WO2019132613A1 - 조영제용 생체 적합성 고분자 복합체 및 이를 포함하는 조영제 - Google Patents
조영제용 생체 적합성 고분자 복합체 및 이를 포함하는 조영제 Download PDFInfo
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- WO2019132613A1 WO2019132613A1 PCT/KR2018/016908 KR2018016908W WO2019132613A1 WO 2019132613 A1 WO2019132613 A1 WO 2019132613A1 KR 2018016908 W KR2018016908 W KR 2018016908W WO 2019132613 A1 WO2019132613 A1 WO 2019132613A1
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- Prior art keywords
- vascular endothelial
- contrast agent
- contrast
- binding
- endothelial cells
- Prior art date
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
Definitions
- the present invention relates to a contrast agent that specifically binds to vascular endothelial cells.
- the present invention relates to a substance specifically binding to vascular endothelial cells; Contrast material; And a linker for linking the contrast material with a substance specifically binding to the vascular endothelial cell.
- Angiography is performed by injecting a contrast agent into the living body through X-ray, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) It is a test.
- CT computed tomography
- MRI magnetic resonance imaging
- PET positron emission tomography
- the contrast agent injected into the blood vessel mixes with the flowing bloodstream and circulates along the blood vessel.
- Types of blood vessels include arteries, veins, capillaries, and the like. These contrast agents allow tissue or blood vessels to be seen during MRI, X-ray CT, and X-ray imaging.
- the average amount of contrast agent used for angiography is greater than the average amount of contrast agent used for contrast imaging for computed tomography (CT). Accordingly, angiography has a problem that the risk of complications caused by the contrast agent is relatively high.
- Contrast-Induced Nephropathy occurs in 0% to 13% of patients undergoing total procedure.
- High-risk patients such as diabetes, hypertension, heart failure, cirrhosis, and older patients More than 75% of the cases show complications.
- the present invention has been made to solve the above-mentioned problems, and it is an object of the present invention to provide a polymer complex specifically binding to vascular endothelial cells and a contrast agent using the same.
- the biocompatible polymer complex for contrast agent includes a substance specifically binding to vascular endothelial cells, a contrast agent, and a linker connecting the specimen to the vascular endothelial cell and the specimen can do.
- the biocompatible polymer conjugate for contrast agent according to the present invention is characterized in that a substance specifically binding to the vascular endothelial cell and a substance capable of specifically binding to the vascular endothelial cell are subjected to an epoxide synthesis reaction, an amine epoxide reaction, a carbonyl-amine condensation reaction, And an EDC / NHS reaction, an EDC / sulf-NHS reaction, and a conjugation reaction.
- the linker may include at least one bond among imine, ester, amide, and peptide bonds.
- the substance specifically binding to the vascular endothelial cells may be at least one substance selected from the group consisting of an extender, an antibody, a peptide, an enzyme and a receptor, and the contrast medium may be a radioactive contrast material, a contrast medium of MRI or ultrasound image May be a substance that improves the performance of the device.
- the conjugated polymer complex specifically binding to the endothelial cells according to the present invention can bind to the endothelial cells for 3 seconds or more.
- the conjugate polymer complex that specifically binds to the endothelial cells according to the present invention can increase the duration of the intravascular contrast agent by binding to the endothelial cells for several minutes to several days.
- the contrast agent that specifically binds to the vascular endothelial cells according to the present invention can prevent and minimize the repeated administration of the contrast agent for obtaining images or images.
- the present invention not only reduces the amount of contrast agent used, but also reduces complications caused by contrast agents in angiography, including angiography or angioplasty.
- FIG. 1 is a schematic view of a contrast agent that specifically binds to vascular endothelial cells.
- FIG. 2 is a schematic diagram of excavator excavation using the Cell-SELEX method.
- Fig. 3 is a schematic view for explaining the principle and effect of contrast of the contrast agent according to the comparative example.
- FIG. 4 is a schematic view for explaining the principle and effect of contrast of the contrast agent according to the embodiment.
- FIG. 5 is a flowchart showing the procedure of angiography using contrast agents according to Comparative Examples and Examples.
- FIG. 6 is a flowchart showing a procedure of a blood vessel intervention using contrast agents according to Comparative Examples and Examples.
- FIGS. 7 and 8 are photographs showing PCR analysis results for identifying target binding substances that specifically bind to vascular endothelial cells.
- the present inventors have conducted extensive studies to develop a contrast agent capable of reducing the amount of contrast agent used by increasing the residence time of an intravascular contrast agent. As a result, they have found that a contrast agent capable of specifically binding to a vascular endothelial cell can be connected to a contrast agent
- the present invention has been accomplished on the basis of these findings.
- the present invention is to provide a contrast agent that specifically binds to vascular endothelial cells.
- the biocompatible polymer complex for contrast agent according to the present invention is a substance specifically binding to vascular endothelial cells; Contrast material; And a linker for linking the contrast agent with a substance specifically binding to the vascular endothelial cell. Accordingly, the contrast agent containing the biocompatible polymer complex for contrast agent can specifically bind to vascular endothelial cells.
- the present invention is directed to a vascular endothelial cell comprising a substance 100 that specifically binds to vascular endothelial cells and a contrast material 200, a substance 100 that specifically binds to the vascular endothelial cells, (200) may be connected by a linker (300).
- the target substance is a vascular endothelial cell
- the target binding substance may mean a substance that specifically binds to vascular endothelial cells.
- a specific substance (100) that specifically binds to vascular endothelial cells contained in the biocompatible polymer complex for a contrast agent and a contrast agent containing the same according to the present invention is for specifically adhering to vascular endothelial cells.
- the biocompatible polymer complex for contrast agent and the contrast agent containing the conjugate according to the present invention can be used to specifically bind vascular endothelial cells to a vascular endothelial cell, Time can be maintained.
- the constant time may be a time in a range of several seconds to several seconds or more, which is a time of three seconds or more.
- the specific binding of the vascular endothelial cell to the vascular endothelial cell (100) may be 2 to 7 days.
- the specific binding of the vascular endothelial cell to the vascular endothelial cell 100 may be 2 to 8 days.
- the specific binding of the vascular endothelial cell-specific substance 100 to the vascular endothelial cell may be maintained for 2 to 10 days.
- the biocompatible polymer conjugate for contrast agent and the contrast agent containing the conjugate according to the present invention are characterized in that the nucleotide contained in the substance (100) specifically binding to the vascular endothelial cell is a DNA hydrolase in vivo or a complementary single nucleotide Vessel information can be delivered until it is degraded by sequence.
- the substance 100 specifically binding to the endothelial cells contained in the biocompatible polymer complex for contrast agent and the contrast agent containing the same according to the present invention may contain a specific base sequence that can be specifically adhered to vascular endothelial cells .
- the substance (100) specifically binding to the vascular endothelial cells contained in the contrast agent according to the present invention may include a spot 110 for binding to vascular endothelial cells.
- a substance (100) that specifically binds to vascular endothelial cells contained in the contrast agent according to the present invention may include a spot 110 for binding to vascular endothelial cells.
- " binding "
- binding " means that the target binding substance can be attached to vascular endothelial cells, which may mean binding affinity or binding activity with a target substance.
- binding activity and binding affinity can be measured by various known methods such as dissociation constants. For example, when different molecules have low dissociation constants, they may exhibit strong binding and strong affinity.
- dissociation constants when different molecules have low dissociation constants, they may exhibit strong binding and strong affinity.
- " specific " as used herein means that a substance specifically binding to vascular endothelial cells such as platemer in specific cell and / or specific base sequences than other cells or base sequences is more frequently, Can mean reacting or binding with longer duration and / or greater affinity.
- the substance (100) specifically binding to the vascular endothelial cell may have one or more types of bioreceptors selected from the group consisting of an extender, an antibody, a peptide, an enzyme, and a receptor, having a base sequence found by the SELEX method.
- the " bioreceptor " is not limited to an abdominal, an antibody, a peptide, an enzyme, and a receptor, but may be various materials capable of attaching or binding to a target substance.
- the substance 100 that specifically binds to the vascular endothelial cells may be an aptamer.
- the aptamers can be highly stable in vivo application.
- a contrast agent can be developed by binding a contrast agent and a contrast material having high specificity to vascular endothelial cells.
- Contrast agents containing a high specificity of vascular endothelial cells can be easily replaced with conventional contrast agents because they can increase the observation time of blood vessels without any difference in administration method or contrast material with conventional contrast agents.
- aptamer refers to a nucleic acid molecule having binding activity to vascular endothelial cells.
- the aptamer of the present invention may be in the form of single-stranded DNA (ssDNA) or single-stranded RNA (ssRNA), but may be in the form of single-stranded DNA , But is not limited thereto.
- the aptamer can specifically bind to the surface of vascular endothelial cells.
- a typical aptamer is 10 kDa to 25 kDa in size (30 to 75 nucleotides) and can bind to its target with an affinity of sub-nanomolar.
- the aptamer can specifically bind to a target selected through binding interactions (e.g., hydrogen bonding, electrostatic complementation, hydrophobic contact, steric exclusion) or specificity in an antibody-antigen complex. That is, the aptamer can specifically bind to the target substance by the specific three-dimensional structure that the base sequence can make.
- " platamer " may include both secondary and tertiary structures such as G-quadruplex and hairpin structure.
- the target material may be a cell, an amino acid, a drug, a protein, or other polymer material.
- the aptamer may specifically have a base sequence capable of specifically binding to vascular endothelial cells and a base sequence complementary thereto.
- the specific binding time with the platemaker and vascular endothelial cells required in the examples may be different.
- a base sequence capable of specifically binding to vascular endothelial cells may be capable of sustaining a specific binding with vascular endothelial cells for more than one hour.
- the base sequence capable of specifically binding to vascular endothelial cells may be capable of sustaining a specific binding to vascular endothelial cells for 6 hours or more.
- a base sequence capable of specifically binding to vascular endothelial cells may be capable of sustaining a specific binding with vascular endothelial cells for more than 12 hours.
- the platemma having substantially binding activity for MLL1 can be included in the scope of the present invention.
- the base sequence capable of specifically binding to vascular endothelial cells may be capable of sustaining a specific binding with vascular endothelial cells for 24 hours or more.
- aptamers having a base sequence in which a part of the sequences are deleted, modified, substituted or added in the above-mentioned sequence having substantially the same or corresponding biological activity are also included in the scope of the present invention.
- homology means the degree to which a given amino acid sequence or base sequence is consistent and can be expressed as a percentage.
- a homologous sequence having the same or similar activity as a given amino acid sequence or base sequence is represented as "% homology ".
- standard software for calculating parameters such as score, identity and similarity, specifically BLAST 2.0, or by sequential hybridization experiments under defined stringent conditions, And the appropriate hybridization conditions to be defined are within the skill of the art and can be determined by methods well known to those skilled in the art (for example, J.
- " stringent conditions " as used herein refers to conditions that allow specific hybridization between polynucleotides. For example, these conditions are specifically described in the literature (e.g., J. Sambrook et al., Same as above).
- the aptamers of the present invention may comprise 50-100 base pairs. Thus, chemical synthesis and mass production can be facilitated and the in vivo stability can be enhanced.
- Each of the nucleotides contained in the platemer of the present invention may be the same or different and each is a nucleotide including a hydroxyl group at the 2 'site of the ribose (for example, a ribose of a pyrimidine nucleotide) (that is, a nucleotide which is not a nucleotide)
- the hydroxyl group may be a nucleotide substituted with any atom or group.
- Examples of such an arbitrary atom or group include a hydrogen atom, a fluorine atom or an -O-alkyl group (e.g., -O-Me group), an -O-acyl group (e.g., -O-CHO group) 2 >).≪ / RTI >
- the aptamers of the present invention may also be modified so that at least one (e.g., 1, 2, 3 or 4) nucleotides are substituted at the 2'-site of the ribose with a hydroxyl group or any of the aforementioned atoms or groups, (E.g., 2, 3, or 4) groups selected from the group consisting of an atom, a hydroxyl group, and -O-Me group.
- the aptamer of the present invention may include a modified sugar residue of each nucleotide in order to improve the binding property and stability to vascular endothelial cells. Modifications of such sugar residues can be made by methods known in the art.
- the aptamer of the present invention may have a modified nucleotide base to enhance binding to vascular endothelial cells.
- the nucleic acid base may be modified through a chemical substitution reaction.
- the aptamer of the present invention may include 3 'and / or 5' modifications such as capping.
- the aptamer of the present invention can bind to a target substance by various binding modes such as ionic bonding using a negative charge of a phosphate group, hydrophobic bonding using a ribose, hydrogen bonding, hydrogen bonding using a nucleic acid base, or stacking bonding.
- the ionic bond using the negative charge of the phosphate group which exists as many as the constituent nucleotides, can strongly bind to the positive charge of lysine or arginine present on the surface of the protein. For this reason, nucleic acid bases not related to direct binding with the target substance can be substituted.
- the portion of the stem structure is already formed of a base pair and is also directed toward the inside of the double helix structure, the nucleic acid base may be difficult to bind directly to the target substance. Therefore, even if the base pair is replaced with another base pair, the activity of the squid polymer may not decrease. Even in a structure in which a base pair is not formed, such as a loop structure, it is needless to say that base substitution can be possible when the nucleotide base does not participate in direct binding with the target molecule.
- the aptamer can be chemically synthesized and easily modified. Aptamer can easily predict the secondary structure by using mfold program, and X-ray analysis or NMR analysis is necessary for more accurate three-dimensional structure analysis.
- the predicted new sequence aptamer can be chemically synthesized easily, and it can be confirmed by an existing analysis system whether or not the aptamer remains active.
- a part important for binding to the vascular endothelial cell of the obtained extramammary can be identified by repeating trial and error as described above, even if a new sequence is added at both ends of the sequence, the activity may not change in most cases have.
- the aptamer has advantages in that it can be highly designed or modified.
- a method for searching for a specific base sequence for binding specifically to the target substance to the substance 100 specifically binding to the endothelial cell may be a SELEX method such as Cell SELEX or GO SELEX.
- the SELEX method can be used to identify aptamer that can specifically bind to vascular endothelial cells.
- the method is not limited to the listed methods, and if it is a method for finding a base sequence capable of specifically binding to a target substance, the SELEX method and the SELEX method, which are improved in order to overcome the problem of classical SELEX, But may include various ways of doing so.
- a more potent tympanic membrane can be selected for vascular endothelial cells.
- Aptamers are being actively developed for the purpose of diagnosis for predicting the onset or the disease of a specific disease such as cancer or for the treatment of the onset or disease of a specific disease.
- Korean Patent No. 10-1405440 discloses a composition for imaging tumorous lesion sites containing platamer as an active ingredient, but it utilizes the specific binding of platemer for imaging of the tumor site of the tumor.
- the contrast medium containing the aptamer of the embodiment may have an increased retention time in the blood vessel, thereby allowing repeated blood vessel images and images to be confirmed or real-time blood vessel images or images can be confirmed after the administration of the contrast agent once.
- the material 100 specifically binding to the vascular endothelial cells contained in the biocompatible polymer complex for contrast agent and the contrast agent containing the conjugate according to the present invention includes the site 110 that binds to the vascular endothelial cells,
- the observation time of the blood vessel can be increased. Accordingly, in the angiographic examination for angiography or angioplasty, if the additional image or image is required due to lack of information on the blood vessel state through the recorded image or image, the contrast agent may not be re-administered to the blood vessel .
- the contrast agent according to the present invention may be capable of both primary acquisition of information such as image or image and acquisition of additional information such as image or image during a single administration time. Therefore, the present invention can prevent and minimize the introduction of the contrast agent, thereby reducing the unnecessary cost, and it is possible to reduce adverse effects such as nephropathy caused by overuse of the contrast agent.
- the contrast material 200 included in the biocompatible polymer complex for contrast agent and the contrast agent containing the contrast agent according to the present invention will be described.
- contrast agent used in the present invention refers to a preparation used to artificially create a difference in contrast degree so as to better visualize blood vessels or tissues for the purpose of diagnosing a condition of organs of a body and diagnosis of diseases. Contrast agents can determine the presence and degree of disease or damage by increasing the visibility and contrast of the surface under study.
- biocompatibility should be excellent in the living body, and stability in the living body should be excellent.
- biocompatible polymer complex for contrast agent of the present invention and the contrast agent containing the conjugate may have biodegradability.
- the contrast agent conjugated with the substance (100) specifically binding to the endothelial cells of the present invention and the contrast material (200) is a biocompatible material having no biotoxicity, so it may be safe to bind to endothelial cells, Has biodegradability that can be separated from vascular endothelial cells by DNA hydrolytic enzymes in vivo so that it may be suitable for application and use in contrast agents that must be removed from the body after the purpose.
- CT magnetic resonance imaging
- MRI magnetic resonance imaging
- MRI magnetic resonance imaging
- MRI positron emission tomography
- CT positron emission tomography
- PET PET
- nuclear imaging including ultrasound imaging, and the like.
- the contrast material 200 included in the biocompatible polymer complex for contrast agent and the contrast agent containing the contrast agent according to the present invention is used for securing images of blood vessels and diseased parts using X-ray, CT, PET, MRI and ultrasound. That is, the contrast material 200 may be a material included in a contrast agent for imaging at least one of X-ray, CT, PET, MRI, and ultrasound.
- the contrast medium 200 included in the contrast agent for X-ray, CT, and PET according to the present invention may include a radioactive material.
- Iodine-based compounds have been extensively used for the contrast medium 200 contained in contrast agents for X-ray and CT.
- the iodine-based compound may mean an aromatic compound containing iodine. Because the density of urethra is large, the degree of absorption of X-ray is large, and thus it is possible to obtain a superior enhancement effect.
- the iodine-based compounds are selected from the group consisting of Iomeprol, Iopramide, Iopamidol, Iopentol, Iotrolan, Iohexol, Ioversol, And may be selected from the group consisting of Ioxilan, Iodixanol and Iobitridol.
- Such an iodine-based compound may comprise at least one amino group (-NH-, -NH 2 ) and at least one hydroxyl group (-OH).
- an iodine-based compound may comprise from one to two amino groups (-NH-, -NH 2 ) and from one to ten hydroxy groups (-OH).
- an iodine-based compound may comprise one to six amino groups (-NH-, -NH 2 ) and one to nine hydroxy groups (-OH).
- iodine-based compounds may contain from 1 to 9 amino groups (-NH-, -NH 2 ) and from 1 to 10 hydroxy groups (-OH). That is, the iodine-based compound may be an aqueous contrast medium containing a hydrophilic group.
- at least one amino group (-NH-, -NH 2 ) and / or at least one hydroxyl group (-OH) of the iodine-based compound may be a functional group that can be linked to the linker.
- the iodine-based compound may be one selected from the group consisting of iodine, hydrogen iodide, sodium iodide, potassium iodide, methyl iodide, cesium iodide, potassium iodate, sodium periodate, calcium iodide, copper iodide and povidone iodine Or more.
- the contrast medium 200 included in the contrast medium for PET includes F-18-FDG (Fluorodeoxy glucose), F-18-FLT (Fluorothymidine), Fluoropropyl carbomethoxy-3b- (4-iodophenyltropane) , C-11-Methionine, C-11-Acetate, C-11-PIB (Pittsburgh compound B), N-13-Ammonia, Rb-82.
- F-18-FDG Fluorodeoxy glucose
- F-18-FLT Fluoropropyl carbomethoxy-3b- (4-iodophenyltropane)
- C-11-Methionine C-11-Acetate
- C-11-PIB Pittsburgh compound B
- N-13-Ammonia Rb-82.
- the contrast material 200 may be a radioactive isotope, a fluorophore, a quantum dot, or magnetic particles, such as super paramagnetic particles or ultrasuper paramagnetic particles, May be various kinds of contrasting materials known in the art, not limited thereto.
- the contrast material 200 included in the biocompatible polymer complex for contrast agent and the contrast agent according to the present invention may include a substance sensitive to radioactivity and may improve image contrast of X-ray, CT, PET, have.
- the contrast material 200 included in the biocompatible polymer complex for contrast agent and the contrast agent according to the present invention may include a contrast material for MRI measurement and may improve the MRI image contrast.
- the contrast material 200 included in the biocompatible polymer composite for contrast agent and the contrast agent according to the present invention may include a contrast material for ultrasonic measurement and improve the contrast of the ultrasound image.
- biocompatible polymer complex for a contrast agent and the contrast agent containing the same according to the present invention can control the intensity of an image.
- a linker 300 connecting the contrast material 100 and the substance 100 specifically binding to the endothelial cells contained in the contrast agent for contrast agent according to the present invention and the contrast agent 300 connecting the contrast agent 200 .
- the present invention can link a substance (100) that specifically binds to vascular endothelial cells capable of specifically attaching to vascular endothelial cells to the vascular material (200) by the linker (300).
- the substance (100) and the contrast material (200) specifically binding to the endothelial cells may be subjected to an epoxide synthesis reaction, an amine epoxide reaction, a carbonyl-amine condensation reaction, a chloroacetic acid-EDC / NHS reaction, an EDC / sulf-NHS reaction and a conjugation reaction.
- the linker 300 can be prepared by reacting an epoxide, an amine epoxide, a carbonyl-amine condensate, a product by EDC / NHS reaction, an EDC / sulf-NHS reaction and a conjugation reaction with a chloroacetic acid, And derivatives thereof.
- the linker 300 can connect the contrast medium 200 to the substance 100 that specifically binds to the endothelial cells, and can bind the endothelial cells 100 in the substance 100,
- the present invention is not limited to the specific synthesis and may have various functional groups as long as it does not cause any damage or loss of specificity to the spot 110 that is bonded to the binding site 110.
- the linker may include at least one of imine, ester, amide, and peptide bonds.
- the amino group and the hydroxy group contained therein may be partially or wholly modified to link with the linker.
- At least one of the amino groups contained in the iodo-based compound may be converted to a double bond by other functional groups including nitrogen, or by a single bond of nitrogen.
- at least one of the amino groups contained in the iodo-based compound may be modified such as an imine or amide to be linked to a substance that specifically binds to vascular endothelial cells.
- At least one of the hydroxyl groups contained in the iodo-based compound may be converted to a double bond by a single bond of oxygen or another functional group containing oxygen such as an ester.
- another functional group containing oxygen such as an ester.
- the iodo-based compound may be linked to a substance that specifically binds to vascular endothelial cells by forming a linker through a carbonyl-amine condensation reaction, wherein the linker may include an imine functional group.
- the number of linkers connected by immigration may be one to six.
- the iodo-based compound may be linked to a substance that specifically binds to vascular endothelial cells by forming a linker through EDC / NHS coupling, wherein the linker may include an ester functional group.
- the number of linkers connected by an ester may be one to nine.
- the iodo-based compound may be linked to a substance that specifically binds to vascular endothelial cells by forming a linker through EDC / NHS coupling, wherein the linker may include an amide functional group (or a peptide bond).
- the number of linkers connected by an amide functional group may be 1 to 9.
- the biocompatible polymer complex for contrast agent and the contrast agent containing the contrast agent according to the present invention can be prepared by using a conventional contrast medium 200 and simultaneously applying specific contrast agent to the vascular endothelial cell 200 that is capable of specifically attaching to the vascular endothelial cell 200
- the linker 300 connects the substance 100 to be bound to the blood vessel 100, thereby preventing a problem that the blood vessel retention time of the contrast material is short.
- the contrast agent that specifically binds to the endothelial cells can be prepared by extracting an aptamer that specifically binds to vascular endothelial cells and connecting the resultant to a contrast material.
- Step 1 Vascular endothelial cells which are the target substances can be cultured.
- a conventional cell culture method was used for the culturing, subculture can be carried out by adjusting the number of cells to 2 ⁇ 10 6 so that they can be directly used in digestion.
- HBSS can be used to recover the sample.
- Step 2 Cell SELEX can be carried out to identify a platelet specific to vascular endothelial cells.
- Step 3 The length of the plastomer sequence can be synthesized separately for 40 and 50 DNA sequences and put together in the recovered sample of Step 1.
- Step 4 After removing the unbonded platamer, heat and osmotic pressure is applied to the platemer and the cells are separated, and the primer and various enzymes selected in the preliminary experiment are added to amplify the platameric sequence (PCR).
- Step 5 After purification of the amplified sequence, the DNA-gel electrophoresis is performed and the target specific tyramander digestion is confirmed by image. (1R)
- Step 6 The above procedure is performed until 24R, and then the whole blood or the endothelial cells are reacted with other cells to extract a sequence not attached to whole blood.
- Step 7 Cloning is carried out to analyze the sequence of the above sequence.
- the cloning process involves isolating and purifying the plasmid sequences with PCR extraction kit, then culturing the plasmids in an emper solid medium, transferring the single colonies to the + Amp liquid medium, and proceeding the sequencing after preparation.
- Step 8 After mass production of the identified sequence, bind the fluorophore at the end of the plasmid sequence to confirm binding and binding affinity.
- Step 9 The identified aptamers are conjugated with contrast media using Epoxide synthesis, amine epoxide reaction, Carbonyl-amine condensation reaction, chloroacetic acid, EDC / NHS and EDC / sulf-NHS reaction.
- Step 10 Confirm the working condition and real sample of the complex of oppressor-contrast agent.
- the test can be selectively performed on the living cells.
- the term " living body " refers to a human or non-human, and the non-human can be a non-human primate, rodent, dog, algae, and the like.
- the aptamer included in the contrast agent according to the present invention may include a base sequence having strong binding and / or strong affinity to vascular endothelial cells. Accordingly, real-time blood vessel information can be obtained in an invasive procedure with an angiographic examination or an angiographic examination by a single administration of contrast agent. This can reduce the number of injections of the in vivo contrast agent and prevent the occurrence of kidney-related complications.
- the new excavation method is as follows.
- a DNA library having various forms is prepared using DNA synthesis and in vitro transcription method (in case of RNA), and a base sequence binding only to the target substance is amplified To find a primer for PRC that does not bind to the base sequence in the target material.
- the various nucleic acid constructs in the nucleic acid construct library (plutamer candidate molecules) have the ability to bind to various target substances and thus the desired target molecules Only nucleic acid constructs that can be combined are selected.
- Unbound nucleic acid constructs such as affinity chromatography can be selectively removed by washing and binding to the target molecule.
- the nucleic acid construct is eluted from the target molecule. After amplifying the nucleic acid, the nucleic acid construct obtained is further repeated 5 to 15 times. .
- the Cell-SELEX process is a cell-to-aptamer-based method for directly identifying specific tympanomas that bind to proteins present on the cell surface without a high-purity protein purification process.
- the advantage of this method is that it is possible to find aptamer that can bind directly to a target protein that has an intact structure in the cell.
- the digestion process of platamer is as follows: primer and library ⁇ cell lines (positive and negative) ⁇ cell culture maintenance ⁇ elution of binding sequence ⁇ PCR procedure ⁇ preparation of single strand DNA ⁇ voice selection ⁇ selection progress monitoring ⁇ selection termination Can proceed.
- the aptamer discovered may comprise 40 or 50 nucleotides.
- the aptamer which was observed to have excellent binding properties to vascular endothelial cells, was found to contain 40 or 50 nucleotides.
- Contrast agents containing excavated platelets and contrast material complexes that specifically bind to vascular endothelial cells to which contrast material is attached to excavated tumors that specifically bind to vascular endothelial cells can be used for X-ray imaging have.
- the excavated platelets and contrast media specifically binding to the vascular endothelial cells to which the contrast material is bound to the excavated platamer that specifically binds to the vascular endothelial cells can be contained in the contrast agent in a predetermined amount.
- the predetermined amount means that the total amount of the contrast agent is 100% by volume or 100% by mass, and the excavated platemer and contrast material specifically binding to the vascular endothelial cells may be 100% by volume or less than 100% by mass it means. That is, the entire contrast medium may include additional constituent materials other than the excavated tympanic and contrast material complex that specifically binds to vascular endothelial cells.
- the contrast agent according to the embodiment can be attached to the endothelial cells for more than 2 minutes, the observation time using the contrast agent can be increased.
- the observation time of the blood vessel is more than 3 seconds to 7 days (more than 5 seconds to several days, 2 minutes to 7 days) If the blood vessel data is insufficient, the image can be stored and acquired after the X-ray angle is reset without additional contrast agent administration.
- the blood vessel observation time using the contrast agent according to the embodiment is more than 3 seconds to 7 days (more than 5 seconds to several days, 2 minutes to 7 days), images obtained in real time are observed In the case of insufficient blood vessel data, monitoring may be possible in real time without administering contrast agent.
- the comparative example is a case of intravascular administration of a general contrast material used in conventional angiography.
- the contrast agent according to the comparative example since the contrast agent according to the comparative example is not attached to the endothelial cells but moves with the bloodstream, the blood vessel should be observed within 3 seconds.
- the contrast agent of the present invention may further comprise an aqueous buffer solution, sterilized water for injection, a chelating agent, a pH adjuster, and the like to prepare a contrast agent composition.
- the injectable preparation containing the contrast agent of the present invention may be prepared by adding other necessary pharmaceutically acceptable isotonic agents, preservatives and the like.
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Abstract
Description
Claims (14)
- 혈관 내피세포에 특이적으로 결합하는 물질;조영물질; 및상기 혈관 내피세포에 특이적으로 결합하는 물질과 상기 조영물질을 연결하는 링커;을 포함하는 조영제용 생체 적합성 고분자 복합체.
- 제 1항에 있어서,상기 혈관 내피세포에 특이적으로 결합하는 물질은 압타머, 항체, 펩타이드, 효소 및 리셉터로 이루어진 군에서 선택되는 것을 포함하는 조영제용 생체 적합성 고분자 복합체.
- 제 1항에 있어서,상기 링커는 이민(imine), 에스테르(ester), 아미드(amide), 펩티드 결합 중 적어도 하나를 포함하는 조영제용 생체 적합성 고분자 복합체.
- 제 1항에 있어서,상기 조영물질은 이오메프롤, 이오프로마이드, 이오파미돌, 이오펜톨, 이오트롤란, 이오헥솔, 이오베르솔, 이옥실란, 이오딕사놀 및 이오비트리돌으로 이루어진 군에서 선택되는 조영제용 생체 적합성 고분자 복합체.
- 제 1항에 있어서,상기 혈관 내피세포에 특이적으로 결합하는 물질은 혈관 내피세포의 표면에 3초 이상 결합할 수 있는 것인 조영제용 생체 적합성 고분자 복합체.
- 제 5항에 있어서,상기 혈관 내피세포에 특이적으로 결합하는 물질은 혈관 내피세포의 표면에 2분 내지 7일 결합할 수 있는 것인 조영제용 생체 적합성 고분자 복합체.
- 제 5항에 있어서,상기 혈관 내피세포에 특이적으로 결합하는 물질은 혈관 내피세포의 표면에 2분 내지 8일 결합할 수 있는 것인 조영제용 생체 적합성 고분자 복합체.
- 제 5항에 있어서,상기 혈관 내피세포에 특이적으로 결합하는 물질은 혈관 내피세포의 표면에 2분 내지 10일 결합할 수 있는 것인 조영제용 생체 적합성 고분자 복합체.
- 제 1항에 있어서,상기 혈관 내피세포에 특이적으로 결합하는 물질은 뉴클레오티드를 포함하는 것인 조영제용 생체 적합성 고분자 복합체.
- 제 1항에 있어서,상기 조영물질은 X-ray, CT, PET, MRI 및 초음파 중 적어도 하나의 영상을 획득하기 위한 것인 조영제용 생체 적합성 고분자 복합체.
- 제 3항에 있어서,상기 링커는 이민 작용기를 포함하고,상기 링커의 개수는 1개 내지 6개인 조영제용 생체 적합성 고분자 복합체.
- 제 3항에 있어서,상기 링커는 에스테르 작용기를 포함하고,상기 링커의 개수는 1개 내지 9개인 조영제용 생체 적합성 고분자 복합체.
- 제 3항에 있어서,상기 링커는 아미드 작용기를 포함하고,상기 링커의 개수는 1개 내지 9개인 조영제용 생체 적합성 고분자 복합체.
- 제 1항 내지 제 13항 중 어느 한 항에 있어서,상기 조영제용 생체 적합성 고분자 복합체를 포함하는 조영제.
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KR101429774B1 (ko) * | 2005-05-09 | 2014-10-02 | 바이오스피어 메디칼 에스.에이. | 마이크로스피어 및 비이온성 조영제를 사용하는 조성물 및방법 |
KR101446908B1 (ko) * | 2006-11-02 | 2014-10-06 | 베리덱스 엘엘씨 | 면역자기적인 mri 조영제들을 사용한 활성화된 혈관 내피의 이미징 |
KR101522560B1 (ko) * | 2014-01-28 | 2015-05-27 | 강원대학교산학협력단 | 생체분자 검출용 형광 소광 입자의 제조방법 및 이에 의해 제조된 생체분자 검출용 형광 소광 입자 |
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KR101429774B1 (ko) * | 2005-05-09 | 2014-10-02 | 바이오스피어 메디칼 에스.에이. | 마이크로스피어 및 비이온성 조영제를 사용하는 조성물 및방법 |
KR101446908B1 (ko) * | 2006-11-02 | 2014-10-06 | 베리덱스 엘엘씨 | 면역자기적인 mri 조영제들을 사용한 활성화된 혈관 내피의 이미징 |
KR101093549B1 (ko) * | 2008-09-25 | 2011-12-14 | 한국과학기술연구원 | 질환의 진단을 위한 표적 펩타이드가 결합된 양친성 키토산나노입자 조영제 |
KR101405440B1 (ko) * | 2012-07-31 | 2014-06-20 | 연세대학교 산학협력단 | 인테그린αvβ3에 특이적 압타머 및 이의 용도 |
KR101522560B1 (ko) * | 2014-01-28 | 2015-05-27 | 강원대학교산학협력단 | 생체분자 검출용 형광 소광 입자의 제조방법 및 이에 의해 제조된 생체분자 검출용 형광 소광 입자 |
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