39 results about "Alpha-v beta-3" patented technology

The invention relates to a radionuclide-marked RGD polypeptide medicine and a preparation method thereof. The medicine comprises RGD polypeptide, a bifunctional Chelator and radioactive Nuclide, wherein the RGD polypeptide is RGD cyclic peptide dimer, namely E(L-c(RGDxK))2, which is synthesized by connecting a connecting agent L and an RGD polypeptide monomer and dimerizing two RGD polypeptide monomers connected with the connecting agent L; the radioactive Nuclide marks the RGD cyclic peptide dimer through the bifunctional Chelator; and a pharmacokinetic modified molecule PKM is also connected between the RGD cyclic peptide dimer and the bifunctional Chelator. The radionuclide-marked RGD polypeptide medicine is Nuclide-Chelator-PKM-E(L-c(RGDxK))2, and is a colorless and transparent liquid injection solution. The radionuclide-marked RGD polypeptide medicine is used for diagnosing and treating integrin alpha v beta 3 positive tumor.

An object of the present invention is to provide m-substituted benzoic acid derivatives having integrin αvβ3 antagonistic activity. The derivatives according to the present invention are compounds represented by formula (I) or pharmaceutically acceptable salts or solvates thereof, which are useful for the treatment or prevention of cardiovascular diseases, angiogenesis-related diseases, cerebrovascular diseases, cancers and metastasis thereof, immunological diseases, osteopathy and other diseases: wherein A represents an optionally substituted heterocyclic group containing two nitrogen atoms, a bicylic group or the like; D represents a bond, >NR4, >CR5R6, O, S, or —NR4—CR5R6—; X represents CH or N; R7 and R8 represent hydroxyl, alkyl or the like; Q represents >C═O or the like; R9 represents hydrogen, alkyl or the like; J represents a bond or alkylene; R10 represents optionally substituted hydroxyl, amino or the like; R11 represents hydrogen, alkyl or the like; m is 0 to 5; n is 0 to 4; and p and q are each 0 to 3.

The invention discloses a dual-targeting ultrasonic contrast agent and a preparation method thereof. The contrast agent is an Integrin alpha v beta 3 / MCP-1 dual-targeting micro-vesicle, the dual-targeting micro-vesicle comprises a lipid shell and a gas inner core, and the external surface of the lipid shell is connected with an Integrin alpha v beta 3 monoclonal antibody and an MCP-1 monoclonal antibody. Through the combined application of different target spots, the targeting efficiency of the contrast agent can be effectively increased, and the degree of enrichment of the carrying genes in the target tissue can be greatly increased. In addition, the contrast agent disclosed by the invention is an ultrasonic contrast agent with double functions of development and treatment, and tumor images can be accurately observed in real time through an ultrasonic imaging system; and after gene transfection is realized through high-strength ultrasonic irradiation, the tumor gene treatment effect can be achieved.

The invention provides a fluorescence probe for targeting tumor cells and new vessels. The fluorescence probe can solve the problem of selective imaging for cancer cells of high-expression integrin alpha v beta3. According to the design of the molecular structure of the fluorescence probe provided by the invention, RGD is used as a recognition group for performing multi-site modification on triaryl fluorophore so as to construct a multivalent probe capable of combining with integrin alpha v beta 3. The probe is capable of selectively imaging the cancer cells of high-expression integrin alpha vbeta 3 at cellular level and is capable of realizing the targeting imaging of a tumor site in vivo. Meanwhile, the synthetic process of the fluorescence probe provided by the invention is simple andeasy, the raw materials are low-cost and easily acquired, the preparation cost is low and the fluorescence probe is easy for popularization.

The invention relates to the technical field of medicine, in particular to an exosome carrier of a target integrin alpha v beta 3 and a preparation method and application of the exosome carrier. Mononuclear suspension cells THP-1 are adopted and stimulated by PMA of the certain concentration to obtain the exosome carrier, the surface of an exosome after separating contains an RGD target molecule metalloprotease disintegrin family 15, and the target integrin receptor alpha v beta 3 can be obtained. The in-vitro releasing experiment shows that the prepared exosome can slowly release loaded chemotherapeutic medicine, and the better capacity of jointly loading genes and the chemotherapeutic medicine is achieved. In the tumor treatment process, the exosome can enhance the effects of cells of aspecificity target overexpression integrin alpha v beta 3 on tumor cells through the chemotherapeutic medicine or gene medicine, apoptosis of tumor cells is promoted, and therefore the exosome carrierforms a targeted and efficient low-toxicity bionic nanoscale delivery system of tumor treatment.

The invention discloses amino cyanine fluorescent dyes connected with cyclopeptide [cyclo(RGD)] and a preparation method therefor and application thereof. The structural formula of the compounds is shown in I. The compounds consist of structural units III and III; the structural unit II is a derived cyanine dye structure which is water soluble fluorescent molecules, the spectrum of which has relatively great Stokes shift, and the molecules have relatively less toxicity to normal cells; the structural unit III is a cyclopeptide structure of a specific ligand of an alpha v beta 3 integrin receptor and can be used for targeted orientation. The fluorescent dyes have the double function characteristic of tumor imaging diagnosis and targeted therapy.

The invention relates to compounds of formula (I): wherein R1, R2, and n are defined in the detailed description and claims. In particular, the present invention relates to the compounds of formula (I) for use in the manufacture and delivery of conjugated moieties such as small molecules, peptides, nucleic acids, fluorescent moieties, and polymers which are linked to alpha-V-beta-integrin antagonists to target cells expressing alpha-V-beta-3.

The invention discloses a cancer cell-targeting structural molecule and a use thereof. A molecule shown in the formula (I) reacts with a connection molecule containing a carboxyl structure and a maleimide group so that the cancer cell-targeting structural molecule is produced by a dehydration synthesis reaction of an amino group and a carboxyl group. The cancer cell-targeting structural molecule can be bonded with a sulfydryl (-SH)-modified nucleotide molecule, can be directly applied to a human body by blood vessel administration, can be specifically bonded with cancer cells expressing integrin family alpha v beta 3 acceptors or with new vessel endothelial cells in cancer tissue, can effectively penetrate a cell membrane by receptor-mediated endocytosis, and can convey the nucleotide molecule into cytoplasm. In the formula (I), n is in a range of 1-10.

The invention provides a 99mTc complex taking iminodiacetic acid as a difunctional chelating agent. Structure of the complex is shown as a formula (1). The complex has the advantages of simplicity in preparation, low cost, high marking rate, radiochemical purity, target to non-target ratio and tumor uptake value, long residence time and low liver-kidney background. The complex can serve as a novel photographic developer marked by technetium-99m and used for positive tumor diagnosis of intergrin alpha v beta 3 receptor to be applied in the technical field of radioactive medicinal chemistry and clinical nuclear medicine.

The invention provides a structure modified RGD polypeptide, a complex formed by the polypeptide and radionuclides and a medicinal composition containing the complex. The medicinal composition is usedfor diagnosing or treating integrin alpha v beta 3 positive tumors. The complex has the following definitions: A in the A-(L)n-RGD polypeptide has a structure as shown in the specification, L represents a linker arm molecule and has a structure as shown in the specification, and m is an integer of 1-8.

The invention belongs to the technical field of biomedicine production or the fields of protein polypeptide drugs and biomedical engineering, and in particular relates to a polypeptide which has high affinity with an integrin receptor and an application of the polypeptide like cancer diagnosis and treatment. The polypeptide is composed of five amino acids, and the sequence is arginine-tryptophan-arginine-asparagine-methionine (Arg-Trp-Arg-Asn-Met). On the basis of an in-vitro flow cytometry affinity determination experiment, the polypeptide disclosed by the invention has quite strong targeting on high-expression cells of the integrin receptor, and through an in-vitro laser confocal cell uptake experiment, the polypeptide can be targeted to high-expression tumor cells of the integrin receptor alpha-v-beta-3 and can basically avoid targeting on low-expression tumor cells and normal cells of the integrin receptor alpha-v-beta-3. An in-vitro cytotoxicity result shows that the 5-peptide disclosed by the invention is basically free from toxicity on cells, and the 5-peptide has a good application prospect in the diagnosis and the treatment of cancers.

The teachings provided herein generally relate to a combination therapy and are directed to pharmaceutical compositions and methods for administering a combination of an αvβ3 antagonist with an αVβ1 antagonist to a subject. The methods are for use in inhibiting, preventing, or reversing angiogenesis, as well as in treating cancer. In some embodiments, the compositions and methods include a combined administration of echistatin and VP12 (ECL12).

The invention discloses an integrin targeted MnOL-Gd hybrid bimetallic paramagnetic nanocolloid (alpha v beta 3-MnOL-Gd NC) and application in magnetic resonance imaging (MRI) of angiogenesis. The alpha v beta 3-MnOL-Gd NC provided by the invention is obtained by coupling alpha v beta 3 targeted specific biomolecules of polyethylene glycol 2000 integrated phosphatidyl ethanolamine to the surfaces of MnOL-Gd hybrid bimetallic paramagnetic nanoparticles. Research shows that, the alpha v beta 3-MnOL-Gd NC is effective in imaging of angiogenesis, and can generate specific angiogenesis imaging high signal contrast 2 hours after injection. Therefore, the alpha v beta 3-MnOL-Gd NC disclosed by the invention can be used for T1 weighted MR molecular imaging of angiogenesis, and is free of obvious allergic reaction side effect, thus providing a new technological means for magnetic resonance imaging of angiogenesis.

The invention relates to the chitosan polymer derivatives of formula I:and pharmaceutically acceptable salts and esters thereof, wherein Y, X1, X4, R1, R2, and n are defined in the detailed description and claims. The chitosan polymer derivatives of formula I bind to or associate with alpha-4-beta-1 (α4β1) and alpha-V-beta-3 (αVβ3) integrin dimers and can be used in delivery formulations to deliver drugs, nucleic acids, or other therapeutic compounds to tissues or cells expressing such integrins.

The present invention discloses a novel lipid material for realizing transfer of triple negative breast cancer targeted drugs. The novel lipid material takes lysine as a connecting group to respectively connect a cholesteric part, a fructose part and an RGD part. Affinities between fructose in the novel lipid material and a fructose transporter GLUT5, and between RGD in the novel lipid material and an integrin receptor alpha v beta 3 are respectively utilized to realize double targeting functions of the triple negative breast cancer and exert stronger targeted treatment effects on the triple negative breast cancer. The novel liquid material can be sued for different dosages of liposomes, nanoparticles, micelle, etc. A prepared paclitaxel-loaded liposome has obvious triple negative breast cancer targeting property and a wide application prospect.

The invention discloses a structural molecule for affinity and target cell uptake capability of enhanced integrin receptor. The structural molecule has a molecular structure shown in a formula (I); the structural molecule is obtained by carrying out reaction between two cRGD oligopeptides and 6-aminocaproic acid, glutamate oligopeptide or / and arginine oligopeptide, 8-amino-3,6-dioxaoctanoic acid or 3-maleimidopropionic acid and the like to perform dehydration condensation on amino and carboxyl. According to the structural molecule disclosed by the invention, tumor cells expressing an alpha v beta 3 receptor and neovascular endothelial cells can be specially combined, the carried molecules such as nucleotide enter cytoplasm through receptor-mediated endocytic uptake, so that the uptake efficiency of expression cells of the alpha v beta 3 receptor is improved and the release of the carried molecules from a target cytoplasm endosome is promoted, and therefore, the structural molecule can be applied to preparation of targeted therapy drugs or disease diagnosis tracer agents.

The invention relates to the chitosan polymer derivatives of formula I: and pharmaceutically acceptable salts and esters thereof, wherein Y, X1, X4, R1, R2, and n are defined in the detailed description and claims. The chitosan polymer derivatives of formula I bind to or associate with alpha-4-beta-1 (α4β1) and alpha-V-beta-3 (αVβ3) integrin dimers and can be used in delivery formulations to deliver drugs, nucleic acids, or other therapeutic compounds to tissues or cells expressing such integrins.

The invention relates to compounds of formula (I): wherein R1, R2, and n are defined in the detailed description and claims. In particular, the present invention relates to the compounds of formula (I) for use in the manufacture and delivery of conjugated moieties such as small molecules, peptides, nucleic acids, fluorescent moieties, and polymers which are linked to alpha-V-beta-3 integrin antagonists to target cells expressing alpha-V-beta-3.

The invention relates to a PEGylated Fe3+ / PEI genetic vector based on functional peptide R9 modification and a preparation method and application of the PEGylated Fe3+ / PEI genetic vector. The genetic vector contains polyethylene glycol modified Fe3+ / polyethyleneimine and a conjugate formed by functional peptides R9. The PEGylated Fe3+ / PEI genetic vector based on functional peptide R9 modification has the advantages that metal ions Fe3 react with PEI at first, PEG modification is carried out to form PEGylated Fe3+ / PEI, then the functional peptide R9 which has ability of improving nuclear delivery and is targeted at alpha v beta 3 is synthesized, R9 is coupled with a PEG-Fe3+ / PEI by a crosslinking technology, and therefore, a novel virogene-free vector system PEG-Fe3 + / PEI is established. On the basis of reducing PEI cytotoxicity, in-vivo targeting property and nuclear delivery ability are improved, then the transfection efficiency of the vector in vivo is improved, and an effective way is searched for final application of gene therapy on clinical treatment.

The invention discloses a type of 1,3-dihydro-1-oxo-2H-isoindole compounds (I) and pharmaceutically acceptable salts thereof and also discloses application of the compounds in preparation of medicines for preventing or / and treating various symptoms or diseases such as tumor metastasis, tumor growth, solid tumor growth, angiogenesis, retinopathy, macular degeneration, osteoporosis, arthritis, smooth muscle cell migration and atherosclerosis caused by integrin alpha v beta 3 mediation. The structural formula is as shown in the specification.

The invention discloses tumor targeted cordycepin nanometer capsules and a preparation method thereof. The method comprises the following steps of firstly preparing RGD modified apolipoprotein A I(ApoAI), and then constructing nanometer capsules from the RGD modified apolipoprotein A I(ApoAI), phospholipid and cordycepin. RGD peptide is a specific ligand of an integrin alpha v beta 3, and the integrin alpha v beta 3 gene is subjected to zero expression or little expression in majority of normal organ systems and normal vascular endothelial cells, and is subjected to overexpression on the surfaces of various tumor cells and tumor regenerated blood vessel endothelial cells, so that after being subjected to RGD modification, the nanometer capsules have good targeting effects on tumors, the effective concentration of cordycepin in tumor positions can be increased, and the antitumor effects of the cordycepin can be reinforced.

The invention discloses an integrin targeted MnOL-Gd hybrid bimetallic paramagnetic nanocolloid (alpha v beta 3-MnOL-Gd NC) and application in magnetic resonance imaging (MRI) of angiogenesis. The alpha v beta 3-MnOL-Gd NC provided by the invention is obtained by coupling alpha v beta 3 targeted specific biomolecules of polyethylene glycol 2000 integrated phosphatidyl ethanolamine to the surfaces of MnOL-Gd hybrid bimetallic paramagnetic nanoparticles. Research shows that, the alpha v beta 3-MnOL-Gd NC is effective in imaging of angiogenesis, and can generate specific angiogenesis imaging high signal contrast 2 hours after injection. Therefore, the alpha v beta 3-MnOL-Gd NC disclosed by the invention can be used for T1 weighted MR molecular imaging of angiogenesis, and is free of obvious allergic reaction side effect, thus providing a new technological means for magnetic resonance imaging of angiogenesis.

The invention discloses a preparation method and application of an engineered exosome, and aims to silence mtp53-S241F and SNRPD2 genes at the same time, destroy splicing body assembly mediated by the genes and inhibit a carcinogenic path of the mtp53 gene. By means of genetic engineering, iRGD-LAMP2B fusion protein is expressed on the surface of the exosome, high-expression alpha v beta 3 integrin on the surface of a tumor cell is specifically combined, and positioning of the exosome on the tumor cell is enhanced.

The invention discloses 1,3-dihydro-1-oxo-2H-isobenzazole compounds (I) and pharmaceutically acceptable salts thereof, and also discloses preparation methods for the compounds, and uses of the compounds in preparing medicines for preventing and / or treating various diseases caused by the mediation of integrin alpha v beta 3, such as tumor metastasis, tumor growth, solid tumor growth, angiogenesis, retinopathy, macular degeneration, osteoporosis, arthritis, smooth muscle cell migration and atherosclerosis symptoms or diseases.

A T cell transduced with a chimeric antigen receptor can be administered to a host to kill cancer cells. The chimeric antigen receptor can include a targeting moiety with a strong binding affinity to Alpha v Beta 3 integrin, including but not limited to an echistatin polypeptide. The targeting moiety can also be modified to have a reduced binding affinity to Alpha 5 Beta 1 integrin.

The invention belongs to the technical field of biological medicine, and discloses a cyclic peptide targeting integrin alpha v beta 3 and application thereof. The structural general formula of the cyclic peptide targeting integrin alpha v beta 3 is shown as a formula I, a formula II or a formula III. The novel thioether bridge bond-containing cyclic peptide which has selectivity and affinity and targets alpha v beta 3 is obtained by a solid-phase synthesis method. A cell binding experiment, an endocytosis experiment and an integrin-extracellular matrix interaction experiment based on ELISA (Enzyme-Linked Immuno Sorbent Assay) detection show that the cyclopeptide has relatively good affinity and specificity on integrin alpha v beta 3, and can be used as a targeting peptide for alpha v beta 3 receptor mediated drug delivery. Furthermore, the cyclic peptide is prepared into a corresponding polypeptide conjugate, the polypeptide conjugate has a nanomole-level inhibition effect on tumor cell inhibition, and compared with a single load drug, the toxicity is obviously reduced, the safety is high, and the polypeptide conjugate shows huge potential and application value in tumor treatment of targeting integrin alpha v beta 3.

The invention discloses a cancer cell-targeting structural molecule and a use thereof. A molecule shown in the formula (I) reacts with a connection molecule containing a carboxyl structure and a maleimide group so that the cancer cell-targeting structural molecule is produced by a dehydration synthesis reaction of an amino group and a carboxyl group. The cancer cell-targeting structural molecule can be bonded with a sulfydryl (-SH)-modified nucleotide molecule, can be directly applied to a human body by blood vessel administration, can be specifically bonded with cancer cells expressing integrin family alpha v beta 3 acceptors or with new vessel endothelial cells in cancer tissue, can effectively penetrate a cell membrane by receptor-mediated endocytosis, and can convey the nucleotide molecule into cytoplasm. In the formula (I), n is in a range of 1-10.

The invention discloses a linker compound of an integrin alpha v beta 3 inhibitor, which is shown as a formula (1) and can be used for a prodrug delivery system, or a tautomer, a mesomer, a raceme, an enantiomer, a diastereoisomer of the linker compound, or a mixture form of the linker compound, or a pharmaceutically acceptable salt, a prodrug or a solvate of the linker compound, and a synthesis method and application of the linker compound. The structure of the formula (1) comprises an alpha v beta 3 integrin antagonist, a connecting unit, a polyethylene glycol (PEG) spacer and a cytotoxic element. IA-LI-PD (1).

The present invention relates to DNA aptamer specifically binding to integrin αvβ3, and a composition for diagnosis of cancer or cancer metastasis comprising the same as an active ingredient. And, the present invention relates to a composition for imaging tumor regions comprising the aptamer, and a contrast medium comprising the same.

The invention discloses an inducing plasmid, a method for preparing a therapeutic exosome by using the inducing plasmid and application of the inducing plasmid. The inducing plasmid comprises fusion oligonucleotide of target gene silencing nucleic acid and a motif, and therapeutic RNA can be directionally sorted into the exosome by the motif; rab system knock-down is achieved through Rab system silencing nucleic acid, the exosome secretion efficiency can be improved, target cell uptake can be promoted, and oriented loading and high-yield secretion of the exosome can be achieved based on the tetracycline induction regulation effect; the cRGD peptide is modified by an exosome membrane phospholipid layer, damage of covalent cross-linking to membrane protein is avoided, an alpha v beta 3 integrin receptor highly expressed on the surface of a tumor cell can be specifically combined, active targeting is achieved, the defect of poor targeting in the prior art is overcome, and precise treatment is achieved.