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WO2019009607A1 - Complexe chélaté, procédé de préparation associé et composition le contenant de diagnostic et de traitement de cancer - Google Patents

Complexe chélaté, procédé de préparation associé et composition le contenant de diagnostic et de traitement de cancer Download PDF

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Publication number
WO2019009607A1
WO2019009607A1 PCT/KR2018/007563 KR2018007563W WO2019009607A1 WO 2019009607 A1 WO2019009607 A1 WO 2019009607A1 KR 2018007563 W KR2018007563 W KR 2018007563W WO 2019009607 A1 WO2019009607 A1 WO 2019009607A1
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WIPO (PCT)
Prior art keywords
chelate complex
cancer
platinum
based drug
paramagnetic metal
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PCT/KR2018/007563
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English (en)
Korean (ko)
Inventor
이민영
최동일
이정희
이원재
Original Assignee
사회복지법인 삼성생명공익재단
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Priority claimed from KR1020180077316A external-priority patent/KR20190005753A/ko
Application filed by 사회복지법인 삼성생명공익재단 filed Critical 사회복지법인 삼성생명공익재단
Publication of WO2019009607A1 publication Critical patent/WO2019009607A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds

Definitions

  • a chelate complex comprising melanoidin, a paramagnetic metal ion, and a platinum-based drug, a method for producing the chelate complex, and a diagnostic and therapeutic composition comprising the chelate complex.
  • Magnetic resonance imaging is a technique for irradiating a sample with low electromagnetic energy and then detecting a magnetic resonance image signal from a water molecule.
  • Magnetic resonance imaging MRI is known to be the most suitable method for the diagnosis of diseases and drug treatment of patients because it is possible to obtain 0 high resolution tissue dissolving ability and non-invasive magnetic resonance imaging that can be repeated several times in a short time.
  • the magnetic resonance imaging signal is determined by the two time parameters T1 and T2, the relaxation time, and the amount of protons in the water molecules resulting from the spin density.
  • the contrast of magnetic resonance imaging is controlled by MRI contrast agents.
  • MRI contrast agents enhance the contrast between normal and abnormal tissues by detecting the difference in T1 / T2 relaxation time caused by strong external magnetic field and high frequency energy after in vivo implantation
  • MRI contrast agents are generally classified into paramagnetic contrast agents and superparamagnetic contrast agents and are classified into T1 contrast agent and TGFR agent by spin relaxation of nuclear magnetic resonance T2 contrast agent.
  • the paramagnetic metal ions used as T1 contrast agents accelerate T1 relaxation and form a bright contrast in T1-weighted images.
  • superparamagnetic iron oxides (SPIOs) used as T2 contrast agents increase the T2 relaxation rate to form dark contrast.
  • SPIOs superparamagnetic iron oxides
  • gadolinium (Gd) itself is highly toxic and can cause anaphylactoid reaction, and it has been pointed out that it can cause serious nephrogenic systemic fibrosis (NSF).
  • NSF nephrogenic systemic fibrosis
  • gadolinium preparations have been reported to be toxic to about 1% of gadolinium in infusion through the blood-brain barrier in healthy subjects. Therefore, in order to overcome the adverse effects of this gadolinium preparation, a new low- Research is underway to develop.
  • T1 contrast media including Gd-DTPA occupy the majority of the contrast media for imaging of the blood vessels of each tissue
  • metal nanoparticles such as iron oxide nanoparticles T1 and T2 dual-mode contrast agents are difficult to release in vivo.
  • the present inventors confirmed that chelating a paramagnetic metal ion and a platinum-based drug in the manufacture of melanoid can be used as a dual-function contrast agent for T1 and T2, and can be used as a contrast agent and a therapeutic agent, and completed the Theragnosis System Respectively.
  • One aspect is melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.
  • the present invention also provides a composition for diagnosing and treating diseases comprising the chelate complex.
  • Other aspects include; amino acid; Paramagnetic metal ion; And a platinum-based drug at a pH of from 6.5 to 8.5 and at a temperature of from 35 to 40 ° C.
  • One aspect is melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.
  • the melanoidins can be produced by extraction in the natural world or by chemical synthesis.
  • the melanoid may be one obtained by the maillard reaction of sugars and amino acids.
  • the Mailard reaction may be carried out under pH conditions of pH 6.5 to 8.5, pH 7 to 8, or pH 7.3 to 7.5, or 35 to 40 ⁇ , 36 ⁇ to 38 ⁇ , or 37 ⁇ .
  • the chelate complex may have a weight average molecular weight of 2,000 Da to 20,000 Da, 3,000 Da to 19,000 Da, 4,000 Da to 18,000 Da, 5,000 Da to 17,000 Da, 5,000 Da to 16,000 Da, or 5,000 Da to 15,000 Da, It is not.
  • the weight average molecular weight of the chelate complex can be controlled to a desired molecular weight by controlling the reaction time.
  • the chelate complex has a weight average molecular weight within this range, it can be used as a T1 contrast agent, a T2 contrast agent, or a T1-T2 dual function contrast agent.
  • the sugar may comprise a monosaccharide, a disaccharide or a mixture thereof.
  • the monosaccharide may include glucose, galactose, mannose, or fructose
  • the disaccharide may include sucrose, lactulose, lactose, maltose, trehalose, or cellobiose.
  • the disaccharide may include sucrose, lactose, maltose, trehalose, or cellobiose.
  • amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, cysteine, proline, serine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, . ≪ / RTI >
  • paramagnetic metal ion refers to a material representing nuclear magnetic resonance imaging. Unpaired spins present in the interior usually exhibit an irregular spin arrangement due to thermal motion. When an external magnetic field is applied As a result of the spin alignment in a certain direction due to the influence, it means a material which is not normally magnetized but is magnetized in the magnetic field direction when an external magnetic field is applied.
  • the paramagnetic metal ion is selected from the group consisting of iron (Fe), manganese (Mn), nickel (Ni), copper (Cu), erbium (Er), europium (Eu), holmium (Ho) Or more, but is not limited thereto.
  • the paramagnetic metal ion may be coordinately bound to melanoid.
  • the paramagnetic metal ion is chelated with melanoid, an excellent MR imaging effect can be exerted on T1-weighted images and T2-weighted images compared with conventionally used contrast agents such as Gd.
  • platinum drug may also be referred to as a platinum-based drug, and may include, without limitation, platinum-containing drugs.
  • the platinum-based drug may include a platinum-based anticancer drug.
  • the platinum-based anticancer agent may be selected from the group consisting of cisplatin, Carboplatin, ornaplastatin, oxaliplatin, znipratin, enoloplatin, rovaplatin or spiroplatin, tetraplatin, ≪ / RTI > galactosyltransferase, meflatin, eplluclatin, or a combination thereof.
  • the platinum-based drug When the platinum-based drug is chelated with melanoidin, the platinum-based drug may be coordinately bound to melanoidin, and the platinum-based drug may be released from the chelate complex by irradiating a laser to the tissue diagnosed as cancer, .
  • the platinum-based drug can be released specifically to the cancer-diagnosed tissue, so that the toxicity of the platinum-based drug can be minimized. Therefore, when the platinum-based drug is chelated with melanoid, it is possible to minimize side effects on organs other than the target due to drug resistance and toxicity of the platinum-based drug.
  • the platinum-based drug may have the general structural formula cis- [PtX 2 (Am)] 2 , where Am has a NH moiety as a stable group, X is a group Lt; / RTI >
  • the platinum-based drug may be specifically released from the chelate complex to cancer tissues by laser irradiation to have an effect of treating cancer.
  • melanoidin Paramagnetic metal ion
  • a chelate complex comprising a platinum-based drug.
  • the pharmaceutical composition may be for cancer treatment.
  • cancer treatment means any action that improves or alleviates the symptoms of cancer by administering a composition comprising the chelate complex of the present invention into the body.
  • the cancer or carcinoma that can be treated with the pharmaceutical composition is not particularly limited, and includes solid cancer and blood cancer.
  • the present invention relates to a pharmaceutical composition for preventing or treating cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, colon cancer, but are not limited to, renal cancer, esophageal cancer, biliary cancer, testicular cancer, rectal cancer, head and neck cancer, cervical cancer, ureter cancer, osteosarcoma, neuronal cell subtype, melanoma, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, But is not limited thereto.
  • the platinum-based drug can be released from the chelate complex to the target tissue by laser irradiation.
  • the platinum-based drug can be chelated with melanoids and exhibit a therapeutic effect of diseases by being specifically released into a target tissue, for example, cancer tissue by laser irradiation.
  • the pharmaceutical composition may be capable of simultaneously performing treatment and magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • the pharmaceutical composition can be used as a T1 contrast agent or a T2 contrast agent and can be used as a T1 contrast agent and a T2 contrast agent, i.e., a T1-T2 dual function contrast agent.
  • MRI Magnetic Resonance Image
  • the pharmaceutical composition may contain 1 to 99 parts by weight, 1 to 50 parts by weight, 1 to 40 parts by weight, 1 to 30 parts by weight, 1 to 20 parts by weight, for example, 1 to 20 parts by weight of the chelate complex based on 100 parts by weight of the total composition. To 10 parts by weight.
  • the pharmaceutical composition is characterized in being capable of monitoring the progress of cancer through MRI contrast while performing chemotherapy with an anticancer agent. Since the progress of cancer can be monitored at the same time as performing the chemotherapy, an appropriate amount of the cancer drug can be administered at an appropriate time. In addition, it is possible to monitor whether or not the effect of the anticancer drug used in the chemotherapy is effective. Therefore, there is an advantage that patient-specific treatment is possible.
  • diagnosis and treatment of disease can be used in combination with “theragnosis ".
  • the term teraginosis which includes both therapy and diagnosis, is used to monitor changes in enzymes, biomarkers, and genes in the body through molecular imaging and medical techniques to determine the presence and progress of the disease. And at the same time provide the progress of customized treatment.
  • Diagnosis of the disease may include cancer diagnosis or angiography.
  • Treatment of the disease may include cancer therapy.
  • the cancer or the carcinoma is not particularly limited, and includes solid cancer and blood cancer. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, colon cancer, But are not limited to, renal cancer, esophageal cancer, biliary cancer, testicular cancer, rectal cancer, head and neck cancer, cervical cancer, ureter cancer, osteosarcoma, neuronal cell subtype, melanoma, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, But is not limited thereto.
  • the chelate complex comprises a paramagnetic metal ion, platinum-based drug, chelated with melanoid.
  • the chelate complex can contain a paramagnetic metal ion and can be used as a contrast agent for diagnosis of diseases, specifically cancer diagnosis or angiography.
  • contrast agent refers to a substance used for diagnostic purposes to artificially create a difference in contrast and display it as an image. The most important reason for using contrast agents is to understand the overall range of lesions that are more accurate for all lesions.
  • the chelate complex may be used as a T1 contrast agent, a T2 contrast agent, or a T1-T2 dual-mode MRI contrast agent.
  • T1 contrast agent refers to a substance that increases signal intensity in a T1 weighted image through a decrease in T1 relaxation time.
  • T2 contrast agent refers to a substance that increases signal intensity in T2-weighted images by decreasing T2 relaxation time.
  • T1 contrast is used, the desired site appears bright (positive contrast) and dark when T2 contrast is used (negative contrast).
  • T1-T2 dual-function contrast agent refers to a substance that can be used as a T1 contrast agent and a T2 contrast agent.
  • the chelate complex may increase the molecular weight or decrease the molecular weight depending on the reaction time of the melanoid, the paramagnetic metal ion, and the platinum-based drug.
  • increasing the reaction time increases the molecular weight of the chelate complex, thereby increasing the function of the T2 contrast agent and reducing the molecular weight of the chelate complex, thereby increasing T1 contrast agent function. That is, it can be used as a T1-T2 dual-function contrast agent by controlling the molecular weight by controlling the reaction time.
  • the molecular weight of the chelate complex that can be used as a T1-T2 dual function contrast agent can be from 5000 Da to 15000 Da, and the reaction time can be from about 3 days to 20 days, but is not limited thereto.
  • T1 and T2 dual-function MRI contrast agents can provide more accurate and detailed information about the disease than a single-function MRI contrast agent.
  • T1 and T2 dual-function MRI contrast agents can enhance diagnostic accuracy due to the high tissue resolution of T1-weighted images and high lesion detection capabilities of T2-weighted images. Since the composition for teragnosia can obtain a contrast effect for a long time, it has a remarkably excellent effect over conventional MRI contrast agents that can obtain a contrast effect only for a short time. In addition, the composition for teraginosis is extremely cytotoxic and specifically acts on target tissues, and thus can be safely used in the body.
  • the composition for teraginosis comprises 1 to 99 parts by weight, 1 to 50 parts by weight, 1 to 40 parts by weight, 1 to 30 parts by weight and 1 to 20 parts by weight of the chelate complex based on 100 parts by weight of the total composition, But it is not limited thereto.
  • composition for teraginosis may further comprise a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier In the case of oral administration, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a pigment and a flavoring agent may be used. , A stabilizer, and the like.
  • a base, an excipient, a lubricant, a preservative, etc. may be used.
  • the formulation of the composition for teraginosis may be variously prepared by mixing with a pharmaceutically acceptable carrier as described above.
  • a pharmaceutically acceptable carrier as described above.
  • it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like in the case of oral administration, and in the case of injections, unit dosage ampoules or a plurality of dosage forms.
  • the contrast agent composition is formulated as an injectable preparation, it may contain a non-toxic buffer solution which appears as blood, as a diluent, for example, a phosphate buffer solution of pH 7.4.
  • the composition may include other diluents or additives in addition to the buffer solution. Excipients and additives that may be added to such injections are well known to those skilled in the art.
  • composition for teraginosus may typically comprise a surfactant that facilitates migration through the membrane.
  • surfactants are those derived from steroids or cationic lipids such as N- [1- (2,3-dioloyl) propyl-N, N, N-trimethylammonium chloride (DOTMA), or cholesterol hemi- , Phosphatidylglycerol, and the like.
  • Another aspect provides a method of diagnosing, monitoring, and treating cancer comprising administering to said individual said chelate complex.
  • the chelate complex can be used for MRI imaging for diagnosis and treatment of cancer, so that cancer progression can be performed and cancer progress can be monitored. It may also be helpful to choose the treatment plan and treatment medication of the patient because the patient can know in advance what the effect of the specific drug will be.
  • a suitable dose of a composition comprising the chelate complex of the present invention will depend on factors such as the formulation method, the mode of administration, the age, weight, sex, pathological condition, food, time of administration, route of administration, excretion rate and responsiveness of the patient And the ordinarily skilled physician can readily determine and prescribe dosages effective for the desired treatment or prophylaxis.
  • Other aspects include; amino acid; Paramagnetic metal ion; And a platinum-based drug at a pH of from 6.5 to 8.5 and at a temperature of from 35 ⁇ ⁇ to 40 ⁇ ⁇ .
  • the chelate complex according to one aspect can control the residence time in the body by controlling the molecular weight by controlling the reaction time, can be safely used without toxicity problem, can simultaneously perform diagnosis and diagnosis of disease, You can monitor the progress of the cancer. It can also be used as a dual-function contrast agent for T1 and T2, and has high tissue resolution and high lesion detection capability.
  • FIG. 2 is a graph showing the T1-weighted MRI image of the chelate complex according to an embodiment.
  • FIG. 3 is a graph showing the results of a T2-weighted MRI image of a chelate complex according to an embodiment.
  • Figure 4 is a graph showing cell viability by treatment of a chelate complex according to one embodiment.
  • Figure 5 is an MR image of a liver cancer mouse model treated with a chelate complex according to one embodiment.
  • the molecular weight of the chelate complex can be controlled by controlling the reaction time because the molecular weight of the chelate complex is increased as the reaction time of the MAlard reaction is increased.
  • the chelate complex solution was lyophilized to obtain a powder form.
  • 1 mL of aqua regia was added to 1 mg of the chelate complex, and the solution was boiled at 200 ° C until all the solution was blown.
  • the solution was redissolved in 10% HCl solution and analyzed by inductively coupled plasma-atomic emission spectroscopy (ICP-AES).
  • ICP-AES inductively coupled plasma-atomic emission spectroscopy
  • the atomic concentration of C, N, O, Fe, and Pt was analyzed by X-ray photoelectron spectroscopy (XPS) analysis of the chelate complex in the form of a lyophilized powder, Respectively.
  • XPS X-ray photoelectron spectroscopy
  • T1 and T2 magnetic resonance images and the relaxation rates of r1 and r2 of the complex prepared by the reaction for 4 days in Example 2 were analyzed using a 3T clinical MRI scanner.
  • the results for T2 are shown in Fig.
  • B16F1 cells were treated with 1 mg / mL of the chelate complex, which was reacted for 4 days, and cultured for 24 hours. Thereafter, a laser with a wavelength of 800 nm was irradiated for 10 minutes. The cell viability after the irradiation was measured and the results are shown in Fig.
  • the chelate complex of the present invention can be safely used in the body since it is not toxic.
  • the chelate complex synthesized according to Example 1 was intravenously injected intraperitoneally into a mouse liver cancer model at 10 mg / mL and MR images were obtained at 30 minutes, 1 hour, 2 hours, 24 hours and 48 hours. The image is shown in Fig.
  • the chelate complex of the present invention confirmed that MRI for liver cancer tissue is possible as a T1-T2 dual-function contrast agent in In vivo.

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Abstract

La présente invention concerne un complexe chélaté comprenant de la mélanoïdine, un ion métallique paramagnétique et un médicament à base de platine, un procédé de préparation associé et une composition le contenant de diagnostic et de traitement. Un complexe chélaté selon un aspect a un temps de séjour in vivo qui peut être régulé par ajustement du poids moléculaire par le biais d'une commande de temps de réaction, peut être utilisé en toute sécurité sans problèmes de toxicité, et permet d'effectuer les contrastes simultanément pour un diagnostic de maladie et une thérapie, de façon à pouvoir effectuer une thérapie anticancéreuse tout en pouvant surveiller l'évolution du cancer. En outre, le complexe chélaté peut être utilisé en tant que milieu de contraste à double fonction T1 et T2, et présente ainsi une résolution tissulaire et une détectabilité de lésion élevées.
PCT/KR2018/007563 2017-07-06 2018-07-04 Complexe chélaté, procédé de préparation associé et composition le contenant de diagnostic et de traitement de cancer WO2019009607A1 (fr)

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KR20170085924 2017-07-06
KR10-2017-0085924 2017-07-06
KR10-2018-0077316 2018-07-03
KR1020180077316A KR20190005753A (ko) 2017-07-06 2018-07-03 킬레이트 복합체, 이의 제조방법 및 이를 포함하는 진단 및 암 치료용 조성물

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10158195A (ja) * 1996-11-28 1998-06-16 Res Inst For Prod Dev 配位結合を利用した薬物−高分子複合体製剤の調製方法
KR20070010671A (ko) * 2005-07-19 2007-01-24 김경일 요실금 검사치료 및 골반저근과 질근육의 바이오피드백 훈련용 장치
JP2008143907A (ja) * 1997-10-27 2008-06-26 Research Corp Technologies Inc 治療成分送達のための磁気共鳴イメージング剤
KR20160081004A (ko) * 2014-12-30 2016-07-08 포항공과대학교 산학협력단 멜라노이딘 및/또는 멜라노이딘의 금속 킬레이팅 복합체를 포함하는 광흡수제, 이의 제조방법, 및 용도

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10158195A (ja) * 1996-11-28 1998-06-16 Res Inst For Prod Dev 配位結合を利用した薬物−高分子複合体製剤の調製方法
JP2008143907A (ja) * 1997-10-27 2008-06-26 Research Corp Technologies Inc 治療成分送達のための磁気共鳴イメージング剤
KR20070010671A (ko) * 2005-07-19 2007-01-24 김경일 요실금 검사치료 및 골반저근과 질근육의 바이오피드백 훈련용 장치
KR20160081004A (ko) * 2014-12-30 2016-07-08 포항공과대학교 산학협력단 멜라노이딘 및/또는 멜라노이딘의 금속 킬레이팅 복합체를 포함하는 광흡수제, 이의 제조방법, 및 용도

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LEE, MIN-YOUNG: "Biodegradable Photonic Melanoidin for Theranostic Applications", A CS NANO, 2016, pages 822 - 831, XP055679751 *

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