessels Thereby completing the invention.
본 발명의 목적은 근적외선 형광체가 결합된 양친성 고분자 나노 입자를 포함하는 암 진단용 조영제를 제공하는 것으로, 상세하게는 암 조직의 신생 혈관의 높은 투과성으로 인하여 암 조직에 선택적으로 축적이 가능한 양친성 고분자 나노 입자 및 근적외선 형광체의 복합체를 제공한다.It is an object of the present invention to provide a cancer diagnostic diagnostic agent containing amphiphilic polymer nanoparticles to which a near infrared ray fluorescent substance is bound, and more particularly to an amphiphilic polymer capable of selectively accumulating in a cancer tissue due to high permeability of a neovascularization Nanoparticles and a near infrared ray fluorescent substance.
또한 본 발명의 다른 목적은 근적외선 형광체가 결합된 양친성 고분자 나노 입자에 소수성 암항제가 봉입된 것을 특징으로 하는 약물 전달체 조성물을 제공한 다.Another object of the present invention is to provide a drug delivery composition characterized in that a hydrophobic cancer antimicrobial agent is encapsulated in amphiphilic polymer nanoparticles to which a near infrared ray fluorescent substance is bound.
상기 목적을 달성하기 위하여, 본 발명은 근적외선 형광체가 결합된 양친성 고분자 나노 입자를 포함하는 암 진단용 조영제를 제공한다.In order to achieve the above object, the present invention provides a cancer diagnostic diagnostic agent comprising amphiphilic polymer nanoparticles to which a near infrared ray fluorescent substance is bound.
상기 양친성 고분자는 친수성 고분자 물질에 소수성 물질이 결합된 것임을 의미한다.The amphiphilic polymer means that a hydrophilic substance is bound to the hydrophilic polymer substance.
상기 친수성 고분자는 덱스트란 (dextran), 키토산 (chitosan), 글라이콜 키토산 (glycol chitosan), 폴리-L-라이신 (poly-L-lysine) 및 폴리아스파르트산 (poly-aspartic acid)으로 구성되는 그룹에서 선택되는 생체 고분자를 의미한다.The hydrophilic polymer may be selected from the group consisting of dextran, chitosan, glycol chitosan, poly-L-lysine and poly-aspartic acid. ≪ / RTI >
또한, 상기 친수성 고분자는 폴리(N-2-(하이드록시프로필)메타아크릴아마이드)(poly(N-2-(hydroxypropyl)methacrylamide), 폴리(디비닐 에테르-코-말레익 언하이드라이드)(poly(divinyl ehter-co-maleic anhydride)), 폴리(스틸렌-코-말레익 언하이드라이드)(poly(styrene-co-maleic anhydride)) 및 폴리(에틸렌 글라이콜)(poly(ethylene glycol))로 구성되는 그룹에서 선택되는 합성 고분자를 의미한다.The hydrophilic polymer may be selected from the group consisting of poly (N-2- (hydroxypropyl) methacrylamide), poly (divinyl ether-co-maleic anhydride) (ethylene-co-maleic anhydride), poly (styrene-co-maleic anhydride) and poly (ethylene glycol) &Quot; means a synthetic polymer selected from the group constituted.
또한 상기 친수성 고분자에 도입되는 소수성 물질은 디옥시콜린산 (deoxycholic acid), 타우로디옥시콜린산(taurodeoxycholic acid), 타우로콜린산 (taurocholic acid), 글리코케노디옥시콜린산 (glycochenodeoxyhoclic acid) 등의 담즙산 유도체; 스테아린산(steric acid), 올레인산(olelic acid) 등의 지방산 유도체이다.The hydrophobic substance introduced into the hydrophilic polymer may be at least one selected from the group consisting of deoxycholic acid, taurodeoxycholic acid, taurocholic acid, glycochenodeoxycholic acid, and the like. Bile acid derivatives; Stearic acid, oleic acid and the like.
상기 근적외선 형광체는 시아닌, 플루오레신(fluorescein), 테트라메틸로드아민(tetramethylrhodamine), 보디피(BODIPY) 및 알렉사(Alexa)로 구성되는 그룹에서 선택된다.The near infrared ray fluorescent substance is selected from the group consisting of cyanine, fluorescein, tetramethylrhodamine, BODIPY and Alexa.
또한, 본 발명의 근적외선 형광체가 결합된 양친성 고분자 나노입자에 추가로 방사선 동위원소, 양자점(quantum dot), MRI 조영제를 동시에 도입할 수 있다.Further, a radioisotope, a quantum dot, and an MRI contrast agent can be simultaneously introduced into the amphiphilic polymer nanoparticles to which the near infrared ray fluorescent material of the present invention is bound.
또한, 본 발명은 상기 근적외선 형광체가 결합된 양친성 고분자 나노 입자에 소수성 항암제를 봉입된 약물 전달체 조성물에 관한 것으로서, 상기 항암제로는 아드리아마이신, 택솔, 시스-플라틴(cis-platin), 미토마이신-C, 다우노마이신(daunomycin), 5-플루오로우라실(5-fluorouracil) 및 독소루비신(doxolubicin) 등의 항암제를 봉입할 수 있다. 상기 약물 전달체는 3일을 주기로 투여되는 것을 특징으로 한다.The present invention also relates to a drug delivery composition comprising a hydrophobic anticancer agent encapsulated in amphiphilic polymer nanoparticles to which the near infrared ray fluorescent substance is bound, wherein the anticancer agent includes adriamycin, taxol, cis-platin, mitomycin An anticancer agent such as C, daunomycin, 5-fluorouracil and doxolubicin can be enclosed. Wherein the drug delivery system is administered every three days.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 암 조기 진단의 비침투적 영상을 위하여 암 조기 진단의 효율성이 우수한 고분자 나노 입자를 제조하기 위한 것으로, 본 발명은 나노 입자로 된 양친성 고분자 및 근적외선 형광체의 복합체로 구성되어 암 조기 진단을 위해 1cm 이하의 작은 암 조직의 진단에 유용한 신규한 암 진단용 조영제를 제공한다.The present invention relates to a method for producing polymer nanoparticles excellent in early detection of cancer for non-invasive imaging of early diagnosis of cancer. The present invention comprises a complex of nanoparticulate amphiphilic polymer and near infrared ray fluorescent substance, The present invention provides a novel cancer diagnostic diagnostic agent useful for the diagnosis of small cancer tissues of 1 cm or less.
상기 고분자 나노 입자는 소수성과 친수성의 균형을 통해 나노 크기의 자기조립체 (self-assemblｙ) 혹은 자기 조립체 (self-aggregate)를 형성할 수 있으며, 암 조직에 선택적으로 축적될 수 있다. 또한, 고분자 나노 입자에 근적외선 투 시가 가능한 근적외선 형광체의 화학적 개질이 용이하다. 최종적으로 근적외선 투시에 의해 암 조직의 선택적인 강한 근적외선 형광을 나타낼 수 있다.The polymer nanoparticles can form nano-sized self-assemblies or self-aggregates by balancing hydrophobicity and hydrophilicity, and can selectively accumulate in cancer tissues. In addition, it is easy to chemically modify near-infrared phosphors capable of transmitting near-infrared rays to polymer nanoparticles. Finally, near-infrared light can show selective strong near-infrared fluorescence of cancer tissue.
상기 고분자는 생체적합성/생분해성을 갖는 고분자는 모두 사용될 수 있으며, 특히 암 조직에 대한 축적 효율이 높고 항암제의 약물 전달체로서 사용되는 생체고분자인 덱스트란 (dextran), 키토산 (chitosan), 글라이콜 키토산 (glycol chitosan), 폴리-L-라이신 (poly-L-lysine), 폴리아스파르트산 (poly-aspartic acid) 등이 사용될 수 있다. 또한 생체 고분자 이외에 폴리(N-2-(하이드록시프로필)메타아크릴아마이드)(poly(N-2-(hydroxypropyl)methacrylamide), 폴리(디비닐 에테르-코-말레익 어하이드라이드)(poly(divinyl ehter-co-maleic anhydride)), 폴리(스틸렌-코-말레익 언하이드라이드)(poly(styrene-co-maleic anhydride)) 또는 폴리(에틸렌 글라이콜)(poly(ethylene glycol))등의 합성 고분자도 사용될 수 있다. 이들 고분자들은 모두 친수성이다.The polymer may be any of biocompatible / biodegradable polymers. In particular, it is preferable to use dextran, chitosan, glycollate, or the like, which is a biomolecule used as a drug delivery system of a cancer drug, Glycol chitosan, poly-L-lysine, polyaspartic acid and the like can be used. In addition to the biopolymers, poly (N-2- (hydroxypropyl) methacrylamide), poly (divinyl (n-2- (hydroxypropyl) methacrylamide) maleic anhydride), poly (styrene-co-maleic anhydride) or poly (ethylene glycol) (poly (ethylene glycol) Polymers can also be used. These polymers are all hydrophilic.
상기 고분자 중에서 글라이콜 키토산이 가장 바람직하며, 글라이콜 키토산은 고분자 사슬 내에 양전자를 많이 함유하고 있어 나노 입자를 제조할 경우, 암 조직에 축척 효율이 현저히 탁월하며, 글라이콜 키토산의 아민기는 소수성 물질 및 근적외선 형광체의 화학적 개질 유도에 가장 적합하다.Among these polymers, glycol chitosan is the most preferable, and glycol chitosan contains a lot of positrons in the polymer chain. When nanoparticles are produced, the scale efficiency of cancer tissue is remarkably excellent, and the amine group of glycol chitosan It is most suitable for inducing chemical modification of hydrophobic materials and near infrared phosphors.
상기 고분자 나노 입자는 생체 내에서 생체적합성/생분해성이 우수하며, 생체내의 안정성이 우수하여 혈액 내에서의 생체 분포도가 높아서 충분한 시간 동안 암 조직에 계속적으로 축적이 되는 특성이 있다.The polymer nanoparticles are excellent in biocompatibility / biodegradability in vivo, have excellent stability in the living body, have a high bio-distribution in blood, and have a characteristic of accumulating continuously in cancer tissues for a sufficient time.
상기 친수성 고분자에 결합되는 소수성 물질은 담즙산 및 디옥시콜린산 (deoxycholic acid), 타우로디옥시콜린산(taurodeoxycholic acid), 타우로콜린산 (taurocholic acid), 글리코케노디옥시콜린산 (glycochenodeoxyhoclic acid) 등의 담즙산 유도체; 스테아린산(steric acid), 올레인산(olelic acid) 등의 지방산 유도체가 사용될 수 있으며, 담즙산을 사용하는 것이 바람직하다.The hydrophobic substance bound to the hydrophilic polymer may be selected from the group consisting of bile acid and deoxycholic acid, taurodeoxycholic acid, taurocholic acid, glycochenodeoxyhoclic acid, and the like. Of bile acid derivatives; Fatty acid derivatives such as stearic acid, oleic acid and the like can be used, and it is preferable to use bile acid.
생체 내 광학 투시를 위해서 상기 양친성 고분자에 시아닌, 플루오레신, 테트라메틸로드아민, 보디피, 알렉사 등과 같은 형광체가 화학적으로 도입된다. 상기 형광체는 양친성 고분자 내의 소수성 물질에 결합하게 된다. 형광체 중에서 특히 시아닌계는 근적외선 빛을 방출 및 흡수하므로 세포, 혈액 및 생체 조직 등과 간섭 혹은 흡수가 최소화됨으로써 가장 바람직하며, 좋은 예는 Cy5.5이다. 근적외선 형광체로 개질된 고분자 나노입자는 근적외선 조사를 이용하여 생체 내 암 조직의 영상화가 가능하며, 방사선 동위원소, 양자점(quantum dot), MRI 조영제를 동시에 도입할 경우 다양한 복합 분자영상이 가능하다. Phosphors such as cyanine, fluorescein, tetramethylolamine, bodipy, and Alexa are chemically introduced into the amphiphilic polymer for in vivo optical penetration. The phosphor binds to the hydrophobic substance in the amphiphilic polymer. Of the phosphors, cyanine is most preferred because it emits and absorbs near-infrared light and thus minimizes interference or absorption with cells, blood and living tissue, and a good example is Cy5.5. The polymer nanoparticles modified with the near infrared ray fluorescent material can be visualized in vivo by using near-infrared irradiation. When a radioisotope, a quantum dot, and an MRI contrast agent are simultaneously introduced, various complex molecular images can be obtained.
본 발명의 근적외선 형광체가 결합된 양친성 고분자 나노입자는 수계에서 안정한 나노입자 구조를 가지며, 암 조직에 축적 효율이 높은 것이 바람직하다. 또한, 근적외선 투시가 암 조직 표적성을 갖는 높은 근적외선 형광 세기를 나타내는 것이 바람직하다. The amphiphilic polymer nanoparticles to which the near infrared ray fluorescent material of the present invention is bound have a stable nanoparticle structure in the water system and preferably have high accumulation efficiency in cancer tissue. Further, it is preferable that the near-infrared fluorescence exhibits a high near-infrared fluorescence intensity having cancer tissue targeting property.
또한, 본 발명은 근적외선 형광체가 결합된 양친성 고분자 나노입자는 암 조기 진단에 유용할 뿐만 아니라, 고분자 나노 입자에 소수성 함암제의 봉입이 가능함으로써, 암 진단과 치료를 동시에 수행할 수 있다.Further, the amphiphilic polymer nanoparticles to which the near infrared ray fluorescent substance is bound are useful for early diagnosis of cancer, and the hydrophobic cancer drug can be enclosed in the polymer nanoparticles, so that cancer diagnosis and treatment can be simultaneously performed.
본 발명의 가장 바람직한 조영제는 키토산 고분자인 친수성 글라이콜 키토산 에 소수성 물질로서 담즙산을 도입시켜 양친성 키토산 유도체를 제조한 후, 근적외선 형광체로서 Cy5.5를 화학적으로 결합시킨 것을 포함하는 것이다. 이와 같은 고분자 나노 입자를 형성하는 담즙산-키토산-Cy5.5 복합체는 하기의 일반식 (Ⅰ)로 나타낼 수 있다. The most preferred contrast agent of the present invention includes an amphipathic chitosan derivative prepared by introducing bile acid as a hydrophobic substance into a hydrophilic glycol chitosan as a chitosan polymer and then chemically bonding Cy5.5 as a near infrared ray fluorescent substance. The cholanic acid-chitosan-Cy5.5 complex forming such polymer nanoparticles can be represented by the following general formula (I).
일반식 (Ⅰ)In general formula (I)
상기 일반식 (Ⅰ)에서 A와 B는 글라이콜 키토산 고분자의 반복 구조인 N-아세틸글루코사민(N-aceylglucosamine)과 N-글루코사민(N-glucosamine) 유도체를 의미하며, C는 친수성 글라이콜 키토산에 소수성 기를 도입하기 위하여 N-글루코사민 유도체 아민의 소수성 담즙산, 지방산 등의 소수성 물질이 화학적으로 결합된 것을 의미하며, D는 나노 입자의 생체 내 영상을 위하여 N-글루코사민 유도체의 아민에 근적외선 형광체, 방사성 동위원소, 양자점 등이 화학적으로 결합되는 것을 의미한다. 또한, a와 b는 글라이콜 키토산의 분자량에 따라서 수 100에서 수 10,000 값을 가지는 것으로서, 글라이콜 키토산의 분자량의 범위에 제한받지 않고, c는 글라이콜 키토산의 나노입자를 제조하기 위하여 20 내지 100의 값을 가지며, d는 10-30이다. In the general formula (I), A and B represent N-acetylglucosamine and N-glucosamine derivatives, which are repeating structures of glycol chitosan polymer, C represents hydrophilic glycol chitosan Glucosamine derivative is chemically bonded to hydrophobic substances such as hydrophobic bile acids and fatty acids of the N-glucosamine derivative amine to introduce a hydrophobic group into the N-glucosamine derivative, and D is a near infrared ray fluorescent substance to the N-glucosamine derivative amine, Isotope, quantum dot, etc. are chemically bonded. Also, a and b are from several hundreds to several ten thousand, depending on the molecular weight of glycol chitosan Value is not limited to the range of the molecular weight of glycol chitosan, c has a value of 20 to 100 and d is 10 to 30 to prepare nanoparticles of glycol chitosan.
상기의 일반식 (Ⅰ)을 기초로 친수성 고분자는 키토산으로, 소수성 물질은 담즙산으로, 근적외선 형광체는 Cy5.5으로 하여 제조된 담즙산-키토산-Cy5.5 복합 체는 자기조립형 또는 자기응집된 형태의 나노 입자로 제조되며 그 크기는 수십에서 수백 나노 미터의 크기를 갖는다. 상기 고분자 나노입자의 복합체는 생체적합성이 우수하고 암 조직 내의 축적 효율이 우수하며, 근적외선, PET/SPECT, 및 CCD 카메라에 의해서 생체 내에서 영상이 가능하다. 특히, 담즙산-키토산-Cy5.5 나노입자 내에 소수성 항암제인 아드리아마이신, 택솔, 시스-플라틴(cis-platin), 미토마이신-C, 다우노마이신(daunomycin) 및 5-플루오로우라실(5-fluorouracil) 등의 약물 봉입이 가능하여 암 조기 진단 및 치료가 가능하다. 또한, 상기 담즙산-키토산-Cy5.5 복합체는 일반 저분자량의 조영제에 비하여 암 조직의 EPR 효과에 의한 암 조직에 대한 선택성이 높아 암 조직의 축적 효율이 현저히 탁월하며, 생체 내의 체류 기간이 저분자량의 조영제보다 크게 증가되어 암 조직의 장기적인 영상이 가능하다. The cholanic acid-chitosan-Cy5.5 complex prepared by preparing the hydrophilic polymer with chitosan, the hydrophobic substance with bile acid, and the near infrared ray fluorescent substance with Cy5.5 based on the above general formula (I) Of nanoparticles, the size of which is in the order of tens to hundreds of nanometers. The complex of the polymer nanoparticles is excellent in biocompatibility and has an excellent accumulation efficiency in cancer tissues and can be imaged in vivo by near infrared rays, PET / SPECT, and CCD cameras. Particularly, in the case of cholanic acid-chitosan-Cy5.5 nanoparticles, hydrophobic anticancer drugs adriamycin, taxol, cis-platin, mitomycin-C, daunomycin and 5-fluorouracil (5- fluorouracil) can be used for early diagnosis and treatment of cancer. In addition, the cholanic acid-chitosan-Cy5.5 complex has a higher selectivity for cancer tissues due to the EPR effect of cancer tissues than the conventional low molecular weight contrast agents, and thus the accumulation efficiency of cancer tissues is remarkably excellent, The contrast medium of the cancer is greatly increased, and long-term imaging of the cancer tissue is possible.
이하, 본 발명은 하기의 실시예 및 실험예에 의하여 더욱 상세히 설명한다. 그러나 하기의 실시예 및 실험예는 본 발명의 예시로써, 본 발명의 권리범위가 이에 의하여 제한되지 않는다.Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are illustrative of the present invention, and the scope of the present invention is not limited thereto.
실시예Example 1. One. 담즙산Bile acid -키토산-- Chitosan - Cy5Cy5 .5 복합체의 제조 .5 Preparation of complex
500mg의 글라이콜 키토산을 60㎖의 물에 용해시키고 90㎖의 메탄올을 가한 후, 100㎖의 메탄올에 담즙산(5-β-cholanic acid) 260mg을 용해시켜 글리콜 키토산 용액에 천천히 적하하였고, 280mg의 1-에틸-3-(3-디메틸-아미노프로필) 카보디 이미드(1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide; EDC)와 420mg의 N-하이드로숙신이미드(N-hydrosuccinimide;NHS)를 50㎖의 메탄올에 녹여 반응액에 가한 다음 상온에서 24시간 동안 교반하였다. 그 후 상기 반응액을 2일 동안 투석하여 미반응 담즙산을 제거한 후 동결 건조하여, 담즙산-글라이콜 키토산 복합체를 제조하였다.500 mg of glycol chitosan was dissolved in 60 ml of water and 90 ml of methanol was added. Then, 260 mg of 5-β-cholanic acid was dissolved in 100 ml of methanol and slowly added dropwise to the glycol chitosan solution. 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide (EDC) and 420 mg of N-hydrosuccinimide; NHS) was dissolved in 50 mL of methanol and added to the reaction solution, followed by stirring at room temperature for 24 hours. Thereafter, the reaction solution was dialyzed for 2 days to remove unreacted bile acid and then lyophilized to prepare a bile acid-glycol chitosan complex.
상기에서 제조된 담즙산-키토산 복합체 100mg를 20㎖의 물에 녹이고 20㎖의 DMSO을 가한 후, 2mg의 근적외선 형광체 Cy5.5의 단활성 하이드록시숙시미마이드 에스트레르 (monoreactive hydroxysuccimimide ester of Cy5.5, Cy-5.5-NHS)를 첨가하여 6시간 반응 후, 용액을 2일간 투석하여 미반응 Cy5.5를 제거한 후 동결 건조하여, 담즙산-글라이콜 키토산-Cy5.5 복합체를 제조하였으며, 이의 제조과정은 하기 반응식 1에서 보는 바와 같다.After 100 mg of the cholanic acid-chitosan complex prepared above was dissolved in 20 ml of water and 20 ml of DMSO was added thereto, 2 mg of a monoreactive hydroxysuccimimide ester of Cy5.5 with a near infrared ray fluorescent material Cy5.5, Cy-5.5-NHS) was added for 6 hours, and the solution was dialyzed for 2 days to remove unreacted Cy5.5 and lyophilized to prepare a bile acid-glycol chitosan-Cy5.5 complex. Is as shown in Scheme 1 below.
실험예Experimental Example 1. One. 담즙산Bile acid -- 글라이콜Glycoll 키토산- The chitosan- Cy5Cy5 .5 복합체의 광학적 특성 .5 Optical properties of composites
담즙산-글라이콜 키토산-Cy5.5 복합체의 광학적 특성을 관찰하기 위하여, 상기 실시예 1에서 제조한 담즙산-글라이콜 키토산-Cy5.5 복합체 1mg을 1㎖의 PBS에 녹인 후, 근적외선 투시와 형광 스펙트럼을 관찰하였다.In order to observe the optical properties of the cholanic acid-glycol chitosan-Cy5.5 complex, 1 mg of the cholanic acid-glycol chitosan-Cy5.5 complex prepared in Example 1 was dissolved in 1 ml of PBS, Fluorescence spectra were observed.
상기 실험 수행의 결과는 도 2에서 보는 바와 같이, 담즙산-글라이콜 키토산-Cy5.5의 근적외선 투시를 한 경우 CCD 카메라 이미지를 살펴보면 근적외선 파장에 서 높은 형광을 발하는 것을 알 수 있으며(도 2a 참조), 담즙산-글라이콜 키토산-Cy5.5 용액에 대한 형광스펙트럼의 경우 여기(exitation) 파장은 675nm이며, 발광(emission)파장은 694nm에서 나타남을 확인할 수 있었다(도 2b 참조). As shown in FIG. 2, when the cholanic acid-glycol chitosan-Cy5.5 was examined by near infrared ray, it was found that the fluorescence emitted from the CCD camera image had a high fluorescence at near infrared wavelengths ) And the fluorescence spectrum of the cholanic acid-glycol chitosan-Cy5.5 solution showed an exitation wavelength of 675 nm and an emission wavelength of 694 nm (see FIG. 2B).
실험예Experimental Example 2. 2. 담즙산Bile acid -- 글라이콜Glycoll 키토산- The chitosan- Cy5Cy5 .5의 나노 입자 형성 .5 formation of nanoparticles
상기 실시예 1에서 제조된 담즙산-글라이콜 키토산-Cy5.5 복합체를 1㎖의 PBS 용액에 녹인 후, 0.45 마이크로 필터로 여과하여 나노 입자를 형성한 후, 전자투과현미경 (TEM)으로 그 입자의 크기를 확인하였다.The cholanic acid-glycol chitosan-Cy5.5 complex prepared in Example 1 was dissolved in 1 ml of a PBS solution and then filtered with a 0.45 microfilter to form nanoparticles. The nanoparticles were then subjected to electrophoretic microscopy (TEM) .
그 결과, 도 3에서 보는 바와 같이 담즙산-글라이콜 키토산-Cy5.5 유도체에 대한 TEM 형상으로 약 100-300나노미터의 평균 입자를 갖는 것임을 확인할 수 있었다.As a result, as shown in FIG. 3, it was confirmed that the TEM image of cholanic acid-glycol chitosan-Cy5.5 derivative had an average particle size of about 100-300 nanometers.
실험예Experimental Example 3. 본 발명의 나노 입자의 암 조직 축적 효과 평가 3. Assessment of cancer tissue accumulation effect of the nanoparticles of the present invention
상기 실험예 2에서 제조한 담즙산-글라이콜 키토산-Cy5.5의 나노입자 용액 100㎕를 피부암 세포가 주입된 쥐에 정맥 주사한 후, 근적외선 조사를 실시하였다. 피부암 세포가 주입된 쥐에 본 발명의 나노 입자를 주입한 후, 일정 시간이 경과한 후에 근적외선 조사를 실시하여 1cm 이하의 작은 암 조직 영상을 획득하였다.100 μl of the cholanic acid-glycol chitosan-Ky5.5 nanoparticle solution prepared in Experimental Example 2 was intravenously injected into rats injected with skin cancer cells and then irradiated with near infrared rays. After injecting the nanoparticles of the present invention into rats injected with skin cancer cells, after a certain period of time, they were irradiated with near infrared rays to obtain small cancer tissue images of 1 cm or less.
그 결과, 도 4에서 보는 바와 같이 담즙산-글라이콜 키토산-Cy5.5의 나노 입자를 투여하여 암 조직의 근적외선 투시 영상을 보면, 쥐에 주입된 피부암의 경우 3-7mm 크기의 작은 암 조직의 영상이 가능함을 확인할 수 있었다. As a result, as shown in FIG. 4, the near infrared ray spectroscopic image of the cancer tissue by administering the cholanic acid-glycol chitosan-Cy5.5 nanoparticles showed that 3-7 mm small cancer tissue It was confirmed that the image was possible.
실험예Experimental Example 4. 항암제가 4. Anticancer drugs 봉입된Enclosed 고분자 나노 입자의 치료 효과 스크리닝 Screening of therapeutic effects of polymer nanoparticles
상기 실험예 2에서 제조된 담즙산-글라이콜 키토산-Cy5.5의 나노 입자에 항암제인 탁솔을 10%의 무게 비율로 봉입한 후, 피부암 세포가 주입된 쥐에 정맥 주사 한 후, 근적외선 조사를 실시하여, 고분자 나노입자의 암 조직 축척 효율 및 생체내에서의 생체분포도를 영상화하였다. 근적외선 조사를 이용하여 고분자 나노입자의 암 조직 축적 효율 및 체내 잔류 시간을 정량분석하여, 고분자 나노 입자형 약물전달체의 치료 주기 및 봉입된 약물의 양을 조절하여 최적의 치료효과를 결정하였다. 본 발명의 나노 입자 5 mg/kg을 종양 유발한 쥐의 정맥에 주입한 후 시간에 따라 나노 입자의 축적을 근적외선으로 확인하였다.The nanoparticles of cholanic acid-glycol chitosan-Cy5.5 prepared in Experimental Example 2 were encapsulated in a 10% weight ratio of anti-cancer agent, and then injected intravenously into rats injected with skin cancer cells, The cancer tissue scaling efficiency and the bio-distribution in vivo of the polymer nanoparticles were imaged. The optimal treatment effect was determined by quantitative analysis of the cancer tissue accumulation efficiency and the residence time of the polymer nanoparticles using the near infrared ray irradiation, by controlling the therapeutic period of the polymer nanoparticle drug delivery system and the amount of the encapsulated drug. After 5 mg / kg of the nanoparticles of the present invention were injected into the tumor-induced rat vein, accumulation of nanoparticles was confirmed by near-infrared rays over time.
그 결과, 도 5에서 보는 바와 같이 본 발명의 나노 입자를 투여하고 3일 후에 본 발명의 나노 입자가 암에 가장 많이 축적됨을 확인할 수 있었다. 따라서, 이를 근거로 하여 항암제 탁솔이 봉인된 나노입자를 이용한 치료 주기는 3일에 한 번씩 약물을 쥐 정맥에 투여하였다.As a result, as shown in FIG. 5, it was confirmed that the nanoparticles of the present invention were accumulated in cancer most 3 days after administration of the nanoparticles of the present invention. Therefore, based on this, the treatment period using the nanoparticles sealed with the anticancer agent Taxol was administered to the mouse vein once every three days.
그 결과, 도 6에서 보는 바와 같이 담즙산-글라이콜 키토산-Cy5.5의 나노 입자에 항암제 탁솔을 봉입한 것을 쥐의 정맥에 주입한 후 치료과정을 근적외선 투시로 스크리닝하는 기술을 나타내고(도 6a 참조), 본 발명의 항암제 탁솔이 봉입된 나노 입자를 투여한 경우는 그렇지 않은 대조군에 비하여 암의 치료가 있음을 확인할 수 있었는바(도 6b 참조), 이는 본 발명의 나노 입자가 암 조직에 대한 축적 효율이 탁월함을 증명하는 것임을 알 수 있다. As a result, as shown in Fig. 6, the technique of injecting the anticancer agent taxol into cholanic acid-glycol chitosan-Cy5.5 nanoparticles into the vein of mice and screening the treatment process with near-infrared light (Fig. 6 (See FIG. 6B), it was confirmed that the nanoparticles encapsulated with the anticancer agent Taxol of the present invention were treated with cancer as compared with the control group not treated with the nanoparticles encapsulated with Taxol, It is proved that the accumulation efficiency is excellent.
상기에서 살펴본 바와 같이, 본 발명의 근적외선 형광체가 결합된 양친성 고분자 나노 입자는 암 조직에 선택적으로 축적이 가능하여, 근적외선 조사 시 1cm 이하의 작은 암의 조기 진단도 가능하므로, 본 발명의 조영제는 암 조기 진단에 아주 유용한 발명이다. 또한 본 발명의 양친성 고분자 나노입자는 약물전달체로 사용할 수 있으며, 이를 인체에 주입할 경우 다양한 조직에서 발생하는 암 조직 치료에 사용이 가능하며 근적외선 투시로 비침습적 방법으로 영상이 가능함으로써 암 치료 효과 및 약물전달체의 효능을 평가하는 스크리닝 기술에 활용할 수 있는 아주 유용한 발명이다.As described above, since the amphiphilic polymer nanoparticles to which the near infrared ray fluorescent material of the present invention is bound can selectively accumulate in cancer tissues, it is possible to perform an early diagnosis of small cancers of 1 cm or less when irradiated with near infrared rays, It is a very useful invention for early diagnosis of cancer. In addition, the amphiphilic polymer nanoparticles of the present invention can be used as a drug delivery system. When injected into the human body, the nanoparticles of the present invention can be used for the treatment of cancer tissues occurring in various tissues. By the non-invasive method, And a screening technique for evaluating the efficacy of a drug delivery system.
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| KR101127402B1 (en) * | 2009-04-30 | 2012-06-12 | 한국과학기술연구원 | Pegylated amphiphilic polymeric nanoparticles abd uses thereof |
| KR20150111080A (en) * | 2014-03-25 | 2015-10-05 | 가톨릭대학교 산학협력단 | Surface charge switching nanoparticles for magnetic resonance imaging and preparing method thereof |
| KR20160000984A (en) * | 2014-06-25 | 2016-01-06 | 한양대학교 산학협력단 | Glucose-sensitive Nano Particle for Cancer Diagnosis and Therapy |
| KR20170052399A (en) * | 2015-11-04 | 2017-05-12 | 한국과학기술연구원 | Peptide-Based Dual-Fluorescence Nanoprobe for Early Diagnosis of Cancer Lymphnode Metastasis and Uses Thereof |
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| KR101093549B1 (en) * | 2008-09-25 | 2011-12-14 | 한국과학기술연구원 | A disease targeted peptide-conjugated amphiphilic chitosan based nanoparticle imaging agent for diagnosis of disease |
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| DE19539409C2 (en) * | 1995-10-11 | 1999-02-18 | Diagnostikforschung Inst | Contrast agent for near infrared diagnostics |
| EP1835888B1 (en) | 2005-01-14 | 2017-07-12 | Korea Institute of Science and Technology | Cholanic acid-chitosan complex forming self-aggregates and preparation method thereof |
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| KR101127402B1 (en) * | 2009-04-30 | 2012-06-12 | 한국과학기술연구원 | Pegylated amphiphilic polymeric nanoparticles abd uses thereof |
| KR20150111080A (en) * | 2014-03-25 | 2015-10-05 | 가톨릭대학교 산학협력단 | Surface charge switching nanoparticles for magnetic resonance imaging and preparing method thereof |
| KR20160000984A (en) * | 2014-06-25 | 2016-01-06 | 한양대학교 산학협력단 | Glucose-sensitive Nano Particle for Cancer Diagnosis and Therapy |
| KR20170052399A (en) * | 2015-11-04 | 2017-05-12 | 한국과학기술연구원 | Peptide-Based Dual-Fluorescence Nanoprobe for Early Diagnosis of Cancer Lymphnode Metastasis and Uses Thereof |
| WO2022173282A1 (en) * | 2021-02-09 | 2022-08-18 | 고려대학교 산학협력단 | Lung lesion localization multi-imaging contrast agent composition for restrictive lung resection |
| KR20230088595A (en) | 2021-12-10 | 2023-06-20 | 사단법인 김해하버드바이오이미징센터 | System and Method for Imaging Non Invasive using NIR Fluorophores for Removing Gossypiboma |
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