KR20160051995A - 광음향 조영효과 및 항암효과를 나타내는 알부민 나노입자 - Google Patents
광음향 조영효과 및 항암효과를 나타내는 알부민 나노입자 Download PDFInfo
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- KR20160051995A KR20160051995A KR1020140149641A KR20140149641A KR20160051995A KR 20160051995 A KR20160051995 A KR 20160051995A KR 1020140149641 A KR1020140149641 A KR 1020140149641A KR 20140149641 A KR20140149641 A KR 20140149641A KR 20160051995 A KR20160051995 A KR 20160051995A
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- nanoparticles
- albumin
- anticancer
- photoacoustic
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Abstract
본 발명은 광음향 조영효과 및 항암효과를 나타내는 알부민 나노입자에 관한 것으로서, 보다 상세하게는 상기 알부민 나노입자는 난용성(poorly water soluble) 물질 및 멜라닌(melanin)을 포함하고, 상기 나노입자의 직경은 100-300 nm이며, 상기 나노입자는 자기 집합체(self-aggregates)를 형성하는 광음향 조영효과 및 항암효과를 나타내는 나노입자를 제공한다. 본 발명의 나노입자를 인체 또는 동물에 주입할 경우 EPR 효과에 의해 암조직에 축적되어, 암 진단 및 치료를 동시에 할 수 있는 장점을 제공한다.
Description
본 발명은 광음향 조영효과 및 항암효과를 나타내는 나노메디슨에 관한 것으로, 보다 상세하게는 멜라닌 및 항암성 약물을 알부민 내부에 포함하여 광음향 조영효과 및 항암효과를 나타내는 나노입자에 관한 것이다.
광음향 영상 기술(Photoacoustic tomography, PAT)은 초음파 이미징의 높은 분해능과 광 이미징의 높은 대조비를 결합하는 방식으로 생체조직의 이미징에 적합한 영상화 기술이다. 이 기술은 확장성이 매우 좋아 가슴 속 수 센티미터에 있는 종양을 영상화하는데도 이용될 수 있다. 즉 레이저를 생체 조직에 조사하면 레이저의 짧은 전자기 펄스가 생체 조직에 흡수됨에 따라 조직 내에서 초기 초음파의 발생원으로 작용하는 조직 부위에서 음향 압력이 발생하고 이렇게 형성된 초음파들은 생체 조직의 표면에 도달하게 되는데 이를 영상화하는 것이 PAT 영상이다. 광음향 영상 기술은 레이저 빛으로 세포에 자극을 주어 세포가 초음파를 방출하도록 하고, 이 초음파를 검출하여 3D 영상을 만드는 원리이기도 하다. 광학영상법과 초음파 영상법을 결합한 광음향 영상 기술은 비침습성, 저렴함, 휴대성, 우수한 명암대조비 및 우수한 공간분해능을 두루 갖추고 있기에 차세대 고분해능 의료영상 기술로 많은 관심을 받고 있다. 현재 이 기술은 근본적으로 빛을 비추어 조사하는 방식이므로 신체의 영상화 깊이에 제한이 있다는 점에서 앞으로 더 많은 발전의 가능성은 있다. 하지만 현재의 영상화 깊이로도 다른 기술들을 보완할 수 있어 많은 활용성이 기대되는 기술이다.
한편, 의료 기술 및 치료의 기술의 발달에 따라서 현재의 진단과 치료를 동시에 진행하기 위한 테라그노시스(theragnosis)기술의 개발이 활발하게 연구되고 있다. 이러한 측면에서 PAT, CT, MR 또는 초음파 조영제를 담체로 약물을 전달함으로써 진단과 치료를 동시에 할 수 있는 조영제의 개발이 시도되고 있다. 하지만 일반적으로 PAT, CT, MR 또는 초음파 진단을 위하여 사용되는 초음파 조영제의 구조는 약물을 담을 수 있는 공간이 매우 협소하고, 포집되는 약물의 대다수가 수난용성 약물이기 때문에 충분한 약물을 적재하기 힘들어 치료의 효과를 비약적으로 상승시키기 어려운 문제가 있다.
상술한 문제를 해결하기 위해 KR 공개특허 10-2013-0010577호(발명의 명칭 : 수난용성 약물을 내부에 포함하는 알부민 나노입자 제조방법)에서는 비펩타이드성 중합체를 알부민과 혼합하여 회합체를 형성한 이후 나노입자를 제조하는 방법에 대해 개시하고 있고,
KR 공개특허 10-2003-0019242호(발명의 명칭 : 파클리탁셀 및 알부민의 나노입자의 제조방법)에서는 분말 형태인 파클리탁셀을 클로로포름을 함유하는 알부민 수용액에 첨가하여 수득된 혼합물을 고압 균질화 처리시켜 나노입자를 제조하는 방법에 대해 개시하고 있다.
그러나 상술한 특허 문헌은 알부민을 이용한 치료용 나노입자의 제조방법에 관한 것일 뿐, 치료 및 진단을 동시에 가능하게 할 수 있는 물질에 관한 것이 아니다.
본 발명자들은 암 환자의 치료와 진단을 동시에 진행할 수 있는 이중-목적(dual-purpose) 나노입자를 개발하기 위해 예의 연구 노력하였다. 그 결과 알부민에 항암 물질로서 파클리탁셀 및 멜라닌을 첨가하여 자기 접합 나노입자를 형성할 경우 나노입자가 EPR 효과에 의해 암조직에 축적되어, 암 진단 및 치료를 동시에 할 수 있다는 사실을 발견하여 본 발명을 완성하였다.
따라서 본 발명의 목적은 암 치료 및 진단용 알부민 나노입자를 제공하는데 있다.
본 발명의 또 다른 목적은 상기 나노입자의 제조방법을 제공하는데 있다.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.
본 발명은 암 치료 및 진단용 나노입자를 제공한다.
본 발명자들은 암 환자의 치료와 진단을 동시에 진행할 수 있는 이중-목적(dual-purpose) 나노입자를 개발하기 위해 예의 연구 노력하였다. 그 결과 알부민에 항암 물질로서 파클리탁셀 및 멜라닌을 첨가하여 자기 접합 나노입자를 형성할 경우 나노입자가 EPR 효과에 의해 암조직에 축적되어, 암 진단 및 치료를 동시에 할 수 있다는 사실을 확인하였다.
본 발명의 일 양태에 따르면, 본 발명은 알부민 나노입자(nanoparticle)에 있어서, 상기 알부민 나노입자는 난용성(poorly water soluble) 물질 및 멜라닌(melanin)을 포함하고, 상기 나노입자의 직경은 100-300 nm이며, 상기 나노입자는 자기 집합체(self-aggregates)를 형성하는 광음향 조영효과 및 항암효과를 나타내는 나노입자를 제공한다.
본 명세서에서 사용하는 용어 '이중-목적(dual-purpose)'은 본 발명의 나노물질이 진단 및 치료에 동시에 사용될 수 있음을 의미할 수 있다.
본 명세서에서 사용하는 용어 '알부민(human serum albumin)'은 생체세포나 체액중에 넓이 분포되어 있는 단순 단백질로 글로블린과 함께 세포의 기초물질을 의미할 수 있다.
본 명세서에서 사용하는 용어 '암'은 형질전환된 세포의 억제되지 않는 증식과 무질서한 성장 결과로 빚어지는 복합적인 질환을 일컬으며, 본 발명에서는 고형암을 의미한다. 고형암이란 혈액암을 제외한 덩어리로 이루어진 모든 암을 의미한다. 고형암의 종류는 간암(Hepatoma), 뇌종양(Brain Tumor), 양성성상세포종 (Low- grade astrocytoma), 악성성상세포종 (High-grade astrocytoma), 뇌하수체 선종 (Pituitary adenoma), 뇌수막종 (Meningioma), 뇌림프종 (CNS lymphoma), 핍지교종 (Oligodendroglioma), 두개내인종 (Craniopharyngioma), 상의세포종 (Ependymoma), 뇌간종양 (Brain stem tumor), 두경부 종양(Head & Neck Tumor), 후두암 (Larygeal cancer), 구인두암 (Oropgaryngeal cancer), 비강/부비동암 (Nasal cavity/PNS tumor), 비인두암 (Nasopharyngeal tumor), 침샘암 (Salivary gland tumor), 하인두암 (Hypopharyngeal cancer), 갑상선암 (thyroid cancer), 구강암 (Oral cavity tumor), 흉부종양(Chest Tumor), 소세포성 폐암 (Small cell lung cancer), 비소세포성 폐암 (NSCLC), 흉선암 (Thymoma), 종격동 종양 (Mediastinal tumor), 식도암 (Esophageal cancer), 유방암 (Breast cancer), 남성유방암 (Male breast cancer), 복부종양 (Abdomen-pelvis Tumor), 위암 (Stomach cancer), 담낭암 (Gall bladder cancer), 담도암 (Billiary tract tumor), 췌장암 (pancreatic cancer), 소장암 (Small intestinal tumor), 대장(직장)암 (Large intestinal tumor), 항문암 (Anal cancer), 방광암 (Bladder cancer), 신장암 (Renal cell carcinoma), 전립선암 (Prostatic cancer), 자궁경부암 (Cervix cancer), 자궁내막암 (Endometrial cancer), 난소암 (Ovarian cancer), 자궁육종 (Uterine sarcoma) 및 피부암(Skin Cancer)을 포함하나, 이에 한정되는 것은 아니다.
본 발명의 바람직한 양태에 따르면, 본 발명의 상기 난용성 물질은 유기계 난용성 약물일 수 있다.
상기 유기계는 분자내 탄소를 포함하는 물질에 대한 의미하는 것으로 이해할 수 있으며, 상기 난용성은 약리학적 활성 제제가 수성 용액 (예: 물, 생리식염수, 주사가능한 덱스트로스 용액 등) 중에 용해되지 않는 것을 의미할 수 있다.
상기 난용성의 의미를 용해도 기준에서 보다 상세히 설명하면 다음과 같다. USP/NF에서는 일반적으로 1 그램의 약물을 특정 온도에서(예: 1 g의 아스피린을 300 ml의 H2O, 5 ml의 에탄올 중에 25에서) 용해시키는데 필요한 용매의 용적으로서 용해도를 표현한다. 다른 참고문헌에서는 문헌[참조: Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition]에 제시된 하기 표 1에 주어진 것과 같은 보다 주관적인 용어를 사용하여 용해도를 기술할 수 있다.
표 1
그러므로, 본 발명의 용어 "난용성"은, 물을 용매로 사용하는 경우, 상기 표 1의 하위의 4개의 용해도 범주, 즉 "불충분한 가용성", "낮은 가용성", "매우 낮은 가용성" 및 "사실상 불용성 또는 불용성"에 속하는 약리학적 활성 제제를 포함할 수 있다.
상기 난용성 물질에는 약제학적 활성 제제, 진단 제제, 영양 제제 등을 포함할 수 있다.
약제학적 활성 제제의 예에는 진통제/해열제 (예: 아스피린, 아세트아미노펜, 이부프로펜, 나프록센 나트륨, 부프레노르핀 하이드로클로라이드, 프로폭시펜 하이드로클로라이드, 프로폭시펜 나프실레이트, 메페리딘 하이드로클로라이드, 하이드로모르폰 하이드로클로라이드, 모르핀 설페이트, 옥시코돈 하이드로클로라이드, 코데인 포스페이트, 디하이드로코데인 비타르트레이트, 펜타조신하이드로클로라이드, 하이드로코돈 비타르트레이트, 레보르판올 타르트레이트, 디플루니살, 트롤아민 살리실레이트, 날부핀 하이드로클로라이드, 메페남산, 부토르판올 타르트레이트, 콜린 살리실레이트, 부탈비탈, 페닐톨록사민 시트레이트, 디펜하이드라민 시트레이트, 메토트리메프라진, 신나메드린 하이드로클로라이드, 메프로바메이트 등); 마취제 (예: 사이클로프로판, 엔플루란, 할로탄, 이소플루란, 메톡시플루란, 아산화질소, 프로포폴 등); 항천식제 (예: 아젤라스틴(Azelastine), 케토티펜(Ketotifen), 트락사녹스(Traxanox) 등); 항생제 (예: 네오마이신, 스트렙토마이신, 클로람페니콜, 세팔로스포린, 암피실린, 페니실린, 테트라사이클린 등); 항우울제(예: 네포팜, 옥시페르틴, 독세핀 하이드로클로라이드, 아목사핀, 트라조돈 하이드로클로라이드, 아미트립틸린하이드로클로라이드, 마프로틸린 하이드로클로라이드, 페넬진 설페이트, 데시프라민 하이드로클로라이드, 노르트립틸린 하이드로클로라이드, 트라닐시프로민 설페이트, 플루옥세틴 하이드로클로라이드, 독세핀 하이드로클로라이드, 이미프라민 하이드로클로라이드, 이미프라민 파모에이트, 노르트립틸린, 아미트립틸린 하이드로클로라이드, 이소카복스아지드, 데시프라민 하이드로클로라이드, 트리미프라민 말레에이트, 프로트립틸린 하이드로클로라이드 등); 항당뇨병제 (예: 비구아니드, 호르몬, 설포닐우레아 유도체 등); 항진균제(antifungal agent)(예: 그리세오풀빈, 켈로코나졸, 암포테리신 B, 니스타틴(Nystatin), 칸디시딘 등); 항고혈압제 (예: 프로파놀롤, 프로파페논, 옥시프레놀롤, 니페디핀(Nifedipine), 레세르핀, 트리메타판 캄실레이트, 페녹시벤즈아민 하이드로클로라이드, 파르길린 하이드로클로라이드, 데세르피딘, 디아족사이드, 구아네티딘 모노설페이트, 미녹시딜, 레스신나민, 나트륨 니트로프루시드, 라우월피아 세르펜티나, 알세록실론, 펜톨아민 메실레이트, 레세르핀 등); 항염증제 (예: (비-스테로이드성) 인도메타신, 나프록센, 이부프로펜, 라미페나존, 피록시캄, (스테로이드성) 코르티손, 덱사메타손, 플루아자코르트, 하이드로코르티손, 프레드니솔론, 프레드니손 등); 항신생물제 (예: 아드리아마이신, 사이클로포스파미드, 악티노마이신, 블레오마이신, 두아노루비신, 독소루비신, 에피루비신, 미토마이신, 메토트렉세이트, 플루오로우라실, 카르보플라틴, 카르무스틴 (BCNU), 메틸-CCNU, 시스플라틴, 에토포시드, 인터페론, 캄프토테신 및 이의 유도체, 페네스테린, 탁산 및 이의 유도체 (예: 파클리탁셀 및이의 유도체, 도세탁셀 및 이의 유도체 등), 빈블라스틴, 빈크리스틴, 타목시펜, 피포설판 등); 항불안제 (예: 로라제팜, 부스피론 하이드로클로라이드, 프라제팜, 클로르디아제폭사이드 하이드로클로라이드, 옥사제팜, 클로라제페이트 디칼륨, 디아제팜, 하이드록시진 파모에이트, 하이드록시진 하이드로클로라이드, 알프라졸람, 드로페리돌, 할라제팜, 클로르메자논, 단트롤렌 등); 면역억제제 (예: 사이클로스포린, 아자티오프린, 미조리빈, FK506 (타크롤리무스) 등); 항편두통제 (예: 에르고타민 타르트레이트, 프로파놀롤 하이드로클로라이드, 이소메텝텐 무케이트, 디클로랄페나존 등); 진정제/수면제 (예: 바비투레이트 (예: 펜토바비탈, 펜토바비탈 나트륨, 세코바비탈 나트륨 등), 벤조디아자핀 (예: 플루라제팜 하이드로클로라이드, 트리아졸람, 토마제팜, 미다졸람 하이드로클로라이드 등) 등); 항협심증제 (예: 베타-아드레날린 차단제, 칼슘 채널 차단제 (예: 니페디핀, 딜티아젬 하이드로클로라이드 등); 니트레이트 (예: 니트로글리세린, 이소소르비드 디니트레이트, 펜타에리트리톨 테트라니트레이트, 에리트리틸 테트라니트레이트 등) 등); 항정신병제 (예: 할로페리돌, 록사핀 석시네이트, 록사핀 하이드로클로라이드, 티오리다진, 티오리다진 하이드로클로라이드, 티오틱센, 플루페나진 하이드로클로라이드, 플루페나진 데카노에이트, 플루페나진 에난테이트, 트리플루오페라진 하이드로클로라이드, 클로르프로마진 하이드로클로라이드, 페르페나진, 리튬 시트레이트, 프로클로르페라진 등); 항조병제(antimanic agent) (예: 리튬 카보네이트 등); 항부정맥제 (예: 브레틸륨 토실레이트, 에스몰롤 하이드로클로라이드, 베라파밀 하이드로클로라이드, 아미오다론, 엔카이니드 하이드로클로라이드, 디곡신, 디기톡신, 멕실레틴 하이드로클로라이드, 디소피라미드 포스페이트, 프로카이나미드 하이드로클로라이드, 퀴니딘 설페이트, 퀴니딘 글루코네이트, 퀴니딘폴리갈락투로네이트, 플레카이니드 아세테이트, 토카이니드 하이드로클로라이드, 리도카인 하이드로클로라이드 등); 항관절염제 (예: 페닐부타존, 설린닥, 페니실라민, 살살레이트, 피록시캄, 아자티오프린, 인도메타신, 메클로페나메이트 나트륨, 골드 나트륨 티오말레에이트, 케토프로펜, 오라노핀, 오로티오글루코스, 톨메틴 나트륨 등); 항통풍제(antigout agent) (예: 콜히친, 알로퓨리놀 등); 항응고제 (예: 헤파린, 헤파린 나트륨, 와파린 등); 혈전용해제 (예: 우로키나제, 스트렙토키나제, 알토플라제 등); 항섬유소용해제 (예: 아미노카프로산 등); 혈류학적 제제(hemorheologic agent) (예: 펜톡시필린 등); 항혈소판제 (예: 아스피린, 엠피린, 아스크립틴 등); 항경련제 (예: 발프로산, 디발프로에이트 나트륨, 페니토인, 페니토인 나트륨, 클로나제팜, 피리미돈, 페노바비톨, 페노바비톨 나트륨, 카바마제핀, 아모바비톨 나트륨, 메트석시미드, 메타비탈, 메포바비탈, 메페니토인, 펜석시미드, 파라메타디온, 에토토인, 페나세미드, 세코바비톨 나트륨, 클로라제페이트 디칼륨, 트리메타디온 등); 항파키슨제 (예: 에토석시미드 등); 항히스타민제/항소양제 (예: 하이드록시진 하이드로클로라이드, 디펜히드라민 하이드로클로라이드, 클로르페니라민 말레에이트, 브롬페니라민 말레에이트, 시프로헵타딘 하이드로클로라이드, 테르페나딘, 클레마스틴 푸마레이트, 트리프롤리딘 하이드로클로라이드, 카비녹사민 말레에이트, 디페닐피랄린 하이드로클로라이드, 페닌다민 타르트레이트, 아자타딘 말레에이트, 트리펠레나민 하이드로클로라이드, 덱스클로르페니라민 말레에이트, 메트딜라진 하이드로클로라이드, 트림프라진 타르트레이트 등); 칼슘 조절에 유용한 제제 (예: 칼시토닌, 부갑상선 호르몬 등); 항세균제 (예: 아미카신 설페이트, 아즈트레오남, 클로람페니콜, 클로람페니콜 팔미테이트, 클로람페니콜 나트륨 석시네이트, 시프로플록사신 하이드로클로라이드, 클린다마이신 하이드로클로라이드, 클린다마이신 팔미테이트, 클린다마이신 포스페이트, 메트로니다졸, 메트로니다졸 하이드로클로라이드, 젠타마이신 설페이트, 린코마이신 하이드로클로라이드, 토브라마이신 설페이트, 반코마이신 하이드로클로라이드, 폴리믹신 B 설페이트, 콜리스티메테이트 나트륨, 콜리스틴 설페이트 등); 항바이러스제 (예: 인터페론 감마, 지도부딘, 아만타딘 하이드로클로라이드, 리바비린, 아시클로비르 등); 항미생물제 (예: 세팔로스포린 (예: 세파졸린 나트륨, 세프라딘, 세파클로르, 세파피린 나트륨, 세프티족심 나트륨, 세포페라존 나트륨, 세포테탄 디나트륨, 세푸톡심 아조틸, 세포탁심 나트륨, 세파드록실 모노하이드레이트, 세프타지딤, 세팔렉신, 세팔로틴 나트륨, 세팔렉신 하이드로클로라이드 모노하이드레이트, 세파만돌 나페이트, 세폭시틴나트륨, 세포니시드 나트륨, 세포라니드, 세프트리악손 나트륨, 세프타지딤, 세파드록실, 세프라딘, 세푸록심나트륨 등), 페니실린 (예: 암피실린, 아목시실린, 페니실린 G 벤자틴, 사이클라실린, 암피실린 나트륨, 페니실린 G 칼륨, 페니실린 V 칼륨, 피페라실린 나트륨, 옥사실린 나트륨, 바캄피실린 하이드로클로라이드, 클록사실린 나트륨, 티카르실린 디나트륨, 아즐로실린 나트륨, 카르베니실린 인다닐 나트륨, 페니실린 G 칼륨, 페니실린 G 프로카인, 메티실린 나트륨, 나프실린 나트륨 등), 에리트로마이신 (예: 에리트로마이신 에틸석시네이트, 에리트로마이신, 에리트로마이신 에스톨레이트, 에리트로마이신 락토비오네이트, 에리트로마이신 시에아레이트, 에리트로마이신 에틸석시네이트 등), 테트라사이클린 (예: 테트라사이클린 하이드로클로라이드, 독시사이클린 하이클레이트, 미노사이클린 하이드로클로라이드 등) 등); 항감염제 (예: GM-CSF 등); 기관지 확장제 (예: 교감신경 모방제(sympathomimetic) (예: 에피네프린 하이드로클로라이드, 메타프로테레놀 설페이트, 테르부탈린 설페이트, 이소에타린, 이소에타린 메실레이트, 이소에타린 하이드로클로라이드, 알부테롤 설페이트, 알부테롤, 비톨테롤, 메실레이트 이소프로테레놀 하이드로클로라이드, 테르부탈린 설페이트, 에피네프린 비타르트레이트, 메타프로테레놀 설페이트, 에피네프린, 에피네프린 비타르트레이트 등), 항콜린제 (예: 이프라트로퓸 브로마이드 등), 크산틴 (예: 아미노필린, 디필린, 메타프로테레놀 설페이트, 아미노필린 등), 비만 세포(mast cell) 안정화제 (예: 크로몰린 나트륨 등), 흡입형 코르티코스테로이드 (예: 플루리솔리드베클로메타손 디프로피오네이트, 베클로메타손 디프로피오네이트 모노하이드레이트 등), 살부타몰, 베클로메타손 디프로피오네이트 (BDP), 이프라트로퓸 브로마이드, 부데소니드, 케토티펜, 살메테롤, 크시나포에이트, 테르부탈린 설페이트, 트리암시놀론, 테오필린, 네도크로밀 나트륨, 메타프로테레놀 설페이트, 알부테롤, 플루니솔리드 등); 호르몬 (예: 안드로겐 (예: 다나졸, 테스토스테론 시피오네이트, 플루옥시메스테론, 에틸토스토스테론, 테스토스테론에나니헤이트, 메틸테스토스테론, 플루옥시메스테론, 테스토스테론 시피오네이트 등), 에스트로겐 (예: 에스트라디올, 에스트로피페이트, 공액 에스트로겐 등), 프로게스틴 (예: 메톡시프로게스테론 아세테이트, 노르에틴드론 아세테이트 등), 코르티코스테로이드 (예: 트리암시놀론, 베타메타손, 베타메타손 나트륨 포스페이트, 덱사메타손, 덱사메타손 나트륨 포스페이트, 덱사메타손 아세테이트, 프레드니손, 메틸프레드니솔론 아세테이트 현탁액, 트리암시놀론 아세토니드, 메틸프레드니솔론, 프레드니솔론 나트륨 포스페이트 메틸프레드니솔론 나트륨석시네이트, 하이드로코르티손 나트륨 석시네이트, 메틸프레드니솔론 나트륨 석시네이트, 트리암시놀론 헥사카토니드, 하이드로코르티손, 하이드로코르티손 시피오네이트, 프레드니솔론, 플루오로코르티손 아세테이트, 파라메타손 아세테이트, 프레드니솔론 테불레이트, 프레드니솔론 아세테이트, 프레드니솔론 나트륨 포스페이트, 하이드로코르티손 나트륨 석시네이트 등), 갑상선 호르몬 (예: 레보티록신 나트륨 등) 등); 혈당강하제 (예: 사람 인슐린, 정제된 소 인슐린, 정제된 돼지 인슐린, 글리부리드, 클로르프로파미드, 글리피지드, 톨부타미드, 톨라자미드 등); 혈지질 저하제 (예: 클로피브레이트, 덱스트로티록신 나트륨, 프로부콜, 로바스타틴, 니아신 등); 단백질 (예: DNase, 알기나제, 초과산화물 디스뮤타제, 리파제 등); 핵산 (예: 본원에서 기술된 임의의 단백질을 포함하는 치료상 유용한 임의의 단백질을 암호화하는 센스 또는 안티-센스 핵산 등); 조혈 자극에 유용한 제제 (예: 에리트로포이에틴 등); 항궤양제/항역류제 (예: 파모티딘, 시메티딘, 라니티딘 하이드로클로라이드 등); 항구토제/진토제 (예: 메클리진 하이드로클로라이드, 나빌론, 프로클로르페라진, 디멘하이드리네이트, 프로메타진 하이드로클로라이드, 티에틸페라진, 스코폴라민 등); 지용성 비타민 (예: 비타민 A, D, E, K 등); 뿐만 아니라 미토탄, 비사딘, 할로니트로소우레아, 안트로사이클린, 엘립티신 등과 같은 기타 약물을 포함할 수 있다.
또한, 약리학적 활성 제제로서 난용성 물질의 추가적인 예에는 "Therapeutic Category and Biological Activity Index" of The Merck Index(12th Ed'n, 1996)에 열거된 화합물이 포함될 수 있다.
본 발명의 바람직한 양태에 따르면, 본 발명의 상기 나노입자는 알부민을 포함하여, 자기 집합체(self-aggregates)를 형성할 수 있다.
상기 나노입자로는 응집성이 있는 단백질을 사용할 수 있으며, 바람직하게는 혈액 내에서 장기간 순환하면서도 응집 구조가 유지되어 약물을 안정적으로 전달할 수 있고, 암 표적성이 있는 공지된 알부민을 사용할 수 있다.
본 명세서에서 사용하는 용어 '자기 집합체(self-aggregates)'는 외부의 힘에 의해 집합되지 않고, 물질이 포함하고 있는 고유의 분자간 인력 또는 척력에 의해 집합체를 형성하는 물질을 의미할 수 있다.
본 발명의 바람직한 양태에 따르면, 본 발명에서 나노입자의 사이즈는 중요하다. 왜냐하면, 암조직에 의해 형성된 엉성한 혈관 조직을 통해서 수십 수백 나노미터 크기의 나노 입자 들이 암조직 주위에 축적할 수 있고, 또한 암조직 주변의 제 역할을 하지 못하는 림프관으로 인해 침투한 나노 전달체는 배출되지 않고, 장기간 암조직에 체류할 수 있는데, 이러한 현상을 EPR(enhanced permeability and retention) 효과라고 하며, 일반적으로 지름이 200 nm 미만의 입자들이 가장 좋은 효율을 나타내기 때문이다.
따라서 본 발명의 나노입자의 사이즈는 바람직하게는 10-500 nm 일 수 있고, 보다 바람직하게는 50-400 nm일 수 있으며, 가장 바람직하게는 100-300 nm일 수 있다.
본 발명의 바람직한 양태에 따르면, 본 발명의 나노물질은 상기 알부민 100 중량부에 대하여 바람직하게는 상기 난용성 물질을 0.1-50 중량부 포함할 수 있고, 보다 바람직하게는 1-10 중량부 포함할 수 있으며, 가장 바람직하게는 3-7 중량부 포함할 수 있다.
본 발명의 바람직한 양태에 따르면, 본 발명의 나노물질은 상기 알부민 100 중량부에 대하여 바람직하게는 상기 멜라닌을 0.1-100 중량부 포함할 수 있고, 보다 바람직하게는 1-20 중량부 포함할 수 있으며, 가장 바람직하게는 9-13 중량부 포함할 수 있다.
본 발명의 바람직한 양태에 따르면, 본 발명의 상기 진단은 PAT(Photoacoustic tomography) 진단이고, 상기 치료는 항암(anti-cancer) 치료일 수 있다.
본 발명의 나노입자는 경구 또는 비경구로 투여할 수 있고, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다.
본 발명의 나노입자의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 한편, 본 발명의 나노입자의 투여량은 바람직하게는 0.001-100 mg/kg(체중)일 수 있다.
본 발명의 다른 양태에 따르면, 본 발명은 다음의 단계를 포함하는 광음향 조영효과 및 항암효과를 나타내는 나노입자의 제조방법을 제공한다: (a) 알부민을 물에 녹인 후 여기에 난용성 약물 및 멜라닌을 주입하여 혼합물을 제조하는 단계; 및 (b) 상기 혼합물에 알코올류를 적하시키는 단계.
본 발명의 바람직한 양태에 따르면, 본 발명의 상기 단계 (b)의 적하시키는 단계에 의해 상기 알부민이 자기 집합체(self-aggregates)를 형성할 수 있다.
본 발명의 바람직한 양태에 따르면, 본 발명의 상기 단계 (b)의 적하 시 적하 속도는 바람직하게는 0.1 ml/minute 내지 10 ml/minute일 수 있고, 보다 바람직하게는 0.5 ml/minute 내지 5 ml/minute일 수 있으며, 가장 바람직하게는 1 ml/minute 내지 2 ml/minute일 수 있다.
상기 단계 (b)의 혼합물의 pH는 바람직하게는 6-10일 수 있고, 보다 바람직하게는 7-9일 수 있으며, 가장 바람직하게는 8-8.5일 수 있다.
일반적으로 알부민은 물에는 작 녹으나 알코올에는 녹지 않기 때문에 수용액상태에서 알부민을 녹인 후에 에탄올을 첨가해주면 뭉쳐 자기 집합체를 형성하는데 이용하여 크기를 조절할 수 있다. 일반적으로 에탄올을 빠르게 첨가하면 입자가 커지며 PH에 따라서도 달라진다.
1 ml/minute 내지 2 ml/minute 적하 속도 및 pH 8-8.5에서 100 nm 내지 300 nm 직경의 나노입자를 제조할 수 있었다.
본 발명의 또 다른 양태에 따르면, 본 발명은 난용성(poorly water soluble) 물질로서 항암물질 및 멜라닌(melanin)을 포함하는 알부민 나노입자, 상기 나노입자의 직경은 100-300 nm이며, 상기 나노입자는 자기 집합체(self-aggregates)를 형성하는 PAT(Photoacoustic tomography) 조영제를 제공한다.
상기 조영제와 관련된 사항은 상기 나노입자 및 상기 나노입자 제조방법에서 상술하였으므로, 본 명세서가 과도하게 복잡해지는 것을 방지하기 위해 그 기재를 생략한다.
본 발명의 또 다른 양태에 따르면, 본 발명은 난용성(poorly water soluble) 물질로서 도세탁셀(Docetaxel), 시스플라틴(cis-platin), 캠토세신(camptothecin), 파클리탁셀(paclitaxel), 타목시펜(Tamoxifen), 아나스테로졸(Anasterozole), 글리벡(Gleevec), 5-플루오로우라실(5-FU), 플록슈리딘(Floxuridine), 류프로리드(Leuprolide), 플로타미드(Flutamide), 졸레드로네이트(Zoledronate), 독소루비신(Doxorubicin), 빈크리스틴(Vincristine), 젬시타빈(Gemcitabine), 스트렙토조토신(Streptozocin), 카보플라틴(Carboplatin), 토포테칸(Topotecan), 벨로테칸(Belotecan), 이리노테칸(Irinotecan), 비노렐빈(Vinorelbine), 히도록시우레아(hydroxyurea), 발루비신(Valrubicin), 레티노익산(retinoic acid) 계열, 메소트렉세이트(Methotrexate), 메클로레타민(Meclorethamine), 클로람부실(Chlorambucil), 부술판(Busulfan), 독시플루리딘(Doxifluridine), 빈블라스틴(Vinblastin), 마이토마이신(Mitomycin), 프레드니손(Prednisone), 테스토스테론(Testosterone), 미토산트론(Mitoxantron), 아스피린(aspirin), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐부타존(phenyltazone), 시클로포스파미드(cyclophosphamide), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 및 코르티코스테로이드(corticosteroid)를 포함하는 군으로부터 선택된 항암물질 및 멜라닌(melanin)을 포함하는 알부민 나노입자, 상기 나노입자의 직경은 100-300 nm이고, 상기 나노입자는 자기 집합체(self-aggregates)를 형성하는 암 치료용 조성물을 제공한다.
상기 암 치료용 조성물과 관련된 사항은 상기 나노입자 및 상기 나노입자 제조방법에서 상술하였으므로, 본 명세서가 과도하게 복잡해지는 것을 방지하기 위해 그 기재를 생략한다.
본 발명의 특징 및 이점을 요약하면 다음과 같다:
(a) 본 발명은 알부민 나노입자(nanoparticle)에 있어서, 상기 알부민 나노입자는 난용성(poorly water soluble) 물질 및 멜라닌(melanin)을 포함하고, 상기 나노입자의 직경은 100-300 nm이며, 상기 나노입자는 자기 집합체(self-aggregates)를 형성하는 광음향 조영효과 및 항암효과를 나타내는 나노입자를 제공한다.
(b) 본 발명의 나노입자를 인체 또는 동물에 주입할 경우 EPR 효과에 의해 암조직에 축적되어, 암 진단 및 치료를 동시에 할 수 있는 장점을 제공한다.
도 1은 본 발명의 나노입자의 조영효과를 확인한 결과를 나타낸다.
도 2는 본 발명의 나노입자의 세포내 침투 효과 확인 결과를 나타낸다.
도 3은 본 발명의 나노입자의 항암효과 확인 결과를 나타낸다.
도 4는 본 발명의 나노입자의 암조직 누적 여부 확인 결과를 나타낸다.
도 5는 본 발명에 따른 나노입자의 암치료효과를 나타낸다.
도 2는 본 발명의 나노입자의 세포내 침투 효과 확인 결과를 나타낸다.
도 3은 본 발명의 나노입자의 항암효과 확인 결과를 나타낸다.
도 4는 본 발명의 나노입자의 암조직 누적 여부 확인 결과를 나타낸다.
도 5는 본 발명에 따른 나노입자의 암치료효과를 나타낸다.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명 하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
실시예
본 명세서 전체에 걸쳐, 특정 물질의 농도를 나타내기 위하여 사용되는 "%"는 별도의 언급이 없는 경우, 고체/고체는 (중량/중량) %, 고체/액체는 (중량/부피) %, 그리고 액체/액체는 (부피/부피) %이다.
제조예
멜라닌을 포함하는 나노입자의 제조
먼저 알부민 20 mg를 H2O 1 ml에 녹인 후에 소수성 물질인 paclitaxel과 melanin을 각각 1 mg, 2 mg 씩 100 ul DMSO(dimethyl sulfioxide)에 녹여 섞었다. 그 후에 ethanol을 1 ml/minute 의 속도로 1.5 ml 넣어준 후 . 8% glutaraldehyde 20 ul를 넣어준 후 ethanol이 전부 기화할 때까지 기다렸다. 만들어진 albumin 입자를 centrifuge(13200 rpm 10 min)으로 down 시킨후에 H2O base를 Phosphate buffered saline(PBS)로 바꾸어주었다. 알부민 입자에 로딩되는 paclitaxel과 melanin은 각각 50 ug/mg(paclitaxel/albumin) ,133.3 ug/mg(melanin/albumin)으로 uv absorbance와 HPLC방법으로 분석하였다.
실험예
실험방법
실험방법 1 : 나노입자의 조영효과 확인 방법
water bath 안에 물을 채운뒤에 tygon tube 안에 본 발명의 나노입자(HMP), 비교군으로는 PBS(phosphate buffer salin), 내부에 아무 것도 적재하지 않은 albumin 입자(HM) 및 melanin만 적재한 입자(MH)들을 넣고 3 cm 위에서 레이져 700 nm 750 nm 800 nm의 파장으로 7.2 mJ, downmix 모드로 조사한뒤에 ultrasound detector를 이용하여 신호를 측정한후 이미지하였다.
실험방법 2 : 나노입자의 세포내 침투 효과 확인 방법
도 2의 A : 제조한 나노입자에 형광(FITC)을 conjugation 시켜서 MDA-MB-231 세포에 처리한 후에 형광현미경으로 관찰하였다. F-actin (붉은색) 염색은 세포골격을 나타내며 파란색은 세포핵을 나타내고 형광을 conjugation 시킨 나노입자를 녹색으로 나타낸다. 도 2의 A를 보듯이 시간이 경과함에 따라 세포내로 유입됨을 확인하였으며 이를 통해 본 발명의 나노입자의 암세포 내에 PA 및 항암제를 잘 전달하는 역할을 확인하였다.
도 2의 B,C 및 D : 제조한 나노입자를 세포에 처리한후 24시간 후에 세포를 모두 걷어내어 pellet형태로 만들어 tube에 담은후 laser를 조사한후 ultrasound를 측정하였다. 도 2의 B에서 세포는 본 발명의 나노입자의 melanin에 의해 갈색으로 변화하였음을 확인하였고 도 2의 C,D 에서 입자를 처리하지 않는 세포보다 본 발명의 나노입자가 월등한 광음향 효과를 보임을 확인하였다.
실험방법 3 : 나노입자의 암조직 누적 여부 확인 방법
도 4의 A : cy5.5가 결합한 본 발명의 나노입자를 MDA-MB-231 세포를 xenograft한 Balb/C nude mouse에 정맥주사 한 후에 optix 장비를 이용하여 입자가 암조직에 효과적으로 도달함을 확인하였다.
도 4의 B : MDA-MB-231 세포를 xenograft한 Balb/C nude mouse를 이용하여 상기 photoacoustic 영상 실험과 동일한 조건으로 진행하였다. 먼저 injection하기 이전의 tumor를 영상하고, 여기에 본 발명의 나노입자를 tail vein injection을 통하여 0.5 m g/mL의 입자를 200 L주입한 후 각각 30분 24시간 후에 영상을 획득하였다. 이를 통해 볼 때 나노입자가 암조직에 누적됨으로써 광음향효과를 통한 암 진단이 가능 할 것으로 확인되었다.
실험예 1 : 나노입자의 조영효과 확인
본 발명의 나노입자의 조영효과를 확인하기 위해 하기 도 1을 참조하면, 하기 도 1의 A 데이터는 본 발명의 나노입자의 조영효과를 확인하기 위한 PAT 영상 결과를 나타낸다. 본 발명의 나노입자(HMP), 비교군으로는 PBS(phosphate buffer salin), 내부에 아무 것도 적재하지 않은 albumin 입자(HM) 및 melanin만 적재한 입자(MH)를 각각 tygon tube에 주입한 이후 water bath 에 넣어서 수면 밑 3 cm 에서의 photoacoustic 효과를 확인 하였다. 밝게 보이는 부분이 PA신호가 나오는 부분으로 노란색 원으로 표시하였고, 본 실험에서 본 발명의 나노물질의 PA 조영 가능성을 확인하였다. 하기 도 1의 B 데이터는 신호의 세기를 정량적으로 계산한 것으로 700 nm 파장 대에서 가장 큰 신호를 보이고 파장이 길어짐에 따라 신호의 세기가 줄어듬을 확인하였다. 이는 흡광도가 파장이 길어질수록 감소하기 때문이다. 본 실험에서 melanin의 적재가 paclitaxel의 적재능력을 방해하지 않는 선에서 듀얼로딩이 잘 됨을 확인하였다.
실험예 2 : 나노입자의 세포내 침투 효과 확인
본 발명의 나노입자의 세포내 침투 효과를 확인하기 위해 하기 도 2를 참조하면, 하기 도 2의 A 데이터는 human breast cancer 인 MDA-MB-231 cell에 조영제 입자가 endocytosis에 의해 cell 안으로 효과적으로 들어감을 확인 한 것으로 빨간색은 F-actin으로 세포골격을 염색하여 세포질 부분을 나타내기 위해 사용하였고, 본 발명의 나노입자는 녹색으로 시간이 갈수록 세포내에 축적됨으로써 암세포에 효과적으로 전달됨을 보여주는 데이터이다. 하기 도 2의 B 데이터는 24 시간 cellular uptake 이후에 cell pellet 이 melanin 입자에 의하여 검은색으로 염색됨을 확인한 데이터고, 하기 도 2의 C 데이터 및 D 데이터는 PA 실험을 통해서 Cell 수준에서도 입자가 로딩된 cell이 PA 신호가 강하게 나올 수 있음을 확인하였다.
실험예 3 : 나노입자의 항암효과 확인
본 발명의 나노입자의 항암 효과를 확인하기 위해 하기 도 3을 참조하면, 하기 도 3의 A데이터는 본 발명의 나노입자의 항암성 효과를 검증 하는 데이터로 본 발명의 나노입자를 처리한 group이 단순히 항암제(PTX)를 처리한 group보다 효과가 더 좋았음을 확인하였다. 하기 도 3의 B 데이터는 통계학적인 분석으로 항암제효과가 있음을 검증하는 데이터이다. 기간이 경과할수록 본 발명의 나노입자가 단순히 항암제를 처리한 것보다 효과가 좋음을 확인 할 수 있었다.
실험예
4 : 나노입자의
암조직
누적 여부 확인
본 발명의 나노입자의 암조직 누적 효과를 확인하기 위해 하기 도 4를 참조하면, 하기 도 4의 A는 본 발명의 나노입자가 정맥주사를 하였을 때 암조직에 누적됨을 보여주는 데이터이다. 붉은 색으로 보이는 부분이 본 발명의 나노입자가 축적된 암조직을 나타내고 있다. 이에 따라 PA신호가 암조직에서 발생하는 데이터가 하기 도 4의 B로 24시간 후에 암조직에서 PA가 발생함을 확인할 수 있다(하얀 원)
실험예
5: 나노입자의 동물모델에서의 암치료효과 확인
도 5는 본 발명에 따른 나노입자의 암치료효과를 나타내는 그래프이다. 본 발명의 나노입자의 암치려효과를 도 5에서 보는 바와 같이, 마우스 동물 모델에서 확인을 하였다, MDA-MB-231 human breast cancer를 xenograft 시킨 nude-mouse에 각각 PBS, 나노입자, PTX를 주입하여 24일간 종양부피변화를 측정하였다.
도 5의 A의 화살표 표시는 마우스 정맥주사 날짜이고, Y축은 종양부피를 말한다. 이를 통해 본 발명의 나노입자의 치려효과를 검증하였다. 도 5의 B는 24일째의 마우스 동물모델의 암크기를 촬영한 것으로 본 발명에 따른 나노입자 (NPs) 군이 치료효과가 뛰어남을 알 수 있다.
Claims (14)
- 알부민 나노입자(nanoparticle)에 있어서,
상기 알부민 나노입자는 난용성(poorly water soluble) 물질 및 멜라닌(melanin)을 포함하고,
상기 나노입자의 직경은 100-300 nm이며,
상기 나노입자는 자기 집합체(self-aggregates)를 형성하는
광음향 조영효과 및 항암효과를 나타내는 나노입자. - 제 1 항에 있어서,
상기 난용성 물질은 유기계 난용성 약물인 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자. - 제 2 항에 있어서,
상기 유기계 난용성 약물은 약제학적 활성 제제, 진단 제제 또는 영양 제제인 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자. - 제 3 항에 있어서,
상기 유기계 난용성 약물은 도세탁셀(Docetaxel), 시스플라틴(cis-platin), 캠토세신(camptothecin), 파클리탁셀(paclitaxel), 타목시펜(Tamoxifen), 아나스테로졸(Anasterozole), 글리벡(Gleevec), 5-플루오로우라실(5-FU), 플록슈리딘(Floxuridine), 류프로리드(Leuprolide), 플로타미드(Flutamide), 졸레드로네이트(Zoledronate), 독소루비신(Doxorubicin), 빈크리스틴(Vincristine), 젬시타빈(Gemcitabine), 스트렙토조토신(Streptozocin), 카보플라틴(Carboplatin), 토포테칸(Topotecan), 벨로테칸(Belotecan), 이리노테칸(Irinotecan), 비노렐빈(Vinorelbine), 히도록시우레아(hydroxyurea), 발루비신(Valrubicin), 레티노익산(retinoic acid) 계열, 메소트렉세이트(Methotrexate), 메클로레타민(Meclorethamine), 클로람부실(Chlorambucil), 부술판(Busulfan), 독시플루리딘(Doxifluridine), 빈블라스틴(Vinblastin), 마이토마이신(Mitomycin), 프레드니손(Prednisone), 테스토스테론(Testosterone), 미토산트론(Mitoxantron), 아스피린(aspirin), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐부타존(phenyltazone), 시클로포스파미드(cyclophosphamide), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 및 코르티코스테로이드(corticosteroid)를 포함하는 군으로부터 선택된 항암제인 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자. - 제 1 항에 있어서,
상기 알부민은 인간혈청 알부민 또는 이의 단편인 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자. - 제 1 항에 있어서,
상기 나노입자는 상기 알부민 100 중량부에 대하여 상기 난용성 물질을 1-10 중량부 포함하는 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자. - 제 1 항에 있어서,
상기 나노입자는 상기 알부민 100 중량부에 대하여 상기 멜라닌을 5-20 중량부 포함하는 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자. - 제 1 항에 있어서,
상기 진단은 PAT(Photoacoustic tomography) 진단이고, 상기 치료는 항암(anti-cancer) 치료인 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자. - 다음의 단계를 포함하는 광음향 조영효과 및 항암효과를 나타내는 나노입자의 제조방법:
(a) 알부민을 물에 녹인 후 여기에 난용성 약물 및 멜라닌을 주입하여 혼합물을 제조하는 단계; 및
(b) 상기 혼합물에 알코올류를 적하시키는 단계. - 제 9 항에 있어서,
상기 단계 (b)의 적하시키는 단계에 의해 상기 알부민이 자기 집합체(self-aggregates)를 형성하는 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자의 제조방법. - 제 9 항에 있어서,
상기 단계 (b)의 적하 시 적하 속도는 0.1 ml/minute 내지 10 ml/minute인 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자의 제조방법. - 제 9 항에 있어서,
상기 단계 (b)의 혼합물의 pH는 7-9로 조절된 것을 특징으로 하는 광음향 조영효과 및 항암효과를 나타내는 나노입자의 제조방법. - 난용성(poorly water soluble) 물질로서 항암물질 및 멜라닌(melanin)을 포함하는 알부민 나노입자, 상기 나노입자의 직경은 100-300 nm이며, 상기 나노입자는 자기 집합체(self-aggregates)를 형성하는 PAT(Photoacoustic tomography) 조영제.
- 난용성(poorly water soluble) 물질로서 도세탁셀(Docetaxel), 시스플라틴(cis-platin), 캠토세신(camptothecin), 파클리탁셀(paclitaxel), 타목시펜(Tamoxifen), 아나스테로졸(Anasterozole), 글리벡(Gleevec), 5-플루오로우라실(5-FU), 플록슈리딘(Floxuridine), 류프로리드(Leuprolide), 플로타미드(Flutamide), 졸레드로네이트(Zoledronate), 독소루비신(Doxorubicin), 빈크리스틴(Vincristine), 젬시타빈(Gemcitabine), 스트렙토조토신(Streptozocin), 카보플라틴(Carboplatin), 토포테칸(Topotecan), 벨로테칸(Belotecan), 이리노테칸(Irinotecan), 비노렐빈(Vinorelbine), 히도록시우레아(hydroxyurea), 발루비신(Valrubicin), 레티노익산(retinoic acid) 계열, 메소트렉세이트(Methotrexate), 메클로레타민(Meclorethamine), 클로람부실(Chlorambucil), 부술판(Busulfan), 독시플루리딘(Doxifluridine), 빈블라스틴(Vinblastin), 마이토마이신(Mitomycin), 프레드니손(Prednisone), 테스토스테론(Testosterone), 미토산트론(Mitoxantron), 아스피린(aspirin), 살리실레이트(salicylates), 이부프로펜(ibuprofen), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐부타존(phenyltazone), 시클로포스파미드(cyclophosphamide), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 및 코르티코스테로이드(corticosteroid)를 포함하는 군으로부터 선택된 항암물질 및 멜라닌(melanin)을 포함하는 알부민 나노입자, 상기 나노입자의 직경은 100-300 nm이고, 상기 나노입자는 자기 집합체(self-aggregates)를 형성하는 암 치료용 조성물.
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