KR101074026B1 - A constrast medium comprising amphiphilic hyaluronic acid-based nanoparticles binded a near-infrared fluorochrome for diagnosing tumor - Google Patents
A constrast medium comprising amphiphilic hyaluronic acid-based nanoparticles binded a near-infrared fluorochrome for diagnosing tumor Download PDFInfo
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- KR101074026B1 KR101074026B1 KR1020080096838A KR20080096838A KR101074026B1 KR 101074026 B1 KR101074026 B1 KR 101074026B1 KR 1020080096838 A KR1020080096838 A KR 1020080096838A KR 20080096838 A KR20080096838 A KR 20080096838A KR 101074026 B1 KR101074026 B1 KR 101074026B1
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- cancer
- acid
- hyaluronic acid
- infrared
- nanoparticles
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Abstract
본 발명은 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자를 포함하는 암 진단용 조영제 및 상기 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자에 소수성 항암제가 봉입된 암 치료용 약물 전달체에 관한 것이다.The present invention relates to a cancer diagnostic contrast agent comprising amphipathic hyaluronic acid complex nanoparticles in which a near-infrared phosphor is bound, and a drug carrier for cancer treatment in which a hydrophobic anticancer agent is enclosed in the amphipathic hyaluronic acid complex nanoparticles in which the near-infrared phosphor is bound.
본 발명에서, 양친성 히알루론산은 암 조직의 신생 혈관에 대한 투과율이 높고 암 조직에 특이적으로 발현되는 CD44 등의 수용체와 친화도가 높아 암 조직에 선택적으로 전달될 수 있고, 수계에서 나노크기의 자기 조립체 (self-aggregates)를 형성할 수 있기 때문에 암 조직에 축적이 용이하여, 본 발명의 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자는 암 진단용 조영제로 응용할 수 있으며, 필요에 따라 소수성 항암제를 봉입하여 암 치료용 약물 전달체로 응용할 수 있다.In the present invention, amphiphilic hyaluronic acid has a high permeability to neovascularization of cancer tissues and has high affinity with a receptor such as CD44, which is specifically expressed in cancer tissues, and thus can be selectively delivered to cancer tissues, and nanoscale in water. It is easy to accumulate in cancer tissues because it can form self-aggregates of, and the amphipathic hyaluronic acid composite nanoparticles conjugated with the near-infrared phosphor of the present invention can be applied as a contrast agent for diagnosing cancer. It can be applied as a drug carrier for cancer treatment by enclosing an anticancer agent.
소수성 물질, 양친성 히알루론산, 조영제, 근적외선 형광체, 약물 전달체 Hydrophobic substances, amphiphilic hyaluronic acid, contrast agents, near-infrared phosphors, drug carriers
Description
본 발명은 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자를 포함하여 생체 내 암 조직을 비침투적으로 영상화하는 신규한 암 진단용 조영제 및 상기 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자에 소수성 항암제가 봉입된 암 치료용 약물 전달체에 관한 것이다.The present invention comprises a novel cancer diagnostic contrast agent for non-invasive imaging of cancer tissues in vivo, including amphipathic hyaluronic acid complex nanoparticles bound to near-infrared phosphors, and hydrophobicity to the amphipathic hyaluronic acid complex nanoparticles bound to the near-infrared phosphors. The present invention relates to a drug carrier for treating cancer containing an anticancer agent.
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 방사선 관련 연구자 대부분이 PET/CT 또는 PET/SPECT에 관한 연구를 진행하고 있기 때문이다. 그러나 임상적으로 가장 많은 활용이 되고 있는 PET/CT 또는 PET/SPECT를 이용한 진단은 비용이 많이 들고 크기가 작은 암을 진단하는데 상당한 어려움이 있다. To date, most of the development of new contrast agents for early diagnosis of cancer has been carried out in position emission tomography (PET), single photon emission computed tomography (SPECT) and computed tomography (CT). This is because most of the radiation researchers in domestic hospitals are currently conducting research on PET / CT or PET / SPECT. However, the diagnosis using PET / CT or PET / SPECT, which is the most clinically used, has considerable difficulty in diagnosing a costly and small sized cancer.
최근 암 조기 진단 및 치료 분야에 있어서 광학 분자 영상 기술의 중요성이 대두되고 있으며, 근적외선 투시에 의한 암 조직 영상법은 기존의 PET/CT 또는 PET/SPECT 진단기술과 비교하여, 방사성 동위원소의 불필요성, 고해상도의 영상, 저렴한 비용 등의 장점을 가지고 있다. Recently, the importance of optical molecular imaging technology is emerging in the field of early diagnosis and treatment of cancer, and cancer tissue imaging by near-infrared fluoroscopy, compared with conventional PET / CT or PET / SPECT diagnosis technology, does not require radioisotopes, It has the advantages of high resolution image and low cost.
그러나, 근적외선 투시에 의한 암 조직 영상법을 사용하기 위해서는 근적외선 파장 (650nm-900nm)의 스펙트럼 범위 내에서 흡수 및 형광 최대치를 갖고, 물에 대한 용해도가 높고 생체 적합성이 우수한 근적외선 형광체의 개발과 더불어, 이러한 근적외선 형광체가 암 조직에 선택적으로 전달·축적될 수 있게 하는 조영제의 개발이 요구된다.However, in order to use cancer tissue imaging by near-infrared vision, with the development of near-infrared phosphors having absorption and fluorescence maximums in the spectral range of the near infrared wavelength (650 nm to 900 nm), high solubility in water and excellent biocompatibility, There is a need for the development of contrast agents that allow such near-infrared phosphors to be selectively delivered and accumulated in cancer tissues.
한편, 오늘날 약 50 여종 이상의 항암제가 융모막암, 백혈병, 윌름즈(Wilms) 종양, 어위 (Ewing) 육종, 횡문근육종, 망막모세포종, 림프종, 균상식육종, 고환암 등에 투여되어 치료효과를 얻고 있다. 최근 암 발생 및 암 세포의 특성에 관한 다수의 연구 결과가 나오면서 새로운 항암제 개발에 관한 연구 또한 활발히 진행되고 있다. 대부분의 항암제는 세포 내 유전 인자의 본체인 핵산의 합성을 억제하거나 핵산에 직접 결합하여 그 기능을 손상시킴으로써 효과를 나타내는데, 이들 항암제는 암 세포뿐만 아니라 정상 세포, 특히 세포 분열이 활발한 정상 조직 세포에도 손상을 입히기 때문에 골수 기능 저하, 위장관 점막 손상, 탈모 등의 부작용이 수반되며 약물의 심각한 독성 및 낮은 용해도로 인하여 기대한 바와는 달리 획기적인 성과를 보여주지 못하였다.On the other hand, more than 50 anticancer drugs have been administered to choriocarcinoma, leukemia, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, retinoblastoma, lymphoma, fungal sarcoma, testicular cancer, etc. Recently, many researches on the development of cancer and the characteristics of cancer cells have emerged, and research on the development of new anticancer drugs is also actively conducted. Most anticancer drugs have an effect by inhibiting the synthesis of nucleic acid, the body of genetic factors in the cell, or by directly binding to the nucleic acid and impairing its function. These anticancer agents are effective not only on cancer cells but also on normal cells, especially normal tissue cells with active cell division. Because of the damage, side effects such as bone marrow dysfunction, gastrointestinal mucosa damage, and hair loss were accompanied, and due to the severe toxicity and low solubility of the drug, the results were not as expected.
따라서, 질병 치료에 사용되는 약물의 부작용을 최소화하기 위하여, 항암제를 암 조직에 선택적으로 투여할 수 있는 새로운 약물 제형 개발이 요구되고 있다.Therefore, in order to minimize side effects of drugs used to treat diseases, there is a need for development of new drug formulations capable of selectively administering anticancer agents to cancer tissues.
따라서, 본 발명은 상기 종래 기술의 문제점을 해결하기 위한 것으로서, 암 조직 신생 혈관에 대한 투과율이 높고 암 조직에 발현되는 CD44 수용체와의 친화도가 높아서 암 조직에 선택적으로 전달될 수 있고, 수계에서 나노크기의 자기 조립체 (self-aggregates)를 형성하여 암 조직에 축적이 용이한 양친성 히알루론산에, 근적외선 투시가 가능한 근적외선 형광체를 화학적으로 결합한 암 진단용 신규 조영제 및 필요에 따라 항암제를 봉입하여, 암 치료가 가능한 신규 약물 전달체를 제공하는 것을 목적으로 하는 것이다.Therefore, the present invention is to solve the problems of the prior art, it has a high permeability to cancer tissue neovascularization and high affinity with the CD44 receptor expressed in cancer tissue can be selectively delivered to cancer tissue, in the water system A new contrast agent for cancer diagnosis, which chemically combines amphipathic hyaluronic acid that forms nano-sized self-aggregates and is easily accumulated in cancer tissue, and a near-infrared fluorescent substance capable of near-infrared vision, and an anticancer agent, if necessary, is encapsulated. It is an object of the present invention to provide novel drug carriers that can be treated.
본 발명은 소수성 물질을 도입한 양친성 히알루론산에, 시아닌, 풀루오레신 (fluorescein), 테트라메틸로드아민 (tetramethylrhodamine), 보디피 (BODIPY) 및 알렉사 (Alexa)로 이루어진 군으로부터 선택되는 근적외선 형광체가 결합된, 양친성 히알루론산 복합체 나노입자를 포함하는 암 진단용 조영제를 제공한다.The present invention relates to amphipathic hyaluronic acid incorporating a hydrophobic substance, wherein a near-infrared phosphor selected from the group consisting of cyanine, fluorescein, tetramethylrhodamine, BODIPY and Alexa Provided is a diagnostic agent for cancer diagnosis comprising the amphiphilic hyaluronic acid complex nanoparticles.
또한, 본 발명은 상기 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자에 소수성 항암제가 봉입된 암 치료용 약물 전달체를 제공한다.In another aspect, the present invention provides a drug carrier for treating cancer in which a hydrophobic anticancer agent is enclosed in the amphipathic hyaluronic acid complex nanoparticles to which the near-infrared fluorescent substance is bound.
본 발명에 있어서, 양친성 히알루론산은 암 조직 신생 혈관에 대한 투과율이 높고 암 조직에 발현되는 CD44 수용체에 대한 친화도가 높기 때문에, 암 조직에 선택적으로 전달될 수 있고, 나노 크기의 자기 조립체 (self-aggregates)를 형성할 수 있기 때문에, 암 조직에 용이하게 축적될 수 있다.In the present invention, amphiphilic hyaluronic acid can be selectively delivered to cancer tissue because of its high permeability to cancer tissue neovascularization and high affinity for CD44 receptor expressed in cancer tissue, Because they can form self-aggregates, they can easily accumulate in cancerous tissues.
따라서, 본 발명의 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자는 근적외선 투시에 의한 암 진단용 조영제로 효율적으로 응용될 수 있다.Therefore, the amphipathic hyaluronic acid composite nanoparticles in which the near-infrared phosphor of the present invention is coupled can be efficiently applied as a contrast agent for cancer diagnosis by near-infrared fluoroscopy.
또한, 본 발명의 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자는 그 안에 소수성 항암제를 봉입하여, 항암제를 암 조직에 선택적으로 투여할 수 있는 암 치료용 약물 전달체로 응용될 수 있다. In addition, the amphipathic hyaluronic acid composite nanoparticles in which the near-infrared fluorescent substance of the present invention is bound can be applied as a drug delivery agent for cancer treatment by encapsulating a hydrophobic anticancer agent therein and selectively administering the anticancer agent to cancer tissue.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세히 설명한다. 하기의 실시예는 본 발명의 예시일뿐, 본 발명의 권리 범위가 이에 의하여 제한되지는 않는다.Hereinafter, the present invention will be described in more detail with reference to the following examples. The following examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 소수성 물질을 도입한 양친성 히알루론산에, 시아닌, 풀루오레신 (fluorescein), 테트라메틸로드아민 (tetramethylrhodamine), 보디피 (BODIPY) 및 알렉사 (Alexa)로 이루어진 군으로부터 선택되는 근적외선 형광체가 결합된, 양친성 히알루론산 복합체 나노입자를 포함하는 암 진단용 조영제에 관한 것이다.The present invention relates to amphipathic hyaluronic acid incorporating a hydrophobic substance, wherein a near-infrared phosphor selected from the group consisting of cyanine, fluorescein, tetramethylrhodamine, BODIPY and Alexa It relates to a contrast agent for diagnosing cancer comprising bound, amphiphilic hyaluronic acid complex nanoparticles.
상기 근적외선 형광체가 결합된 양친성 히알루론산 복합체란 친수성 히알루론산에 소수성 기를 도입하여 양친성 히알루론산을 형성하고, 이렇게 형성된 양친성 히알루론산에 근적외선 형광체를 결합시킨 형태를 가리키는 것이고, 상기 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자란 상기 복합체가 수계에서 나노크기의 자기 조립체 (self-assemblｙ 또는 self-aggregate)를 형성한 것을 가리키는 것이다.The amphipathic hyaluronic acid complex conjugated with the near-infrared fluorescent substance refers to a form in which a amphiphilic hyaluronic acid is formed by introducing a hydrophobic group into the hydrophilic hyaluronic acid, and the near-infrared fluorescent substance is bonded to the amphipathic hyaluronic acid thus formed, and the near-infrared fluorescent substance is bound to Amphiphilic hyaluronic acid composite nanoparticles refer to the complexes forming nano-sized self-assembly (self-assemblxy or self-aggregate) in water.
상기 소수성 물질로는 담즙산 유도체 또는 지방산 유도체를 들 수 있는데, 구체적으로, 상기 담즙산 유도체의 예로는 디옥시콜산 (deoxycholic acid), 타우로디옥시콜산 (taurodeoxycholic acid), 타우로콜산 (taurocholic acid), 글리코케노디옥시콜산 (glycochenodeoxycholic acid), 타우로케노디옥시콜산 (taurochenodeoxycholic acid) 등이 있고, 지방산 유도체의 예로는 스테아르산 (stearic acid), 올레산 (oleic acid) 등이 있다. 담즙산을 사용하는 것이 바람직하다.The hydrophobic material may include bile acid derivatives or fatty acid derivatives. Specifically, examples of the bile acid derivatives include deoxycholic acid, taurodeoxycholic acid, taurocholic acid, and tacoholic acid. Kenodioxycholic acid (glycochenodeoxycholic acid), taurochenodeoxycholic acid and the like, and examples of fatty acid derivatives include stearic acid (stearic acid), oleic acid (oleic acid). Preference is given to using bile acids.
상기 히알루론산은 친수성 고분자로, 본 발명에서는 히알루론산뿐만 아니라 기타 친수성 고분자도 사용될 수 있다. 친수성 고분자로는 생체 적합성을 갖는 모든 고분자가 사용될 수 있는데, 특히, 암 조직 축적 효율이 높고 항암제의 약물 전달체로 사용되는 덱스트란 (dextran), 키토산 (chitosan), 글라이콜 키토산 (glycol chitosan), 히알루론산 (hyaluronic acid), 폴리-L-라이신 (poly-L-lysine), 폴리아스파르트산 (poly-aspartic acid)으로부터 선택되는 생체 고분자 등이 사용될 수 있다. 또한, 폴리(N-2-(하이드록시프로필)메타아크릴아마이드)(poly(N-2(hydroxypropyl)methacry -lamide), 폴리(디비닐 에테르-코-말레익 언하이드라이드) (poly(divinyl ehter-co-maleic anhydride)), 폴리(스틸렌-코-말레익 언하이드라이드) (poly(styrene-co-maleic anhydride)), 폴리(에틸렌 글라이콜) (poly(ethylene glycol)) 등의 합성 고분자도 사용될 수 있다. The hyaluronic acid is a hydrophilic polymer, in the present invention, not only hyaluronic acid but also other hydrophilic polymers may be used. As the hydrophilic polymer, any polymer having biocompatibility may be used. In particular, dextran, chitosan, glycol chitosan, which are highly effective in accumulating cancer tissue and used as drug carriers for anticancer drugs, A biopolymer selected from hyaluronic acid, poly-L-lysine, polyaspartic acid, and the like can be used. In addition, poly (N-2- (hydroxypropyl) methacrylamide) (poly (N-2 (hydroxypropyl) methacry-lamide), poly (divinyl ether-co-maleic hydride) (poly (divinyl ehter synthetic polymers such as (co-maleic anhydride)), poly (styrene-co-maleic anhydride), and poly (ethylene glycol) May also be used.
히알루론산을 포함한 상기 친수성 고분자는 저분자 물질과 비교할 때, 암 조 직의 EPR 효과에 의하여 암조직에 대한 선택성이 높아 암 조직의 축적 효율이 현저히 탁월한 장점이 있다.The hydrophilic polymer including hyaluronic acid has a merit that the selectivity to cancer tissue is high due to the EPR effect of the cancer tissue, and the accumulation efficiency of the cancer tissue is remarkably excellent when compared with the low molecular weight material.
사용되는 고분자, 엄밀하게는 사용되는 고분자 나노입자의 특성에 따라 암 조직 주변의 축적 효율이 결정되는데, 상기 친수성 고분자 중에서 히알루론산이 특히 바람직하다. 히알루론산은 암 조직의 EPR 효과에 의하여 암조직에 대한 선택성이 높을뿐만 아니라, 암 세포 및 조직에 특이적으로 발현되는 CD44 수용체와 친화도가 높아 나노입자 제조시 암 조직에 대한 선택적 축적 효율이 매우 탁월하기 때문이다. 이 외에도 히알루론산은 히알루론산의 카르복실기가 소수성 물질 및 근적외선 형광체의 화학적 개질 유도에 가장 적합하다는 장점이 있다. Accumulation efficiency around cancer tissue is determined according to the characteristics of the polymer used, strictly the polymer nanoparticles used, and hyaluronic acid is particularly preferable among the hydrophilic polymers. Hyaluronic acid not only has high selectivity for cancer tissues due to EPR effect of cancer tissues, but also has high affinity with CD44 receptor which is specifically expressed in cancer cells and tissues. Because it is excellent. In addition, hyaluronic acid has the advantage that the carboxyl group of hyaluronic acid is most suitable for inducing chemical modification of hydrophobic materials and near-infrared phosphors.
상기 소수성 물질을 도입한 양친성 히알루론산을 비롯한 양친성 고분자는 소수성과 친수성의 균형을 통하여, 수계에서 암 조직에 안정한 나노크기의 자기 조립체를 형성할 수 있는데, 이렇게 형성된 나노크기의 자기 조립체는 생체 내에서 생체적합성/생분해성이 우수하고 생체 내에서의 안정성이 우수하여 혈액 내에서의 생체 분포도가 높아서 충분한 시간 동안 암 조직에 계속적으로 축적이 되는 특성이 있다. 또한, 양친성 히알루론산을 비롯한 양친성 고분자는 근적외선 투시가 가능한 근적외선 형광체의 화학적 개질이 용이하여, 최종적으로 근적외선 투시시 암 조직의 선택적인 강한 근적외선 형광을 나타낼 수 있다.Amphiphilic polymers, including amphiphilic hyaluronic acid introduced with the hydrophobic material, can form a nanoscale magnetic assembly stable to cancer tissue in the water system through a balance between hydrophobicity and hydrophilicity. It has excellent biocompatibility / biodegradability in the inside and excellent stability in the living body, so that the biodistribution in the blood is high, and thus it is continuously accumulated in cancer tissue for a sufficient time. In addition, amphiphilic polymers, including amphiphilic hyaluronic acid, are easy to chemically modify the near-infrared fluorescent substance that is capable of near-infrared light, and finally may exhibit selective strong near-infrared fluorescence of cancer tissue in near-infrared light.
본 발명에 있어서, 근적외선 형광체는 양친성 히알루론산 등 양친성 고분자의 생체 내에서의 위치 및 정량 분석을 위한 광학 투시를 위하여 결합되는 것으로, 양친성 고분자 내의 소수성 물질과 결합한다. 본 발명에서 사용되는 근적외선 형광 체의 예로는 시아닌, 풀루오레신 (fluorescein), 테트라메틸로드아민 (tetramethylrhodamine), 보디피 (BODIPY), 알렉사 (Alexa) 등을 들 수 있으며, 특히 시아닌계는 근적외선 빛을 방출 및 흡수하므로 세포, 혈액 및 생체 조직 등과 간섭 혹은 흡수가 최소화되기 때문에 가장 바람직하다. 바람직한 예는 Cy5.5이다.In the present invention, the near-infrared phosphor is bound for optical perspective for in vivo location and quantitative analysis of an amphiphilic polymer such as amphiphilic hyaluronic acid, and binds to a hydrophobic material in the amphiphilic polymer. Examples of near-infrared phosphors used in the present invention include cyanine, fluorescein, tetramethylrhodamine, BODIPY, Alexa, and the like. It is most preferable because it emits and absorbs the cells, blood and biological tissues, etc., so that interference or absorption is minimized. Preferred example is Cy5.5.
근적외선 형광체가 결합된 양친성 히알루론산 등 양친성 고분자 복합체 나노입자는 근적외선 조사를 이용하여 생체 내 암 조직을 영상화할 수 있으며, 방사성 동위원소, 양자점 (quantum dot), MRI 조영제를 동시에 도입할 경우 다양한 복합 분자 영상도 가능하다. 따라서, 본 발명의 암 진단용 조영제는 방사성 동위원소, 양자점 (quantum dot) 또는 MRI 조영제를 더 포함할 수 있다. Amphiphilic polymer composite nanoparticles such as amphipathic hyaluronic acid combined with near-infrared phosphors can image cancer tissues in vivo using near-infrared irradiation, and when radioactive isotopes, quantum dots, and MRI contrast agents are introduced simultaneously, Complex molecular imaging is also possible. Therefore, the contrast agent for diagnosing cancer of the present invention may further include radioisotopes, quantum dots, or MRI contrast agents.
본 발명에 있어서, 상기 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자의 분자량은 103 내지 106이고, 나노입자의 크기는 10 내지 800 nm이다.In the present invention, the molecular weight of the amphipathic hyaluronic acid composite nanoparticles to which the near-infrared phosphor is bound is 10 3 to 10 6, and the size of the nano particles is 10 to 800 nm.
본 발명의 근적외선 형광체가 결합된 양친성 히알루론산 복합체의 바람직한 구체예인 담즙산-히알루론산-Cy5.5 복합체의 구조는 다음 일반식 (1)로 나타낼 수 있다.The structure of the bile acid-hyaluronic acid-Cy5.5 complex, which is a preferred embodiment of the amphipathic hyaluronic acid complex to which the near-infrared phosphor of the present invention is bound, can be represented by the following general formula (1).
[일반식 (1)][General Formula (1)]
상기 일반식 (1)에서 A와 B는 히알루론산 고분자의 반복 구조인 N-아세틸-D- 글루코사민과 D-글루쿠론산 유도체를 의미하며, C는 친수성 히알루론산에 소수성기를 도입하기 위하여 D-글루쿠론산 유도체 카르복실기에 결합된 소수성 담즙산을 의미하며, D는 나노입자의 생체 내 영상을 위하여 D-글루쿠론산 유도체 카르복실기에 결합된 근적외선 형광체, 방사성 동위원소, 양자점 등을 의미한다. In Formula (1), A and B denote N-acetyl-D-glucosamine and D-glucuronic acid derivatives, which are repetitive structures of the hyaluronic acid polymer, and C denotes D-glu to introduce a hydrophobic group to the hydrophilic hyaluronic acid. It refers to a hydrophobic bile acid bound to the curonic acid derivative carboxyl group, D means a near-infrared phosphor, radioisotope, quantum dots, etc., bound to the D-glucuronic acid derivative carboxyl group for in vivo imaging of the nanoparticles.
또한, a는 히알루론산의 분자량에 따라서 수 100에서 수 10,000의 값을 가지는 것이고, b는 히알루론산 복합체의 나노입자를 제조하기 위하여 10~100의 값을 가지며, c는 10~30이다. In addition, a has a value of the
상기 담즙산-히알루론산-Cy5.5 복합체는, 히알루론산에 소수성 물질로서 담즙산을 도입하여 양친성 히알루론산 유도체를 제조한 후, 근적외선 형광체로서 Cy5.5를 화학적으로 결합시켜 제조되며, 다음 반응식으로 나타낸 공정에 따라 제조된다.The bile acid-hyaluronic acid-Cy5.5 complex is prepared by introducing bile acid as a hydrophobic substance into hyaluronic acid to prepare an amphiphilic hyaluronic acid derivative, and then chemically bonding Cy5.5 as a near-infrared phosphor, and is represented by the following scheme. Manufactured according to the process.
상기 담즙산-히알루론산-Cy5.5 복합체 역시 자기조립형 또는 자기응집된 형태의 나노입자로 제조되며 수십에서 수백 나노 미터의 크기를 갖는다. 제조된 담즙산-히알루론산-Cy5.5 복합체 고분자 나노입자는 생체적합성이 우수하고 암 조직 내 축적 효율이 우수하며, 근적외선, PET/SPECT 및 CCD 카메라에 의해서 생체 내에서 영상이 가능하다. The bile acid-hyaluronic acid-Cy5.5 complex is also made of nanoparticles in self-assembled or self-aggregated form and has a size of tens to hundreds of nanometers. The produced bile acid-hyaluronic acid-Cy5.5 composite polymer nanoparticles have excellent biocompatibility and excellent accumulation efficiency in cancer tissue, and can be imaged in vivo by near-infrared, PET / SPECT and CCD cameras.
전술한 바와 같이, 담즙산-히알루론산-Cy5.5 복합체 나노입자를 비롯한 본 발명의 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자는 암 조직에 선택적으로 전달될 수 있기 때문에, 비침습적 암 진단을 위한 조영제로서 응용될 수 있다. As described above, the amphipathic hyaluronic acid composite nanoparticles conjugated to the near-infrared phosphor of the present invention, including bile acid-hyaluronic acid-Cy5.5 complex nanoparticles, can be selectively delivered to cancer tissues, thereby providing a noninvasive diagnosis of cancer. It can be applied as a contrast agent.
근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자를 비롯한 근적외선 형광체가 결합된 양친성 고분자 복합체 나노입자를 포함하는 조영제의 경우 일반 저분자량의 조영제보다 암 조직의 EPR 효과에 의하여 암조직에 대한 선택성이 높아 암 조직의 축적 효율이 현저히 탁월하며, 생체 내의 체류 기간이 저분자량의 조영제보다 크게 증가되어 암 진단의 효율성을 높일 수 있다. 특히, 담즙산-히알루론산-Cy5.5 복합체 나노입자는 암 세포 및 조직에 특이적으로 발현되는 CD44 수용체와 친화도가 높아 암 조직에 대한 선택적 전달·축적 효율이 탁월하다. Contrasts containing amphiphilic polymer composite nanoparticles bound to near-infrared phosphors, including amphiphilic hyaluronic acid composite nanoparticles bound to near-infrared phosphors, have a higher selectivity to cancer tissues due to EPR effects of cancer tissues than conventional low molecular weight contrast agents. As a result, the accumulation efficiency of cancer tissue is remarkably excellent, and the retention period in vivo is significantly increased than that of low molecular weight contrast agent, thereby increasing the efficiency of cancer diagnosis. In particular, bile acid-hyaluronic acid-Cy5.5 complex nanoparticles have high affinity with CD44 receptor specifically expressed in cancer cells and tissues, and thus, excellent efficiency of selective delivery and accumulation to cancer tissues.
또한, 본 발명의 양친성 히알루론산은 약물 전달체로서 사용이 가능하고, 소수성 항암제를 물리/화학적으로 쉽게 봉입할 수 있으므로 암 진단뿐만 아니라 암 치료로서 활용이 가능하다. 담즙산-히알루론산-Cy5.5 복합체 나노입자는 그 내부에 소수성 항암제인 아드리아마이신, 택솔, 시스-플라틴(cis-platin), 미토마이신-C, 다우노마이신(daunomycin) 및 5-플루오로우라실(5-fluorouracil) 등의 약물 봉입이 가능하여, 암 진단 및 치료가 가능하다. In addition, the amphiphilic hyaluronic acid of the present invention can be used as a drug carrier, and since the hydrophobic anticancer agent can be easily encapsulated physically and chemically, it can be utilized as a cancer diagnosis as well as a cancer treatment. Bile acid-hyaluronic acid-Cy5.5 complex nanoparticles contain hydrophobic anticancer agents adriamycin, taxol, cis-platin, mitomycin-C, daunomycin and 5-fluorouracil Drug encapsulation such as (5-fluorouracil) is possible, and cancer diagnosis and treatment are possible.
본 발명의 담즙산-히알루론산-Cy5.5 복합체 나노입자를 비롯한 본 발명의 근 적외선 형광체가 결합된 양친성 고분자 복합체 나노입자는 그 내부에 소수성 항암제를 봉입하여 암 치료용 약물 전달체로 응용될 수 있다.Amphiphilic polymer composite nanoparticles conjugated to the near-infrared phosphor of the present invention, including the bile acid-hyaluronic acid-Cy5.5 composite nanoparticles of the present invention, can be applied as drug delivery agents for cancer treatment by enclosing a hydrophobic anticancer agent therein. .
따라서, 본 발명은 또한, 상기 근적외선 형광체가 결합된 양친성 히알루론산 복합체 나노입자를 비롯한 근적외선 형광체가 결합된 양친성 고분자 복합체에 소수성 항암제가 봉입된 암 치료용 약물 전달체에 관한 것이다.Accordingly, the present invention also relates to a drug delivery drug for cancer treatment in which a hydrophobic anticancer agent is enclosed in an amphipathic polymer complex in which a near-infrared phosphor is bound, including the amphipathic hyaluronic acid complex nanoparticle in which the near-infrared phosphor is bound.
상기 소수성 항암제는 실시예 2에 기재된 바와 같은 방법에 의하여 봉입될 수 있으며, 봉입되는 소수성 항암제의 양은 약물 전달체 중량의 1 내지 60 중량%인 것이 바람직하다. The hydrophobic anticancer agent may be encapsulated by the method as described in Example 2, and the amount of the hydrophobic anticancer agent encapsulated is preferably 1 to 60% by weight of the drug carrier weight.
상기 소수성 항암제로는 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 (Streptozotocin), 카보플라틴 (Carboplatin), 토포테칸 (Topotecan), 벨로테칸 (Belotecan), 이리노테칸 (Irinotecan), 비노렐빈 (Vinorelbine), 히드록시우레아 (hydroxyurea), 발루비신 (Valrubicin), 레티노산 (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 (phenylbutazone), 시클로포스파미드 (cyclophosphamide), 메클로에타민 (mechlorethamine), 덱사메타손 (dexamethasone), 프레드니솔론 (prednisolone), 셀레콕시브 (celecoxib), 발데콕시브 (valdecoxib), 니메슐리드 (nimesulide), 코르티손 (cortisone) 및 코르티코스테로이드 (corticosteroid)를 들 수 있다. The hydrophobic anticancer agent is docetaxel (Docetaxel), cis-platin (cis-platin), camptothecin (camptothecin), paclitaxel (tamlitaxel), Tamoxifen (Anasterozole), Gleevec, 5-fluoro Uracil (5-FU), Fluxuridine, Leuprolide, Flotamide, Zoledronnate, Doxorubicin, Vincristine, Gemcitabine ( Gemcitabine), streptozotocin (Streptozotocin), Carboplatin, Topotecan, Velotecan, Irinotecan, Vinorelbine, Hydroureurea, Valrubicin, Retinoic Acid retinoic acid series, Methotrexate, Mechlorethamine, Chlorambucil, Busulfan, Doxifluridine, Vinblastin, Mytoma Mitomycin, Prednisone, Testosterone, Mitoxantron, Aspirin Salicylates, Ibuprofen, Ibuprofen, Naproxen, Phenopropene fenoprofen, indomethacin, phenylbutazone, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, celecoxib, foot Decoxib, Nimesulide, cortisone and corticosteroids.
본 발명의 약물 전달체로 치료가 가능한 암의 종류로는 편평상피세포암, 자궁암, 자궁경부암, 전립선암, 두경부암, 췌장암, 뇌종양, 유방암, 간암, 피부암, 식도암, 고환암, 신장암, 대장암, 직장암, 위암, 신장암, 방광암, 난소암, 담관암, 담낭암 등을 들 수 있다.Types of cancer that can be treated with the drug delivery system of the present invention include squamous cell carcinoma, uterine cancer, cervical cancer, prostate cancer, head and neck cancer, pancreatic cancer, brain tumor, breast cancer, liver cancer, skin cancer, esophageal cancer, testicular cancer, kidney cancer, colon cancer, Colorectal cancer, stomach cancer, kidney cancer, bladder cancer, ovarian cancer, bile duct cancer, gallbladder cancer, and the like.
실시예 1: 담즙산 (5-β-cholanic acid)-히알루론산-Cy5.5 복합체 나노입자의 제조 Example 1 Preparation of Bile Acid ( 5-β-cholanic acid) -Haluronic Acid-Cy5.5 Composite Nanoparticles
1-1 담즙산-히알루론산-Cy5.5 복합체의 제조1-1 Preparation of Bile Acid-Haluronic Acid-Cy5.5 Complex
600 mg의 히알루론산을 120 ml의 포름아미드에 용해시키고 200 ml의 디메틸 포름아미드에 아미노에틸-5-β-콜라노아미드 (cholanoamid) 133 mg을 용해시켜 글리콜 히알루론산 용액에 천천히 적하하였고, 243 mg의 1-에틸-3-(3-디메틸-아미노프로필) 카보디이미드(1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide; EDC)와 143 mg의 N-하이드로숙시니미드(N-hydrosuccinimide;NHS)를 40 ml의 디메틸 포름아 미드에 용해시켜 반응액에 가한 다음 상온에서 24시간 동안 교반하였다. 이후 상기 반응액을 2일간 투석하여 미반응 아미노에틸-5-β-콜라노아미드를 제거한 후 동결건조하여, 담즙산 (cholanic acid)-히알루론산 복합체를 제조하였다. 제조된 담즙산-히알루론산 복합체 240 mg를 50 ml의 물에 용해시키고 아디프산 디하이드라지드 (adipic acid dihydrazide) 518 mg를 20 ml의 물에 용해시켜 천천히 적하하였고, 29 mg의 1-에틸-3-(3-디메틸-아미노프로필) 카보디이미드(1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide; EDC)와 20 mg의 하이드록시 벤조 트리아졸 (N-Hydroxybenzotriazole; HOBt)을 2 ml의 메탄올에 녹여 반응액에 가한 다음 상온에서 24시간 교반하였다. 이후 상기 반응액을 2일간 투석하여 미반응 아디프산 디하이드라지드를 제거한 후 동결 건조하여, 담즙산-히알루론산-아디픽하이드라지드(adipichydrazide) 복합체를 제조하였다. 제조된 담즙산-히알루론산-아디픽하이드라지드 복합체 120 mg를 25 ml의 물에 용해시키고 17 mg의 근적외선 형광체 단활성 Cy5.5의 하이드록시숙시미마이드 에스테르 (Cy-5.5-NHS)를 첨가하여 6시간 반응 시킨 후, 용액을 2일간 투석하여 미반응 Cy5.5를 제거하고 동결 건조하여, 담즙산-히알루론산-Cy5.5 복합체를 제조하였다. 600 mg hyaluronic acid was dissolved in 120 ml of formamide and 133 mg of aminoethyl-5-β-cholanoamid in 200 ml of dimethyl formamide was slowly added dropwise to the glycol hyaluronic acid solution, 243 mg. 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide (1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide; EDC) and 143 mg of N-hydrosuccinimide ; NHS) was dissolved in 40 ml of dimethyl formamide, added to the reaction solution, and stirred at room temperature for 24 hours. Thereafter, the reaction solution was dialyzed for 2 days to remove unreacted aminoethyl-5-β-collanoamide and then lyophilized to prepare a bile acid (cholanic acid) -hyaluronic acid complex. 240 mg of the prepared bile acid-hyaluronic acid complex was dissolved in 50 ml of water, 518 mg of adipic acid dihydrazide was dissolved in 20 ml of water, and slowly added dropwise, and 29 mg of 1-ethyl- 2 ml of 3- (3-dimethyl-aminopropyl) carbodiimide (1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide (EDC) and 20 mg of hydroxy benzotriazole (HOBt) Was dissolved in methanol, added to the reaction solution, and stirred at room temperature for 24 hours. Thereafter, the reaction solution was dialyzed for 2 days to remove unreacted adipic acid dihydrazide and freeze-dried to prepare a bile acid-hyaluronic acid-adipichydrazide complex. 120 mg of the prepared bile acid-hyaluronic acid-adipichydrazide complex was dissolved in 25 ml of water and 17 mg of near-infrared phosphor monoactive Cy5.5 was added to add hydroxysuccinimide ester (Cy-5.5-NHS). After reacting for 6 hours, the solution was dialyzed for 2 days to remove unreacted Cy5.5 and freeze-dried to prepare a bile acid-hyaluronic acid-Cy5.5 complex.
1-2. 합성된 담즙산-히알루론산-Cy5.5 복합체 나노입자 형성1-2. Synthesis of Synthetic Bile Acid-Hyaluronic Acid-Cy5.5 Complex Nanoparticles
상기 1-1에서 제조된 담즙산-히알루론산-Cy5.5 복합체를 1 mL의 PBS 용액에 용해시킨 후, 0.45 마이크로 필터로 여과하여 동적 광 산란 장치 (dynamic laser scattering; DLS) 및 전자 투과 현미경 (TEM)으로 입자의 크기를 구하였다.The bile acid-hyaluronic acid-Cy5.5 complex prepared in 1-1 above was dissolved in 1 mL of PBS solution, filtered through a 0.45 micro filter, and then subjected to dynamic laser scattering (DLS) and electron transmission microscopy (TEM). The particle size was determined by
담즙산-히알루론산-Cy5.5 유도체 분석 결과, 도 1에 나타낸 바와 같이, 입자 의 크기는 TEM 형상으로 약 200 내지 400 나노미터의 평균입자를 갖는 것임을 확인할 수 있었다.As a result of the analysis of the bile acid-hyaluronic acid-Cy5.5 derivative, it was confirmed that the particle size had an average particle of about 200 to 400 nanometers in a TEM shape.
실시예 2. 캠토세신이 봉입된 담즙산-히알루론산-Cy5.5 복합체 나노입자 약물 전달체 제조Example 2 Preparation of Bile Acid-Haluronic Acid-Cy5.5 Complex Nanoparticle Drug Carrier Containing Camptocecin
40 mg의 담즙산-히알루론산-Cy5.5 복합체 나노입자를 8 ml의 증류수에 용해시켰다. 캠토세신 2 mg를 0.5의 디메틸설파이드에 용해시켰다. 담즙산-히알루론산-Cy5.5 복합체 나노입자가 들어있는 용액에 캠토세신 용액을 한 방울씩 떨어뜨리면서 초음파 분산기(sonicator)를 사용하여 나노입자 안에 봉입시킨 후, 봉입되지 않은 약물은 여과장치를 이용하여 제거하고, 이어서 동결 건조하여, 캠토세신이 봉입된 담즙산-히알루론산-Cy5.5 복합체 나노입자 약물 전달체를 제조하였다.40 mg of bile acid-hyaluronic acid-Cy5.5 composite nanoparticles were dissolved in 8 ml of distilled water. 2 mg of camptocecin was dissolved in 0.5 dimethylsulfide. The solution containing the bile acid-hyaluronic acid-Cy5.5 composite nanoparticles was dropped dropwise into the nanoparticles using an ultrasonic sonicator while dropping the captocecin solution drop by drop. Removed, and then lyophilized to contain bile acid-hyaluronic acid-Cy5.5 composite nanoparticles encapsulated with camptocecin. Drug carriers were prepared.
실험예 1. 담즙산-히알루론산-Cy5.5 복합체의 광학적 특성 Experimental Example 1. Optical Properties of Bile Acid-Haluronic Acid-Cy5.5 Complex
실시예 1에서 제조된 담즙산-히알루론산-Cy5.5의 광학적 특성을 관찰하기 위하여, 담즙산-히알루론산-Cy5.5 1 mg을 1 mL의 PBS에 용해시킨 후, 근적외선 투시를 관찰하였다.In order to observe the optical properties of the bile acid-hyaluronic acid-Cy5.5 prepared in Example 1, 1 mg of bile acid-hyaluronic acid-Cy5.5 was dissolved in 1 mL of PBS, followed by near-infrared observation.
실험 결과는 도 2에 나타난 바와 같이, 담즙산-히알루론산-Cy5.5 용액의 근적외선 투시를 한 경우, CCD 카메라 이미지를 살펴보면 근적외선 형광필터를 사용할 경우 근적외선 파장에서 높은 형광을 발하는 것을 알 수 있었다.As shown in FIG. 2, when near-infrared viewing of bile acid-hyaluronic acid-Cy5.5 solution was performed, the CCD camera image showed that the near-infrared fluorescent filter emits high fluorescence at near-infrared wavelength.
실험예 2. 담즙산-히알루론산-Cy5.5 복합체 나노입자의 암 조직 축적 효과 평가 Experimental Example 2 Evaluation of cancer tissue accumulation effect of bile acid-hyaluronic acid-Cy5.5 complex nanoparticles
실시예 1에서 제조한 담즙산-히알루론산-Cy5.5 복합체 나노입자 용액 100 ㎕를 피부암 세포가 주입된 쥐에 정맥 주사한 후, 근적외선 조사를 실시하였다. 피부암 세포가 주입된 쥐에 나노입자를 주입한 후, 일정 시간이 경과한 후에 근적외선 조사를 실시하여 1 cm 미만의 작은 암 조직 영상을 획득하였다.100 μl of the bile acid-hyaluronic acid-Cy5.5 complex nanoparticle solution prepared in Example 1 was injected intravenously into mice injected with skin cancer cells, followed by near-infrared irradiation. After injecting the nanoparticles into the skin cancer cells injected mice, after a certain period of time, near-infrared irradiation was performed to obtain a small cancer tissue image of less than 1 cm.
그 결과, 도 3a에서 보는 바와 같이 담즙산-히알루론산-Cy5.5 복합체 나노입자를 투여하여 암 조직의 근적외선 투시 영상을 보면, 3 내지 7 mm 크기의 작은 암 조직의 영상이 가능함을 확인할 수 있었다.As a result, as shown in FIG. 3A, when the bile acid-hyaluronic acid-Cy5.5 complex nanoparticles were administered to look at near-infrared images of cancer tissues, it was confirmed that images of small cancer tissues having a size of 3 to 7 mm were possible.
담즙산-히알루론산-Cy5.5 복합체 나노입자를 이용하여 적출된 장기들 및 근육 조직과 암 조직의 근적외선 투시 영상과 형광량의 정량적 분석 결과는 도 4에 나타낸 바와 같았다.Quantitative analysis results of near-infrared images and fluorescence of organs and muscle tissues and cancer tissues extracted using bile acid-hyaluronic acid-Cy5.5 complex nanoparticles were shown in FIG. 4.
실험예 3. 항암제가 봉입된 히알루론산-담즙산 나노입자 약물 전달체의 특성 분석 Experimental Example 3 Characterization of Hyaluronic Acid-Bile Acid Nanoparticle Drug Carrier Enclosed with Anticancer Agent
분자량이 서로 상이한 히알루론산-담즙산 고분자에 각각 항암제를 봉입한 후, 약물이 봉입된 히알루론산-담즙산 나노입자의 크기를 동적 광 산란 장치로 분석하고, 약물의 봉입 효율을 HPLC 및 UV 분광기를 통하여 분석하였다. 히알루론산-담즙산 고분자에 대한 약물의 봉입량, 약물의 봉입 효율 및 나노입자의 크기 등을 표 1에 나타내었다. After the anticancer agent was encapsulated in the hyaluronic acid-bile acid polymer having different molecular weights, the size of the drug-containing hyaluronic acid-bile acid nanoparticles was analyzed by a dynamic light scattering device, and the encapsulation efficiency of the drug was analyzed by HPLC and UV spectroscopy. It was. Table 1 shows the amount of drug encapsulation, the efficiency of drug encapsulation, and the size of nanoparticles in the hyaluronic acid-bile acid polymer.
[표 1]항암제가 봉입된 히알루론산-담즙산 나노입자 약물 전달체의 특성 분석Table 1 Characterization of hyaluronic acid-bile acid nanoparticle drug carriers packed with anticancer drugs
(분자량)sample
(Molecular Weight)
(㎎)HMH
(Mg)
(㎎)drug
(Mg)
(%)Encapsulation efficiency
(%)
(중량%)Encapsulation
(weight%)
(nm)Particle size
(nm)
도 1a는 실시예 1에서 제조된 담즙산-히알루론산-Cy5.5 나노입자의 평균 직경을 동적 광 산란 장치 (dynamic laser scattering; DLS)로 측정한 결과이고, 도 1b는 실시예 1에서 제조된 담즙산-히알루론산-Cy5.5 나노입자를 전자 투과 현미경 (TEM)으로 촬영한 사진이다.Figure 1a is a result of measuring the average diameter of the bile acid-hyaluronic acid-Cy5.5 nanoparticles prepared in Example 1 by dynamic laser scattering (DLS), Figure 1b is a bile acid prepared in Example 1 Hyaluronic acid-Cy5.5 nanoparticles taken with an electron transmission microscope (TEM).
도 2는 실시예 1에서 제조된 담즙산-히알루론산-Cy5.5 나노입자의 광학적 특성을 CCD 이미지로 나타낸 것이다.Figure 2 shows the optical characteristics of the bile acid-hyaluronic acid-Cy5.5 nanoparticles prepared in Example 1 in a CCD image.
도 3a는 종양에 있는 담즙산-히알루론산-Cy5.5 나노입자의 근적외선 이미지를 나타낸 것이고, 도 3b와 3c는 각각 몸 전체 및 종양 부위의 담즙산-히알루론산-Cy5.5 나노입자의 시간에 따른 형광 세기를 그래프로 나타낸 것이다.Figure 3a shows a near infrared image of the bile acid-hyaluronic acid-Cy5.5 nanoparticles in the tumor, Figures 3b and 3c shows the fluorescence over time of the bile acid-hyaluronic acid-Cy5.5 nanoparticles of the entire body and tumor site, respectively It is a graph of intensity.
도 4a 담즙산-히알루론산-Cy5.5 나노입자가 장기, 정상 조직 및 암 조직에 축적되는 정도를 영상화한 것이고, 도 4b는 축적 정도를 정량적으로 분석한 결과를 나타낸 것이다.FIG. 4A is an image of the degree to which bile acid-hyaluronic acid-Cy5.5 nanoparticles accumulate in organs, normal tissues, and cancer tissues, and FIG. 4B shows the results of quantitative analysis of the accumulation levels.
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