WO2021245539A1 - 약물 전달과 내재화 효율이 강화된 약물복합체 - Google Patents
약물 전달과 내재화 효율이 강화된 약물복합체 Download PDFInfo
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- WO2021245539A1 WO2021245539A1 PCT/IB2021/054774 IB2021054774W WO2021245539A1 WO 2021245539 A1 WO2021245539 A1 WO 2021245539A1 IB 2021054774 W IB2021054774 W IB 2021054774W WO 2021245539 A1 WO2021245539 A1 WO 2021245539A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a drug complex with enhanced drug delivery and cellular internalization efficiency, and more specifically, specific It relates to a unit drug complex, characterized in that a binding group capable of mutual binding with other drug complexes is additionally linked to the drug complex in which the targeting substance and drug are linked to each other.
- the background gisum nested action is the cell is a generic term to define a process for absorbing and / or discharging the extracellular substance combination, such as molecules, 3 ⁇ 4 i _ viruses, particles and microorganisms and pass them to a specific organ in the cytoplasm.
- Endocytosis is largely divided into phagocytosis and pinocytosis.
- the endocytosis is again macropinocytosis, clathrin-mediated endocytosis, and caveolin-mediated It can be divided into endocytosis, clathrin- and caveolin-independent endocytosis.
- the pathway of endocytosis may vary depending on the size of the endocytic vesicle, the nature of the cargo such as ligands, receptors and lipids, and the mechanism of vesicle formation (Conner SD et al, Nature 2003; 422:37- 44).
- macropyocytosis mainly transports extracellular material into cells by >1 um plasma membrane entrapment
- clathrin-mediated endocytosis is ⁇ 120 nm
- caveolin-mediated endocytosis is ⁇ 60 nm
- clathrin-mediated endocytosis is ⁇ 60 nm.
- Trin- and caveolin-independent endocytosis introduces extracellular material into cells with the size of intracellular vesicles of ⁇ 90 nm.
- the endocytosis of extracellular substances is the internalization of drugs capable of specifically binding to molecules (eg, receptors) widely expressed on cell membranes into target cells. It plays an important role.
- a method for effectively internalizing a drug into a target cell it is effective by introducing a molecule (eg, a ligand) that can specifically bind to a molecule (eg, a receptor) widely expressed in a cell membrane (eg, a receptor).
- a molecule eg, a ligand
- a receptor eg, a receptor
- 2021/245539 - €1/162021/054774 can induce endocytosis (Marsh M. et al, Cell 2006; 124:729-40; Smith AE et al, Science 2004; 304:237-42).
- the drug-bound receptor is collected at the intrusion site by surface diffusion. If this collection does not occur smoothly, endocytosis does not occur effectively within a short time.
- Mgiogenesis refers to a process in which new capillaries are formed from existing microvessels, and is known to play an important role in the development process, wound healing, and female reproductive cycle as a normal physiological action.
- diseases caused by angiogenesis not being controlled autonomously and by pathological growth.
- abnormally excessive angiogenesis is tumor or cancer growth and metastasis (metastasis), diabetic retinopathy (diabetic retinopathy), age-related macular degeneration.
- angiogenesis is associated with coronary artery disease, stroke, myocardial infarction, ulcer or delayed wound healing.
- a tumor particularly a malignant tumor (cancer)
- cancer is a disease in which internal or external factors act on cells constituting the body to divide irregularly, so that the cells themselves proliferate unintentionally, out of the control that composes the body. means Furthermore, it invades surrounding tissues, metastasizes to other organs through blood vessels and lymphatic vessels, and grows. At this time, angiogenesis is one of the important mechanisms of tumor.
- angiogenesis-related diseases exhibit serious conditions, and various therapeutic agents have been developed to treat them.
- the excessive therapeutic dose is repeatedly administered, and resistance to the therapeutic agent is likely to occur, and a clear therapeutic effect cannot be expected in many cases.
- target receptors which are targets of therapeutic agents for angiogenesis-related diseases, exist in vascular endothelial cells, and thus target specific receptors due to blood pressure, blood flow, vascular permeability, etc. 2021/245539 €1/162021/054774 Since the binding between the targeting substance and the receptor can be dissociated and released within a short time, the therapeutic agent is administered in high doses repeatedly for a long-term therapeutic effect, causing various side effects.
- targeted cancer therapy which has recently been spotlighted, is a treatment method that targets a tumor-specific biomarker unlike existing treatment methods. epidemiological therapy, etc. Because pharmaceuticals used for tumor-targeted therapy are delivered by targeting tumor-specific biomarkers, damage to normal cells is minimized and tumor cell death is induced. In order for a drug used for such a tumor-targeting treatment to exert an effective anticancer effect, it must have high selectivity and binding ability to tumor cells, and must be effectively delivered to tumor cells through cell internalization. In order to enhance the cellular internalization of drugs, ligands including multimeric compounds capable of binding to multiple target receptors simultaneously have been developed (Wu Z.
- the present inventors have focused on the fact that, in the case of a conventional drug complex used for the diagnosis or treatment of various diseases such as angiogenesis-related diseases, the internalization efficiency of the drug is very low due to the limitation of endocytosis in the body.
- Patent Document 1 PCT/KR2011/003801
- Non-Patent Document 1 Conner S.D. et al., Nature 2003; 422:37-44;
- Non-Patent Document 2 Marsh M. et al., Cell 2006; 124: 729-40;
- Non-Patent Document 3 Smith A.E. et al., Science 2004; 304:237-42;
- Non-Patent Document 4 Wu Z. et al., JNucl Med 2007; 48:1536-1544. SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel drug complex with improved drug delivery efficiency by remarkably increased internalization of cells.
- the present invention is characterized in that a binding group capable of mutual binding with another unit drug complex is further linked to a drug complex in which a drug and a targeting substance that specifically binds to a target cell are linked. Provides a unit drug complex.
- the present invention also provides the above-mentioned unit drug complex (first unit drug complex); And it provides a drug complex comprising the unit drug complex and another drug complex (second unit drug complex) that can be mutually bound through a bonding group.
- the present invention also provides a pharmaceutical composition for treating various diseases including the drug complex, preferably a pharmaceutical composition for treating angiogenesis-related diseases.
- the present invention also provides a composition for diagnosing various diseases, preferably a composition for diagnosing angiogenesis-related diseases, including the drug complex.
- the present invention also provides a pharmaceutical composition for diagnosing and treating various diseases including the drug complex, preferably a pharmaceutical composition for diagnosing and treating angiogenesis-related diseases.
- the present invention also provides a method for treating various diseases comprising administering the drug complex.
- the present invention also provides a variety of 2021/245539 €1/162021/054774 Provides diagnostic methods for diseases.
- the present invention also provides the use of the drug complex for the treatment of various diseases.
- the present invention also provides the use of the drug complex for the diagnosis of various diseases.
- the present invention also provides the use of the drug complex for the manufacture of a medicament for the treatment of various diseases.
- BRIEF DESCRIPTION OF THE DRAWINGS FIG. is a schematic diagram showing the structure of the unit drug complex of the present invention.
- 18 is a schematic diagram briefly expressing the principle of operation of the present invention. 3 shows are fluorescence imaging results confirming the effect of enhancing intracellular influx by the generation of cross-linkages between binders according to an embodiment of the present invention.
- FIG. 38 is a numerical result of fluorescence intensity of a fluorescence imaging result confirming the effect of enhancing intracellular influx by the generation of cross-linkage between binders according to an embodiment of the present invention.
- Figure 3 (:) is a result of - ⁇ analysis of a fluorescence image confirming the effect of promoting intracellular influx by the generation of cross-linkage between the conjugates according to an embodiment of the present invention.
- 4 is an in vitro biodistribution ( ⁇ 0 ) (1 1; 13 ⁇ 41 011) experimental result of the drug complex according to an embodiment of the present invention.
- 5 is a result confirming the difference in retention in the tumor according to the sequentially administered dose of the unit drug complex according to an embodiment of the present invention.
- the present invention is a drug complex in which a drug and a targeting substance that specifically binds to a target cell are linked, a unit characterized in that a binding group capable of mutual binding with another unit drug complex is further linked It is about drug complexes .
- the targeting material may be characterized in that it specifically binds to a target that is specifically expressed or overexpressed in a target cell, and the drug may be characterized as a therapeutic or diagnostic drug. It is not limited.
- the targeting substance and the drug may be characterized in that they are connected by a linker, but the targeting substance and the drug may be directly connected without a linker.
- the bonding group may be characterized in that it is further connected to the linker, but may be bonded to other sites of the drug complex.
- the bonding group may be characterized in that at least one.
- the unit drug complex first unit drug complex
- it relates to a drug complex comprising the unit drug complex and another drug complex (second unit drug complex) that can be mutually bound through a bonding group.
- the bonding group included in the first unit drug complex is named as a first bonding group
- the bonding group included in the second unit drug complex is referred to as the second bonding group.
- the first unit drug complex and the second unit drug complex may be characterized in that the first bonding group and the second bonding group are mutually bonded.
- the targeting substance introduced into the first unit drug complex and the targeting substance introduced into the second unit drug complex may be the same or different from each other, but all of the targeting substances are specifically expressed or overexpressed in the same target cell It may be characterized in that it specifically binds to the target.
- the drug introduced into the first unit drug complex and the drug introduced into the second unit drug complex may be the same or different from each other .
- the present invention may also be a multi-drug complex in which a plurality of unit drug complexes can be multi-bonded by one or more linking group pairs.
- the present invention also provides the above-mentioned unit drug complex (first unit drug complex); and another drug complex (second unit drug complex) having a second bonding group capable of mutual bonding with the first bonding group of the first unit drug complex.
- the present invention also provides the above-mentioned unit drug complex (first unit drug complex); and another drug complex (second unit drug complex) having a second bonding group capable of mutual bonding with the first bonding group of the first unit drug complex.
- the second unit drug complex is a drug complex in which a second targeting material that specifically binds to a target specifically expressed or overexpressed in a target cell and a therapeutic or diagnostic drug are linked, the first unit of the drug complex It is characterized in that a second bonding group capable of mutual bonding with the bonding group is further connected.
- the present invention relates to a drug complex in which a second targeting substance that specifically binds to a target specifically expressed or overexpressed in a target cell and a therapeutic or diagnostic drug are linked, and the first binding group of the first unit drug complex is mutually It relates to a second unit drug complex, characterized in that a second bonding group capable of binding is further linked.
- the present invention relates to a drug complex in which the first unit drug complex and the second unit drug complex are formed by bonding a first bonding group and a second bonding group. 2021/245539 €1/162021/054774 When the first unit drug complex and/or the second unit drug complex according to the present invention is used, rapid targeting to target cells, for example, cancer cells is possible.
- the existing anticancer drugs have slow tumor intake pharmacokinetics, high dose administration is unavoidable because they inhibit normal cells and cause a decrease in drug efficacy due to rapid metabolism in the body, but the first unit drug complex and/or the second unit according to the present invention
- a drug complex When a drug complex is used, it has the advantage of being able to rapidly and selectively target the cell membrane proteins of tumors in an amount that is stable in the blood and has little to no toxicity .
- the first unit drug complex and/or the second unit drug complex according to the present invention there is an advantage in that the internalization action of the drug can be enhanced.
- the cancer cell internalization of existing anticancer drugs depends only on the natural intracellular uptake mechanism, but when using the first unit drug complex and/or the second unit drug complex according to the present invention, the desired target cell, for example, cancer
- the conjugates binding substances between the membrane protein and the target compound
- a cluster is formed, which accelerates the endocytosis and consequently enhances the internalization of the drug into the cell .
- the targeting substance (first targeting substance) introduced into the first unit drug complex and the targeting substance (second targeting substance) introduced into the second unit drug complex are specifically expressed or overexpressed in target cells.
- Any material capable of specifically binding to a target may be used without limitation.
- specific expression in target cells means that it is not expressed in normal cells but specifically expressed only in target cells, and overexpression in target cells means that it is abnormally expressed more in target cells than in normal cells. means that 2021/245539 €1/162021/054774
- the first targeting material and the second targeting material may target the same target or different targets, and may be different materials even when targeting the same target.
- both the first targeting material and the second targeting material targeting EGF receptor are EGF receptors may be an antibody to
- the first targeting material may be an antibody against EGF receptor
- the second targeting material may be EGF, which is a ligand for EGF receptor.
- the CDR complementarity-determining region
- variable region may be different from each other.
- Substances capable of specifically binding to a target specifically expressed in the target cell include an antibody, an aptamer, a peptide such as a ligand (ligMd), a carbohydrate, and a low molecular weight compound ( small molecules), but is not limited thereto.
- ligMd ligand
- small molecules low molecular weight compound
- the term ''antibody'' includes not only the form of a whole antibody, but also an antigen-binding fragment of the antibody molecule.
- a complete antibody has a structure having two full-length light chains and two full-length heavy chains, and each light chain is linked to a heavy chain by a disulfide bond.
- the heavy chain constant region has gamma (Y), mu (I), alpha (a), delta (5) and epsilon (8) types and subclasses gamma 1 (yl), gamma 2 (y2), gamma 3 (y3). ), gamma 4 (y4), alpha 1 (al) and alpha 2 (a2).
- the constant region of the light chain has kappa (K) and lambda (X) types.
- Antigen-binding fragment or antibody fragment of an antibody refers to a fragment having an antigen-binding function, and includes Fab, F(ab'), F(ab')2 and Fv.
- Fab has a structure having variable regions of light and heavy chains, constant regions of light chain and the first constant region (CH1) of heavy chain, and has one antigen-binding site.
- Fab' differs from Fab in that it has a hinge region comprising one or more cysteine residues at the C-terminus of the heavy chain CH1 domain.
- F(ab')2 antibody is the hinge region of Fab'. 2021/245539 - €1/162021/054774 cysteine residue is formed by forming a disulfide bond.
- Fv is a minimal antibody fragment having only a heavy chain variable region and a light chain variable region.
- a double-chain Fv two-chain Fv
- the heavy chain variable region and the light chain variable region are connected by non-covalent bonds
- single-chain Fv single-chain Fv
- scFv single-chain Fv
- Such antibody fragments can be obtained using proteolytic enzymes (for example, by restriction digestion of the whole antibody with papain to obtain Fab, and by digestion with pepsin to obtain F(ab')2 fragments), genes It can also be produced through recombinant technology.
- An “Fv” fragment is an antibody fragment that contains a complete antibody recognition and binding site. This region consists of a dimer in which one heavy chain variable domain and one light chain variable domain are tightly and substantially covalently associated, eg, scFv.
- a “Fab” fragment contains the variable and constant domains of a light chain and the variable and first constant domains (CH1) of a heavy chain.
- F(ab')2 antibody fragments generally comprise a pair of Fab fragments covalently linked near their carboxy terminus by a hinge cysteine between them.
- a “single chain Fv” or “scFv” antibody fragment comprises the VH and VL domains of an antibody, which domains are present within a single polypeptide chain.
- the Fv polypeptide may further comprise a polypeptide linker between the VH and VL domains that enables the scFv to form the desired structure for antigen binding.
- the targeting material of the drug complex refers to a material capable of binding to a target that is specifically expressed or overexpressed in a target cell, for example, RGD (arginine(R)- glycine(G)-aspartic acid(D)) peptide, glutamate-urea-lysine (GUL) motif binding to prostate specific membrane antigen (PSMA), EGF binding to EGF receptor , VEGF-A or VEGF-B that binds to a vascular endothelial growth factor (VEGF) receptor, but is not limited thereto.
- RGD arginine(R)- glycine(G)-aspartic acid(D)
- GUL glutamate-urea-lysine motif binding to prostate specific membrane antigen
- PSMA prostate specific membrane antigen
- EGF binding to EGF receptor VEGF-A or VEGF-B that binds to a vascular endothelial growth factor (VEGF) receptor, but is not limited thereto.
- the target specifically expressed or overexpressed in the target cell means a protein that is specifically expressed in relation to a disease or overexpressed compared to a normal state, as described above,
- a receptor or a tumor-specific antigen may be exemplified, but the present invention is not limited thereto.
- Targets specifically expressed in the target cells include integrins such as integrin avp3, prostate-specific membrane antigen (PSMA), CD3, CD4, CD6, CDlla, CD 19, CD20, CD22, CD30, CD33, CD38, CD40, CD52, TNF receptors such as CD62, CD79b, CD80, CGRP, OX-40, CTLA4, 4-1BB, PD-1, EGF receptor, TNF (tumor necrosis factor)-a, Fc receptor, folate receptor, GD2, HER2, Her2/neu, HER3, HER4, VEGF receptor, interferon receptor, IgE receptor, IGF-1 receptor, interleukin 2 receptor, interleukin 5 receptor, interleukin 6 receptor, interleukin 17 receptor A, interleukin 31 receptor, interleukin 36 receptor, B7 -H3 and CCR4 may be exemplified, but are not limited thereto.
- PSMA prostate-specific membrane antigen
- CD3, CD4, CD6, CDlla CD 19,
- RGD Arginine(R)-glycine(G)-aspartic acid(D)
- RGD Arginine(R)-glycine(G)-aspartic acid(D)
- the RGD peptide used as an aspect of the present invention is a targeting material that specifically binds to integrin avp3, a membrane protein involved in tumor neovascularization, and has three amino acids as basic structures: arginine-glycine-aspartic acid. And it can be used as a targeting material for the diagnosis or treatment of tumors.
- the glutamate-urea-lysine motif that can be used in another embodiment may be a targeting material that targets PSMA, which is known as a biomarker of prostate cancer, but is not limited thereto.
- the target cell is a disease, preferably a cell target for diagnosis or treatment of an angiogenesis-related disease or a cell target for diagnosis or treatment of prostate cancer, for example, a tumor cell, atherosclerosis. It may be a triggering cell, a myocardial infarction-inducing cell, etc. 2021/245539 1 ⁇ (:1 ⁇ 2021/054774
- the drugs included in the first unit drug complex and the second unit drug complex may be the same drug or different drugs .
- the drug is a diagnostic drug and As a concept that includes all therapeutic drugs, the diagnostic drug may be characterized as a fluorescence dye or a diagnostic gamma-ray/positron radioisotope, but is not limited thereto, and the therapeutic drug is a photodynamic therapy ( A photosensitizer used in photodynamic therapy, a molecule containing the isotope boron (10B) used in boron neutron capture therapy, and alpha/beta radiation used in nuclear medicine therapy It may be characterized in that it is selected from the group consisting of radioisotope and anticancer agent used in anticancer chemotherapy, but is not limited thereto.
- the drug may be a low molecular weight compound, synthetic drug, peptide, protein or antibody, but limited thereto Exemplarily, the drug is maytansinoid, auristatin, aminopterin, actinomycin, bleomycin, thalisomycin, camptothecin, N8-acetyl spermidine, 1-(2 chloro
- cytosine arabinoside rludarabine (fludarabine), tamoxifen (tamoxifen), raloxifene (raloxifene), megestrol (megestrol), goserelin, leuprolide acetate, rlutamide (flutamide), bicalutamide, EB1089, CB1093, KH1060, verteporfm, phthalocyanine, photosensitizer Pe4, demethoxy-hypocrellin A ), interferon-a (Interferon-a), interferon-y (Interferon-y tumor necrosis factor, gemcitabine, velcade, revalmid, thalamid) , lovastatin (lovastatin), 1-methyl-4-phenyl pyridinium ion (1-methyl- 4-phenylpyridiniumion), star right cephalosporin (staurosporine), who is ill tinoyi D (actinomycin D
- the radioisotope emits gamma rays or positrons to provide diagnostic results, or beta rays or alpha rays It can be an isotope that emits radiation and provides therapeutic efficacy, for example, 11C, 18F, 99mTc, 188Re, 125/123/124/1311, 89Zr, 64/67Cu, 68Ga, 177Lu, 90Y, 225Ac or 211At. may be, but is not limited thereto. 2021/245539 ? €1/162021/054774
- Tetramethylrhodamine (TRITC), alexa fluor series, or cyanine (Cy) may be a fluorescent dye, but is not limited thereto. It is preferable that the drugs contained in the first unit drug complex and the second unit drug complex according to the present invention are different from each other . In this way, when the drugs included in the first unit drug complex and the second unit drug complex are different, there is an advantage that combination therapy can be implemented in a jumbo type through the loading and delivery of multiple drugs. That is, the resistance of cancer to existing anticancer drugs shortens the cycle of use of anticancer drugs and eventually leads to discontinuation of treatment for patients. By introducing , customized treatment and combination treatment to respond to resistance are possible.
- the first bonding group and the second bonding group may be used without limitation as long as they are bonding groups capable of bonding in the body, and the bonding group is a bonding group by a click reaction, a bonding group by a host-guest chemical action, or an avidin-biotin bonding group may be, but is not limited thereto.
- the binding may be characterized in that it is a binding by a click reaction, a binding by a host-guest interaction, or an avidin-biotin bond, but is not limited thereto, and the interaction between two or more unit drug complexes is It will be apparent to those skilled in the art that cross-linking can occur without limitation in the body to induce it.
- the bonding group is a bonding group using a click reaction.
- the click reaction without a copper catalyst is known to be a reaction in which a bond is formed within a short time even in an aqueous environment such as the body (Jwett JC et al. Chem. Soc. Rev. 2010;39: 1272-1279.) .
- the bonding group by the click reaction may be an azide-ADIBO (azadib enzocycl oocty ne) bonding group, a trans cyclooctene (TCO)-tetrazine bonding group, or an alkynes-cyclopentadienones bonding group, but is not limited thereto.
- the host-guest interaction is a host compound and 2021/245539 €1/162021/054774 It is an interaction showing high binding strength in the form of a non-covalent bond between the guest compounds.
- the linking group may use an avidin-biotin interaction.
- the avidin-biotin interaction is one of the strong non-covalent bonds that exist in nature, and is selective binding, and above all, has the advantage of having a stronger binding force than the antibody-antigen binding (Jain A. et al. J Control Release.
- the first targeting substance and drug contained in the first unit drug complex and/or the second targeting substance and drug contained in the second unit drug complex are linked by a linker or may be directly linked without a linker.
- the first targeting substance and the first linking group included in the first unit drug complex and / or the second targeting substance and the second binding group included in the second unit drug complex are linked by a linker or can be directly linked without a linker.
- the first targeting substance, drug, and first linking group included in the first unit drug complex are linked by a linker (linking group) having three or more functional groups as shown in FIG. may be, but is not limited thereto.
- the first targeting agent, the drug, and the first binding group may each be linked by a linker or may be directly linked .
- the linker may be an amino acid, hydrocarbon or PEG chain, but is not limited thereto. That is, the linker may be used without limitation as long as it is a material known in the art having an atomic or molecular group and other functional groups suitable for linking a targeting substance and a drug, and further linking a binding group thereto.
- the unit drug complex (first unit drug complex) 2021/245539 €1/162021/054774 In a drug complex comprising the unit drug complex and another drug complex (second unit drug complex) that can be mutually bound through linkages (first linkage group and second linkage group) It relates.
- the mutual binding may be characterized as a binding by a click reaction, a binding by a host-guest interaction, or an avidin-biotin binding, but is not limited thereto.
- the bond by the click reaction may be characterized as an azide-ADffiO bond, a TCO-tetrazine bond, or an alkynes-cyclopentadienones bond, but is not limited thereto.
- the host-guest bond by chemical action may be characterized as a cucurbituril-adamantane bond or a cyclodextrin-amino acid bond, but is not limited thereto.
- the present invention relates to a pharmaceutical composition for treating angiogenesis-related diseases comprising the unit drug complex.
- the pharmaceutical composition may include two or more different unit drug complexes.
- the different two or more unit drug complexes may mean that the linking groups that function to allow the drug complexes constituting each unit drug complex to interact are different in the two or more unit drug complexes. Also, it may mean that each drug bound to a plurality of unit drug complexes constituting two or more unit drug complexes is different from each other.
- the first unit drug complex and the second unit drug complex may be administered at the same time, but preferably may be characterized in that they are administered sequentially.
- the first unit drug complex is administered prior to the second unit drug complex, and after the first unit drug complex reaches and binds to the target of the target cell, the second unit drug complex is administration is preferred .
- the second unit drug complex is administered from 1 minute to 600 minutes, preferably from 5 minutes to 480 hours, more preferably from 10 minutes to after administration of the first unit drug complex It is preferably administered after 300 minutes, most preferably 30 to 240 minutes have elapsed.
- the second unit drug complex may be used in the same amount as the first unit drug complex.
- one or more unit drug complexes may be used per first unit drug complex, for example, 1 to 10 types of unit drug complexes administered per first unit drug complex, preferably 1 to 5 types may be used.
- the angiogenesis-related disease is benign tumor, malignant tumor (cancer), diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, endometriosis, psoriasis, chronic inflammation, coronary artery disease, atherosclerosis, It may be characterized as selected from the group consisting of stroke, ulcer and myocardial infarction, but is not limited thereto.
- the present invention relates to a composition for diagnosing angiogenesis-related diseases comprising the unit drug complex.
- the angiogenesis-related disease is benign tumor, malignant tumor (cancer), diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, endometriosis, psoriasis, chronic inflammation, coronary artery disease, atherosclerosis, It may be characterized as selected from the group consisting of stroke, ulcer and myocardial infarction, but is not limited thereto.
- the present invention relates to a composition for diagnosing and treating angiogenesis-related diseases, including the unit drug complex, so that diagnosis and treatment can be performed simultaneously.
- the first unit drug complex is administered prior to the second unit drug complex, the drug contained in the first unit drug complex is a diagnostic drug, and the drug contained in the second unit drug complex is for treatment characterized as a drug 2021/245539 ? €1/162021/054774 can.
- the first unit drug complex is administered prior to the second unit drug complex, the drug contained in the first unit drug complex is a therapeutic drug, and the drug contained in the second unit drug complex is for diagnosis It may be characterized as a drug.
- the angiogenesis-related disease is benign tumor, malignant tumor (cancer), diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, endometriosis, psoriasis, chronic inflammation, coronary artery disease, atherosclerosis, It may be characterized as selected from the group consisting of stroke, ulcer and myocardial infarction, but is not limited thereto.
- the pharmaceutical composition is any one selected from the group consisting of injections, oral preparations, patches, solutions, capsules, granules, tablets, powders, sprays, ointments, gels, mucosal administration preparations and suppositories It may be characterized in that it is formulated in a dosage form, but is not limited thereto.
- These formulations can be prepared by conventional methods used for formulation in the art or by methods disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and are formulated into various formulations according to each disease or component. can be However, the above description is exemplary, and the formulation to which the present invention is applicable is not limited thereto.
- the pharmaceutical composition may be characterized in that it further contains acceptable excipients, and the adjuvant may be, for example, a carrier.
- a pharmaceutically acceptable carrier may be used in a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltotextrin solution, glycerol, ethanol, and one or more of these components, and if necessary, an antioxidant, buffer , and other conventional additives such as a bacteriostatic agent may be added.
- diluents such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.
- an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.
- an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.
- an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.
- the adjuvant or carrier usable in the present invention is not limited to the above description.
- composition of the present invention may be administered parenterally (for example, intravenously, subcutaneously, orally, (terminology) intraperitoneally or topically) according to a desired method,
- the dosage varies according to the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and severity of disease.
- the dosage regimen and dosage will vary according to the age, weight and response of the individual patient. Appropriate administration regimens and dosages should be determined by one of ordinary skill in the art taking these factors into account.
- the composition of the unit drug complex is divided into a targeting substance, a binding group, a drug, and a linker as shown in FIG.
- Targeting substance refers to a substance capable of binding to a target that is specifically expressed or overexpressed in a target cell, for example, a ligand that specifically binds to an integrin receptor involved in tumor angiogenesis, a receptor related to PSMA It means a ligand that binds to, a ligand that binds to an EGF receptor, a ligand that binds to a vascular endothelial growth factor (VEGF) receptor, and the like, but is not limited thereto.
- VEGF vascular endothelial growth factor
- the bonding group is a functional group that induces cross-linking in the body between different unit drug complexes, and may spontaneously or non-covalently bond when positioned close to each other, for example, bonding by click reaction, host-guest interaction binding or avidin-biotin binding.
- the bonding group used for bonding by the click reaction may be characterized as azide-ADIBO, TCO-tetrazine, or alkynes-cyclopentadienones, but is not limited thereto.
- the bonding group used for host-guest chemistry may be cucurbituril-adamatane or cyclodextrin-amino acid, but is not limited thereto.
- the avidin-biotin bonding group may be characterized as avidin-biotin, 2021/245539 €1/162021/054774 but not limited to this. Modes in which the plurality of unit drug complexes are mutually bound through a bonding group are very diverse, and some aspects will be described in detail as follows.
- One or a plurality of second unit drug complexes may be bound to the first unit drug complex according to the present invention. When one second unit drug complex is bound to the first unit drug complex, bonding by a click reaction between bonding groups for cross-linking in the body, bonding by host-guest interaction, or avidin-biotin bonding may be used.
- a bonding group for bonding unit drug complexes when expressed as showa, one showa may be included in each unit drug complex.
- the linking group structure of the first unit drug complex may be different than the structure in which one second unit drug complex is bound.
- the bonding group introduced into the unit drug complex in the bonding method selected for cross-linking in the body can be expressed as Showa.
- the first unit drug complex may include one or more sho as a binding group, and this unit drug complex may be bound to a plurality of second unit drug complexes comprising
- a plurality of shows included in the unit drug complex may be connected to the unit drug complex in various forms, specifically, as shown below, may be connected in the form of a linear, cyclic, branched, etc., but limited thereto it doesn't happen
- the show means a coupler that can interact, as described in the coupler described above, and as a specific example, ⁇ 6- ⁇ 41 ) 180, avidin-biotin, and the like, and may have 1 to 30 linking groups, and _ is a linker, and _ is a linking group, as shown in FIG.
- a drug is a concept that includes both diagnostic drugs and therapeutic drugs.
- the diagnostic drug may be characterized as a fluorescence dye or diagnostic gamma-ray/positron emitting radioisotope, but is not limited thereto, and the therapeutic drug is a photosensitizer used in photodynamic therapy.
- linker refers to a substance having an atomic or molecular group and other functional groups that further link a targeting substance, a drug, and a bonding group.
- the linker may be an amino acid, hydrocarbon or PEG chain, but is not limited thereto.
- the present invention relates to a kit for diagnosing angiogenesis-related disease or a kit for treating angiogenesis-related disease containing one or two or more of the above unit drug complexes.
- the present invention relates to the use of the drug complex for use in the treatment of angiogenesis-related diseases.
- the present invention relates to the use of the drug complex for the manufacture of a medicament for the treatment of angiogenesis-related diseases. In another aspect of the present invention, it relates to the use of the drug complex for use in the diagnosis of angiogenesis-related diseases. In another aspect, the present invention relates to the use of the drug complex for preparing a reagent for the diagnosis of angiogenesis-related diseases. In another aspect of the present invention, it relates to the use of the drug complex for use in the treatment and diagnosis of angiogenesis-related diseases. In another aspect, the present invention relates to the use of the drug complex for the manufacture of a medicament for the treatment and diagnosis of angiogenesis-related diseases.
- the unit drug complex according to the present invention can be used for fluorescence image-guided surgery, nuclear imaging, photodynamic therapy (PDT), boron neutron It can be used in various diagnostic and treatment methods such as boron neutron capture therapy (BNCT), radioimmunotherapy, and targeted chemotherapy. Accordingly, the present invention relates to a method for treating angiogenesis-related diseases, comprising the following steps: (a) administering a first unit drug complex to a subject in need of treatment for angiogenesis-related diseases; and
- the present invention relates to a method for diagnosing angiogenesis-related diseases comprising the following steps:
- the present invention relates to a method for diagnosing and treating angiogenesis-related diseases comprising the following steps:
- the drug complex according to the present invention has the following characteristics.
- the unit drug complex according to the present invention can rapidly target cells on which the unit drug complex acts. In general, if it does not specifically bind to a target cell or the pharmacokinetics of uptake into the target cell is slow, it inhibits the function of normal cells other than the target cell and reduces the drug efficacy due to metabolism in the body. 2021/245539 - €1/162021/054774 There is a problem that increases the dose.
- the drug complex according to the present invention introduces a targeting material that specifically binds to a target cell, thereby exhibiting a high therapeutic effect with a small dose, thereby preventing toxicity or side effects caused by high dose administration.
- the drug complex according to the present invention enhances cell internalization. If the cellular internalization of conventional tumor cell-targeted therapeutics depends only on the natural intracellular uptake mechanism, the unit drug complex according to the present invention induces mutual binding of the unit drug complex in the body by introducing a linking group that induces cross-linking in the body. do.
- the sequential administration method in which a unit drug complex having such a binding group is first administered and then other unit drug complexes capable of mutually binding to the binding group is administered is a targeting substance in which each unit drug complex specifically binds to a target cell. Because it contains, it specifically binds to the target on the target cell.
- a plurality of unit drug complexes bound to these target cells are cross-linked in the body, and a cluster is formed by induced cross-linking in the body between the formed conjugates, and this cluster accelerates endocytosis and promotes internalization of the drug into cells. Even low-dose administration can effectively deliver drugs to target cells.
- the bonding group applied to the unit drug complex may introduce one or more identical or different bonding groups (for example, a click reaction bonding group, a host-guest bonding group, etc.);
- a group may be formed by inducing cross-linking in the body between three or more different unit drug complexes by combining the unit drug complexes introduced with different bonding groups with other unit drug complexes that interact therewith, They may be different drugs.
- multi-purpose treatment and combination treatment can be customized through the present invention.
- a plurality of unit drug complexes may have different binding groups and different drugs, and a plurality of different unit drug complexes may contain as many different drugs as possible, so it is very useful for multi-purpose treatment and combination treatment. can be utilized.
- one unit drug complex of the present invention contains a drug for diagnosis, and the other unit drug complex contains a drug for treatment. 2021/245539 €1/162021/054774 Diagnosis and treatment may occur simultaneously if drugs are included.
- the present invention will be described in more detail through examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not to be construed as being limited by these examples.
- Example 1. Preparation of drug complex 1-1.
- the targeting material selected as an embodiment of the present invention is an integrin for tumor angiogenesis
- peptide A is D-[C(RGD£K)] 2 by linking two cyclicRGDfKs with aspartic acid (D)
- peptide B is composed of cydicRGDftC and tyrosine. It is Dc(RGDyK)-c(RGDfK) linking the contained cyclicRGDyK with aspartic acid (D)
- the targeting material was synthesized based on the literature BC Lee et al., RSC Advances 2013; 3:782-792.
- the unit drug complex used in the present invention is as follows: Each unit drug complex has a form in which a targeting substance, drug, and bonding group are connected through a linker, and various methods for connecting each component with a linker are known in the art. Although widely known, in this example, each drug complex was prepared using an amide bond.
- a unit drug complex targeting the parent show was prepared.
- the selected targeting material is a motif that binds to the show (5X11 ⁇ yes 1 ⁇ 111 no 6-1q6 -1> 116), and the structure is as shown in the formula below.
- the Fluorescence Resonance Energy Transfer (FRET) method measures the fluorescence resonance energy between two fluorescent dyes occurring between 1 and 10 nm to determine the interaction between two compounds.
- FRET Fluorescence Resonance Energy Transfer
- the conditions of the FRET experiment for comparing and confirming the cell internalization effect were designed as described in Table 1 below, and the unit drug complexes used in this experiment are unit drug complexes 1 and 2 and unit drug complexes 3 and 4, respectively.
- the post-conjugation targeting described in Table 1 below refers to a form in which each unit drug complex is cross-linked in advance before in vitro experiments. For example, before targeting, azide, which is a binding group of unit drug complex 1, and unit drug complex
- Post-targeting conjugation refers to the technique according to the present invention, and if unit drug complexes 1 and 2 are described as an example, unit drug complex 1 is targeted and bound to a target cell, and then to the same target cell Targeting and binding unit drug complex 2, in this case, unit drug complex 1 and unit drug complex as a pair of unit drug complexes
- Fluorescent images were analyzed using a forward confocal laser scanning microscopy (confocal microscopy, Nikon A1 Rsi) Z-stack analysis was analyzed using NIS Elements Imaging software (version 5 .01 , NKON).
- the results of the fluorescence imaging according to the experimental conditions described in Table 1 are shown in FIGS. 3A and 3B, the fluorescence imaging photograph is shown in FIG. 3A, and the fluorescence imaging result is shown as a numerical graph according to the fluorescence intensity in FIG. 3B.
- the result of treating each of the unit drug complexes 1 or 2 alone, which can check the tumor cell uptake ability of each drug complex shows that the FITC channel and the TRITC channel, which can read the wavelength of each fluorescent dye of the unit drug complex, are applied to the target cells, respectively. It shows that the unit drug complex is ingested.
- the result of treating the target competitor in the unit drug complex 1 no fluorescence signal could be confirmed in the FITC channel, indicating that the unit drug complex 1 selectively binds to the target cell. there was.
- fluorescence wavelength analysis was performed on the FITC channel and TRITC channel that can read the wavelength of each fluorescent dye of the unit drug complex, and the FRET channel that can read the wavelength when the unit drug complex binds.
- the analysis results are as shown in FIGS. 3A and 3B, and the drug complex as a post-conjugation target 2021/245539 ? €1/162021/054774
- the unit drug complex used in this experiment is a drug complex 5, in which the unit drug complex 5 labeled with iodine, a radioactive isotope, unit drug complex 6 not labeled with a radioactive isotope, and drug complexes 5 and 6 are combined.
- 6 is 5 units of the drug complex and the stability test of the drug complex 5-61 line 10 - 11 ⁇ : was measured using a. Centrifuged for 5 minutes at 3500 $ 111 from human blood. 2021/245539 €1/162021/054774 The obtained serum was used.
- the radioactive isotope-labeled compound unit drug complex 5 and drug complex 5-6 (3.7 was treated with 0.5 11 serum. For 4 hours after treatment, 10 minutes, 30 minutes, 60 minutes, 120 minutes, and 5/240 minutes) As a result of measuring stability using the 1 ⁇ line 10 - 11 ⁇ : (61080 3 ⁇ 411 ) at four time points, both drug complexes were found to be more than 90% stable for 4 hours, confirming that they can be used for subsequent in vivo binding experiments (results not shown).
- the unit drug complex used in this experiment is a unit drug complex 7 incorporating non-radioactive iodine and a drug complex 6-7 in which the unit drug complexes 6 and 7 are combined.
- the target cell binding ability of the unit drug complex 7 and the drug complex 6-7 was conducted using 11-87140 cells (Korea Cell Line Bank), which are known to have high integrin 01 3 expression. known as competitive inhibitors of the cells (0.037 was treated, and each of the unit drug complex 7 and drug complex 6-7 was treated at each concentration (0 ⁇ 5 111 ) and incubated for 1 hour.
- the tumor intake remained at least 60% for 2 hours regardless of the dose of the unit drug complex 6.
- the smallest amount, 0.18 mg/kg of unit drug complex 6 was sequentially treated, more than 95% of the tumor intake was maintained up to 2 hours, and the tumor retention effect was most pronounced.
- Example 4-4 Comparison of retention enhancement effect in tumor cells for 24 hours in tumor model mice In Example 4-4, the retention enhancement effect in the tumor for a short time according to sequential treatment of the unit drug complex was confirmed. This was observed over a longer period of time.
- the intratumoral uptake maintenance effect and half-life at 1 hour, 2 hours, 4 hours, and 24 hours were compared by imaging .
- the tumors were excised at 10 minutes and 24 hours after administration of the unit drug complex to confirm the effect of enhancing retention in tumor cells ex vivo.
- 2021/245539 ? €1/162021/054774 As a result, as shown in FIG. 6, when the unit drug complex 5 was administered alone, it was found to decrease to less than half of their initial intake within 4 hours, but the unit drug complex In the case of sequential administration of 5 and 6, the intratumoral intake was found to maintain about 60% of the initial intake up to 24 hours.
- the drug complex according to the present invention can act on tumor cells for a long time after internalization into tumor cells.
- the drug complex according to the present invention contains a targeting material that specifically binds to a target cell, so that rapid targeting to the target cell is possible.
- each Linking groups that can interact with the drug complex are additionally introduced, so when each drug complex is sequentially injected, the linkers bond with each other in the body and cross-linking between the conjugates (different drug complexes bound to the target cell) Inducing the drug complex to form a kind of cluster. Clustering of these drug complexes on the target cell surface artificially enhances the effect of internalization of cells by endocytosis.
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CN202180043422.5A CN115702007A (zh) | 2020-06-01 | 2021-06-01 | 具有提高的药物递送和内化效率的药物偶联物 |
BR112022024287A BR112022024287A2 (pt) | 2020-06-01 | 2021-06-01 | Conjugado de medicamento com eficiência melhorada de distribuição de medicamento e internalização |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20110128732A (ko) * | 2010-05-24 | 2011-11-30 | 서울대학교산학협력단 | 트리카르보닐 테크네슘-99m 또는 레늄-188 표지 고리 알지디 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 신생혈관 관련 질환의 진단 또는 치료용 약학적 조성물 |
KR102250737B1 (ko) * | 2020-06-01 | 2021-05-11 | 주식회사 비아이케이테라퓨틱스 | 약물 전달과 내재화 효율이 강화된 약물복합체 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102009027625A1 (de) | 2009-07-10 | 2011-01-13 | Robert Bosch Gmbh | Elektrische Schaltung zur Übertragung von Signalen zwischen zwei Mastern und einem oder mehreren Slaves |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20110128732A (ko) * | 2010-05-24 | 2011-11-30 | 서울대학교산학협력단 | 트리카르보닐 테크네슘-99m 또는 레늄-188 표지 고리 알지디 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 신생혈관 관련 질환의 진단 또는 치료용 약학적 조성물 |
KR102250737B1 (ko) * | 2020-06-01 | 2021-05-11 | 주식회사 비아이케이테라퓨틱스 | 약물 전달과 내재화 효율이 강화된 약물복합체 |
Non-Patent Citations (14)
Title |
---|
BC LEE ET AL., RSC ADVANCES, vol. 3, 2013, pages 782 - 792 |
CHOI JI YOUNG: "Development of novel cell-internalizing peptides using in vivo intermolecular conjugation as an avenue for enhancing the effect of anti-angiogenic therapy on tumors", THESIS : GRADUATE SCHOOL OF SEOUL NATIONAL UNIVERSITY, 1 August 2019 (2019-08-01), pages 1 - 98, XP055877768 * |
CHOONG MO KANG, HYUNJUNG KIM, HYUN-JUNG KOO, GWANG IL AN, YEARN SEONG CHOE, JOON YOUNG CHOI, KYUNG-HAN LEE, BYUNG-TAE KIM: "Preparation and evaluation of 64Cu-labeled streptavidin/biotin-based RGD dimer for dual PET/optical imaging of αvβ3 receptor expression", JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, vol. 58, no. S1, 2015, pages S130, XP009532708, ISSN: 0362-4803, DOI: 10.1002/jlcr.3302_2 * |
CONNER S.D. ET AL., NATURE, vol. 422, 2003, pages 37 - 44 |
JAIN A. ET AL., J CONTROL RELEASE., vol. 245, 2017, pages 27 - 40 |
JEWETT J.C. ET AL., CHEM. SOC. REV., vol. 39, 2010, pages 1272 - 1279 |
KANG CHOONG MO, KOO HYUN-JUNG, AN GWANG IL, CHOE YEARN SEONG, CHOI JOON YOUNG, LEE KYUNG-HAN, KIM BYUNG-TAE: "Hybrid PET/optical imaging of integrin αVβ3 receptor expression using a 64Cu-labeled streptavidin/biotin-based dimeric RGD peptide", EJNMMI RESEARCH, vol. 5, no. 60, 1 January 2015 (2015-01-01), pages 1 - 10, XP055877752, DOI: 10.1186/s13550-015-0140-0 * |
MARESCA K.P. ET AL., J MED CHEM, vol. 52, 2009, pages 347 - 357 |
MARSH M. ET AL., CELL, vol. 124, 2006, pages 729 - 40 |
RONDON AURÉLIE, SCHMITT SÉBASTIEN, BRIAT ARNAUD, TY NANCY, MAIGNE LYDIA, QUINTANA MERCEDES, MEMBRENO ROSEMERY, ZEGLIS BRIAN M., NA: "Pretargeted radioimmunotherapy and SPECT imaging of peritoneal carcinomatosis using bioorthogonal click chemistry: probe selection and first proof-of-concept", THERANOSTICS, vol. 9, no. 22, 1 January 2019 (2019-01-01), AU , pages 6706 - 6718, XP055877758, ISSN: 1838-7640, DOI: 10.7150/thno.35461 * |
SMITH A.E. ET AL., SCIENCE, vol. 304, 2004, pages 237 - 42 |
VERONIKA ROSECKER, DENK CHRISTOPH, MAURER MELANIE, WILKOVITSCH MARTIN, MAIRINGER SEVERIN, WANEK THOMAS, MIKULA HANNES: "Cross‐Isotopic Bioorthogonal Tools as Molecular Twins for Radiotheranostic Applications", CHEMBIOCHEM, XP055718718, ISSN: 1439-4227, DOI: 10.1002/cbic.201900042 * |
WU Z. ET AL., J NUCL MED, vol. 48, 2007, pages 1536 - 1544 |
YU G. ET AL., THERANOSTICS, vol. 9, 2019, pages 3047 - 3074 |
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WO2024087332A1 (zh) * | 2022-10-26 | 2024-05-02 | 深圳先进技术研究院 | 一种用作靶蛋白降解剂的双功能化合物及其在靶蛋白溶酶体降解中的应用 |
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