WO2018208137A9 - 빌리루빈 유도체 및 금속을 포함하는 입자 - Google Patents
빌리루빈 유도체 및 금속을 포함하는 입자 Download PDFInfo
- Publication number
- WO2018208137A9 WO2018208137A9 PCT/KR2018/005515 KR2018005515W WO2018208137A9 WO 2018208137 A9 WO2018208137 A9 WO 2018208137A9 KR 2018005515 W KR2018005515 W KR 2018005515W WO 2018208137 A9 WO2018208137 A9 WO 2018208137A9
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- WIPO (PCT)
- Prior art keywords
- bilirubin
- bilirubin derivative
- metal
- particles
- present
- Prior art date
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Definitions
- the present invention was made by the task number 2018M3A9B5023527 under the support of the Ministry of Science and Technology, Ministry of Information and Communication of the Republic of Korea.
- the research institute of the above project is Korea Research Foundation, the project name is "Bio / medical technology development project” Development of Targeted and Responsive Drug Delivery Platform Technology, "and the host institution is Korea Advanced Institute of Science and Technology, Research Period 2018.04.01-2020.12.31.
- the present invention relates to particles comprising a bilirubin derivative and a metal, a use thereof and a manufacturing method.
- Naturally occurring building blocks consisting of metal-organic coordination complexes
- metal-organic coordination complexes have long been the source of scientific inspiration.
- the coordination of specific metals and organic ligands can be controlled by a variety of mechanisms, such as metalloproteins, photosynthesis (Mg (II) -porphyrin), oxygen transport (Cu (II) -heme)
- Mg (II) -porphyrin photosynthesis
- Cu (II) -heme oxygen transport
- These metal-organic complexes show potential not only in the biomedical field, but also in the chemical field, including sensors, separation processes and catalysis. However, its application range was severely limited due to toxicity problems and time-consuming manufacturing steps.
- Bilirubin is the final metabolite of the heme metabolism of our bodies, a naturally occurring metal-organic coordinator.
- the inventors have hinted at the formation of gallstone, a pathological phenomenon that occurs in the pathway of bile drainage in the strategy of the present invention for using bilirubin as a metal-organic coordination material.
- Gallstones are calculus formed in bile ducts by binding bile acids to metals due to abnormal bile metabolism.
- Bilirubin is excreted as bile acid, and black pigmented gallstone in gallstones is known as the final product of the complex consisting of bilirubin, copper and / or bilirubin and calcium in the bile acid.
- bilirubin Because bilirubin has a rich functional group with unpaired electrons or nonbonding electron pairs, it can react with cationic metal ions to form metal-organic coordination complexes without external linkers. However, since bilirubin is very hydrophobic, it is not easily dissolved in a solvent, so it was not easy to use it chemically.
- the present inventors have developed bilirubin nanoparticles composed of a complex of bilirubin and a hydrophilic polymer to solve the application problem due to the hydrophobicity of the bilirubin and have been registered in Korean Patent No. 10-1681299, Are incorporated herein by reference.
- Another object of the present invention is to provide an imaging agent for imaging which comprises the above-mentioned bilirubin derivative particles.
- ROS reactive oxygen species
- ROS reactive oxygen species
- the present invention provides the following inventions (1) to (17).
- a bilirubin derivative particle comprising a bilirubin derivative and a metal.
- the metal is selected from the group consisting of Cu, Ga, Rb, Zr, Y, Tc, In, Ti, Gd, Mn, Fe, Au, Pt, Pd, Ag, Co, Mn,
- the bilirubin derivative particle is an ion or a metal compound of a metal selected from the group consisting of Ni, Fe, Cr, Na, K, Rb, Cs, Mg, Ca, Sr, Ba, Ra and lanthanide.
- bilirubin derivative particle according to any one of 1 to 3, wherein the metal is superparamagnetic iron oxide nanoparticle (SPION) or gold nanoparticle.
- SPION superparamagnetic iron oxide nanoparticle
- the bilirubin derivative particle according to claim 5 wherein the bilirubin derivative particle has a metal located at the center and the bilirubin derivative surrounding the metal.
- bilirubin derivative particle is a platinum-based anticancer drug selected from the group consisting of:
- bilirubin derivative particle according to any one of 1 to 9, wherein the bilirubin derivative is conjugated with a hydrophilic molecule to bilirubin.
- composition of claim 10 wherein the hydrophilic molecule is selected from the group consisting of dextran, carbodextran, polysaccharide, cyclodextran, pluronic, cellulose, starch but are not limited to, starch, glycogen, carbohydrate, monosaccharide, bisaccharide and oligosaccharide, polyphosphagen, polylactide, polylactide- But are not limited to, poly (lactic-co-glycolic acid), polycaprolactone, polyanhydride, polymaleic acid and derivatives of polymalic acid, But are not limited to, polyalkylcyanoacrylate, polyhydroxybutylate, polycarbonate, polyorthoester, polyethyleneglycol, polypropylene glycol Polyethylenimine, poly-L-lysine, polyglycolide, polymethylmethacrylate, polyvinylpyrrolidone, poly (acrylate), polyvinylpyrrolidone, (poly [acrylate]), poly (acrylamide
- PEG polyethylene glycol
- the PEG is selected from the group consisting of methoxy polyethylene glycol (PEG), succinimide of PEG propionic acid, succinimide of PEG butanoic acid, PEG-succinimidyl succinate, succinimide of carboxymethylated PEG, benzotriazole carbonate of PEG, PEG-succinimidyl succinate, PEG-HNS (branched PEG-NHS), PEG succinimidyl succinate, succinimide of carboxymethylated PEG, PEG-glycidyl ether, PEG-oxycarbonylimidazole, PEG nitrophenyl carbonates, PEG-aldehyde, PEG succinimidyl carboxymethyl ester (PEG-glycidyl ether, succinimidyl carboxymethyl ester and PEG succinimidyl ester.
- PEG methoxy polyethylene glycol
- RTI ID 0.0 > 11. < / RTI &
- a composition comprising any one of 1 to 14 bilirubin derivative particles.
- composition of claim 15, wherein said composition is a contrast agent composition for imaging.
- composition according to 17, wherein the contrast agent composition for imaging is for magnetic resonance imaging, CT diagnosis, PET diagnosis or optical diagnosis.
- composition of claim 15, wherein said composition is a pharmaceutical composition for the treatment of cancer.
- composition of claim 18, wherein the cancer is selected from the group consisting of gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, rectal cancer and cervical cancer.
- composition of claim 15 wherein said composition is a pharmaceutical composition for the treatment and diagnosis of inflammatory diseases.
- a process for preparing a bilirubin derivative particle comprising a metal and a bilirubin derivative comprising the steps of:
- step (b) comprises the steps of:
- step (b) comprises forming a particle comprising a bilirubin derivative and enclosing a metal.
- composition of claim 15, wherein said composition is for detecting reactive oxygen species (ROS).
- ROS reactive oxygen species
- composition of claim 24, wherein said composition is a contrast agent composition.
- a sensor device for detecting reactive oxygen species (ROS) comprising one or more bilirubin derivative particles.
- An active oxygen species detection method comprising the steps of:
- step (b) is selected from the group consisting of precipitation of the bilirubin derivative particles, absorbance according to wavelength, transparency of the suspension, concentration of metal ions in the suspension, and intensity of the MRI image signal ≪ / RTI >
- a method for imaging comprising administering to a subject a composition comprising any one of the bilirubin derivative particles of any one of claims 1 to 14.
- a method of treating cancer comprising administering to a subject a composition comprising any one of the bilirubin derivative particles of any one of claims 1 to 14.
- a method of treating and diagnosing an inflammatory disease comprising administering to a subject a composition comprising a bilirubin derivative particle of any one of 1 to 14.
- a bilirubin derivative particle comprising a bilirubin derivative and a metal.
- the present inventors have tried to develop nanoparticles capable of utilizing the coordinate binding property of bilirubin for various purposes, hinting at gallstones, which are complexes formed between copper (Cu) and bilirubin, which is an organic ligand in the human body.
- hydrophilic molecules were introduced into bilirubin to produce water-soluble bilirubin derivatives and bilirubin derivative particles formed by self-assembly of these bilirubin derivatives, and their chelating effects on various metals and the possibility of utilizing them as a therapeutic agent for imaging diagnostic agents, inflammatory diseases and cancer diseases Respectively.
- the bilirubin derivative particles of the present invention form a metal complex through coordination with the metal.
- the metal complex of the present invention means that several different ion molecules, atomic groups or the like around one or more metal atoms or ions form a group of atoms in order to impart orientation and three-dimensionally.
- the ion molecule or atomic group coordinated to the central metal atom or ion here is called a ligand.
- the bilirubin derivative particle of the present invention the bilirubin derivative becomes a ligand, and the metal binding to the bilirubin derivative becomes a central metal ion.
- the coordination bond is formed between the carboxyl group, the pyrrol ring or the lactam group of the metal ion and the bilirubin derivative.
- the metal included by binding with the bilirubin derivative of the present invention through coordination bonding is Cu, Ga, Rb, Zr, Y, Tc, In, Ti, Gd, Mn, A group consisting of lanthanide metals such as Pd, Ag, Co, Mn, Zn, Gd, Mo, Ni, Fe, Cr, Na, K, Rb, Cs, Mg, Ca, Sr, Ba, But is not limited thereto.
- the bilirubin derivatives of the present invention bind to various metal particles including superparamagnetic iron oxide nanoparticles (SPION) and gold nanoparticles (AuNP).
- SPION superparamagnetic iron oxide nanoparticles
- AuNP gold nanoparticles
- the bilirubin derivative of the present invention binds to SPION (superparamagnetic iron oxide nanoparticle) to form nanoparticles (FIGS. 6A to 6C), and the SPION-conjugated bilirubin derivative particles are used for clinical use , which is superior to the Feridex, a T2-weighted MR contrast agent, and can be used as a contrast agent for MRI enhancement (FIG. 7).
- the bilirubin derivative particles of the present invention can eliminate active oxygen.
- the bilirubin derivative particles containing SPION of the present invention are aggregated in response to hypochlorite treatment, which is a reactive oxygen species (ROS) generator (FIG. 8) Can be used to treat inflammation by scavenging free radicals.
- ROS reactive oxygen species
- the above-mentioned bilirubin derivative particles of the present invention can be also useful as a pharmaceutical composition for treating inflammatory diseases.
- the bilirubin derivative particles of the present invention are also useful as pharmaceutical compositions for the treatment of cancer or angiogenesis due to the anticancer activity and angiogenesis inhibitory action of the bilirubin derivative particles themselves as disclosed in Korean Patent No. 10-1681299 Can be used.
- the bilirubin derivative particles are formed in such a manner that a metal is located at a central portion and the bilirubin derivative surrounds the periphery of the metal.
- the bilirubin derivative particle containing the metal of the present invention is characterized in that a plurality of metal particles form a cluster metal particle form and a single metal particle form in which each metal particle is uniformly distributed , ≪ / RTI > in the form of two distinct particles.
- the present inventors applied both methods to construct PEG-bilirubin-coated iron oxide nanoparticles to confirm whether the bilirubin derivative particles of the present invention can be produced in the above two forms. As a result, the present inventors confirmed that two types of particles were successfully produced using the PEG-bilirubin skin in the TEM image (FIG. 6C).
- the metal contained in the bilirubin derivative particles of the present invention is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, heptaplatin). < / RTI > As shown in the following examples, the bilirubin derivative particles of the present invention were able to effectively load cisplatin (Fig. 15). The expected binding form between the cisplatin and the bilirubin derivative particle of the present invention is shown in FIG.
- the bilirubin derivative particle comprising the platinum-based anticancer agent of the present invention can release an anticancer agent loaded by light, active oxygen or acidic pH stimulation around (Figs. 17A and 17B)
- the bilirubin derivative particle of the present invention can be used as an effective ingredient for treating cancer due to the above-described anti-cancer / angiogenesis inhibitory action of the bilirubin derivative itself as well as loading and release characteristics of the platinum-based anticancer drug.
- " means a hydrophilic or amphipathic compound formed by conjugation with a hydrophilic molecule of bilirubin.
- the bilirubin derivative of the present invention forms a coordination bond with a metal component to form the bilirubin derivative particle of the present invention.
- the hydrophilic molecule is conjugated to the carboxyl group of bilirubin to form a hydrophilic or amphipathic bilirubin derivative
- a hydrophilic or amphipathic bilirubin derivative Amphiphiles: ACS Symposium Series 1st Edition by Ramanathan Nagarajan and Various Self- Assembly Behaviors of Amphiphilic Molecules in Ionic Liquids By Bin Dong and Yanan Gao, DOI: 10.5772 / 59095.
- the carboxyl group of the bilirubin is conjugated with an amine group of a hydrophilic molecule through an amine conjugation (ex.
- the inventors of the present invention used pegylated bilirubin (PEG-BR, PEG-PEG as a bilirubin derivative according to the present invention through simple action of forming an amide bond in a carboxylate using a hydrophilic compound PEG (Poly Ethylene Glycol) - bilirubin, pegylated bilirubin).
- PEG-BR Poly Ethylene Glycol
- Hydrophilic molecules that can be used in the present invention include, for example, dextran, carbodextran, polysaccharide, cyclodextran, pluronic, cellulose Starch, glycogen, carbohydrate, monosaccharide, bisaccharide and oligosaccharide, polyphosphagen, polylactide, poly (lactic acid), polyglycerol, Poly (lactic-co-glycolic acid), polycaprolactone, polyanhydride, polymaleic acid and derivatives of polymaleic acid, polyalkyl But are not limited to, polyalkylcyanoacrylate, polyhydroxybutylate, polycarbonate, polyorthoester, polyethyleneglycol, Polypropylene glycol, polypropylene glycol, polypropylene glycol, polypropylene glycol, polyethylenimine, poly-L-lysine, polyglycolide, polymethylmethacrylate, polyvinylpyrrolidone, Acrylates), poly (vinyl esters), poly (
- the hydrophilic polymer is polyethylene glycol or a derivative thereof.
- the polyethylene glycol derivatives include, for example, methoxy polyethylene glycol (PEG), succinimide of PEG propionic acid, succinimide of PEG butanoic acid, Succinimide of carboxymethylated PEG, PEG of benzotriazole carbonate of PEG, PEG-succinimidyl succinate, PEG-HNS (branched PEG-NHS), PEG succinimidyl succinate, PEG-glycidyl ether, PEG-oxycarbonylimidazole, PEG nitrophenyl carbonates, PEG-aldehyde, PEG succinimidyl carboxymethyl ester ( PEG succinimidyl carboxymethyl ester) and PEG succinimidyl ester (PEGylated polymers for medicine: from conjugation to self-assembled systems, Jorlemon et al., Chem. Commun.,
- the average molecular weight of the polyethylene glycol is 200 to 20000 Da.
- hydrophilic molecule usable in the present invention is a peptide composed of two or more (e.g. 2-50) amino acids.
- the amino acids include not only natural amino acids but also unnatural amino acids.
- Hydrophilic amino acids include glutamine, aspartic acid, glutamic acid, threonine, asparagine, arginine, and serine.
- hydrophobic amino acids include phenylalanine, tryptophan, isoleucine, leucine, proline, methionine, valine and alanine.
- Uncoded hydrophilic amino acids include, for example, Cit and hCys. Those skilled in the art can readily synthesize hydrophilic peptides based on this information and peptide synthesis techniques and use them in the production of bilirubin nanoparticles.
- the range of the hydrophilic molecule includes not only the above-mentioned compounds but also derivatives thereof. More specifically, the hydrophilic molecules may have an amine group or a hydroxyl group, or be modified to have an amine group or a hydroxyl group. It is apparent to those skilled in the art that the carboxyl group of the bilirubin of the present invention can be conjugated very easily through an amide bond with an amine group of the hydrophilic molecule or via an esterification reaction with a hydroxyl group.
- an imaging agent for imaging comprising the metal-containing bilirubin derivative particles.
- the imaging contrast agent can be used for magnetic resonance (MR) diagnosis, CT (computed tomography) diagnosis, PET (positron emission tomography) diagnosis, or optical diagnosis .
- MR magnetic resonance
- CT computed tomography
- PET positron emission tomography
- the optical diagnostic application of the present invention includes a photo-acoustic diagnosis and a diagnostic method (use) using fluorescence images.
- the photoacoustic diagnosis was verified through the examples of the present invention by binding a cisplatin metal to a bilirubin derivative.
- the fluorescence image shows fluorescence characteristics of a lanthanide metal such as Eu (III) and Tb (III)
- a bilirubin derivative By coupling a bilirubin derivative to the metals, fluorescence emitted by the lanthanide metal can be detected by controlling the fluorescence wavelength band or intensity of the lanthanide metal.
- the bilirubin derivative thereof particles of the invention are nuclear medicine imaging by introducing a variety of metal ions into the bilirubin derivative without the use of external linker (64 Cu, 68 Ga, 82 Rb, 89 Zr, 90 Y, 99 mTc, 111 In, 201 TI), MR imaging (Gd, Mn, Fe), and CT imaging (Au).
- the conventional contrast agent used in magnetic resonance imaging or computed tomography has a ligand manipulated by providing an external linker and a metal to the complex, but the bilirubin derivative of the present invention can bind to the metal quickly and effectively without a separate linker .
- a pharmaceutical composition for treating and diagnosing cancer comprising bilirubin derivative particles containing the metal.
- the cancer is not limited to gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, rectal cancer, and cervical cancer .
- the bilirubin derivative particles of the present invention exhibit anti-angiogenic activity and can be used for prevention and treatment of cancer. Specifically, when the bilirubin derivative particles such as cisplatin or the like such as cisplatin are loaded into the body, they are accumulated in the tumor tissue by the EPR effect. At this time, when light is irradiated from the outside to the tumor tissue, the bilayer bilirubin- Hydrophilic layer containing a hydrophilic optical isomer, whereby the nanoparticles are collapsed, whereby the anticancer drug contained in the nanoparticles is released into the tumor tissue and the cancer can be treated. At the same time, the monomer decomposed from the nanoparticles binds to albumin, and the fluorescence is released from the tumor tissue, and the tumor tissue can be imaged using the fluorescence.
- the bilirubin derivative particles such as cisplatin or the like such as cisplatin are loaded into the body, they are accumulated in the tumor tissue by
- the bilirubin derivatives of the present invention can be obtained by reacting 64 Cu, SPION (superparamagnetic iron oxide nanoparticle), gold nanoparticles (GNP) and Ni, Mn, Gd, Mg, Metal ions and platinum-based anticancer agents and coordination complexes, so that chelation of various metals is possible and the present invention can be applied to various applications (FIGS. 5A and 5B).
- the bilirubin derivative particles of the present invention selectively accumulate in the tumor tissue and cause a photothermal effect of generating a high temperature when irradiated with light of a specific wavelength from the outside, and thus can be used for the treatment of cancer diseases.
- the present inventors first applied cisplatin-bilirubin derivative particles to in-vivo photo-acoustical imaging in a mouse of a tumor xenograft model and found that the light-acoustical signal was gradually increased after intravenous injection (Fig. 18) By confirming that the surface temperature of the tumor sharply increases to 55-60 ° C within 5 minutes after exposure to 808 nm light, the bilirubin derivative particles of the present invention exhibit photo- thermal therapy, PTT) (Fig. 19).
- a pharmaceutical composition for the treatment and diagnosis of inflammatory diseases comprising the above-mentioned metal-containing bilirubin derivative particles.
- the bilirubin derivative particles of the present invention can be utilized as ROS-sensitive substances for diagnosis and treatment of inflammatory diseases.
- the bilirubin derivative particles administered parenterally in the body can target the inflammatory site by the EPR effect.
- the bilirubin derivative particles can exhibit anti-inflammatory activity by eradicating abnormal levels of active oxygen at the site of inflammation, so that inflammation can be treated.
- Inflammatory diseases to which the present invention is applicable include inflammatory bowel disease, atopic dermatitis, edema, dermatitis, allergy, asthma, conjunctivitis, periodontitis, rhinitis, otitis media, atherosclerosis, sore throat, tonsillitis, Inflammatory bowel disease, inflammatory bowel disease, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, rhabdomyosarcoma, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, Sjogren ' s syndrome and multiple sclerosis.
- the bilirubin derivative particle of the present invention can coordinate bond with a metal ion.
- the bilirubin derivative particles coordinated with metal ions of the present invention react with reactive oxygen species such as hypochlorous acid to release metal ions as the particles collapse.
- a bilirubin derivative particle coordinated with a manganese ion (Mn 2 + ) reacts with active oxygen species such as hypochlorous acid to release manganese ions. Therefore, the T1 value of manganese ion image when manganese ions are coordinated with and released from the bilirubin derivative is changed, and the intensity of the MRI image is different, thereby detecting reactive oxygen species.
- composition of the present invention is a pharmaceutical composition
- a pharmaceutically acceptable carrier is included.
- the pharmaceutically acceptable carriers are those conventionally used in the formulation and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- the pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.
- the pharmaceutical composition of the present invention can be administered parenterally, for example, intravenously, intraperitoneally, intramuscularly, subcutaneously or locally.
- parenterally for example, intravenously, intraperitoneally, intramuscularly, subcutaneously or locally.
- oral administration rectal administration, inhalation administration, and expiratory administration are also possible.
- the appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, age, body weight, sex, degree of disease symptoms, food, administration time, route of administration, excretion rate and responsiveness of the patient Ordinarily skilled physicians can easily determine and prescribe dosages effective for the desired treatment.
- the pharmaceutical composition of the present invention may be formulated into a unit dosage form by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or may be manufactured by intruding into a multi-dose container.
- the formulations may be in the form of solutions, suspensions or emulsions in an oil or aqueous medium, and may additionally contain dispersing or stabilizing agents.
- the present invention provides a method for producing a bilirubin derivative particle comprising a metal and a bilirubin derivative comprising the steps of:
- the step (b) may comprise the following steps:
- a particle made of a bilirubin derivative may be prepared and metal may be enclosed.
- Bilirubin is conjugated with hydrophilic molecules to produce hydrophilic or amphipathic bilirubin.
- the carboxyl group of bilirubin is activated by using EDC (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide) or EDC / NHS, and a conjugate through a hydrophilic molecule having an amine group (-NH 2 ) .
- the hydrophilic molecule conjugated with the bilirubin is the hydrophilic molecule described above, which has an amine group or has an amine group.
- carboxyl group of the bilirubin is conjugated through esterification reaction with the hydroxyl group of the hydrophilic molecule.
- EDC is added to dissolve bilirubin in an organic solvent (e.g., dimethylsulfoxide, DMSO) to activate the carboxyl group present in the bilirubin to induce the desired reaction, and incubate at room temperature for about 10 minutes Respectively.
- an organic solvent e.g., dimethylsulfoxide, DMSO
- a bilirubin derivative conjugated with a hydrophilic molecule is synthesized by adding a hydrophilic molecule having an amine group at the end (for example, polyethylene glycol) and reacting for a predetermined time.
- the final bilirubin derivative having the amide bond formed by the reaction between the carboxyl group and the amine group is separated and extracted purely from the by-product through the silica column.
- amphipathic bilirubin derivatives for example, pegylated bilirubin
- the amphipathic bilirubin derivatives for example, pegylated bilirubin
- the amphipathic bilirubin derivatives are induced to coordinate bond with various metal particles or metal ions to make them into practically usable nanoparticles.
- the following specific production methods are illustrative and not intended to limit the scope of the present invention.
- an amphipathic bilirubin derivative conjugated with a hydrophilic molecule is dissolved in an organic solvent such as chloroform or dimethylsulfoxide, and dried under a nitrogen gas condition to form a lipid film layer. Thereafter, when the lipid film layer of the produced bilirubin derivative is hydrated with an aqueous solution, self-assembled bilirubin nanoparticles can be obtained.
- the desired metal may be sealed in the bilirubin derivative without any other additives such as a chelator or a linker, . Unreacted metal ions and the like can be removed through a size exclusion column or dialysis to finally obtain a desired reactant.
- the step (b-2) of enclosing the metal with the bilirubin derivative particle of the present invention may be performed simultaneously with the step (b-1) of preparing the bilirubin nanoparticle with the bilirubin derivative.
- step b-1 after bilayering nanoparticles of the bilirubin derivative are hydrated in an aqueous solution to prepare bilirubin nanoparticles (step b-1), the metal ion aqueous solution is mixed and reacted (step b-2)
- the metal ion aqueous solution is hydrated while mixing, the metal ions are enclosed in the bilirubin derivative particles in the same manner as the steps (b-1) - (b-2) are performed in order.
- it is more efficient to form a complex by mixing the aqueous solution of metal ions with an aqueous solution of bilirubin nanoparticles in the order of steps (b-1) to (b-2).
- the method of coating bilirubin derivatives with metal nanoparticles is slightly different from the method of enclosing metal ions.
- the bilirubin derivative of the present invention can form particles coated with a single layer of metal ions.
- the layer When the layer is originally coated with the iron nanoparticles (SPION) through a ligand exchange method
- the oleic acid layer is removed and the carboxyl group of the bilirubin derivative (e.g., pegylated bilirubin) is coated with the metal nanoparticles through a chelation reaction with the core portion of the iron nanoparticle (SPION).
- the carboxyl group of the bilirubin derivative e.g., pegylated bilirubin
- the bilirubin derivative of the present invention can form particles coated with a metal particle cluster.
- bilirubin derivatives for example, pegylated bilirubin
- an organic solvent for example, chloroform
- SPION particles dissolved in methanol
- the pure SPION nanoparticles can be separated from each other by the magnet isolation method using the magnet after each process.
- the method for coating a bilirubin derivative on gold nanoparticles comprises dissolving the bilirubin derivative obtained in step (a) in water, not an organic solvent, It can be obtained by reacting for a certain time.
- the bilirubin derivative surrounds the core portion of the nanoparticles and is coated.
- composition for detecting reactive oxygen species comprising the above-described bilirubin derivative particles of the present invention.
- reactive oxygen species refers to an oxygen species that is more reactive and more active than the normally present ground trioxide ( 3 O 2 ).
- the active oxygen species may be selected from the group consisting of superoxide (O 2 - ), hydrogen peroxide (H 2 O 2 ), hydroxyl radical (OH), 1 O 2 singlet oxygen .
- the active oxygen species may be organic hydroperoxide (ROOH), Alkoxy radical (RO). And a peroxy radical (ROO), or ozone (O 3), and nitrogen dioxide (NO 2).
- a sensor device for detecting reactive oxygen species comprising the above-described bilirubin derivative particles of the present invention.
- the sensor device for detection is not particularly limited and can be used in the art to detect physical-chemical changes due to contact of active oxygen species with bilirubin derivative particles of the present invention Any device may be used.
- the present invention provides a method for detecting reactive oxygen species comprising the steps of:
- the active oxygen species detection method of the present invention will be described step by step.
- the above step is a step of contacting the suspension containing the bilirubin derivative particles of the present invention and a sample to be detected with active oxygen species to react the active oxygen species with the bilirubin derivative particles in the suspension.
- the bilirubin derivatives of the present invention are reactive with active oxygen species. Therefore, when the bilirubin derivative in the suspension comes into contact with the active oxygen species in the sample, the bilirubin derivative forming the shell of the metal particle due to the reaction with the active oxygen is separated from the metal particles. As a result, the metal particles having hydrophobicity meet with each other to form an aggregate or a precipitate.
- the sample includes, but is not limited to, urine, saliva, blood (plasma, serum, blood cells), and tissues (tissues of lesions such as liver, pancreas and skin) of human or animal.
- the sample also includes other materials such as solutions containing compounds that generate reactive oxygen species.
- the above step is a step of comparing the change of the suspension caused by the reaction of the bilirubin derivative with the reactive oxygen species in the sample, compared with the control group.
- the control group refers to a change in suspension depending on the kind and concentration of reactive oxygen species, i) measured beforehand, and ii) the kind and concentration of reactive oxygen species measured simultaneously with the step (a).
- the change of the suspension of step (b) includes the precipitation of the bilirubin derivative particles, the absorbance according to the wavelength, the transparency of the suspension, the concentration of the metal ion in the suspension and the intensity of the MR image signal
- the present invention is not limited thereto.
- the method of the present invention commonly uses the above-described bilirubin derivative particles of the present invention and the composition or apparatus comprising the same, the description common to both of them is omitted in order to avoid the excessive complexity of the present specification.
- an imaging method comprising the step of administering a composition comprising a bilirubin derivative particle to a subject.
- the present invention provides a method of treating cancer comprising administering to a subject a composition comprising bilirubin derivative particles.
- a method of treating and diagnosing an inflammatory disease comprising administering to a subject a composition comprising bilirubin derivative particles.
- administering refers to administration of a therapeutically or diagnostically effective amount of a composition of the present invention to a subject (subject) .
- a “therapeutally effective amount” of a composition means the amount of composition sufficient to provide a therapeutic or prophylactic effect to the subject to which the composition is to be administered, including a “ prophylactically effective amount ".
- diagnostically effective amount " of a composition is meant the amount of composition sufficient to provide a diagnostic effect to the subject to which the composition is to be administered.
- subject as used herein includes, without limitation, humans, mice, rats, guinea pigs, dogs, cats, horses, cows, pigs, monkeys, chimpanzees, baboons or rhesus monkeys. Specifically, the object of the present invention is human.
- the method of imaging of the present invention the method of treating cancer, and the method of treating and diagnosing an inflammatory disease are methods comprising the step of administering a composition for each use comprising bilirubin derivative particles, which is an embodiment of the present invention.
- the redundant contents are omitted in order to avoid the excessive complexity described in this specification.
- the present invention provides a hydrophilic bilirubin derivative particle containing a metal, its use and a method for producing the same.
- the bilirubin derivative particle of the present invention forms a coordination bond with various metals, it can be used for MR diagnosis, CT diagnosis, photo-acoustic diagnosis, PET diagnosis, or optical diagnosis.
- the bilirubin derivative particles of the present invention exhibit anti-inflammatory activity and anticancer activity due to the antioxidative activity and anticancer activity of bilirubin itself as well as the above diagnostic use, so that they can be used simultaneously for treatment of inflammatory diseases or cancer diseases
- the concept of theranostices (theranostics) is the concept of theranostices (theranostics).
- the bilirubin derivative particle of the present invention is decomposed by stimulation with light or active oxygen, thereby releasing the drug encapsulated therein to the outside.
- the bilirubin derivative particles of the present invention are reactive with active oxygen species, they can be used as a composition, a sensor, a kit, a contrast agent, or an apparatus for detecting the kind and concentration of active oxygen species.
- Fig. 1 shows an example of an application method using the bilirubin derivative particles of the present invention.
- FIG. 2 is a diagram showing a labeling process using a radioactive isotope 64 Cu for use in manufacturing the bilirubin derivative particle of the present invention and PET imaging.
- FIG. 3 is a graph showing labeling efficiency according to pH and temperature in order to confirm reaction conditions for optimizing the radiolabelling efficiency.
- Figure 4 is a representative micro-PET image of a mouse with PC-3 tumor (yellow arrow) after 1, 3, and 6 hours post intravenous injection of 64 Cu-bilirubin particles (axial image, upper coronal image, lower).
- FIG. 5A shows the colorimetric measurement of PEG-bilirubin and metal ion during the reaction, and is a photograph of a suspension of bilirubin particles before (upper) and after (lower) reaction with a specific metal ion.
- Figure 5b shows the colorimetric measurement of PEG-bilirubin and metal ion during reaction, showing the UV / Vis spectrum of a suspension of bilirubin particles before and after reaction with a specific metal ion.
- FIG. 6A shows the production of an iron oxide-based MR probe using PEG-bilirubin.
- the lipid fim method on the left side is a method in which iron oxide forming a cluster is located at the center and PEG- Enclosed bilirubin derivative particles of the present invention, and 2) the sonication method on the right produces single iron oxide nanoparticles coated with the PEG-bilirubin layer.
- 6B is a diagram showing the principle of coordination bonding between PEG-bilirubin and superparamagnetic iron oxide.
- Figure 6c is a representative TEM image showing clustered iron oxide nanoparticles with a PEG-bilirubin shell (left) and monodispersed iron oxide nanoparticles (right).
- Figure 7 shows the characteristics of SPION coated with PEG-bilirubin, showing the T2 relaxation rate as a function of iron concentration and the T2-weighted MR phantom image of SPION coated with PEG-bilirubin in aqueous solution.
- FIG. 8 shows TEM images of SPION coated with PEG-bilirubin before and after ROS stimulation, showing SPION coated with PEG-bilirubin.
- FIG. 9A shows the SPION coated with PEG-bilirubin, which is a sequential MR phantom image showing ROS-reactivity according to ROS concentration of SPION coated with PEG-bilirubin.
- FIG. 9B shows the characteristics of SPION coated with PEG-bilirubin, which is a graph of T2 relaxation value change according to ROS concentration of SPION coated with PEG-bilirubin.
- FIG. 10 is a graph showing the expression level of Nox2 gene in macrophages measured by RT_qPCR in macrophages.
- FIG. 11A shows the results of microscopic observation of the degree of macrophage smearing between PEG-DSPE-coated SPION and PEG-BR SPION-treated groups under ROS production conditions.
- FIG. 11B is a graph comparing the degree of macrophage smearing between the PEG-DSPE-coated SPION and the PEG-BR SPION-treated group by the MRI phantom experiment as a macrophage sample collected from the abdominal cavity of a mouse.
- FIG. 12 shows that when the PEG-BR coated gold nanoparticles are reacted with reactive oxygen species, a strong photothermal effect occurs in the NIR region as the PEG-BR coating is peeled off and the gold nanoparticles cohere with each other Fig.
- FIG. 13 is a graph showing a CT image of a mouse using gold nanoparticles coated with PEG-BR.
- Figure 14 shows a negatively stained TEM image of cisplatin-loaded bilirubin particles.
- FIG. 16 is a diagram showing an estimated reaction mechanism of PEG-bilirubin particles and cisplatin.
- FIGS. 17A and 17B are diagrams showing various conditions (pH, ROS) and cisplatin release patterns with time in PEG-bilirubin particles encapsulated with cisplatin.
- Figure 18 is a semi-quantitative analysis of xenotransplant tumors of nude mice in a photoacoustic image with time after injection and pixel values in corresponding tumors.
- FIG. 19 shows an infrared thermographic image at different time intervals of a tumor xenografted mouse exposed to a near infrared (NIR) laser at an output intensity of 800 mW / cm 2 .
- NIR near infrared
- FIGS. 20 and 21 are graphs showing the results of phototherapy using light after injecting cisplatin-encapsulated PEG-bilirubin particles into a xenograft tumor of a nude mouse, and observing the results by period.
- FIG. 22 is a graph showing changes in the concentration of active oxygen species in the aqueous solution of iron nano-particles coated with pegylated bilirubin according to the present invention.
- FIG. 23 is a graph showing changes in the concentration of NaOCl as an active oxygen species in an aqueous solution of iron nano-particles coated with pegylated bilirubin of the present invention.
- FIG. 24 is a graph showing a change with the concentration of AAPH (2,2'-Azobis (2-amidinopropane) dihydrochloride) as an active oxygen species in an aqueous solution of iron nanoparticles coated with pegylated bilirubin of the present invention.
- FIG. 25 is a graph showing changes in concentration of hydrogen peroxide as an active oxygen species in an aqueous solution of iron nano-particles coated with pegylated bilirubin of the present invention.
- FIG. 26 is a graph showing the results of visual observation of a solution of gold nanoparticles (PEG-BR GNP) coated with pegylated bilirubin of the present invention before and after reacting each kind of active oxygen species (H 2 O 2 , NaOCl, AAPH) This figure shows the change.
- PEG-BR GNP gold nanoparticles coated with pegylated bilirubin of the present invention before and after reacting each kind of active oxygen species (H 2 O 2 , NaOCl, AAPH)
- FIG. 27 is a graph showing the absorbance of the solution before and after reacting the aqueous solution of the pegylated bilirubin-coated gold nanoparticle (PEG-bilirubin gold nanoparticle) of the present invention with each kind of active oxygen species (H 2 O 2 , NaOCl, AAPH) This figure shows the change.
- FIG. 28 is a graph showing the change in the concentration of PEG-thiol-coated gold nanoparticles in the aqueous solution of each kind of active oxygen species (H 2 O 2 , NaOCl, AAPH) as a control group for the pegylated bilirubin of the present invention
- Fig. 3 is a graph showing the change in absorbance of the solution before and after the reaction.
- FIG. 29 is a schematic view of a bilirubin derivative particle formed by coordinating manganese ion (Mn 2 + ).
- FIG. 30 is a view showing a process for producing bilirubin derivative nanoparticles coordinated with manganese ion (Mn 2 + ) as a paramagnetic element for use in MRI imaging. After making nanoparticles with PEG-bilirubin, manganese ions are mixed to form coordinated manganese ions.
- FIG. 31 is a schematic diagram showing that particles containing a bilirubin derivative and a metal of the present invention can detect or diagnose active oxygen.
- the hydrophobic bilirubin is converted into hydrophilic bilirubin, or decomposed into fragments of bilirubin to weaken the binding and break down the nanoparticles .
- the manganese ions in the coordination bond are separated and the image of the MRI image is enhanced.
- FIG. 32 is a graph showing the manner in which bilirubin derivative particles coordinated with manganese ions of the present invention release manganese ions by active oxygen stimulation.
- FIG. 33 is a TEM image showing a state before hypochlorite treatment of bilirubin derivative (PEG-BR) nanoparticles coordinated with manganese ions as active oxygen generating material.
- PEG-BR bilirubin derivative
- FIG. 34 shows MRI T1-weighted images of bilirubin nanoparticles coordinated with manganese before and after treatment with hypochlorite.
- Example 1 Preparation of the bilirubin derivative (PEG-BR) particles of the present invention
- the present inventors produced a bilirubin derivative conjugated with polyethylene glycol as a hydrophilic molecule to bilirubin as a previous step for producing bilirubin and a metal-containing bilirubin derivative using the complex formation effect of bilirubin.
- EDC Ethyl-3- (3-dimethylaminopropyl) carbodiimide
- DMSO dimethylsulfoxide
- carboxyl group present in bilirubin to induce a desired reaction.
- polyethylene glycol having an amine group at the terminal thereof was added, and the reaction was conducted for a predetermined time to synthesize a bilirubin derivative in which a carboxyl group of bilirubin and an amine group of polyethylene glycol were conjugated to an amide bond.
- the prepared final bilirubin derivative was separated and extracted purely from the by-product through a silica column.
- the amphiphilic bilirubin derivative conjugated with polyethylene glycol prepared in Example 1-1 was dissolved in an organic solvent such as chloroform or dimethylsulfoxide and dried under a nitrogen gas atmosphere to prepare a lipid film layer.
- the lipid film layer of the prepared bilirubin derivative was hydrated with an aqueous solution to prepare self-assembled bilirubin particles dissolved in the aqueous solution.
- the coordination bond between the 64 Cu ion and the bilirubin derivative of the present invention can be formed with a pyrrole group, a lactam group, or a carboxyl group of bilirubin.
- bilirubin derivative particles having 64 Cu ions coordinated to the bilirubin derivative (PEG-BR) particles prepared in Example 1 were injected into the tumor-bearing rats, and the in vivo performance was preliminarily confirmed by PET imaging. As a result, 64 Cu-bilirubin particles clearly visualized the tumor in a time-dependent manner. The highest tumor uptake at 1 hour, 3 hours, and 6 hours after injection was about 2.15, 2.81, and 3.75% (ID) / g (Fig. 4).
- the metal-organic coordination complex forming ability of the bilirubin derivative particles of the present invention for various metals is applicable to various applications including metal ion detection systems.
- a hexane solution in which iron oxide nanoparticles (SPION) was dissolved in the aqueous bilirubin nanoparticle solution prepared in Example 1 was added to form a water layer And the hexane layer were divided to form a boundary.
- An artificial pressure was applied to the boundaries using a sonicator, and the two layers were mixed for a certain period of time to prepare particles having a bilirubin derivative (PEG-BR) coated on the surface of the iron oxide nanoparticles (FIG. 6A).
- the principle of the reaction is that the oleic acid layer originally coated on the iron nanoparticles (SPION) is removed and the carboxyl group of the bilirubin derivative (PEG-BR) And coating the metal nanoparticles through chelation reaction with the core portion of the iron nanoparticles (FIG. 6B).
- the present inventors confirmed that two types of particles of the above-described Examples 3-1 and 3-2 were successfully prepared using the PEG-bilirubin skin in the TEM image (FIG. 6C).
- the bilirubin derivative (PEG-BR) prepared in Example 1-1 was dissolved in water instead of an organic solvent, and then the gold nanoparticles were immediately reacted with the aqueous solution in which gold nanoparticles were dissolved Lt; / RTI >
- the principle of the reaction is that the bilirubin derivative (PEG-BR) surrounds the nanoparticle core portion in place of the citrate layer which is coated with gold nanoparticles on the principle similar to the SPION coating in Example 3-1 .
- Example 4 Bilirubin derivative particles comprising metal (metal nanoparticles) of the present invention ROS Reactivity
- the present inventors conducted an MRI phantom study to study the properties of SPION coated with PEG-bilirubin in the form of monodisperse particles.
- the bilirubin derivative of the present invention exhibited a relaxivity value superior to that of ferredox (Fig. 7).
- LEG lipopolysaccharide
- macrophage or peritoneal fluid to make an artificial inflammatory condition
- SPION coated with PEG-bilirubin and PEG-distearoylphosphatidylethanolamine (PEG-DSPE) Were examined for their phagocytosis patterns using optical microscopy and MR phantom images.
- Gold nanoparticles are widely studied as CT contrast agents in the preclinical region. Like SPION, the surface of gold nanoparticles coated with citric acid can be replaced by pegylated bilirubin (PEG-BR) by coordination bonds.
- PEG-BR pegylated bilirubin
- the successful binding of pegylated bilirubin to gold nanoparticles was confirmed by TEM image and CT phantom image, and the change of UV-Vis wavelength after chelation, and the reactive oxygen species-specificity of gold nanoparticles coated with bilirubin, The reactivity (ROS-responsiveness) was confirmed by observing the gold nanoparticles coated with the control group pegylated thiol.
- the PEG-BR coated gold nanoparticles react with reactive oxygen to peel off the PEG-BR coating, thereby aggregating the gold nanoparticles that have lost the ligand, thereby causing the gold nanoparticles to migrate to the near infrared region (NIR region) which has a strong photothermal effect (Fig. 12).
- NIR region near infrared region
- the gold nanoparticle-based contrast agent coated with PEG-BR can be used not only as a diagnostic tool using CT, but also as a tool for the treatment of photothermal effects in response to reactive oxygen species in tumors.
- FIG. 13 shows that PEG-BR gold NP of the present invention was obtained for 6 hours after intravenous injection at a concentration of 500 mg / kg (based on 10 mg / mouse, gold).
- a thick arrow indicates the aorta, and a thin arrow indicates the border of the liver.
- FIG PEG-BR gold NP of the present invention from the CT image 13 can confirm this angiography possible while reliably take the vascular long-term circulation on in vivo, can be also seen that the excellent effect even as imaging the liver.
- the nanoparticles loaded with cisplatin the most representative metal drug used for tumors, were prepared to demonstrate the chelating effect of forming the complex of the bilirubin derivative particles of the present invention and the therapeutic effect on tumors (FIG. 14).
- Cisplatin has a platinum metal skeleton and has been used with nano-carriers.
- FIG. 16 is a schematic diagram showing the binding principle of the pegylated bilirubin and cisplatin.
- cisplatin As a result of cisplatin release experiments with various conditions (pH, ROS) and time in cisplatin-encapsulated bilirubin nanoparticles, cisplatin showed the highest release rate in response to ROS, followed by intracellular lysosomal Showed a high release rate at acidic conditions (pH 5.5), which is known to be similar to the environment, and the lowest release rate at physiological pH (FIGS. 17A and 17B).
- the bilirubin derivative particles containing the metal of the present invention can stably contain a platinum-based drug called cisplatin and selectively release the drug in a surrounding micro environment.
- Example 6 Photo-acoustical and mechanical properties of the bilirubin derivative particles containing the metal (platinum-based anticancer agent) Light heat activation
- the nanoparticles of the present invention in which pegylated bilirubin is coordinately bound to cisplatin, the present inventors have found that such metal-coordination complexes can be converted into photo- Was used for photo-thermal therapy (PTT).
- PTT photo-thermal therapy
- the bilirubin derivative of the present invention Upon application to in vivo photo-acoustic imaging in mice of the tumor xenograft model, the bilirubin derivative of the present invention was found to gradually increase the light-acoustical signal after intravenous injection (Fig. 18). Therefore, the possibility of photothermal therapy was confirmed under the same conditions, and it was confirmed that the surface temperature of the tumor rapidly increased to 55 ⁇ 60 ° C within 5 minutes after exposure to 808 nm light (FIG. 19). As a result, a significant tumor volume reduction effect was observed over time in the group treated with photothermal therapy using actual light (FIGS. 20 and 21).
- Example 7 Particles of the bilirubin derivative particles containing the metal of the present invention On active oxygen species Reactivity to
- Example 7-1 Of the bilirubin derivative particles containing iron nanoparticles On active oxygen species Confirmation of reactivity (visual color change)
- a suspension containing pegylated bilirubin-coated iron nanoparticles was prepared in the same manner as in the above example. Then, NaOCl (100, 10, 1, 0.1, 0 mM) and AAPH * , 1, 0.1, and 0 mM) and hydrogen peroxide (100 mM) were added to each concentration, and the results were visually observed with an optical microscope. [ * 2,2'-Azobis (2-amidinopropane) dihydrochloride (AAPH)] Further, iron nanoparticles coated with pegylated DSPE ** were used as a negative control. [ ** 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)]
- Example 7-2 Of the bilirubin derivative particles containing gold nanoparticles On active oxygen species Confirmation of reactivity (absorbance change)
- the absorbance of the bilirubin derivative particles before and after reacting the active oxygen species was measured. Specifically, the change of the solution before and after the pegylated bilirubin coated gold nanoparticles were reacted with each type of reactive oxygen species was determined by visual observation and absorbance measurement.
- the bilirubin derivative particles of the present invention can be usefully used for discriminating kinds and concentrations of active oxygen species.
- Example 8 Manganese ion coordination bond Of the bilirubin derivative particles On active oxygen species Reactivity to
- Example 8-1 Manganese ion coordination Preparation of conjugated bilirubin derivative particles
- Bilirubin derivative particles were prepared by coordinating manganese ions (Mn 2 + ) in order to further confirm the reactivity and change of the active oxygen species of the bilirubin derivative particles containing the metal of the present invention.
- a schematic diagram of a bilirubin derivative nanoparticle in which manganese ions are coordinated to each other and a manufacturing method thereof are shown in FIG. 29 and FIG. Specifically, 5) in Example 1 giving a strong bilirubin derivative (PEG-BR) particles to prepare an aqueous solution, mix in the PEG-BR: The mole ratio of MnCl 2 1: 1 MnCl 2 so that the The aqueous solution was dispensed using a syrynge pump.
- PEG-BR strong bilirubin derivative
- Example 8-2 Manganese ion coordination Of conjugated bilirubin derivative particles On active oxygen species Reactivity confirmation (ion concentration, TEM Image and MR image)
- FIG. 31 shows that when the bilirubin derivatives coordinated with manganese ions of the present invention react with active oxygen, bilirubin, which is a hydrophobic bilirubin, is converted into hydrophilic bilirverine, which weakens the binding and breaks down the nanoparticles.
- active oxygen can be imaged using MRI as it exits.
- bilirubin nanoparticles coordinated with manganese ions was placed in a dialysis bag (Float A-Lyzer, MW cutoff: 20K), and 1 ml of NaOCl was added to 99 ml of distilled water. After shaking at room temperature, manganese Dialysis of ions was proceeded. The amount of manganese contained in each fraction was measured by ICP-MS (Agilent ICP-MS 7700S (Bio-Rad Laboratories, Inc.)) at a fixed time (0, 1, 2, 3, 6, 12, 24, 48 and 72 hr) ).
- the present inventors also observed morphological changes of the bilirubin derivatives (PEG-BR) nanoparticles of the present invention having manganese ions coordinated thereto before and after treatment with hypochlorite by a transmission electron microscope. The results are shown in Fig. As shown in FIG. 33, bilirubin derivative particles in which manganese ions were coordinated before active oxygen (hypochlorous acid) stimulation were gathered together into small spheres, but after the stimulation, the binding of manganese ions and bilirubin changed, I could confirm the figure.
- the present inventors also measured the intensity change of the MR image signal before and after hypochlorite treatment of the bilirubin derivative (PEG-BR) nanoparticles in which the manganese ions of the present invention were coordinated.
- the measurement parameters were a 17-cm bore size 3-Tesla MRS 3000 scanner (MR Solutions, Surrey, United Kingdom) and the measurement parameters of the horizontal T1- It was like:
- the bilirubin derivative (PEG-BR) nanoparticles in which the manganese ions were coordinated to the present invention had enhanced brightness of MRI T1-weighted images after treatment with active oxygen (hypochlorous acid).
- active oxygen hypochlorous acid
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Abstract
Description
신호 대 잡음 비 (T/N contrast ratio) = (신호의 평균 크기) / {(잡음의 표준편차) * 100} | |
NaOCl 반응 전 | 10003/(110*100) = 90.9% |
NaOCl 반응 후 | 19024/(110*100) = 172.9% |
Claims (15)
- 빌리루빈 유도체 및 금속을 포함하는 빌리루빈 유도체 입자.
- 제 1 항에 있어서, 상기 빌리루빈 유도체 입자는 빌리루빈 유도체와 상기 금속이 배위결합을 통해 구성된 것을 특징으로 하는 빌리루빈 유도체 입자.
- 제 1 항에 있어서, 상기 배위결합은 빌리루빈 유도체의 카르복실기, 락탐기, 또는 피롤 링과 상기 금속 사이에 형성하는 것을 특징으로 하는 빌리루빈 유도체 입자.
- 제 1 항 내지 제 3 항 중 어느 한 항에 있어서, 상기 금속은 Cu, Ga, Rb, Zr, Y, Tc, In, Ti, Gd, Mn, Fe, Au, Pt, Pd, Ag, Co, Mn, Zn, Gd, Mo, Ni, Fe, Cr, Na, K, Rb, Cs, Mg, Ca, Sr, Ba, Ra 및 란탄족 금속으로 이루어진 군으로부터 선택된 금속의 이온 또는 금속 화합물인 것을 특징으로 하는 빌리루빈 유도체 입자.
- 제 1 항 내지 제 3 항 중 어는 한 항에 있어서, 상기 금속은 초상자성 산화철 나노입자(SPION: superparamagnetic iron oxide nanoparticle)또는 금 나노입자인 것을 특징으로 하는 빌리루빈 유도체 입자.
- 제 1 항 내지 제 3 항 중 어느 한 항에 있어서, 상기 금속은 플래티넘(Pt) 이온 또는 시스플라틴(cisplatin), 카르보플라틴(carboplatin), 옥살리플라틴(oxaliplatin), 네다플라틴(nedaplatin), 및 헵타플라틴(heptaplatin)으로 이루어진 군으로부터 선택된 플래티넘 계열 항암제인 것을 특징으로 하는 빌리루빈 유도체 입자.
- 제 1 항 내지 제 3 항 중 어느 한 항에 있어서, 상기 금속은 64Cu, 68Ga, 82Rb, 89Zr, 90Y, 99mTc, 111In, 및 201TI로 이루어진 군으로부터 선택된 방사성 동위원소인 것을 특징으로 하는 빌리루빈 유도체 입자.
- 제 1 항 내지 제 3 항 중 어느 한 항에 있어서, 상기 빌리루빈 유도체는 빌리루빈에 친수성 분자가 컨쥬게이션된 것을 특징으로 하는 빌리루빈 유도체 입자.
- 제 8 항에 있어서, 상기 친수성 분자는 덱스트란 (dextran), 카르보덱스트란(carbodextran), 폴리사카라이드(polysaccharide), 사이클로덱스트란 (cyclodextran), 풀루란 (pluronic), 셀룰로오즈(cellulose), 녹말(starch), 글리코겐(glycogen), 카르보하이드레이트 (carbohydrate), 단당류 (monosaccharide), 이당류(bisaccharide) 및 올리고당류 (oligosaccharide), 폴리포스파젠 (polyphosphagen), 폴리락타이드(polylactide), 폴리락티드-코-글리콜라이드 (poly(lactic-co-glycolic acid)), 폴리카프로락톤(polycaprolactone), 폴리안하이드라이드 (polyanhydride), 폴리말릭산 (polymaleic acid) 및 폴리말릭산의 유도체, 폴리알킬시아노아크릴레이트 (polyalkylcyanoacrylate), 폴리하이드로옥시부틸레이트(polyhydroxybutylate), 폴리카르보네이트 (polycarbonate), 폴리오르소에스테르 (polyorthoester), 폴리에틸렌 글리콜 (polyethyleneglycol), 폴리프로필렌글리콜, 폴리에틸렌이민(polyethylenimine), 폴리-L-라이신 (poly-L-lysine), 폴리글리콜라이드 (polyglycolide), 폴리메틸메타아크릴레이트 (polymetacrylate), 폴리비닐피롤리돈 (polyvinylpyrrolidone), 폴리(아크릴산염)(poly[acrylate]), 폴리(아크릴아마이드)(poly[acrylamide]), 폴리(비닐에스테르)(poly[vinylester]), 폴리(비닐알콜)(poly[vinyl alcohol]), 폴리스티렌(polystryene), 폴리옥사이드(polyoxide), 폴리일렉트로라이트(polyelectrolyte), 폴리(1-니트로프로필렌)(poly[1-nitropropylene]), 폴리(N-비닐피롤리돈)(poly[N-vinyl pyrrolidone]), 폴리비닐아민(poly[vinyl amine]), 폴리(베타-히드록시에틸 메타아크릴레이트)(Poly[beta-hydroxyethylmethacrylate]), 폴리에틸렌 옥사이드(Polyethyleneoxide), 폴리(에틸렌옥시드-b-프로필렌 옥사이드(Poly[ethylene oxide-bpropyleneoxide]), 폴리라이신(Polylysine), 및 펩티드로 이루어진 군으로부터 선택된 것을 특징으로 하는 빌리루빈 유도체 입자.
- 제 1 항 내지 제 9 항 중 어느 한 항의 빌리루빈 유도체 입자를 포함하는 조성물.
- 제 10 항에 있어서, 상기 조성물은 영상진단용 조영제 조성물인 것을 특징으로 하는 조성물.
- 제 10 항에 있어서, 상기 조성물은 암의 치료용 약제학적 조성물인 것을 특징으로 하는 조성물.
- 제 10 항에 있어서, 상기 조성물은 염증성 질환의 치료 및 진단용 약제학적 조성물인 것을 특징으로 하는 조성물.
- 제 10 항에 있어서, 상기 조성물은 활성산소종(reactive oxygen species, ROS) 검출용인 것을 특징으로 하는 조성물.
- 다음의 단계를 포함하는 금속 및 빌리루빈 유도체를 포함하는 빌리루빈 유도체 입자의 제조방법:(a) 빌리루빈을 친수성 분자와 컨쥬게이션하여 빌리루빈 유도체를 제조하는 단계; 및(b) 상기 빌리루빈 유도체와 금속을 배위결합하여 금속이 봉입된 빌리루빈 유도체 입자를 제조하는 단계.
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RU2019138568A RU2756753C2 (ru) | 2017-05-12 | 2018-05-14 | Частицы, содержащие производное билирубина и металл |
JP2020513477A JP2020523404A (ja) | 2017-05-12 | 2018-05-14 | ビリルビン誘導体及び金属を含む粒子 |
CA3063337A CA3063337A1 (en) | 2017-05-12 | 2018-05-14 | Particles comprising bilirubin derivative and metal |
AU2018267526A AU2018267526B2 (en) | 2017-05-12 | 2018-05-14 | Particles comprising bilirubin derivative and metal |
CN201880042226.4A CN111182926A (zh) | 2017-05-12 | 2018-05-14 | 包含胆红素衍生物及金属的粒子 |
US16/343,043 US11896681B2 (en) | 2017-05-12 | 2018-05-14 | Particles comprising bilirubin derivative and metal |
EP18799160.9A EP3622969A4 (en) | 2017-05-12 | 2018-05-14 | PARTICLES COMPRISING A BILIRUBIN DERIVATIVE AND A METAL |
JP2022206483A JP2023052056A (ja) | 2017-05-12 | 2022-12-23 | ビリルビン誘導体及び金属を含む粒子 |
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EP1320532A1 (en) * | 2000-06-14 | 2003-06-25 | Duke University | Tetrapyrroles |
US20080070971A1 (en) * | 2006-03-06 | 2008-03-20 | Wang Xiang H | Medical Use of Bilirubin and its Structural Analogues |
US20120305802A1 (en) * | 2009-08-11 | 2012-12-06 | Erik Herz | Nanoparticles and Methods of Generating Coherent Emission Therefrom |
EP3088353B8 (en) | 2013-12-27 | 2020-04-08 | Bilix Co., Ltd. | Bilirubin particles and their preparation for use in therapy |
WO2017070676A1 (en) * | 2015-10-23 | 2017-04-27 | Massachusetts Instittue Of Technology | Nanoparticles comprising a metal core surrounded by a monolayer for lymph node targeting |
KR20170059597A (ko) | 2015-11-23 | 2017-05-31 | (주)이노큐디 | 멀티 광 스펙트럼의 복합 양자점을 혼합한 캡슐 |
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RU2019138568A3 (ko) | 2021-06-15 |
AU2018267526A1 (en) | 2020-01-02 |
CN111182926A (zh) | 2020-05-19 |
CA3063337A1 (en) | 2019-12-05 |
RU2019138568A (ru) | 2021-06-15 |
US11896681B2 (en) | 2024-02-13 |
WO2018208137A2 (ko) | 2018-11-15 |
EP3622969A2 (en) | 2020-03-18 |
RU2756753C2 (ru) | 2021-10-05 |
KR102254093B1 (ko) | 2021-05-20 |
AU2018267526B2 (en) | 2021-09-16 |
JP2023052056A (ja) | 2023-04-11 |
WO2018208137A3 (ko) | 2019-03-28 |
KR20210059683A (ko) | 2021-05-25 |
KR102292960B1 (ko) | 2021-08-24 |
EP3622969A4 (en) | 2020-05-27 |
JP2020523404A (ja) | 2020-08-06 |
BR112019023725A2 (pt) | 2020-05-26 |
US20200230261A1 (en) | 2020-07-23 |
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