Imaging Diagnostic Composition and Method

Abstract

The present invention provides a composition. The composition includes a micelle having an outer shell containing one or more polymer-flavonoid conjugates, an inner shell optionally containing one or more flavonoid oligomers, and an imaging agent encapsulated within the shell. The present invention also provides a method for performing an imaging diagnosis using the composition.

Description

Technical Field

[0001] The present invention provides a composition for diagnostic imaging. The composition has an outer shell formed by one or more hydrophilic polymer-flavonoid conjugates, optionally has an inner shell formed by one or more flavonoid oligomers, and contains micelles having a contrast agent encapsulated therein. The present invention also provides a method for performing diagnostic imaging using the composition.

Background Art

[0002] Imaging modalities including computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound (US), and photoacoustic (PA) are widely used for disease diagnosis, treatment effect evaluation, and disease progression monitoring.

[0003] Computed tomography (CT) CT is a powerful diagnostic imaging means with low cost, deep tissue penetrability, high spatial resolution, and high resolution. The uses of CT scans are as follows: · Brain or head CT scan: Check for stroke, bleeding, tumors, and other abnormalities, and examine the skull. · Chest CT scan: Provide further insight into abnormalities after a standard chest X-ray examination. · Neck CT examination: Search for enlarged glands and lymph nodes and examine stiffness. · Spinal CT examination: Detect spinal problems such as spinal stenosis, intervertebral disc herniation, or fractures. · Sinus CT scan Detect and diagnose obstructions and sinus diseases. · Pelvic or abdominal CT examination Examine the organs in this area and diagnose unexplained abdominal pain.

[0004] However, a low signal-to-noise ratio reduces the ability of CT to distinguish adjacent tissues. For this reason, heavy atoms such as iodine, tungsten, and barium are suitable as contrast agents for CT images due to their large X-ray attenuation coefficients. These drawbacks can be compensated for by applying contrast agents, but chemical stability, solubility, density, and toxicity have become severe challenges for clinical applications. CT contrast agents include, without limitation, iohexol, iodixanol, iopamidol, iopromide, ioversol, ioxilan, cholografin meglumine, conray, conray 30, conray 43, cystoconray II, cystoconray, cystografin dilute, cystografin, gastrografin, renografin-76, ethiodol, hexabrix, or isovue, sodium diatrizoate, meglumine, ioxaglate, ioxaglate, sodium ioxaglate, iotalamic acid, iron oxide, sodium iotalamate, Au@BSA, gold nanoparticles, Bi-DTPA, N1177, dextran-coated cerium oxide nanoparticles, Bi-NU-901, PVB-Bi2S3, Er3+-doped Yb2O3, FePt nanoparticles, AuNPs-PEG, metrizoate, iodivitrol, barium, or carbon dioxide.

[0005] Magnetic resonance imaging (MRI) The excellent features of MR imaging include, similar to molecular imaging, relatively high temporal and spatial resolution, excellent tissue contrast and tissue permeability, not using ionizing radiation, non-invasive continuous examinations, and the ability to simultaneously acquire anatomical structures and physiological functions. The applications of MRI include spinal cord and brain abnormalities, cysts, tumors and other body abnormalities, joint abnormalities and injuries, breast tissue for cancer screening, the female pelvic region for identifying problems such as uterine fibroids and endometriosis, suspected uterine abnormalities, abdominal or liver diseases.

[0006] However, the weakness of MR imaging is its low sensitivity, which requires the introduction of imaging contrast agents and the development of powerful signal amplification strategies. Examples of MRI contrast agents include, but are not limited to, gadopentetate, gadoterate, gadobutrol, gadoteridol, gadobenate, gadoxetate, gadobutrol, gadodiamide, gadofosveset, dimeglumine gadopentetate, gadoxentate, gadocollate, gadopentetate dimeglumine, gadoxetate, gadoteric acid meglumine, disodium gadoxetate, trisodium gadofosveset, mangafodipir, gadobenate dimeglumine, ferumoxyl, ferumoxide, iron oxide, EP-3533, ManlCS1, USPIO-g-sLex, MS-325, PVP-IO (iron oxide coated with polyvinylpyrrolidone (PVP)), ProCA (protein-based MRI contrast agent), SPION, SPION-AN-FA, or Fe3O4.

[0007] Positron emission tomography (PET) and single photon emission computed tomography (SPECT) PET has high sensitivity, unlimited depth penetration, and quantitative capabilities. PET has become a powerful method for cancer diagnosis and functional imaging of other abnormalities. PET is more sensitive in diagnosing small-sized cancer tissues that cannot be detected by CT or MRI, especially when the cancer tissue is still buried in the organ and there is no budding on the organ surface detectable by MRI or CT. PET is often used for follow-up observation at the initial stage of post-treatment cancer cell regrowth.

[0008] Among the various radiopharmaceuticals used in molecular and metabolic imaging by PET, the contrast agent most useful for cancer imaging is fluorodeoxyglucose. After intravenous injection, FDG (2-deoxy-2-[18F]fluoro-glucose) is taken up by cancer cells in the same way as normal glucose. Subsequently, through the conversion of FDG to FDG-6-monophosphate by the intracellular enzyme hexokinase, the metabolite is trapped within cancer cells. On the other hand, SPECT, an excellent nuclear imaging technology based on the detection of gamma-ray photons, is utilized for imaging because it has a shorter detection time, higher specificity, and a more affordable price compared to PET. However, SPECT generally has lower sensitivity and lower spatial resolution than PET. When compared with CT, since radionuclides continuously emit high-energy gamma rays or positrons, the radiation exposure by PET or SPECT significantly increases. Therefore, reducing the usage amount of radionuclides while maintaining the imaging ability has become an important issue in the development of PET / SPECT contrast agents.

[0009] PET agents include, without limitation, 89Zr, rubidium chloride Rb-82, neuraceq, vizamyl, florbetapir F-18, choline C-11, amyvide, Ga-68 dotatate, axumin, flutetamol F-18, cardiogen-82, florbetaben F-18, fluciclovine F-18, Ruby-Fill, cerianna, netsotspot, Ga-68 dotatoc, tauvid, Ga-68 psma-11, detectnet, fluoroestradiol F-18, Cu-64 dotatate, florotaucipir F-18, piflufolastat F-18, pylarify, illuccix, or locametz, C-11, Ga-68, C11-PiB, Cu-64 ATSM, LMI1195, F-18 TFB, F-18 FSPG, F18-FDS, Ga-68-apotransferrin, F-18 AV-133, F-18 AV-45, F-18-T808, F-18-T807, or F-18-GE-180.

[0010] SPECT can be used in oncology, neuroimaging, cardiology, infectious diseases, biodistribution, and musculoskeletal imaging. SPECT agents include, without limitation, gallium(III), Tc99m, I-131, Tc-99m MDP, Tc-99m MAA, Tc-99m PYP, Tc-99m sulfur colloid, I-131 metaiodobenzylguanidine (MIBG), Tl-201, Ga-67, I-123, Tc-99m O4, TcO4-, Tc-99m phytate, Tc-99m DISIDA, Tc-99m DTPA, Tc-99m MAG3, Tc-99m DMSA, Tc-99m HMPAO, Tc-99m ECD, Tc-99m MIBI, Tc-99m sestamibi, Tl-201, I-131 OIH, I-131 6b-iodomethyl-19-norcholesterol (NP59), Ga-67, Xe-133, Kr-81m, In-111, or I-123 IMP, Lu-177, I-123 iodoamphetamine, Cu-64, As-72, Zr-89, I-124, C-11, Ga-68, F-18, Tc-99m CN5DG, Ro 16-0154, In111-DOTA-5D3, Tc99m-HYNIC-TMTP1 or QT-DTC-bisbiotin, etc.

[0011] Ultrasonic imaging Ultrasonic imaging is a non-invasive imaging method with high soft tissue contrast and does not irradiate patients with radiation. Ultrasonic imaging is used to classify benign solid lesions with a negative accuracy rate of 99.5% and is applicable to both imaging diagnosis and treatment.

[0012] In this imaging method, various types of bubbles are used as imaging contrast agents with sizes ranging from nanometers to micrometers. Unfortunately, characteristics such as the size distribution and stability of these bubbles are greatly affected by physiological conditions.

[0013] Ultrasound agents include, without limitation, Albunex, Bisphere, Luminity, Echogen, Echovist, Filmix, Imavist, Levovist, Myomap, Optison, Quantison, Sonavist, Sonazoid, SonoGen, SonoVue, Lumason, PB127, etc.

[0014] Ultrasound scans can be used on the heart, joints, uterus, blood vessels, muscles, bladder, kidneys, etc.

[0015] Photoacoustic (PA) imaging PA imaging is a new technology with great potential for enhancing ultrasound with rich optical contrast and could serve as a portable and relatively low-cost single modality for local imaging. The core strengths of PA imaging are high spatial / temporal resolution, clinically appropriate imaging depth, the ability to image both endogenous and exogenous chromophores, and its potential of not using ionizing radiation. Common endogenous chromophores include water (both free and bound), oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), melanin, lipids, etc. Many of the exogenous agents are low molecular weight dyes such as indocyanine green (ICG), methylene blue dye (MBD), nanoparticles, or reporter gene agents. Different from current microbubble-based ultrasound contrast agents, PAI can image low molecular weight substances that easily extravasate, target cell membrane molecules, or enter the target cells to target intracellular molecules, and thus potentially provide valuable molecular data to clinicians.

[0016] PA agents include, without limitation, ICG, CuS, WS2, MoS2, Ag2S, Co9Se8, ZnS, Nb2C, Bi2S3, carbon dots, indocyanine green, methylene blue, IR800 dye, Evans blue, etc.

[0017] PA can be used for detecting brain lesions, monitoring blood flow dynamics, diagnosing breast cancer, etc.

[0018] The above-described imaging methods have insufficient contrast capabilities to distinguish normal tissues from diseased lesions and require contrast agents to enhance the image differences. To obtain the necessary image differences, patients are administered these contrast agents in amounts of several grams, which can cause serious side effects.

[0019] Flavonoid Flavonoids have a general structure of a 15-carbon skeleton consisting of two phenyl rings (A and B) and one heterocyclic ring (C, a ring containing embedded oxygen). [Chemical formula]

[0020] This carbon structure can be abbreviated as C6-C3-C6. According to the IUPAC nomenclature, flavonoids can be classified as follows: · Flavonoids or bioflavonoids. · Isoflavonoids, derived from the 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure. · Neoflavonoids, derived from the 4-phenylcoumarin (4-phenyl-1,2-benzopyrone) structure. [Summary of the Invention]

[0021] The present invention provides a composition for diagnostic imaging for enhancing signals of diagnostic imaging techniques for monitoring diseases, prognostic diagnosis, and assisting in diagnosis, and for formulating treatment plans for diseases. The composition includes micelles having an outer shell formed by one or more hydrophilic polymer-flavonoid conjugates, optionally an inner shell formed by one or more flavonoid oligomers, and an imaging agent encapsulated within the shell. [Brief Description of the Drawings]

[0022]

Figure 1

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Figure 4

Figure 5

[0023] Definitions

[0024] The term "epigallocatechin gallate" refers to an ester of epigallocatechin and gallic acid and is used interchangeably with "epigallocatechin-3-gallate" or EGCG.

[0025] The term "oligomeric EGCG" (OEGCG) refers to 2 to 50, preferably 3 to 20 monomers of covalently linked EGCG. OEGCG preferably contains 4 to 12 EGCG monomers.

[0026] The term "polyethylene glycol-epigallocatechin gallate conjugate" or "PEG-EGCG" refers to polyethylene glycol (PEG) conjugated with one or two molecules of EGCG. The term "PEG-EGCG" refers to both the PEG-mEGCG conjugate (monomeric EGCG) and the PEG-dEGCG (dimeric EGCG) conjugate.

[0027] The present invention provides a composition for diagnostic imaging for enhancing signals of diagnostic imaging techniques for monitoring diseases, prognostic diagnosis, and assisting in diagnosis, and for formulating treatment plans for diseases. The composition includes micelles having an outer shell formed of one or more hydrophilic polymer-flavonoid conjugates, optionally an inner shell formed of one or more flavonoid oligomers, and an imaging agent encapsulated within the shell.

[0028] Flavonoid The flavonoids suitable for the present invention have the general structure of Formula I. [Chemical formula] In the formula, R1 is H or phenyl; R2 is H, OH, gallic acid, or phenyl; where the phenyl is optionally substituted with one or more (e.g., 2 to 3) hydroxyl groups; R3 is H, OH, or =O (oxo); or R1 and R2 together form a closed-loop ring structure; or R2 and R3 form a closed-loop ring structure.

[0029] The 2, 3, 4, 5, 6, 7, or 8 positions of Formula I may be linked to a group containing hydrocarbon, halogen, oxygen, nitrogen, sulfur, phosphorus, boron, or metal.

[0030] Examples of the flavonoids of Formula I include the following: [Chemical formula]

[0031] Preferred flavonoid compounds of formula I include the following: EGCG (CAS#989-51-5), EC (CAS#490-46-0), EGC (CAS#970-74-1) or ECG (CAS#1257-08-5). [Chemical formula]

[0032] Hydrophilic polymer-flavonoid conjugate As used throughout this application and in the specification herein, the hydrophilic polymer-flavonoid conjugate refers to a conjugate of a hydrophilic polymer and a flavonoid compound of formula I.

[0033] A hydrophilic polymer refers to a polymer that is soluble in polar solvents and can form hydrogen bonds. Examples of hydrophilic polymers suitable for the polymer-flavonoid conjugate of the present invention include poly(ethylene glycol), aldehyde-derivatized hyaluronic acid, hyaluronic acid, dextran, diethyl acetal conjugate (e.g., diethyl acetal PEG), succinic acid D-α-tocopheryl polyethylene glycol, aldehyde-derivatized hyaluronic acid-tyramine, hyaluronic acid-aminoacetyl aldehyde diethyl acetal conjugate-tyramine, cyclotriphosphazene core phenoxymethyl(methylhydrazono)dendrimer or thiophosphoryl core phenoxymethyl(methylhydrazono)dendrimer, acrylamide, oxazoline, imine, acrylic acid, methacrylic acid, diol, oxirane, alcohol, amine, anhydride, ester, lactone, terephthalic acid, amide and ether polyacrylamide, poloxamer, poly(N-isopropylacrylamide), poly(oxazoline), polyethyleneimine, poly(acrylic acid), polymethacrylate, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinyl pyrrolidone), polyether, poly(allylamine), polyanhydride, poly(β-amino ester), poly(butylene succinate), polycaprolactone, polycarbonate, polydioxanone, poly(glycerol), polyglycolic acid, poly(3-hydroxypropionic acid), poly(2-hydroxyethyl methacrylate), poly(N-(2-hydroxypropyl)methacrylamide), polylactic acid, poly(lactic-co-glycolic acid), poly(orthoester), poly(2-oxazoline), poly(sebacic acid), poly(terephthalic acid-co-phosphate), povidone and copolymers, which are non-limiting examples.

[0034] Preferred hydrophilic polymers include poly(ethylene glycol), hyaluronic acid, dextran, polyethyleneimine, poloxamer, povidone, D-α-tocopheryl, and polyethylene glycol succinate. The molecular weight of the hydrophilic polymer in the polymer-flavonoid conjugate is generally 1K to 100K, preferably 2K to 40K, 2K to 50K, 2K to 80K, 3K to 80K, or 5K to 40K daltons. In one embodiment, the polymer contains an aldehyde group bonded to the 5-, 6-, 7-, or 8-position (preferably the 6- or 8-position) of the A-ring of the flavonoid compound.

[0035] In one embodiment, the polymer contains a thiol group bonded to R1 or R2 of the B-ring of the flavonoid (when R1 or R2 is -OH).

[0036] The poly(ethylene glycol) (PEG)-flavonoid conjugate, as used herein throughout this application, refers to a conjugate of PEG and a flavonoid compound of Formula I. The molecular weight of PEG in the PEG-flavonoid conjugate is generally 1K to 100K, preferably 3K to 80K, more preferably 5K to 40K.

[0037] In one embodiment, PEG contains an aldehyde group bonded to the 5, 6, 7, or 8-position (preferably 6 or 8) of the A-ring of the flavonoid compound. In another embodiment, PEG contains a thiol group bonded to R1 or R2 of the B-ring of the flavonoid (when R1 or R2 is -OH).

[0038] In one embodiment, the PEG - flavonoid conjugate is PEG - EGCG in which PEG is conjugated to one or two molecules of epigallocatechin gallate (EGCG). PEG - EGCG can be prepared, for example, by conjugating aldehyde - terminated PEG to EGCG via the reaction of a free aldehyde group with the 5-, 6-, 7 - or 8 - position (preferably the 6 - or 8 - position) of formula I (see WO2006 / 124000 and WO2009 / 054813). PEG - EGCG can also be prepared by conjugating thio - terminated PEG to EGCG via the reaction of a free thio group with R1 or R2 of formula I, wherein R1 or R2 is a phenyl group (see WO2015 / 171079).

[0039] Flavonoid oligomer A flavonoid oligomer is a conjugate of one type of flavonoid with one or more types of flavonoids. The flavonoid oligomer can contain the same flavonoid (homo - oligomer) or different flavonoids (hetero - oligomer). Flavonoid oligomers useful in the present invention generally have 2 to 20, preferably 4 to 12, of one or mixed species of flavonoids.

[0040] In some embodiments, the flavonoid oligomer is oligomeric EGC (OEGCG), oligomeric EC (OEC), oligomeric EGC (OEGC) or oligomeric ECG (OECG). OEGCG refers to 3 - 20 monomers of covalently - bound EGCG. OEGCG can be synthesized, for example, at the 5, 6, 7, or 8 - position (preferably the 6 - or 8 - position) of the A - ring according to WO2006 / 124000.

[0041] Since the A - ring is present in all flavonoids described in formula 1, other oligomeric flavonoids can also be produced in the same manner according to WO2006 / 124000. For example, OEC, OEGC and OECG can also be produced according to WO2006 / 124000.

[0042] MINC - agent MINC (Multi-pathway Immune-modulating Nanocomplex Combination therapy) is a platform technology that utilizes the bioactivity of hydrophilic polymer-flavonoid conjugates and / or flavonoid oligomers that form micelles in solution. This application utilizes the MINC platform to encapsulate additional imaging agents to form nanoparticle compositions for diagnostic imaging.

[0043] MINC-agents are micelles having a shell formed by one or more hydrophilic polymer-flavonoid conjugates and optionally one or more flavonoid oligomers, and having an imaging agent encapsulated within the shell. As used herein, the imaging agent refers to a molecule that can enhance the contrast quality of imaging techniques by the MINC technology.

[0044] In one embodiment, the MINC-agent is a micelle containing a hydrophilic polymer-flavonoid conjugate, such as a PEG-EGCG conjugate, with an imaging agent encapsulated within the shell (see Figure 1).

[0045] In another embodiment, the MINC-agent is a micelle containing a hydrophilic polymer-flavonoid conjugate (such as a PEG-EGCG conjugate) in the outer core, a flavonoid oligomer (such as oligomeric EGCG (OEGCG)) in the inner core, together with an encapsulated imaging agent (see Figure 2).

[0046] In this application, the MINC-agent can be used in computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound, photoacoustic (PA) imaging with the same injection procedure as conventional contrast agents. Compared with conventional contrast agents, the MINC-agent has the advantages that (1) it has a longer residence time in tissues, (2) it accumulates more at the target site due to the enhanced permeability and retention (EPR) effect, and (3) it has less accumulation at off-target sites and lower toxicity. Taken together, the MINC-agent has higher signal intensity and higher safety than conventional imaging agents.

[0047] Imaging agents for CT MINC agents include, without limitation, iohexol, ioxodol, diatrizoate, metrizoate, iopamidol, iopromide, ioversol, ioxilan, meglumine iothalamate, Conray, Conray 30, Conray 43, Cysto-Conray II, Cysto-Conray, diluted meglumine iothalamate, meglumine iothalamate, Gastrografin, Renografin-76, ethiodol, Hexabrix, or isovue, meglumine, ioxaglate, ioxaglate, sodium ioxaglate, iotalamic acid, iron oxide, sodium iotalamate, Bi-DTPA, N1177, Bi-NU-901, PVB-Bi2S3, Er3+-doped Yb2O3, iobitridol, barium, and carbon dioxide.

[0048] Imaging agents in MINC agents for MRI include, without limitation, gadopentetate, gadoterate, gadodiamide, gadoxetate, gadobutrol, gadoteridol, gadobenate, gadobenemide, gadodiamide, gadofosveset, dimeglumine gadopentetate, gadoxentate, gadocolic acid, gadomer 17, gadoxetic acid, meglumine gadoterate, disodium gadoxetate, trisodium gadofosveset, mangafodipir, gadobenate dimeglumine, ferumoxyl, ferumoxide, iron oxide, EP-3533, ManlCS1, USPIO-g-sLex, MS-325, PVP-IO, ProCA, SPION, SPION-AN-FA, and Fe3O4.

[0049] Imaging agents in MINC agents for PET include, without limitation, 89Zr, rubidium chloride Rb-82, neuraceq, vizamyl, florbetapir F-18, choline C-11, amyloid, Ga-68 dotatate, axumin, flutemetamol F-18, cardiogen-82, florbetaben F-18, fluciclovine F-18, Ruby-Fill, cerianna, netsot, Ga-68 dotatoc, tauvid, Ga-68 psma-11, detectnet, fluoroestradiol F-18, Cu-64 dotatate, florotaucipir F-18, piflufostat F-18, pylarify, illuccix, or locametz, C-11, Ga-68, C11-PiB, Cu-64 ATSM, LMI1195, F-18 TFB, F-18 FSPG, F18-FDS, Ga-68-apotransferrin, F-18 AV-133, F-18 AV-45, F-18-T808, F-18-T807, and F-18-GE-180.

[0050] Imaging agents in SPECT with MINC agents include, without limitation, gallium(III), Tc-99m, I-131, Tc-99m MDP, Tc-99m MAA, Tc-99m PYP, Tc-99m sulfur colloid, I-131 metaiodobenzylguanidine (MIBG), Tl-201, Ga-67, I-123, Tc-99m O4, TcO4-, Tc-99m phytate, Tc-99m DISIDA, Tc-99m DTPA, Tc-99m MAG3, Tc-99m DMSA, Tc-99m HMPAO, Tc-99m ECD, Tc-99m MIBI, Tc-99m sestamibi, Tl-201, I-131 OIH, I-131 6β-iodomethyl-19-norcholesterol (NP59), Ga-67, Xe-133, Kr-81m, In-111, or I-123 IMP, Lu-177, I-123 iodoamphetamine, Cu-64, As-72, Zr-89, I-124, C-11, Ga-68, F-18, Tc-99m CN5DG, Ro 16-0154, In111-DOTA-5D3, Tc99m-HYNIC-TMTP1 and QT-DTC-bisbiotin.

[0051] In one embodiment, the composition for image diagnosis comprises a MINC-agent and one or more pharmaceutically acceptable excipients which are inert ingredients suitable for administration to a subject. The pharmaceutically acceptable excipients can be selected by those skilled in the art using conventional criteria. Pharmaceutically acceptable excipients include, without limitation, physiological saline and aqueous electrolyte solutions; ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose; pH adjusters and buffers such as salts of hydroxides, phosphates, citrates, acetates, borates, and salts of trolamine; antioxidants such as salts, acids, and / or bases of bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetylcysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, ascorbyl palmitate, etc.; surfactants such as phospholipids like lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol; poloxamer and poloxamine; polysorbates such as polysorbate 80, polysorbate 60, and polysorbate 20; polyethers such as polyethylene glycol and polypropylene glycol; polyvinyls such as polyvinyl alcohol and polyvinyl pyrrolidone (PVP, povidone); cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose and their salts; petroleum derivatives such as mineral oil, white petrolatum; fats such as lanolin, peanut oil, palm oil, soybean oil; mono-, di-, and triglycerides; polysaccharides such as dextran; glycosaminoglycans such as sodium hyaluronate are included.

[0052] Method of image diagnosis CT (Computed Tomography) Imaging In CT image diagnosis, the difference in mass density of a lesion (such as a tumor) relative to normal tissue is detected using X-rays by the Hounsfield value (HV: Hounsfield Value). The HV is calculated by measuring the difference in X-ray attenuation between the lesion and another tissue.

[0053] When using a CT contrast agent, the CT image signal can be enhanced with higher sensitivity than CT alone. CT contrast agents are often used for the detection of tumors. Since tumor tissues are highly vascular, the CT contrast agent accumulates more in tumors than in surrounding tissues, resulting in a higher HV.

[0054] In one aspect, the present invention relates to an imaging diagnosis method based on CT imaging.

[0055] This method includes administering the above effective amount of micelles to a subject in need thereof, performing a CT scan, measuring the difference in X-ray attenuation between the lesion and normal tissue, and determining the location and / or size of the lesion. Including.

[0056] In this method, the CT scan is performed on the whole body, brain, head, chest, neck, spine, paranasal sinuses, pelvis, or abdomen.

[0057] In one embodiment, the lesion is a tumor, autoimmune disease, cardiovascular disease, central nervous system disease, infectious disease, and inflammatory lesion.

[0058] In one embodiment, the micelles are administered by intravenous injection, intraarterial injection, intrathecal injection, or orally.

[0059] A CT contrast agent, such as iohexol, is usually intravenously injected at a concentration of 350 mg / mL and an injection volume of 60 - 100 mL for whole-body imaging diagnosis to detect the presence and size of tumors.

[0060] In the present invention, MINC-iohexol is used by intravenous injection in the same manner as the iohexol injection procedure, at an iohexol concentration and injection volume equal to or lower than that.

[0061] Conventional CT imaging timing was limited to a short period of 10 to 15 minutes immediately after contrast agent administration because, beyond this time, the renal secretion of the contrast agent is rapid, leading to an extremely degraded image quality. The imaging time of the MINC-agent can be extended to 1 to 2 hours or more after injection without degrading the quality of the imaging signal. This advantage brings more convenience and accuracy to the CT scans of patients. The MINC-agent can be used in all CT imaging devices to which CT contrast agents are applied for enhancing the contrast signal and extending the detection time.

[0062] (Magnetic Resonance Imaging) MRI Imaging

[0063] MRI is a medical imaging technique used in radiology to form images of the anatomical structures and physiological processes of the body. MRI scanners use a strong magnetic field, magnetic field gradients, and radio waves to generate images of internal organs. MRI is widely used in hospitals and clinics for disease diagnosis, staging, and follow-up. Compared to CT, MRI provides better contrast in images of soft tissues such as the brain and abdomen.

[0064] MRI for imaging anatomical structures and blood flow does not require a contrast agent because various properties of tissues and blood naturally provide contrast. However, for more specialized imaging, exogenous contrast agents can be administered intravenously, orally, or intra-articularly. The most commonly used intravenous contrast agents are based on gadolinium chelates. MRI contrast agents can improve the visibility of internal structures more reliably than MRI alone when determining the location and size of lesions. MRI contrast agents are used, for example, when measuring organ changes such as for tumor detection.

[0065] In one aspect, the present invention relates to a method for image diagnosis based on MRI imaging.

[0066] This method comprises administering the effective amount of the micelles in the present application to a subject in need thereof; performing MRI; measuring the difference in magnetic resonance signals generated by the magnetic field between the lesion and the normal tissue to detect the lesion; and determining the location and / or size of the lesion, comprising.

[0067] In one embodiment, the lesion is a tumor, autoimmune disease, cardiovascular disease, central nervous disease, infectious disease, or inflammatory lesion.

[0068] In one embodiment, the imaging organ is the brain, breast, spinal cord, bladder, uterus, ovary, blood vessel, lymph node, heart, liver, biliary tract, kidney, spleen, intestine, pancreas, and adrenal gland.

[0069] In one embodiment, the micelles are administered intravenously, orally, or intra-articularly.

[0070] In the present invention, MINC-gadopentetic acid dimeglumine is used by intravenous injection in the same manner as the gadopentetic acid dimeglumine injection procedure, at the same gadopentetic acid dimeglumine concentration and injection volume. For example, gadopentetic acid dimeglumine is usually intravenously injected at a concentration of 470 mg / mL and an injection volume of 14 to 18 mL for whole-body imaging diagnosis to detect the presence and size of tumors.

[0071] The imaging timing of MRI is generally limited to a short time of 60 to 90 minutes immediately after the administration of the contrast agent. This is because when more time elapses, the renal secretion of the contrast agent speeds up, resulting in extremely degraded image quality. The imaging time of the MINC-agent can be extended to 2 to 3 hours or more after injection without degrading the quality of the imaging signal, providing more convenience and accuracy for the patient's MRI scan. The MINC-agent can be used for enhancing the contrast signal and extending the detection time in all MRI imaging devices to which MRI contrast agents are applied.

[0072] Single Photon Emission Computed Tomography (SPECT) Imaging SPECT imaging is a nuclear medicine tomography method using gamma rays. SPECT imaging is similar to the conventional nuclear medicine planar imaging method (i.e., scintigraphy) using a gamma camera, but can provide precise 3D information. This information is usually displayed as cross-sectional slices of the patient, but can be freely reformatted or manipulated as needed.

[0073] In this technique, it is necessary to administer a radioisotope (radionuclide) that emits gamma rays to the patient, usually by injection into the bloodstream. The radioisotope may be a simple soluble dissolved ion such as an isotope of gallium(III). In most cases, the radioisotope marker is bound to a specific ligand to create a radioligand, which binds to a specific type of tissue according to its properties. Thereby, the combination of the ligand and the radiopharmaceutical is transported to and bound at the target location in the body, and the ligand concentration can be observed with a gamma camera.

[0074] SPECT imaging agents can generate SPECT imaging signals with better visibility when determining the location and size of lesions.

[0075] In one aspect, the present invention relates to a method for diagnostic imaging based on SPECT imaging.

[0076] The method comprises administering the above effective amount of micelles in the present application to a subject in need thereof, performing SPECT imaging, measuring the difference in signal intensity of gamma rays between the lesion and normal tissue, and determining the location and / or size of the lesion, and including.

[0077] In one embodiment, the disease lesion includes a lesion caused by a tumor, an autoimmune disease, a cardiovascular disease, a central nervous system disease, an infection, or an inflammation.

[0078] In one embodiment, the imaging organ is the brain, heart, thyroid, bone, lung, liver, kidney, parathyroid, gastrointestinal system (stomach, intestine), salivary gland, pancreas, spleen, adrenal gland, prostate, ovary, testis, blood flow of the extremities (arms, legs), lymphatic system, bladder, breast.

[0079] In one embodiment, the micelles are administered intravenously.

[0080] Compared with conventional imaging agents, the MINC-agent can accumulate more in inflammatory lesions. Therefore, the signal intensity and image quality at the lesion site are improved compared with conventional imaging agents. The MINC-agent can be used in all SPECT imaging devices to which SPECT imaging agents are applied.

[0081] MINC-Tc99m can be used at the same Tc99m concentration and injection volume by intravenous injection similar to the Tc99m injection procedure. For example, Tc99m is usually intravenously injected at a concentration of 20 mCi and an injection volume of 1 - 2 mL for whole-body imaging diagnosis to detect the presence and size of tumors, and for coronary angiography imaging, it is intravenously injected at a concentration of 10 mCi and an injection volume of 1 - 2 mL.

[0082] Positron Emission Tomography (PET) PET is a functional imaging technique that visualizes and measures changes in metabolic processes, blood flow, local chemical composition, and other physiological activities, including absorption, using a radioactive substance known as a radioactive tracer. Depending on the target process in the body, various tracers are used for various imaging purposes. PET is a common imaging technique and a medical scintigraphy technique used in nuclear medicine. A radiopharmaceutical (a drug with a radioactive isotope bound to it) is injected into the body as a tracer. Gamma rays are emitted and detected by a gamma camera, and a three-dimensional image is formed similar to an X-ray image.

[0083] In one aspect, the present invention relates to a method for image diagnosis based on PET imaging.

[0084] The method comprises administering the above effective amount of micelles to a subject in need thereof; performing positron emission tomography (PET) imaging; measuring a three-dimensional image formed by gamma rays generated from positrons emitted by the imaging agent; and determining the location and / or size of the lesion. Including.

[0085] In one embodiment, the lesion is a tumor, autoimmune disease, cardiovascular disease, central nervous system disease, infectious disease, and inflammatory lesion.

[0086] In one embodiment, the imaging organ is the brain, heart, lung, liver, bone, thyroid, digestive system, lymphatic system, prostate, ovary, testis, adrenal gland, soft tissue.

[0087] In one embodiment, the micelles are administered intravenously.

[0088] The MINC-agent can be used in all PET imaging devices to which a PET imaging agent is applied. Compared with conventional imaging agents, the MINC-agent can accumulate more in inflammatory lesions. Therefore, the signal intensity and image quality of the MINC-agent are improved compared with those of conventional imaging agents.

[0089] PET scans using 18F-FDG as a tracer are widely used in clinical oncology. FDG is a glucose analog that is taken up by cells that use glucose and phosphorylated by hexokinase (the mitochondrial form of which is significantly elevated in rapidly growing malignant tumors). The metabolic trapping of the radioactive glucose molecule enables the use of PET scans. MINC-18F-FDG is used at similar 18F-FDG concentrations and injection volumes by intravenous injection, similar to the injection procedure for 18F-FDG. In the case of PET imaging, for example, F18-FDG is typically intravenously injected at a concentration of 10 mCi and an injection volume of 1 - 2 mL for whole-body imaging to detect the presence and size of tumors, and at a concentration of 5 mCi and an injection volume of 1 - 2 mL for coronary vascular imaging.

[0090] The following examples further illustrate the present invention. These examples are merely intended to exemplify the present invention and are not to be construed as limiting.

Example

[0091] Active ingredient OEGCG: OEGCG is oligomeric EGCG. OEGCG is prepared according to WO2006 / 124000.

[0092] PEG-EGCG: PEG-EGCG is PEG conjugated to one or two EGCGs. PEG-EGCG is prepared according to WO2006 / 124000, WO2009 / 054813, or WO2015 / 171079.

[0093] MINC-agent: The MINC-agent can be prepared by encapsulating the agent within micelles formed by PEG-EGCG and OEGCG according to the methods of WO2006 / 124000 or WO2009 / 054813. Alternatively, the MINC-agent can be prepared by encapsulating the agent within micelles formed by PEG-EGCG according to the methods of WO2011 / 112156 or WO2015 / 171079.

[0094] Example 1. Preparation of MINC-agent for CT imaging

[0095] Materials Iohexol, diatrizoate, and metrizoate were purchased from Echo Chemical. Iopamidol was purchased from Wuhan honestchem.

[0096] Methods The MINC-agent was prepared according to WO2006 / 124000. Briefly, iohexol, iopamidol, diatrizoate, and metrizoate were prepared in PBS. Subsequently, the flavonoid oligomer OEGCG was added to each contrast agent / PBS, followed by addition of the polymer-flavonoid PEG-EGCG. After incubating the mixture at room temperature, unreacted OEGCG and PEG-EGCG were removed using a 10K MWCO centrifugal filter. The nanoparticle size was measured using DLS (Anton Paar Litesizer 500), and the results are shown in Figure 3.

[0097] Results Figure 3 shows that PEG-EGCG and OEGCG generated MINC-iohexol (A), MINC-iopamidol (B), MINC-diatrizoate (C), and MINC-metrizoate (D) micelles having a single peak with a particle size similar to around 50 - 300 nm. This result indicates that homogeneous nanoparticles (micelles) were successfully formed at the desired size, and unencapsulated agents were not detected by DLS.

[0098] These data indicate that iohexol, diatrizoate, metrizoate, and iopamidol, which are CT contrast agents, were formed by the MINC platform.

[0099] Example 2. Preparation of MINC-Agents for MRI Imaging

[0100] Materials Gadopentetate was purchased from Seven Star Pharmaceutical. Gadodiamide was purchased from Labseeker Inc. Gadoxetate was purchased from Amadis Chemical. Gadoterate was purchased from Toronto Research Chemical.

[0101] Methods The MINC-agents were prepared according to WO2006 / 124000. Briefly, gadopentetate, gadodiamide, gadoxetate, and gadoterate were incubated in PBS. Subsequently, the flavonoid oligomer OEGCG was added to the contrast agent, followed by the addition of the polymer-flavonoid PEG-EGCG. After incubating the mixture at room temperature, unreacted OEGCG and PEG-EGCG were removed using a 10K MWCO centrifugal filter. The nanoparticle size was measured using DLS (Anton Paar Litesizer 500), and the results are shown in Figure 4.

[0102] Results Figure 4 shows that PEG-EGCG and OEGCG generated MINC-gadopentetate (A), MINC-gadodiamide (B), MINC-gadoxetate (C), and MINC-gadoterate (D) micelles having a single peak with a particle size similar to around 50 - 300 nm. This result indicates that homogeneous nanoparticles (micelles) were successfully formed at the desired size, and unencapsulated agents were not detected by DLS.

[0103] These data support that gadopentetate, gadodiamide, gadoxetate, and gadoterate, which are contrast agents, can be formed on the MINC platform.

[0104] Example 3. MINC-gadopentetate enhanced the contrast signal more than gadopentetate dimeglumine in MRI tumor imaging.

[0105] Materials MINC-gadopentetate is gadopentetate encapsulated within OEGCG and PEG-EGCG (see Example 2). The LLC1 mouse lung cancer cell line was obtained from ATCC, USA. Male C57BL / 6 mice were obtained from Jackson Laboratories, USA.

[0106] Methods This experiment is to confirm that MINC-gadopentetate can be used as a contrast agent for tumor detection.

[0107] In this experiment, an in vivo xenograft tumor model was used. Briefly, two male C57BL / 6 mice bearing LLC1 mouse lung cancer xenografts (6 - 8 weeks) were divided into two groups (n = 1) with minimal body weight difference. Gadopentetate or MINC - gadopentetate was intravenously injected into the two groups of mice at a dose of 93.8 mg / kg. MRI imaging was performed using a BRUKER BIOSPEC 70 / 30 MRI. The animals were placed prone on the imaging bed with their legs extended. After the mice were anesthetized, a T1 - weighted gradient - echo protocol was continuously performed at 0.5 hour, 2 hours, and 24 hours after injection. The imaging parameters for the T1 - weighted images were TR / TE = 8.0 / 4.2, flip angle = 30°, field of view 50×30 mm, matrix size 192×192, and coronal slice thickness 2 mm, and TR / TE = 8.0 / 4.5, flip angle = 30°, field of view 45×45 mm, matrix size 192×192, and axial slice thickness 2 mm. To normalize the signal intensity for the T1 - weighted images, the tumor region was selected as the region of interest (ROI). The signal intensity of the ROI was normalized to the intensity of the muscle near the hip. Three images were taken at each time point, and the statistic was calculated by the Student t - test. **: p < 0.01.

[0108] Results As a result of MRI imaging, MINC - gadopentetate showed higher imaging intensity in the tumor than free gadopentetate (Figure 5).

[0109] Example 4. Comparison of Contrast Signals between MINC - Iohexol and Iohexol in CT Tumor Imaging (Predictive Example)

[0110] Objective This experiment aims to demonstrate the tumor - targeting effect of MINC - iohexol. Using tumor - bearing mice, the signal intensities of MINC - iohexol and iohexol present in the tumor are evaluated. MRI imaging can be used to confirm the efficiency of the contrast agent delivered to the tumor.

[0111] Materials MINC-iohexol is iohexol encapsulated within OEGCG and PEG-EGCG and is prepared according to WO2006 / 124000. Iohexol is purchased from Echo Chemical. The MCF-7 human breast cell line is obtained from ATCC, USA. Female athymic nude mice are obtained from Jackson Laboratories, USA.

[0112] Methods To confirm that MINC-iohexol can be used as a contrast agent for tumor detection, an in vivo xenograft tumor model is used. Briefly, six female athymic nude mice bearing MCF-7 human breast cancer xenografts (6 - 8 weeks) are divided into two groups (n = 3) to minimize the body weight difference. These two groups of mice are intravenously injected with iohexol and MINC-iohexol at doses of 0.02 - 100 mg / kg, respectively. Micro-CT imaging is performed using a hybrid small animal scanner (Inveon SPECT / CT; Siemens Medical Solutions USA, Inc.). The animals are placed prone on the imaging bed with their legs extended. Five minutes after injection, the mice undergo high-resolution anatomical CT (360 projections, 80 kVp / 500 A transmission energy, effective pixel size 96 m) imaging. The micro-CT images are reconstructed using the cone beam algorithm with commercially available software (Cobra Exxim) and the intensity values are converted to Hounsfield units (HU). Quantitative analysis is measured using Inveon Research Workspace (Siemens Medical Solutions USA, Inc.). Briefly, a complex and irregular volume of interest (VOI) is drawn on the micro-CT image and the average count in each VOI is determined.

[0113] Example 5. MINC-Gadopentetate is used as a contrast agent for the detection of type 1 diabetes using MRI (predictive example).

[0114] Objective This example aims to demonstrate that MINC-gadopentetate improves the contraction signal of pancreatic islets compared to free gadopentetate. MRI imaging is used to confirm the difference in contrast signals between normal and inflamed pancreatic islets.

[0115] Materials MINC-gadopentetate is gadopentetate encapsulated within OEGCG and PEG-EGCG and is prepared according to WO2006 / 124000. Gadopentetate is obtained from Seven Star pharmaceutical. The glucose meter is obtained from Glucometer Elite, Bayer. NOD / Lt, Eα16 / NOD, NOD-RAG- / - , BDC2.5 / NOD, BDC2.5 / B6.H-2g7 / g7, or BDC2.5 / NOD-RAG- / - mice are obtained from Bar Harbor, ME, USA or other sources.

[0116] Methods To confirm that MINC-gadopentetate can be used as a contrast agent for pancreatic islets in type 1 diabetes, a mouse model can be used. Briefly, NOD / Lt, Eα16 / NOD, NOD-RAG- / -, BDC2.5 / NOD, BDC2.5 / B6.H-2g7 / g7, or BDC2.5 / NOD-RAG- / - mice are bred under specific pathogen-free conditions. Diabetes is monitored by measuring glucose in the urine and confirmed by measuring blood glucose levels. Gadopentetate and MINC-gadopentetate are intravenously injected into type 1 diabetic mice at doses of 0.025 - 250 mmol Gd / kg, respectively. T2 measurements are performed on an 8.5 Tesla microimaging system and reported as the tissue R2 relaxation rate (R2 = 1 / T2) using standard procedures.

[0117] Example 6. Comparison of Contrast Signals between MINC-Tc99m and Tc99m in SPECT Tumor Imaging (Predictive Example)

[0118] Objective This example is to demonstrate that MINC-Tc99m improves the contrast signal in the tumor region compared to free Tc99m. SPECT imaging is used to confirm the contrast difference between normal and tumor.

[0119] Materials MINC-Tc99m is Tc99m encapsulated within OEGCG and PEG-EGCG and is prepared according to WO2006 / 124000. Tc99m is obtained from Lantheus medical image, Inc, USA or other sources. Male athymic nude mice are obtained from Jackson Laboratories, USA or other sources. The HeLa human ovarian cancer cell line is obtained from ATCC, USA.

[0120] Methods To confirm that MINC-Tc99m can be used as a contrast image for tumor detection, an in vivo xenograft tumor model is used. Briefly, 5-week-old male nude mice are subcutaneously injected with 1×10 6 HeLa cells / mouse into the right forelimb. The tumor volume is expected to reach 0.4 - 0.7 cm 3 about 3 weeks after injection. Then, MINC-Tc99m (0.1 μCi - 500 μCi) in PBS is intravenously injected via the tail vein. The mice are anesthetized with 2% isoflurane through a mask on the imaging bed. Mice with tumors are scanned by SPECT 30 minutes, 90 minutes, 150 minutes, and 240 minutes after injection using a NanoSPECT In Vivo Animal Imager (Bioscan Ltd., Washington, D.C.) at a tube voltage of 80 kV, a tube current of 450 μA, and a slice thickness of 45 μm. All image data are reconstructed and analyzed using the In Vivo Scope software provided by the manufacturer.

[0121] The contrast agent Tc99m encapsulated in this example can be substituted with I-131, Tc-99m MDP, Tc-99m MAA, Tc-99m PYP, Tc-99m sulfur colloid, I-131 metaiodobenzylguanidine (MIBG), Tl-201, Ga-67, I-123, Tc-99m O4, TcO4-, Tc-99m phytate, Tc-99m DISIDA, Tc-99m DTPA, Tc-99m MAG3, Tc-99m DMSA, Tc-99m HMPAO, Tc-99m ECD, Tc-99m MIBI, Tc-99m sestamibi, Tl-201, I-131 OIH, I-131 6β-iodomethyl-19-norcholesterol (NP59), Ga-67, Xe-133, Kr-81m, In-111 or I-123 IMP.

[0122] Example 7. Comparison of Contrast Signals between MINC-89Zr and 89Zr in PET Tumor Imaging (Predictive Example)

[0123] Objective This example shows that MINC-89Zr improves the contrast signal in the tumor region compared to free 89Zr. PET imaging is used to confirm the contrast difference between normal and tumor.

[0124] Materials MINC-89Zr is prepared according to WO2006 / 124000 by encapsulating 89Zr in OEGCG and PEG-EGCG. 89Zr is obtained from Lantheus medical image, Inc. USA or Cisbio) or other sources. Female nude NCr mice are obtained from Jackson Laboratories, USA) or other sources. Isoflurane is obtained from Baxter Healthcare, USA or other sources. The 4T1 breast cancer cell line is obtained from ATCC, USA.

[0125] Methods To confirm that 89Zr-MINC can be used as a contrast agent for tumor detection, an in vivo xenograft tumor model is used. Briefly, female nude NCr mice (8-10 weeks old, n = 8) with 4T1 breast tumors are injected via the lateral tail vein with 9.3 ± 1.5 MBq (range, 7.8-11.5 MBq) of free 89Zr or 89Zr-MINC (lipids 3-4 mmol) in 200-250 mL of PBS solution, respectively. At predetermined time points (2, 24, 48, 120 hours), the animals are anesthetized with a mixed gas of isoflurane and oxygen (introduction 2%, maintenance 1%) and scanned using an Inveon PET scanner (manufactured by Siemens Healthcare Global). A whole-body PET static scan recording at least 50 million simultaneous count events is performed for 10-20 minutes. The energy window is 350-700 keV and the simultaneous count timing window is 6 ns. The image data is normalized to correct for the non-uniform response of the PET, dead-time count loss, positron branching ratio, and physical attenuation with respect to the incident time. The count rate in the reconstructed image is converted to radioactivity concentration (%ID / g of tissue) using a system calibration factor obtained from imaging a mouse-sized phantom containing 89Zr. The images are analyzed using ASIPro VMTM software (Concorde Microsystems). The activity concentration is quantified by averaging the maximum values of at least five regions of interest drawn on adjacent slices of the tissue of interest.

[0126] In this example, the contrast agent 89Zr to be encapsulated can be replaced with rubidium chloride Rb-82, neuraceq, vizamyl, florbetapir F-18, choline C-11, amyvist, Ga-68 dotatate, axumin, flutemetamol F-18, cardiogen-82, florbetaben F-18, fluciclovine F-18, Ruby-Fill, cerianna, netsot, Ga-68 dotatoc, tauvid, Ga-68 psma-11, detectnet, fluorodestradiol F-18, Cu-64 dotatate, florotaucipir F-18, piflufostat F-18, pylarify, illuccix, or locametz.

[0127] The present invention, as well as the methods and processes for manufacturing and using it, are described in terms that are complete, clear, concise, and accurate, so that anyone skilled in the art can manufacture and use it. It should be understood that the above content describes a preferred embodiment of the present invention and that modifications can be made thereto without departing from the scope of the invention as set forth in the claims. To particularly point out and clearly claim the subject matter regarded as the present invention, the following claims conclude this specification.

Claims

1. A diagnostic imaging composition comprising an outer shell containing one or more polymer-flavonoid conjugates, an inner shell optionally containing one or more flavonoid oligomers, and a micelle having a diagnostic imaging agent encapsulated within the shell; The polymer is a hydrophilic polymer having a molecular weight of 1,000 to 100,000 daltons, and is selected from the group consisting of poly(ethylene glycol) (PEG), hyaluronic acid, dextran, polyethyleneimine, poloxamer, povidone, D-α-tocopherol, and polyethylene glycol succinate; The aforementioned flavonoid has the following structure: 【Chemistry 1】 It is EGCG, EC, EGC, or ECG, as indicated by; The flavonoid oligomer comprises 2 to 20 flavonoids of EGCG, EC, EGC, or ECG; and, The diagnostic imaging composition is characterized in that the diagnostic imaging agent is a computed tomography (CT) imaging agent, a magnetic resonance imaging (MRI) imaging agent, a positron emission tomography (PET) agent, a single-photon emission computed tomography (SPECT) agent, an ultrasound agent, and a photoacoustic (PA) imaging agent.

2. The diagnostic imaging composition according to claim 1, wherein the micelle has an outer shell containing PEG-EGCG and an inner shell containing an EGCG oligomer.

3. The aforementioned diagnostic imaging agent, Iohexol, Iodixanol, Diatrizoate, Metrizoate, Iopamidol, Iopromide, Ioversol, Ioxiran, Chlografin Meglumine, Conley, Conley 30, Conley 43, Cyst Conley II, Cyst Conley, Cystgrafin Dilute, Cystgrafin, Gastrografin, Renographin-76, Ethiodol, Hexabrix, or isovue, Meglumine, Ioxagrate, Ioxagrate, Ioxagrate Sodium, Iotalamic Acid, Iron Oxide, Sodium Iotalamate, Bi-DTPA, N1177, Bi-NU-901, PVB-Bi2S3, Er3+ Doped Yb2O3, Iovitridol, Barium, and Carbon Dioxide: The diagnostic imaging composition according to claim 1 or 2, which is a CT imaging agent selected from the group consisting of the following.

4. The aforementioned diagnostic imaging agent, Gadopentetate, gadoterate, gadodiamide, gadoxetate, gadobutrol, gadoteridol, gadobenate, gadovercetamide, gadodiamide, gadophosbecet, gadopentetate dimeglumine, gadoxentate, gadocoretinic acid, gadomer 17, gadoxetic acid, gadoteric acid meglumine, gadoxetate disodium, gadophosbecet trisodium, mangahodipyl, gadobenate dimeglumine, fermoxyl, fermoxide, iron oxide, EP-3533, ManlCS1, USPIO-g-sLex, MS-325, PVP-IO, ProCA, SPION, SPION-AN-FA, and Fe3O4: The diagnostic imaging composition according to claim 1 or 2, which is an MRI imaging agent selected from the group consisting of the following.

5. The aforementioned diagnostic imaging agent, 89Zr, Rubidium Chloride Rb-82, neuraceq, vizamyl, florbetapyr F-18, choline C-11, amivid, Ga-68 dotatate, axumin, flutemetamol F-18, cardiogen-82, florbetaben F-18, flucyclovin F-18, Ruby-Fill, cerianna, netspot, Ga-68 dotatoc, tauvid, Ga-68 psma-11, detectnet, fluoroestradiol F-18, Cu-64 dotatate, flortausipyr F-18, pifluforastat F-18, pylarify, illuccix, or locametz, C-11, Ga-68, C11-PiB, Cu-64 ATSM, LMI1195, F-18 TFB, F-18 FSPG, F18-FDS, Ga-68-apotransferrin, F-18 AV-133, F-18 AV-45, F-18-T808, F-18-T807, and F-18-GE-180: The diagnostic imaging composition according to claim 1 or 2, which is a PET imaging agent selected from the group consisting of the following.

6. The aforementioned diagnostic imaging agent, Gallium(III), Tc-99m, I-131, Tc-99m MDP, Tc-99m MAA, Tc-99m PYP, Tc-99m Sulfur Colloid, I-131 Metaiodobenziganidine (MIBG), Tl-201, Ga-67, I-123, Tc-99m O4, TcO4-, Tc-99m phytate, Tc-99m DISIDA, Tc-99m DTPA, Tc-99m MAG3, Tc-99m DMSA, Tc-99m HMPAO, Tc-99m ECD, Tc-99m MIBI, Tc-99m sestamibi, Tl-201, I-131 OIH, I-131 6b-iodomethyl-19-norcholesterol (NP59), Ga-67, Xe-133, Kr-81m, In-111, or I-123 IMP, Lu-177, I-123 iodoamphetamine, Cu-64, As-72, Zr-89, I-124, C-11, Ga-68, F-18, Tc-99m CN5DG, Ro 16-0154, In111-DOTA-5D3, Tc99m-HYNIC-TMTP1 and QT-DTC-bisbiotin: The diagnostic imaging composition according to claim 1 or 2, which is a SPECT imaging agent selected from radioactive isotopes consisting of the above.

7. The diagnostic imaging composition according to claim 6, wherein the radioisotope is bound to a ligand.

8. A diagnostic imaging method, To administer an effective amount of the imaging diagnostic composition described in claim 3 to a subject requiring diagnosis, Perform a computed tomography (CT) scan. Measuring the difference in X-ray attenuation between lesions and normal tissue, and, To determine the location and / or size of the lesion, The method, including the method described above.

9. The method according to claim 8, wherein the CT scan is performed on the whole body, brain, head, chest, neck, spine, sinuses, pelvis, or abdomen.

10. A diagnostic imaging method, To administer an effective amount of the imaging diagnostic composition described in claim 4 to a subject requiring diagnosis, Perform magnetic resonance imaging (MRI). Detecting lesions by measuring the difference in magnetic resonance signals generated by the magnetic field between the lesion and normal tissue, and, To determine the location and / or size of the lesion, The method, including the method described above.

11. A diagnostic imaging method, To administer an effective amount of the imaging diagnostic composition described in claim 5 to a subject requiring diagnosis, Perform positron emission tomography (PET) imaging. Measuring a three-dimensional image formed by gamma rays generated from positrons emitted by an imaging agent, and, To determine the location and / or size of the lesion, The method, including the method described above.

12. A diagnostic imaging method, To administer an effective amount of the imaging diagnostic composition described in claim 6 to a subject requiring diagnosis, Perform single-photon emission computed tomography (SPECT) imaging. Measuring the difference in gamma ray signal intensity between diseased tissue and normal tissue, and, To determine the location and / or size of the lesion, The method, including the method described above.

13. The method according to claim 9, wherein the lesion is a tumor, an autoimmune disease, a cardiovascular disease, a central nervous system disease, an infection, and an inflammatory lesion.

14. The method according to claim 10, wherein the diagnostic imaging agent is administered intravenously.

Images