KR20120136034A - Fused biomaterial both for diagnosing and treating diseases - Google Patents
Fused biomaterial both for diagnosing and treating diseases Download PDFInfo
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- KR20120136034A KR20120136034A KR1020110055007A KR20110055007A KR20120136034A KR 20120136034 A KR20120136034 A KR 20120136034A KR 1020110055007 A KR1020110055007 A KR 1020110055007A KR 20110055007 A KR20110055007 A KR 20110055007A KR 20120136034 A KR20120136034 A KR 20120136034A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
Abstract
The present invention relates to a fusion biomaterial for simultaneous diagnosis or treatment, and more particularly, to a specific disease, for example, atherosclerosis or tumor, while a fusion protein in which a cell-penetrating peptide and a portion of a cell membrane protein are fused is modified in a fluorescent substance. By binding to a cell membrane of a cell having a strong binding force such as to allow the cells to recognize the lesion site, it is possible to target a specific lesion site in vivo, diagnose a molecule, diagnose the treatment, and the like.
Description
According to the present invention, a fusion protein in which a cell-penetrating peptide and a portion of a cell membrane protein are fused is bound to a cell membrane of a cell having strong binding ability to a specific disease, for example, atherosclerosis or a tumor, while being modified with a fluorescent substance, and thus the cell is a lesion site. The present invention relates to a fusion biomaterial for simultaneous diagnosis or treatment, which enables targeting of specific lesion sites, molecular imaging, and treatment in vivo.
Atherosclerosis is a risk factor such as hyperlipidemia, diabetes, hypertension, and lifestyle changes that stimulate endothelial cells and deposit vascular fat to form atherosclerotic plaques. Thickening of blood vessel walls (Nicholls, 2009, Curr Opin Lipidol , 20, 491-496). In particular, if the coronary artery is blocked by arteriosclerosis, it may cause myocardial infarction and heart failure. To date, the diagnosis of atherosclerosis remains in an indirect method of measuring the level of cholesterol and triglycerides in the blood, or the symptoms appear after the disease has progressed to a large extent, such as myocardial infarction. Is just stopping. Therefore, attention has recently been focused on the early and accurate diagnosis of atherosclerosis by non-invasive methods (Glaudemans et. al ., 2010, Eur J Nucl Med Mol Imaging , 37, 2381-2397). The problem is to find a molecule that is expressed or activated at the site of atherosclerotic lesion, and to find a substance such as a ligand or an antibody that specifically binds to the atherosclerotic lesion and introduce a commercially available contrast agent to diagnose it. The application of materials reacting with is very low (Jaffer et. al ., 2007, Circulation , 116, 1052-1061).
The ongoing development of molecular imaging diagnostics reveals a near-infrared fluorescent probe (Deguchi) that uses specific peptide sequences that serve as substrates for these proteases to image the activity of some proteases in atherosclerotic lesions. et al ., 2006, Circulation , 114, 55-62; Jaffer et al., 2007, Circulation , 115, 2292-2298), the My Ilo peroxy secreted by macrophages in atherosclerotic lesions dehydratase (myeloperoxidase) enzyme activity detected MR molecular imaging (Chen et al ., 2004, Magn Reson Med , 52, 1021-1028), MRI molecular imaging using T1 contrast media (Saam et al. al ., 2005, Arterioscler Thromb Vasc Biol , 25, 234-239), PET / CT arteriosclerosis molecular imaging (Davies et al ., 2005, Stroke , 36: 2642-2647, etc., but current paradigm-specific molecular and imaging techniques have limitations, and thus new paradigm techniques are needed.
Recently, monocytes were isolated at the animal model level, and 111- indium oxine was added to obtain SPECT-CT images (Kircher et. al., 2008, Circulation, 117 , 388-395), studies to image macrophages (macrophage) with iodine or a gold nanoparticle contrast agent (Hyafil et al ., 2007, Nat Med , 13, 636-641), but these nanoparticles are released from the cells and attached to all parts of the body is known as a big limitation of the diagnosis.
SUMMARY OF THE INVENTION An object of the present invention is to provide a use as a nano biomaterial capable of cell delivery, cell therapy, diagnostic or therapeutic system through a new peptide-based fusion biomaterial for delivering a highly binding cell to a lesion site while recognizing a specific disease. It is.
In order to achieve the above object,
A fusion protein having one or more cell-penetrating peptides (CPPs) bound to the cell membrane proteins; And
Provided is a fusion biomaterial comprising monocytes or tumor-friendly cells bound to the fusion protein.
According to one embodiment, the fusion protein is characterized in that the pharmaceutically active ingredient is further bound.
The present invention also provides a fusion biomaterial according to the present invention to which a fluorescent substance is bound.
The present invention is also a fusion biomaterial according to the present invention is bonded fluorescent material; And
Provided is a contrast agent composition comprising a pharmaceutically acceptable carrier.
The present invention is also a fusion biomaterial according to the present invention is bonded fluorescent material; And
Provided is a contrast diagnostic or therapeutic contrast composition comprising a pharmaceutically acceptable carrier.
According to one embodiment, the contrast agent composition is characterized in that it is used for the simultaneous diagnosis or treatment of atherosclerosis or tumor.
The present invention is also a fusion biomaterial according to the present invention is bonded fluorescent material; And
Provided are multiple diagnostic probes, including diagnostic probes.
The fusion biomaterial of the present invention is capable of simultaneously diagnosing or treating a disease by binding to cells of the lesion site by specifically recognizing a lesion site such as a specific disease, for example, atherosclerosis or a tumor. Therefore, it can be usefully used as a material for diagnosis or treatment by being applicable to drugs or cell delivery, cell therapy, molecular imaging and the like.
1 is a cell-penetrating peptide at the C-terminus of the cell membrane protein, the bio-pin of the present invention is a bio-pin of the structure modified with a fluorescent dye at the N-terminus of the fusion biomaterial of the present invention A schematic diagram (top view) showing the manufacturing process and a schematic diagram (bottom view) showing an operating mechanism that specifically binds to a lesion site through delivery of the fusion biomaterial to cells or tissues.
Figure 2 shows the amino acid sequence of the bio-pin (BPin-44) of the present invention is a cell-penetrating peptide fused at the C-terminal center around the cell membrane protein.
Figure 3 shows the structure of a biopin according to an embodiment of the present invention, the BPin-44 italic sequence is TAT-CPP which is a kind of cell penetration peptide, the underlined sequence is
4 is a confocal microscope photograph obtained by treating a cell after modifying the fluorescent dye Dylight405 NHE-ester at the N-terminus of the bioffin of the present invention.
FIG. 5 shows fluorescence spectrometer by attaching monocyte THP-1 cells stained with green fluorescent dye (DiO) conjugated with Dylight405 NHE-ester-modified biopin BPin-44 to TNF-alpha-treated endothelial cells. It is a graph calculated from absorbance / emission (484 nm / 501 nm) values measured by a fluorescent spectrometer.
Figure 6 shows the level of ICAM-1, VCAM-1 increased by TNF-alpha through the immunoblotting results for the cell lysate of the HUVECs of FIG.
FIG. 7 is a three-dimensional image of the process of FIG. 5, in which THP-1 (green) is simultaneously photographed on the top of HUVECs (red) and Dylight405 NHE-ester is modified in THP-1. This image shows that BioPin BPin-44 (blue) is inserted (pictured right).
EMBODIMENT OF THE INVENTION Hereinafter, the structure of this invention is demonstrated concretely.
The present invention aims to develop a biopin that can increase the physical binding between cells rather than a method of overexpressing a specific gene that is difficult to predict biological changes in cells and has side effects.
In general, therapeutic effects may vary depending on how effectively the delivered cells initially attach to target organs and tissues in cell delivery and cell therapy techniques. Various attempts to efficiently deliver delivery cells to target tissues using methods of overexpressing specific genes or polymeric compounds are disproving. Therefore, unlike the conventional genetic engineering method or cell transfer technology using polymers, the development of biopin to insert peptide-like pins into delivery cells will suggest the possibility as a material for cell delivery and cell therapy and nano-bio applications using them. .
Accordingly, the present invention provides a fusion protein in which at least one cell-penetrating peptide (CPP) is bound to a cell membrane protein; And
The present invention relates to a fusion biomaterial comprising monocytes or tumor-friendly cells bound to the fusion protein.
The fusion protein has a structure in which one or more cell penetrating peptides are bound to a portion of the cell membrane protein, and more specifically, the cell penetrating peptide may be bound to one or both ends of the cell membrane protein.
As used herein, "biopin" refers to a fusion protein for immobilizing a biological material, eg, a cell. In particular, the two components used in the biopin consists of a specific membrane protein and a cell penetrating peptide of the mammalian cell, the cell penetrating peptide wherein the specific membrane protein of the cell is bound to one end of the membrane protein, It is to form a fin structure forming the end. More specifically, the specific membrane protein of the cell is placed in the center, and the cell penetrating peptide is fused at the inner part of its intracellular site and the extracellular site, and the outer part of the cell. The fusion protein prepared by fusion of fluorescent material, contrast agent, nanodevice, etc. was named biopin. When the bioffin is delivered to the target cell, the cell penetrating peptide, which is located in the cell membrane and is fused to the inner part of the cell, is directed toward the inside of the cell, and the fluorescent substance, contrast agent, and nanodevice are exposed to the outside of the cell to recognize the target cell or tissue. (See FIG. 1, top drawing). The target cell may mainly select a cell having strong binding ability to a lesion site of a specific disease, for example, monocytes, tumor-friendly cells, and the like. When the bioffin is bound to the cell membrane, the target cell is recognized when the lesion is delivered to the cell or tissue, the binding force with the cells of the lesion site is increased (see Fig. 1, lower figure). Thus, no tissue specific binding component exhibiting target orientation is required separately.
As used herein, the term "tumor affinity cell" refers to a cell having a strong affinity for tumor cells, for example, natural killer cells, macrophages and the like.
The cell membrane protein is not particularly limited as long as it is a membrane protein of mammalian cells. Preferably, the transmembrane domain is preferable. For example, the cell membrane protein that does not affect cell death, including opioid receptor delta transmembrane domain 1 (OPRD TM1) and the like, is not particularly limited.
The cell-penetrating peptide (CPP) or protein transduction domain (PTD) is a specific protein, virus, Refers to a substance peptide capable of delivering DNA, RNA, fat, carbohydrates or chemical compounds into the cytoplasm or nucleus of eukaryotic or prokaryotic cells.
The cell penetrating peptide is not particularly limited, but Ant- (Antennapedia), a trans-activating transcriptional activator (Tat) protein derived from human immunodeficiency virus type I (HIV-1), an antennapedia homeodomain of Drosophila Or penetratin peptide, Mph-1 of mouse transcription factor, VP22 of HSV-1 and HP4 of herring protamine.
In addition, the cell penetrating peptides may comprise cell-specific PTDs having specificity for a particular cell type or condition. One example of such a cell-specific PTD is the Hn1 synthetic peptide described in US Patent Publication 2002-0102265.
In addition, the cell penetrating peptide may be a synthetic peptide. An example of such a synthetic peptide is a peptide in which Ho et al . Modified 47-57 residues of Tat protein to optimize the protein delivery ability of HIV's Tat protein (Ho et. al . (2001) Cancer Res 61 (2): 474-7).
In a specific embodiment of the invention, the cell penetrating peptide comprises Tat: YGRKKRRQRRR (SEQ ID NO: 2) of HIV.
According to one embodiment of the present invention, the fusion protein of the present invention may be in a form in which the amino acid sequence described in SEQ ID NO: 2 is bonded to one end of the amino acid sequence described in SEQ ID NO: 1.
Fusion proteins of the present invention can be prepared by methods known in the art for synthesizing peptides. For example, it may be prepared by a method of synthesis in vitro through genetic recombination and protein expression systems or peptide synthesizers.
Accordingly, the present invention provides a recombinant vector expressing the fusion protein.
As used herein, a "recombinant vector" refers to a gene construct that is capable of expressing a protein of interest in a suitable host cell and comprises an essential regulatory element operably linked to express a gene insert.
Such vectors include, but are not limited to, plasmid vectors, cosmid vectors, bacteriophage vectors, viral vectors, and the like. Suitable expression vectors include signal sequences or leader sequences for membrane targeting or secretion in addition to expression control elements such as promoters, operators, initiation codons, termination codons, polyadenylation signals and enhancers, and can be prepared in various ways depending on the purpose. The promoter of the vector may be constitutive or inducible. Further, the expression vector includes a selection marker for selecting a host cell containing the vector, and includes a replication origin in the case of a replicable expression vector.
The recombinant vector of the present invention may be prepared by inserting a nucleic acid encoding a cell membrane protein into a general E. coli strain expression vector, pHis / TAT. In a preferred embodiment of the present invention, although pHis / TAT was used as the expression vector for E. coli, the expression vector is not necessarily limited thereto. All E. coli expression vectors that can be generally used may be used without limitation.
In a preferred embodiment of the present invention, a DNA fragment comprising the OPRD TM1 domain coding gene (SEQ ID NO: 1) and the cell penetrating peptide coding gene (SEQ ID NO: 2) of the present invention using a pHis / TAT vector, which is a vector for E. coli strain expression. Recombinant vectors were prepared by insertion (see FIG. 2).
The invention also provides a transformant transduced with a recombinant vector expressing the fusion protein of the invention.
The transformation may include any method of introducing a nucleic acid into an organism, cell, tissue or organ, and may be carried out by selecting a suitable standard technique according to the host cell as known in the art. These methods include electroporation, plasma fusion, calcium phosphate (CaPO4) precipitation, calcium chloride (CaCl2) precipitation, agitation with silicon carbide fibers, agrobacterial mediated transformation, PEG, dextran sulfate, lipofect Such as but not limited to.
In addition, since the expression amount of the protein and the expression are different depending on the host cell, the host cell most suitable for the purpose may be selected and used.
Examples of host cells include Escherichia coli), Bacillus subtilis (Bacillus subtilis), Streptomyces (Streptomyces), Pseudomonas (Pseudomonas), Proteus Mira Billy's (Proteus but are not limited to, prokaryotic host cells such as mirabilis or Staphylococcus . In addition, fungi (e.g., Aspergillus ), yeast (e. G., Pichia < pastoris), Mai access to the Yasaka Auxerre Vichy kids (Saccharomyces cerevisiae), investigating car break in Rome Seth (Schizosaccharomyces), Castello La Neuro Chrysler Corporation (Neurospora Cells derived from higher eukaryotes, including lower eukaryotic cells such as crassa )), insect cells, plant cells, mammals, and the like can be used as host cells.
The transformant can be easily prepared by introducing the recombinant vector into any host cell. In a preferred embodiment of the present invention, a transformant was prepared by introducing the recombinant vector pHis / TAT into E. coli strain BL21 (DE3).
The present invention also provides a method for producing a fusion protein comprising the step of separating and purifying a culture of a transformant transduced with a recombinant vector expressing the fusion protein of the present invention.
The fusion protein is preferably purified by culturing the transformant according to a conventional culture method. The fusion protein may have any modification to a part of the amino acid sequence to the extent that does not affect the cytokine production capacity depending on the insert introduced into the recombinant vector, that is, the coding sequence. By modification is meant modification by deletion, insertion or substitution.
The invention also provides polyclonal antibodies that specifically bind to the fusion proteins of the invention.
Although the manufacturing method of the said polyclonal antibody is not specifically limited, It is preferable to manufacture according to the following method.
The fusion protein of the present invention is immunized by one to several injections into SPF (specific pathogen free) animals. After a certain time after the final immunization, whole blood is taken and serum is obtained to obtain polyclonal antibodies to the proteins of the invention.
The immunized animal is not particularly limited as long as it is an animal normally used for immunization, but is preferably a rat. The number, duration and method of administration for the immunization are not particularly limited because they can be modified or changed at the level of those skilled in the art.
In the fusion biomaterial of the present invention, the fusion protein may be located on the cell membrane of monocytes or tumor-friendly cells.
Examples of the monocytes include THP-1, but are not particularly limited thereto.
Examples of the tumor-friendly cells include natural killer cells or macrophages, but are not particularly limited thereto.
In the fusion biomaterial of the present invention, the fusion protein may be used for the treatment of a disease by further introducing a pharmaceutically active ingredient directly or using another medium by chemical, physical covalent or non-covalent binding.
The pharmaceutically active ingredient is not particularly limited, but siRNA, antisense, anticancer agents, antibiotics, hormones, hormonal antagonists, interleukin, interferon, growth factor, tumor necrosis factor, endotoxin, lymphokoxy, urokinase, streptokinase, tissue plasminogen activator , Protease inhibitors, alkylphosphocholines, radioisotope-labeled components, cardiovascular drugs, gastrointestinal drugs, or nervous system drugs may be used alone or in combination.
The anticancer agent is not particularly limited thereto, for example, epirubicin, docetaxel, gemcitabine, paclitaxel, cisplatin, carboplatin, Taxol, procarbazine, cyclophosphamide, diactinomycin, daunorubicin, etoposide, tamoxifen doxorubicin ), Mitomycin, mitomycin, bleomycin, plecomycin, transplatinum, vinblastin, methotrexate, and the like can be used.
The invention also relates to a fused biomaterial according to the invention to which a fluorescent substance is bound.
The fluorescent material may be directly or indirectly linked with the fusion protein by chemical, physical covalent or non-covalent bonds.
The fluorescent material is not particularly limited, but Dylight 488 NHE-ester dye, VybrantTM DiI, VybrantTM DiO, quantum dots nanoparticles, fluorosane, rhodamine, lucifer yellow, B-phytoerythrin, 9-a Chridine isothiocyanate, Lucifer Yellow VS, 4-acetamido-4'-isothio-cyanatostilbene-2,2'-disulfonic acid, 7-diethylamino-3- (4'-iso Thiocyatophenyl) -4-methylcoumarin, succinimidyl-pyrenebutyrate, 4-acetamido-4'-isothiocyanatostilben-2,2'-disulfonic acid derivative, LC ™ -Red 640 , LC ™ -Red 705, Cy5, Cy5.5, lysamine, isothiocyanate, erythrosine isothiocyanate, diethylenetriamine pentaacetate, 1-dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalene sulfonate, 2-sothitoudinyl-6-naphthalene sulfonate, 3-phenyl-7-isocyanatocoumarin, 9-isothiocyanatoacrylic , Credin Orange 9-I (Soti (2-benzoxazoylyl) phenyl) melimide saradiazole, stilbene, pyrene, ibendomer, silica containing fluorescent substance, group II / IV semiconductor quantum dots, III / Group V semiconductor quantum dots, group IV semiconductor quantum dots, or an isocomponent hybrid structure, preferably, the fluorescent material may include quantum dot nanoparticles, Cy3.5, Cy5, Cy5.5, Cy7, ICG ( indocyanine green), Cypate, ITCC, NIR820, NIR2, IRDye78, IRDye80, IRDye82, Cresy Violet, Nile Blue, Oxazine 750, Rhodamine800, lanthanide series and Texas Red, In the case of the quantum dots nanoparticles, group II-VI or group III-V compounding may be used. In this case, the quantum dot nanoparticles may be selected from the group consisting of CdSe, CdSe / ZnS, CdTe / CdS, CdTe / CdTe, ZnSe / ZnS, ZnTe / ZnSe, PbSe, PbS InAs, InP, InGaP, InGaP / ZnS and HgTe More than one can be used.
The present invention is also a fusion biomaterial according to the present invention is bonded fluorescent material; And
It relates to a contrast agent composition comprising a pharmaceutically acceptable carrier.
The fusion biomaterial of the present invention can be used as a contrast agent capable of imaging a target site through a magnetic resonance and an optical imaging device because the fluorescent material is physically combined.
Such pharmaceutically acceptable carriers include carriers and vehicles commonly used in the medical field and specifically include ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances Water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silicon dioxide But are not limited to, silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose based substrate, polyethylene glycol, sodium carboxymethylcellulose, polyarylate, wax, polyethylene glycol or wool.
In addition, the contrast agent composition of the present invention may further include a lubricant, a wetting agent, an emulsifier, a suspending agent, or a preservative in addition to the above components.
In one embodiment, the contrast agent composition according to the present invention may be prepared as an aqueous solution for parenteral administration, preferably a buffer solution such as Hank's solution, Ringer's solution or physically buffered saline solution Can be used. Aqueous injection suspensions may contain a substrate capable of increasing the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
Another preferred embodiment of the contrast agent composition of the present invention may be in the form of a sterile injectable preparation of a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e. G., Tween 80) and suspending agents.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (for example, a solution in 1,3-butanediol). Vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally used as a solvent or suspending medium. For this purpose, any non-volatile oil including synthetic mono or diglycerides and less irritant may be used.
The contrast agent composition of the present invention may be used to obtain an image by detecting a signal emitted from a fluorescent fusion protein by administering to a tissue or cell isolated from a diagnosis subject.
In order to detect a signal emitted by the fluorescent fusion protein, it is preferable to use a magnetic resonance imaging apparatus (MRI) and optical imaging.
A magnetic resonance imaging apparatus puts a living body in a strong magnetic field and irradiates a radio wave of a specific frequency to absorb energy into an atomic nucleus such as hydrogen in a biological tissue to make the state high in energy, And the energy is converted into a signal, processed by a computer, and imaged. Since the magnetic or radio waves are not disturbed by the bone, a sharp three-dimensional tomographic image can be obtained at the end, transverse, or any angle with respect to the hard bone around or the brain or the bone marrow. In particular, the magnetic resonance imaging apparatus is preferably a T2 spin-spin relaxation magnetic resonance imaging apparatus.
The present invention is also a fusion biomaterial according to the present invention is bonded fluorescent material; And
A contrast diagnostic or therapeutic contrast composition comprising a pharmaceutically acceptable carrier.
The fusion biomaterial of the present invention includes the fluorescence of the fusion protein by physically and chemically binding to a pharmaceutically active ingredient and thus nano probes and drugs such as separation, diagnosis or treatment of biological molecules through magnetic resonance and optical imaging devices, or It can be used for a delivery vehicle and the like.
As a representative example of a biological diagnosis using the fusion biomaterial, molecular magnetic resonance imaging or a magnetic relaxation sensor may be mentioned. As the size of the fusion protein increases, it shows a larger T2 contrast effect, which can be used as a sensor for detecting biomolecules. That is, when a specific biomolecule induces fusion protein fusion, T2 magnetic resonance imaging effect is increased. Biomolecules are detected using these differences.
In addition, the fusion biomaterial of the present invention can be used for atherosclerosis or various diseases associated with tumors such as gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer and cervical cancer. It can be used to diagnose and / or treat.
More specifically, since the monocytes of the fusion biomaterial of the present invention recognize and specifically bind to cells of the atherosclerotic lesion site, the atherosclerosis may be specifically treated through a drug capable of treating atherosclerosis bound to the fusion protein. Can be. In addition, tumor-friendly cells of the fusion biomaterial of the present invention can also be specifically treated through the above mechanism.
The present invention is also a fusion biomaterial according to the present invention is bonded fluorescent material; And
A multiple diagnostic probe comprising a diagnostic probe is provided.
The diagnostic probe may be a T1 magnetic resonance imaging probe, an optical diagnostic probe, a CT diagnostic probe, or a radioactive isotope.
For example, when the T1 magnetic resonance imaging diagnostic probe is coupled to a fluorescent fusion peptide, the multiple diagnostic probe may simultaneously perform T2 magnetic resonance imaging and T1 magnetic resonance imaging, and when the optical diagnostic probe is combined, magnetic resonance imaging and optical imaging may be performed. At the same time, CT diagnostic probes can be combined to perform MRI and CT diagnosis at the same time. In addition, when combined with radioisotope, MRI, PET, and SPECT can be performed simultaneously.
The T1 magnetic resonance imaging diagnostic probe may include a Gd compound or a Mn compound, and the optical diagnostic probe may be an organic fluorescent dye (dye), a quantum dot, or a dye labeled inorganic support (eg SiO 2 , Al 2). O 3 ), CT diagnostic probes include I (iodine) compounds, or gold nanoparticles, and radioisotopes include In, Tc, F, and the like.
Hereinafter, the present invention will be described in more detail with reference to Examples of the present invention, but the scope of the present invention is not limited by the following Examples.
Example 1 Preparation of Fusion Protein (Biopin) According to Recombination Method
pHis / TAT expression vector (Kwon JH et al ., 2007, Biochem Biophys Res Commun ., 363, 399-404). The OPRD by the cDNA as a template using two primers, Primer-1, 5'-TCGTCCCATATGGGATCCCTGGCAATCGCC ATCACC-3 '( Nde I site underlined) and Primer-2, 5'-AGGCATCTCGAGTTAGCGGCGGCGCTGGCGGCGTTTCTTGCGGCCGTAAGTGTACCGGACGATGCCGAA- 3' ( Xho I site underlined) PCR DNA fragments were obtained, cut with respective restriction enzymes ( Bam HI / Xho I), put into a pHis / TAT expression vector, expressed in Escherichia coli BL21 (DE3), and separated and purified by Ni-NTA affinity chromatography. In this case, the C-based peptide was composed of 31 amino acids from the 48th amino acid (leucine, L), the first domain part of the OPRD protein consisting of 7 transmembrane domains of 372 amino acids, to the 78th amino acid (threonine, T). Bioffin was prepared in which the TAT cell penetrating peptide was fused at the end (see FIGS. 2 and 3).
Example 2 Preparation of Fusion Protein (Biopin) Through Peptide Synthesis
Fusion proteins of the present invention can be prepared using a peptide synthesizer. FIG. 3 shows a sequence for preparing bioffin (BPin-44) fused to a cell penetrating peptide at the C-terminus of the first domain of OPRD, which was synthesized by a peptide synthesizer by Bio-Synthesis (USA).
Example 3 Preparation of Monocytes Containing Fluorescent Dye Modified Bioffins
DyLight405 NHS Ester (Thermo, USA) was dissolved in 100 μl of dimethylformonamide and 0.1 mg of peptide BPin-44 was added thereto. After 1 hour of reaction at room temperature, dialysis (Slide-A-Lyzer Mini Dialysis Units, Thermo, USA) was used to remove the unmodified dye.
Monocyte THP-1 cells were cultured in a Petri dish with RPMI medium (Gibco, USA), and then treated with min-trypsin-EDTA and trypsin-neutralizing solution in a 1: 1 ratio for 5 minutes to separate the cells. Treated with a cell-modified dye (VybrantTM DiO, Invitrogen, USA) at a final concentration of 2 ㎍ / mL, reacted for 30 minutes in a 37 ℃ CO 2 incubator, washed three times with PBS and prepared by centrifugation at 1,200 rpm for 3 minutes .
The cells (5 × 10 4 cells) were treated with 100 nM of fluorescent dye-modified peptides and then left for 1 hour in a 37 ° C. CO 2 incubator. After centrifugation and PBS washing was repeated three times.
In order to confirm that the fluorescent dye-modified bioffin is located on the cell membrane, rat cardiac myoblast H9c2 cells cultured in DMEM medium were placed in a microtube and CellMask ™ Plasma Membrane Stains (Invitrogen, USA) was added to the final tube. Treated at a concentration of μg / mL and left for 30 minutes in a 37 ℃ CO 2 incubator. After washing three times with centrifugation and phosphate-buffered saline (PBS) and resuspended in DMEM medium was prepared by 500μl again.
After treatment with a mounting solution (3 drops) in the cell chamber for observation using confocal microscopy, CellMask ™ Plasma Membrane Stains (red) using an LSM700 confocal microscope (Carl Zeiss, Germany) (Abs 554 / Em 567 nm) and Dylight 405 NHE-ester (blue) (Abs 400 nm / Em420 nm).
As shown in Figure 4, it was confirmed that the peptide is located in the cell membrane.
<Example 4> fluorescence dye modified peptide binding monocytes binding to endothelial cells
HUVECs (5 × 10 4 cells / well) were incubated in EGM medium (Lonza, USA) in 24-well plates, then starvated with 0.5% EBM medium for 4 hours to TNF-alpha (10 ng / mL). Time was processed. CellMask ™ Plasma Membrane Stains (Invitrogen, USA) was prepared by treatment at a concentration of 5 μg / mL for 30 minutes in a 37 ° C. CO 2 incubator and then washed three times with PBS.
Here, THP-1 cells treated with the fluorescent dye modified peptide prepared in Example 3 were resuspended by treating 400 μl of DMEM medium containing 10% FBS. It was sprinkled onto stained HUVECs and left in a 37 ° C. CO 2 incubator for 30 minutes. After washing several times with PBS to remove the unattached THP-1 cells, 200 μl of 0.1% Triton X-100 was added to quantify the attached cells, and then after 5 minutes, they were removed by fluorescence spectrometer Victor3 (Fluorescent Spectrometer Victor3, Perkin). -Elmer, USA) was used to measure the Abs 484nm / Em 501nm wavelength (Fig. 5).
As shown in Figure 5, when treated with endothelial cells stimulated by TNF-alpha fluorescence dye-modified peptide-binding monocytes, it was confirmed that the binding force increased compared to the control (unstimulated endothelial cells).
In addition, immunoblotting using anti-ICAM-1 and anti-VCAM-1 antibodies to confirm that HUVECs were properly stimulated by TNF-alpha resulted in ICAM-1 (intercellular cell) by TNF-alpha. adhesion molecule-1) and vascular cell adhesion molecule 1 (VCAM-1) expression increased (FIG. 6).
In addition, three-dimensional images of HUVECs and THP-1 co-examination, HUVECs and fluorescein-modified BPin-44 co-imaging images were used to confirm that the actual fluorescent dye-modified BPin-44 was inserted into THP-1 cells bound to HUVECs. THP-1 cell position and fluorescence dye modified BPin-44 position was confirmed to be the same (FIG. 7).
<110> Industry-Academic Cooperation Foundation, Yonsei University
<120> Fused biomaterial both for diagnosing and treating diseases
<160> 2
<170> Kopatentin 2.0
<210> 1
<211> 31
<212> PRT
<213> Homo sapiens
<220>
<221> DOMAIN
(222) (1) .. (31)
<223> human opioid
Claims (14)
Fusion biomaterial comprising monocytes or tumor-friendly cells bound to the fusion protein.
The cell membrane protein is a fusion biomaterial comprising opioid receptor delta transmembrane domain 1 (OPRD TM1) of the opioid receptor delta.
The cell penetrating peptide is at least one selected from the group consisting of a trans-activating transcriptional activator (Tat), Antp, Mph-1, VP22 and HP4.
The fusion protein is a fusion biomaterial in which the amino acid sequence of SEQ ID NO: 2 is bonded to one end of the amino acid sequence of SEQ ID NO: 1.
The fusion protein is a fusion biomaterial that binds to the cell membrane of monocytes or tumor-friendly cells.
Tumor-friendly cells are fusion biomaterials that are natural killer cells or macrophages.
The fusion protein is a fusion biomaterial further comprising a pharmaceutically active ingredient.
Pharmaceutically active ingredients include siRNA, antisense, anticancer agents, antibiotics, hormones, hormonal antagonists, interleukins, interferons, growth factors, tumor necrosis factors, endotoxins, lymphokoxy, urokinase, streptokinase, tissue plasminogen activators, protease inhibitors, alkyl phosphates A fusion biomaterial, which is at least one selected from the group consisting of pocholine, a radioisotope labeled component, a cardiovascular drug, a gastrointestinal drug, and a nervous system drug.
Fluorescent materials include Dylight 488 NHE-ester dye, VybrantTM DiI, VybrantTM DiO, quantum dots nanoparticles, Cy3.5, Cy5, Cy5.5, Cy7, indocyanine green, Cypate, ITCC, NIR820, NIR2, At least one fusion biomaterial selected from the group consisting of IRDye78, IRDye80, IRDye82, Cresy Violet, Nile Blue, Oxazine 750, Rhodamine 800, Lanthanide and Texas Red.
A contrast agent composition comprising a pharmaceutically acceptable carrier.
A contrast agent composition for simultaneous diagnosis or treatment comprising a pharmaceutically acceptable carrier.
Contrast agent composition for simultaneous diagnosis or treatment of atherosclerosis or tumor.
Multiple diagnostic probes, including diagnostic probes.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020110055007A KR20120136034A (en) | 2011-06-08 | 2011-06-08 | Fused biomaterial both for diagnosing and treating diseases |
| US14/005,047 US9110059B2 (en) | 2011-03-15 | 2012-03-15 | Bio-pin |
| EP12758083.5A EP2708561A4 (en) | 2011-03-15 | 2012-03-15 | Bio-pin |
| PCT/KR2012/001890 WO2012124998A2 (en) | 2011-03-15 | 2012-03-15 | Bio-pin |
| JP2013558789A JP5968343B2 (en) | 2011-03-15 | 2012-03-15 | Bio pin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020110055007A KR20120136034A (en) | 2011-06-08 | 2011-06-08 | Fused biomaterial both for diagnosing and treating diseases |
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| KR20120136034A true KR20120136034A (en) | 2012-12-18 |
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| KR1020110055007A KR20120136034A (en) | 2011-03-15 | 2011-06-08 | Fused biomaterial both for diagnosing and treating diseases |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018079882A1 (en) * | 2016-10-28 | 2018-05-03 | 서강대학교산학협력단 | Compound for positron emission tomography image of atherosclerotic arterial plaque, and method for producing same |
| CN112368377A (en) * | 2018-06-14 | 2021-02-12 | 爱维斯健有限公司 | Pharmaceutical composition comprising a fusion protein of a cell penetrating peptide and adenosine deaminase for the treatment of severe combined immunodeficiency |
| CN114874339A (en) * | 2022-05-27 | 2022-08-09 | 清华大学 | Protein adhesive and preparation method and application thereof |
-
2011
- 2011-06-08 KR KR1020110055007A patent/KR20120136034A/en not_active Application Discontinuation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018079882A1 (en) * | 2016-10-28 | 2018-05-03 | 서강대학교산학협력단 | Compound for positron emission tomography image of atherosclerotic arterial plaque, and method for producing same |
| CN112368377A (en) * | 2018-06-14 | 2021-02-12 | 爱维斯健有限公司 | Pharmaceutical composition comprising a fusion protein of a cell penetrating peptide and adenosine deaminase for the treatment of severe combined immunodeficiency |
| CN114874339A (en) * | 2022-05-27 | 2022-08-09 | 清华大学 | Protein adhesive and preparation method and application thereof |
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