CN113750247A - Tumor targeting drug, preparation method and application thereof - Google Patents

Tumor targeting drug, preparation method and application thereof Download PDF

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CN113750247A
CN113750247A CN202010500919.2A CN202010500919A CN113750247A CN 113750247 A CN113750247 A CN 113750247A CN 202010500919 A CN202010500919 A CN 202010500919A CN 113750247 A CN113750247 A CN 113750247A
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tumor
drug
therapy
acid
sodium
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李娟�
高倩倩
吴爱国
曹奕
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Ningbo Institute of Material Technology and Engineering of CAS
Cixi Institute of Biomedical Engineering CIBE of CAS
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Ningbo Institute of Material Technology and Engineering of CAS
Cixi Institute of Biomedical Engineering CIBE of CAS
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Abstract

The application discloses a tumor-targeted drug, a preparation method and an application thereof, wherein the tumor-targeted drug comprises an active targeting unit and an anti-tumor drug molecule; the active targeting unit and the antitumor drug molecules are sequentially connected through a chelation reaction and/or a chemical coupling reaction. The invention provides a medicament for actively targeted therapy of tumors on the basis of a new tumor target neuropeptide YY3 receptor, and can realize targeted chemical drug therapy, photothermal therapy, photodynamic therapy, sonodynamic therapy or magnetocaloric therapy, thereby realizing the effect of precise therapy of tumors.

Description

Tumor targeting drug, preparation method and application thereof
Technical Field
The invention relates to the technical field of medical use, in particular to a tumor targeting medicament, a preparation method and application thereof.
Background
Cancer, also known as malignant tumor, is one of the major diseases that seriously jeopardize human health and life. The timely, efficient and accurate treatment of cancer is not only related to the life health and the quality of life of people, but also to the sustainable development of economy and society. Traditional methods of tumor treatment mainly include surgical resection, chemotherapy (chemotherapy), and radiation therapy (radiotherapy). However, tumor tissues are not easy to mark in the operation process, and protocarcinoma cells are easy to transfer, so that the postoperative recurrence is easy to occur. Chemotherapy and radiotherapy also have significant killing effects on normal tissues, have large side effects, and tumor cells are easy to resist chemotherapy and radiotherapy. Therefore, the development of novel and highly effective tumor treatment methods has become a focus of research.
The molecular targeted therapy is to design corresponding therapeutic drugs aiming at the well-defined carcinogenic sites on the cellular molecular level, and the drugs enter the body to specifically select the carcinogenic sites to combine and take effect, so that tumor cells are specifically killed, normal tissues are less affected, and the direction of tumor therapy development is provided.
The neuropeptide YY3 receptor (NPYY3R) belongs to a G protein coupled receptor superfamily, and the over-expression of NPYY3R is found in clinical cases of diseases such as esophageal cancer, breast cancer, renal cancer, ovarian cancer, lung cancer, colorectal cancer, leukemia and the like, and the expression of the receptor is low in normal tissues and organs. This suggests that NPYY3R is a potential target for tumor-targeted therapy.
Disclosure of Invention
The invention provides a tumor targeting drug which can actively target tumor cells over-expressed by neuropeptide YY3 receptors, and connected anti-tumor drug molecules can realize at least one of chemical drug therapy, photo-thermal therapy, photodynamic therapy, sonodynamic therapy and magnetocaloric therapy, and have great significance in the aspect of accurate treatment and application of tumors.
According to an aspect of the present application, there is provided a tumor-targeted drug comprising an active targeting unit and an anti-tumor drug molecule; the active targeting unit and the antitumor drug molecules are sequentially connected through a chelation reaction and/or a chemical coupling reaction.
Optionally, the active targeting unit actively targets tumor cells over-expressed by neuropeptide YY3 receptor;
the antitumor drug molecules are used for at least one of chemical drug therapy, photothermal therapy, photodynamic therapy, sonodynamic therapy and magnetocaloric therapy.
Optionally, the active targeting unit is selected from at least one of a polypeptide, an antibody, and a small molecule inhibitor.
Optionally, the polypeptide is selected from CTCE-9908, T140, TC14012, T22, POL6326, POL5551, LY2510924, RCP168, TF14016, FC131, DV3 and at least one of the above polypeptide derivatives;
the antibody is selected from at least one of BMS-936564, MEDI3185, Anti-VLA-4mAb, hz515H7, Clone 12G5, LY2624587, PF-06747143 and antibody derivatives thereof;
the small molecule inhibitor is selected from at least one of AMD3100, BKT140, AMD3465, IT1t, AMD11070, KRH-3955, MSX-122 and derivatives thereof.
Alternatively, the CTCE-9908, T140, TC14012, T22, POL6326, POL5551, LY2510924, RCP168, TF14016, FC131, DV3 polypeptides are all antibodies against CXCR4 and also against Y3R.
Optionally, the antineoplastic drug molecules for chemotherapy are selected from at least one of alkylating agents, antimetabolites, antitumor antibiotics, plant anticancer drugs, antitumor hormones, and immunological agents;
optionally, the alkylating agent is selected from at least one of nimustine, carmustine, lomustine, cyclophosphamide, ifosfamide, and glycyl mustard.
Optionally, the antimetabolite is selected from at least one of 5-fluorouracil (5-Fu), doxifluridine, deoxyfluoroguanosine, mercaptopurine, tegafur, thioguanine, gemcitabine, carmofur, hydroxyurea, methotrexate, eufordine, and ancitabine.
Optionally, the antitumor antibiotic is selected from at least one of doxorubicin (Dox), epirubicin, daunorubicin, pelomycin, pingyangmycin, pirarubicin, mitomycin, actinomycin D.
Optionally, the plant anticancer drug is at least one selected from paclitaxel (Taxol), hydroxycamptothecin, irinotecan, cephalotaxel, vinorelbine, taxotere, topotecan, vincristine, vindesine, vinblastine, teniposide, etoposide and elemene.
Optionally, the anti-tumor hormone is selected from at least one of atamestan, anastrozole, aminoglutethimide, letrozole, formestane, megestrol, and tamoxifen.
Optionally, the immunological agent is selected from at least one of glucocorticoids, microbial metabolites, antimetabolites, polyclonal and monoclonal anti-lymphocyte antibodies, alkylating agents.
Optionally, the anti-tumor drug molecules for photothermal therapy are selected from at least one of group-modified noble metal nanoparticles, group-modified metal chalcogenide nanoparticles, group-modified carbon-based nanomaterials, organic near-infrared dyes, and porphyrin liposome nanoparticles;
the group is selected from at least one of hydroxyl, carboxyl and amino.
Optionally, the hydroxyl-modified gold nanomaterial is selected from gold nanomaterials modified with polyethylene glycol (PEG).
Optionally, the carboxyl-modified gold nanomaterial is selected from a gold nanomaterial modified with polylactic-co-glycolic acid (PLGA).
Optionally, the amino-modified gold nanomaterial is selected from gold nanomaterials modified with Distearoylphosphatidylethanolamine (DSPE).
Optionally, the hydroxyl-modified metal chalcogenide nanoparticles are selected from metal chalcogenide nanoparticles modified with polyethylene glycol (PEG).
Optionally, the carboxyl-modified metal chalcogenide nanoparticles are selected from polylactic-co-glycolic acid (PLGA) -modified metal chalcogenide nanoparticles.
Optionally, the amino-modified metal chalcogenide nanoparticles are selected from Distearoylphosphatidylethanolamine (DSPE) -modified metal chalcogenide nanoparticles. Optionally, the noble metal nanoparticles are selected from nanoparticles prepared from at least one of silver, gold, ruthenium, rhodium, palladium, platinum and iridium.
Optionally, the gold nanomaterial is selected from at least one of gold nanospheres (Au NPs), gold nanorods (Au NRs), gold nanocages, and gold nanoplates.
Optionally, the metal chalcogenide nanoparticles are selected from at least one of copper sulfide nanoparticles, cuprous sulfide nanoparticles, zinc sulfide nanoparticles, cuprous selenide nanoparticles.
Optionally, the carbon-based nanomaterial is selected from at least one of carbon nanotubes, carbon nanorods, carbon nanospheres, graphene oxide, and carbon dots.
Optionally, the organic near-infrared dye is selected from at least one of IR780, IR783, IR808, IR825, IR908, IR1045, indocyanine green (ICG), prussian blue.
Optionally, the antineoplastic drug molecules for photodynamic therapy are selected from at least one of porphyrins, chlorophylls, phthalocyanines, fused ring quinones, 2-seleniucl, PPA-904, Cercosporin (Cercosporin), polypeptide Gly-Pro-Leu-Gly-Ile-Ala-Gly-gln (gplgiagq), Methylene Blue (Methylene Blue).
Optionally, the porphyrin-like compound is selected from at least one of Purpurin 18(Purpurin 18), 5-aminolevulinic acid (5-ALA), Talaporfin (Talaporfin), hematoporphyrin derivative (HPD), dimethylporphyrin ether (DHE), and photosensitizer Photofrin.
Optionally, the chlorophyll-like compound is selected from at least one of pheophorbide a (pyrophoride a), pyropheophorbide a (pyropheophorbide a), chlorin e6(Ce6), N-asparaginyl chlorin (NPe6), pyropheophorbide a-hexyl ether derivative (HPPH).
Optionally, the phthalocyanine compound is selected from at least one of phthalocyanine, naphthalocyanine, zinc phthalocyanine, disulfo-diphthalimide methyl zinc phthalocyanine and sulfonated aluminum phthalocyanine.
Optionally, the fused ring quinone photosensitizer is selected from at least one of Hypocrellin A, Hypocrellin B, hypericin, and buckwheat alkali.
The antineoplastic drug molecules used for sonodynamic therapy are selected from at least one of porphyrin and derivatives thereof, acridine compounds, dye compounds, antineoplastic drugs and metal complexes.
Optionally, the porphyrin and its derivatives are selected from at least one of hematoporphyrin (Photodyn), hematoporphyrin methyl ether, ATX-70, protoporphyrin IX.
Optionally, the acridine compound is selected from at least one of acridine red and acridine orange.
Optionally, the dye compound is selected from at least one of rose bengal B, hypocrellin B, eosin B and erythrosine.
Optionally, the antitumor drug is selected from at least one of cisplatin, daunorubicin, and doxorubicin (Dox).
Optionally, the metal complex is selected from at least one of iron complexes, magnesium complexes, and sodium complexes.
Optionally, the antineoplastic drug molecules for magnetothermal therapy are selected from Fe3O4、Fe2O3、Fe、MnFe2O4、Co、Mn0.4Zn0.6Fe2O4、Mn0.4Zn0.6Fe1.96-Gd0.06O4、CoFe2O4、Co0.95Fe2.05O4At least one of (1).
Optionally, the linking method in step (2) is a chelate coordination method and/or a chemical coupling method.
Optionally, the antineoplastic drug molecules for magnetothermal therapy are selected from Fe with an outer layer containing a wrapper3O4、Fe2O3、Fe、MnFe2O4、Co、Mn0.4Zn0.6Fe2O4、Mn0.4Zn0.6Fe1.96-Gd0.06O4、CoFe2O4、Co0.95Fe2.05O4At least one of (1).
According to another aspect of the present application, there is also provided a method for preparing the tumor-targeted drug, the method at least comprising:
the tumor targeting drug can be obtained by reacting a mixture containing an active targeting unit, a condensing agent and/or a chelating agent and an anti-tumor drug molecule.
Optionally, the method comprises at least: and reacting the mixture containing the active targeting unit, the condensing agent and the anti-tumor drug molecules to obtain the tumor targeting drug.
Optionally, the method comprises at least: and reacting the mixture containing the active targeting unit, the condensing agent, the chelating agent and the antitumor drug molecules to obtain the tumor targeting drug.
Optionally, the method comprises at least:
(1) obtaining a material with a neuropeptide YY3 receptor targeting function (namely an active targeting unit);
(2) connecting the material with the neuropeptide YY3 receptor targeting function in the step (1) with an anti-tumor drug molecule.
Optionally, the material with the neuropeptide YY3 receptor targeting function in the step (1) can be combined with the tumor cells over-expressed by the neuropeptide Y3 receptor with high specificity.
Optionally, the reaction conditions are: the reaction temperature is 0-80 ℃; the reaction time is 5 minutes to 48 hours.
Alternatively, the condensing agent is selected from 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC), N-hydroxysuccinimide (NHS), Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), 4-pyrrolidinopyridine (4-PPY), 4-Dimethylaminopyridine (DMAP), 1-hydroxy-7-azobenzotriazol (HOAt), 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), N-hydroxy-phthalimide (NHPI), 2-hydroxy-3 a,4,4,7 a-tetrahydro-1H-4, 7-methylisoindole-1, 3(2H) -dione (NHNI), pentafluorophenol (PFPOH), 2- (7-azobenzotriazol) -N, n, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1, 1,3, 3-tetramethyluronium Hexafluorophosphate (HCTU), 1- (1-pyrrolidinyl-1H-1, 2, 3-triazolo [4,5b ] pyridin-1-ylmethylene) -pyrrolidinyl-hexafluorophosphate N-oxide (HAPyU), O- (benzotriazol-1-yl) -N, N, N ', N' -bis (tetramethylene) urea hexafluorophosphate (HBPyU), benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate (TBTU), O- (N-succinamidediimino) -bis (dimethylamino) carbenium tetrafluoroborate (TSTU) ) O- (5-norbornenyl-2, 3-dicarboximide) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TNTU), 7-azabenzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (AOP), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (3H-1,2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tris-1-pyrrolidinophosphonium hexafluorophosphate (PyAOP), diphenylphosphinic chloride (DPP-Cl), diethyl cyanophosphate (DECP), Diphenylphosphate (DPPA), thiodimethylphosphorylazide (MPTA), Bis (2-oxo-3-oxazolidinyl) phosphorylidene chloride (BOP-Cl), benzotriazol-1-yloxy-N, N dimethyl-azomethine hexachloroantimonate (BOMI), 5- (1H-benzotriazol-1-yloxy) -3, 4-dihydro-1-methyl-2H-pyrroline hexachloroantimonate (BDMP), 1- (1H-benzotriazol-1-yloxy) benzyl-methylene-pyrrole hexachloroantimonate (BPM), 2-bromo-1-methylpyrrole hexachloroantimonate (BMMP), 5- (3',4' -dihydro-4 ' -oxo-1 ',2', 3' -benzotriazin-3 ' -yloxy) -3, 4-dihydro-1-methyl-2H-pyrroline (DOMP), 5- (7-azobenzotriazol-1-yloxy) -3, 4-dihydro-1-methyl-2H-pyrroline hexachloroantimonate (AOMP), 5- (pentafluorobenzyloxy) 3, 4-dihydro-1-methyl-2H-pyrroline hexachloroantimonate (FOMP), 5- (succinimidyloxy) -3, 4-dihydro-1-methyl-2H-pyrroline hexachlorophosphate (SOMP), 2-bromo-1-ethylpyridine tetrafluoroborate (BEP), 2-fluoro-1-methylpyridine tetrafluoroborate (FEP), 2-bromo-1-ethylpyridine hexachloroantimonate (BEPH), 2-fluoro-1-ethylpyridine hexachloroantimonate (FEPH), 2-bromo-3-ethyl-4-methylthiazole hexafluoroborate (BEMT), 2-chloro-1, 3-dimethyl-1H-benzimidazole hexafluorophosphate (CMBI), chloro-tris (pyrrolidinyl) phosphine hexafluorophosphate (PyCloP), 2,4, 6-trimorpholinyl-s-triazine (CMMM).
Alternatively, the chelating agent is selected from 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetracarboxylic acid (DOTA), 2, 4-di-tert-amylphenol (DTAP), tetracarboxylic acid ethylenediaminetetraacetic acid (EDTA), aminotrimethylenephosphonic Acid (ATMP), sodium Ethylenediaminetetramethylenephosphonate (EDTMPS), 1-hydroxyethylidene-1, 1-diphosphonic acid (HEDP), diethylenetriaminepentamethylenephosphonic acid (DTPMPA), sodium Polyacrylate (PAAS), sodium ethylenediamine dipentyleneacetate (EDDHA-Na), 2-phosphonobutane-1, 2, 4-tricarboxylic acid (PBTCA), 2-hydroxyphosphonoacetic acid (HPAA), hexamethylenediaminetetramethylenephosphonic acid (HDTMPA), bis-1, 6-ethylenetriaminepentamethylenephosphonic acid (bhmtpma), Polyaspartic Acid (PASP), polyepoxysuccinic acid (PESA), Maleic acid-acrylic acid copolymer (MA-AA), nitrilotriacetic acid (NTA), iminodiacetic acid (IDA), Dimethyloxyethylglycine (DEG), N-hydroxyethylethanamine triacetic acid (HEDTA), sodium tripolyphosphate, sodium pyrophosphate, trisodium phosphate, sodium citrate, sodium gluconate, sodium potassium tartrate and sodium silicate.
Optionally, the molar ratio of the active targeting unit, the condensing agent and/or the chelating agent to the antitumor drug molecules is 1-10:3-30: 1-10.
Optionally, the mixture further comprises a solvent;
the solvent is at least one selected from water, methanol, ethanol, propanol, ethylene glycol, glycerol, N-dimethylformamide, acetonitrile, tetrahydrofuran and pyridine.
Optionally, the reaction is carried out in a microwave reactor.
According to another aspect of the application, a tumor-targeted drug is also provided, which comprises at least one of the tumor-targeted drug and the tumor-targeted drug prepared by the method.
According to another aspect of the application, the application of the tumor-targeted medicine and the tumor-targeted medicine prepared by the method in preparing a tumor treatment medicine is also provided, wherein the tumor comprises at least one of esophageal cancer, breast cancer, kidney cancer, ovarian cancer, lung cancer, colorectal cancer and leukemia with high expression of neuropeptide YY3 receptor.
Optionally, the method comprises at least: and (3) continuously stirring a mixture containing the active targeting unit, the antitumor drug molecules for chemical drug therapy, the condensing agent and the solvent at 0-80 ℃ for reaction for 5 minutes-48 hours, and purifying to obtain the tumor targeting drug.
Optionally, the method comprises at least: and (3) continuously stirring a mixture containing the active targeting unit, the anti-tumor drug molecules for photothermal therapy, the condensing agent and the solvent at 0-80 ℃ for reaction for 5 minutes-48 hours, and purifying to obtain the tumor targeting drug.
Optionally, the method comprises at least: and (3) continuously stirring a mixture containing the active targeting unit, the anti-tumor drug molecules for photodynamic therapy, the condensing agent and the solvent at 0-80 ℃ for reaction for 5 minutes-48 hours, and purifying to obtain the tumor targeting drug.
Optionally, the method comprises at least: and (3) continuously stirring a mixture containing the active targeting type unit, the anti-tumor drug molecules for sonodynamic therapy, the condensing agent and the solvent at 0-80 ℃ for reacting for 5 minutes-48 hours, and purifying to obtain the tumor targeting drug.
Optionally, the method comprises at least: and (3) continuously stirring a mixture containing the active targeting type unit, the anti-tumor drug molecules for the magnetic thermal treatment, the condensing agent, the chelating agent and the solvent at 0-80 ℃ for reaction for 5 minutes-48 hours, and purifying to obtain the tumor targeting drug.
Alternatively, the method for preparing the polypeptide in the present application comprises: and (3) sequentially connecting amino acids protected by Fmoc to resin through microwave reaction of an automatic polypeptide synthesizer according to a specified sequence, taking a small amount of resin after the reaction is finished, performing cutting analysis, and determining the polypeptide to be the polypeptide of the specified sequence through mass spectrometry.
The application also provides an application of the tumor targeting drug or the tumor targeting drug prepared by the method in the preparation of a tumor treatment drug, wherein the tumor comprises at least one of esophageal cancer, breast cancer, kidney cancer, ovarian cancer, lung cancer, colorectal cancer and leukemia with high expression of neuropeptide YY3 receptor.
The beneficial effects that this application can produce include:
(1) the tumor targeting drug is a drug for tumor treatment, and has the tumor targeting performance and the tumor killing function;
(2) the invention provides a medicament for actively targeted therapy of tumors on the basis of a new tumor target neuropeptide YY3 receptor, and can realize targeted chemical drug therapy, photothermal therapy, photodynamic therapy, sonodynamic therapy or magnetocaloric therapy, thereby realizing the effect of precise therapy of tumors.
Drawings
FIG. 1 is a graph showing the results of targeting Compound A1 to cancer cells in example 1;
FIG. 2 is a graph showing the results of the tumor mouse therapy with Compound A1 in example 1.
Detailed Description
The following examples are given to further illustrate the present invention, but the present application is not limited to these examples. It should be noted that the following examples are not to be construed as limiting the scope of the present invention, and that the skilled person in this field could make modifications and variations of the present invention without departing from the spirit or essential attributes thereof.
Chemical reagents such as raw materials and the like related to the embodiments of the application are all commercial products without special description; wherein the antibody and the small molecule inhibitor are purchased from MedChemexpress; various signal molecules were purchased from the national pharmaceutical group chemical reagents, Shanghai Biyuntian Biotechnology, Inc., and Shanghai Aladdin Biotechnology, Inc.
The cell lines OE19, MDA-MB-231, A498, A549, LS180 corresponding to esophageal, breast, kidney, lung and colorectal cancers to which the present application relates were all purchased from the American cell dictionary and tested after culture according to the instructions.
The automatic microwave synthesizer for polypeptide in the embodiment of the application is Biotage Initiator + SP Wave.
EXAMPLE 1 Synthesis of Compound A1(CTCE-9908-Dox)
Synthesis of a1 according to the following procedure:
DMF is used as a solvent, amino acids protected by Fmoc are sequentially connected to resin through microwave reaction of an automatic polypeptide synthesizer according to the sequence of the polypeptide CTCE-9908, a small amount of resin is taken for cutting analysis after the reaction is finished, and after the polypeptide is determined to be CTCE-9908 through mass spectrometry, chemotherapeutic drugs Dox and a condensing agent EDC/NHS are added to continue to carry out microwave reaction for 5 minutes at 45 ℃. And taking a small amount of resin for detection after the reaction is finished. After confirming that the reaction after Dox grafting is finished, washing the crude product for multiple times by using a solvent DMF until a filtrate is clear, cutting the synthesized resin by using 90% trifluoroacetic acid and removing amino acid side chain protection, and then purifying the resin by using a preparative chromatography until the purity is 99%, wherein the purification process is automatically monitored by the preparative chromatography. Precipitating the crude product in glacial ethyl ether, centrifuging, collecting precipitate, washing, redissolving with deionized water, filtering and freeze-drying to obtain the compound A1.
EXAMPLE 2 Synthesis of Compounds A2-A55
The concrete operations of the compounds A2 to A55 in this example were the same as in example 1; wherein, when synthesizing A45-A55, the condensing agent is added, meanwhile, the chelating agent DOTA with equal molar quantity is also added, and the rest conditions are shown in Table 1.
TABLE 1
Figure BDA0002524657540000051
Figure BDA0002524657540000061
EXAMPLE 3 Synthesis of Compound A56(BMS-936564-5-Fu)
Compound a56 was synthesized as follows:
mixing the antibody BMS-936564, the chemotherapeutic drug 5-Fu, the condensing agent EDC/NHS and the solvent DMF in a molar ratio of 1:1:3:3 in a microwave reaction instrument for microwave reaction at 25 ℃ for 15 minutes. After the reaction is finished, the crude product is dialyzed in a large amount of DMF to remove redundant 5-Fu and condensing agent EDC/NHS, the solution is changed for a plurality of times until the dialyzate is clarified, the crude product is precipitated in glacial ethyl ether, the precipitate is collected by centrifugation, washed, redissolved by deionized water, filtered and lyophilized to obtain the compound A56.
Example 4 Synthesis of Compounds A57-A90
The concrete operations of the compounds A57 to A90 in this example were the same as in example 3; wherein, when synthesizing A84-A90, the condensing agent is added, meanwhile, the chelating agent DOTA with equal molar quantity is also added, and the rest conditions are shown in Table 2.
TABLE 2
Figure BDA0002524657540000062
Figure BDA0002524657540000071
EXAMPLE 5 Synthesis of Compound A91(AMD3100-Taxol)
Compound a91 was synthesized as follows:
mixing a small molecule inhibitor AMD3100, a chemotherapeutic drug Taxol, a condensing agent EDC/NHS and a solvent DMF in a molar ratio of 1:1:3:3 in a microwave reactor, and carrying out microwave reaction for 10 minutes at 35 ℃. And after the reaction is finished, dialyzing the crude product in a large amount of DMF to remove redundant Taxol and a condensing agent EDC/NHS, changing the solution for many times until the dialyzate is clarified, precipitating the crude product in glacial ethyl ether, centrifuging, collecting the precipitate, washing, redissolving by using deionized water, filtering and freeze-drying to obtain the compound A91.
Example 6 Synthesis of Compounds A92 to A125
The specific procedures for compounds A92-A125 in this example were the same as in example 5; wherein, when synthesizing A119-A125, the condensing agent is added, meanwhile, the chelating agent DOTA with equal molar quantity is also added, and the rest conditions are shown in Table 3.
TABLE 3
Figure BDA0002524657540000072
Figure BDA0002524657540000081
Example 7 intracellular phagocytosis assay
Phagocytosis experiments of human esophageal cancer cells were performed on the compounds a1 to a11, a56 to a62, and a91 to a97 in examples 1 to 6.
Example 1 testing of the synthesized compound a1 was as follows:
105 human esophageal cancer cells were seeded in 6-well plates at 37 ℃ with 5% CO2Incubate overnight. To this was then added equimolar concentrations (measured as the concentration of Dox in the compound) of free Dox and a 1. After incubating for 12 hours, cells were collected, washed with PBS for three times, and then examined for absorption intensity of 10000 human esophageal cancer cells with an ultraviolet-visible absorption spectrometer, respectively, and signals were collected at 450nm, and the results are shown in fig. 1. It can be seen from the figure that the synthesized compound A1 has the property of actively targeting human esophageal cancer tumor cells.
The test methods of the other compounds were the same as those of A1 except that the compounds corresponded to the components A1 to A11, A56 to A62 and A91 to A97, respectively, and the test apparatuses used therefor were different. The test results are similar to those described above, and all the results lead to the conclusion that the synthesized compound has active targeting on human esophageal cancer tumor cells.
Example 8 in vivo chemotherapeutic drug treatment experiment in human esophageal carcinoma mice
The compounds A1-A11, A56-A62 and A91-A97 in examples 1 to 6 were used in a chemotherapy experiment for human esophageal cancer mice. The test of compound a1 in example 1 is typically represented by the following:
the obtained compound A1 was formulated with PBS water to a drug concentration of 5mg/mL, and injected into mice by tail vein injection at 100. mu.L. Mice were observed for relative volume changes of tumors in the back, once every two days, for a total of 5 injections. The results are shown in fig. 2, and compound a1 has a good inhibitory effect on human esophageal cancer.
Example 9 in vivo photothermal therapy experiment in human Breast cancer-bearing mice
The compounds A12-A22, A63-A69 and A98-A104 in examples 1-6 were used in photothermal therapy experiments of human breast cancer mice. The test of compound a12 in example 2 is typically represented by the following:
the obtained compound A12 was formulated with PBS water to a drug concentration of 5mg/mL, and injected into mice by tail vein injection at 100. mu.L. The injection is performed once every two days, 5 times in total, and the relative volume change of the tumor on the back of the mouse is observed after the photothermal treatment. The result is similar to that in figure 2, the compound A12 has better inhibiting effect on human breast cancer through photothermal treatment.
Example 10 in vivo photodynamic therapy experiment on human renal carcinoma mice
The compounds A23-A33, A70-A76, A105-A111 in examples 1 to 6 were subjected to photodynamic therapy experiments in mice with human kidney cancer. The test of compound a23 in example 2 is typically represented by the following:
the obtained compound A23 was formulated with PBS water to a drug concentration of 5mg/mL, and injected into mice by tail vein injection at 100. mu.L. The injection is performed every other day, 5 times in total, and the relative volume change of the tumor on the back of the mouse is observed after photodynamic therapy. The results are similar to those in fig. 2, and the compound A23 has better inhibition effect on human kidney cancer through photodynamic therapy.
Example 11 in vivo sonodynamic therapy experiment on human Lung cancer mice
The compounds A34-A44, A77-A83 and A112-A118 of examples 1 to 6 were used in the sonodynamic therapy of human lung cancer mice. The test of compound a34 in example 2 is typically represented by the following:
the obtained compound A34 was formulated with PBS water to a drug concentration of 5mg/mL, and injected into mice by tail vein injection at 100. mu.L. The injection was performed every two days for a total of 5 times, and the relative volume change of the tumor in the back of the mice was observed after the sonodynamic treatment. The result is similar to that in figure 2, the compound A34 has better inhibiting effect on human lung cancer through sonodynamic treatment.
Example 12 in vivo magnetocaloric therapy experiments in human colorectal cancer-bearing mice
The compounds A45-A55, A84-A90 and A119-A125 in examples 1 to 6 were subjected to a magnetocaloric therapy experiment for human colorectal cancer mice. The test of compound a45 in example 2 is typically represented by the following:
the obtained compound A45 was formulated with PBS water to a drug concentration of 5mg/mL, and injected into mice by tail vein injection at 100. mu.L. The injection was performed every two days for a total of 5 times, and the relative volume change of the tumor in the back of the mice was observed after the magnetic heat treatment. The result is similar to that in fig. 2, compound a45 has better inhibitory effect on human colorectal cancer by magnetocaloric treatment.
Example 13 in vivo treatment experiments in tumor-bearing mice
The compounds A2-A125 from examples 1 to 6 were used in tumor-bearing mouse therapy experiments under conditions corresponding to examples 8 to 12. The therapeutic effects are shown in tables 4 to 8. The inhibition rate is calculated by taking the ratio of the tumor volume of the compound group to the tumor volume of the control group on the twentieth day.
TABLE 4
Figure BDA0002524657540000091
Figure BDA0002524657540000101
Figure BDA0002524657540000111
Note: + + + + + + indicates an inhibition of greater than 85%; + + + + represents an inhibition ratio of 60% to 85%; + represents an inhibition rate of 40% to 60%; + represents an inhibition rate of 40% or less.
TABLE 5
Figure BDA0002524657540000112
Figure BDA0002524657540000121
Note: + + + + + + indicates an inhibition of greater than 85%; + + + + represents an inhibition ratio of 60% to 85%; + represents an inhibition rate of 40% to 60%; + represents an inhibition rate of 40% or less.
TABLE 6
Figure BDA0002524657540000122
Figure BDA0002524657540000131
Figure BDA0002524657540000141
Note: + + + + + + indicates an inhibition of greater than 85%; + + + + represents an inhibition ratio of 60% to 85%; + represents an inhibition rate of 40% to 60%; + represents an inhibition rate of 40% or less.
TABLE 7
Figure BDA0002524657540000142
Figure BDA0002524657540000151
Note: + + + + + + indicates an inhibition of greater than 85%; + + + + represents an inhibition ratio of 60% to 85%; + represents an inhibition rate of 40% to 60%; + represents an inhibition rate of 40% or less.
TABLE 8
Figure BDA0002524657540000161
Figure BDA0002524657540000171
Note: + + + + + + indicates an inhibition of greater than 85%; + + + + represents an inhibition ratio of 60% to 85%; + represents an inhibition rate of 40% to 60%; + represents an inhibition rate of 40% or less.
Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.

Claims (10)

1. A tumor-targeted drug, which is characterized by comprising an active targeting unit and an anti-tumor drug molecule; the active targeting unit and the antitumor drug molecules are sequentially connected through a chelation reaction and/or a chemical coupling reaction.
2. The tumor targeting drug according to claim 1, characterized in that said actively targeted unit actively targets tumor cells overexpressing the neuropeptide YY3 receptor;
the antitumor drug molecules are used for at least one of chemical drug therapy, photothermal therapy, photodynamic therapy, sonodynamic therapy and magnetocaloric therapy.
3. The tumor targeting drug according to claim 1, wherein the active targeting unit is selected from at least one of a polypeptide, an antibody, and a small molecule inhibitor.
4. The tumor targeting drug according to claim 3, wherein said polypeptide is selected from the group consisting of CTCE-9908, T140, TC14012, T22, POL6326, POL5551, LY2510924, RCP168, TF14016, FC131, DV3 and at least one of the above polypeptide derivatives;
the antibody is selected from at least one of BMS-936564, MEDI3185, Anti-VLA-4mAb, hz515H7, Clone 12G5, LY2624587, PF-06747143 and antibody derivatives thereof;
the small molecule inhibitor is selected from at least one of AMD3100, BKT140, AMD3465, IT1t, AMD11070, KRH-3955, MSX-122 and derivatives thereof.
5. The tumor-targeted drug according to claim 2, wherein the antitumor drug molecules for chemotherapeutic treatment are selected from at least one of alkylating agents, antimetabolites, antitumor antibiotics, plant-based antitumor drugs, antitumor hormones, and immunological agents;
the anti-tumor drug molecules for photothermal therapy are selected from at least one of group-modified noble metal nanoparticles, group-modified metal chalcogenide nanoparticles, group-modified carbon-based nanomaterials, organic near-infrared dyes and porphyrin liposome nanoparticles;
the group is selected from at least one of hydroxyl, carboxyl and amino;
the antineoplastic drug molecules for photodynamic therapy are selected from at least one of porphyrin compounds, chlorophyll compounds, phthalocyanine compounds, fused ring quinone photosensitizer, 2-Selenouracil, PPA-904, cercosporin, polypeptide Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln and methylene blue;
the antineoplastic drug molecules for sonodynamic therapy are selected from at least one of porphyrin and derivatives thereof, acridine compounds, dye compounds, antineoplastic drugs and metal complexes;
the antitumor drug is at least one of cisplatin, daunorubicin and adriamycin;
the antineoplastic drug molecules for magnetic thermal therapy are selected from Fe3O4、Fe2O3、Fe、MnFe2O4、Co、Mn0.4Zn0.6Fe2O4、Mn0.4Zn0.6Fe1.96-Gd0.06O4、CoFe2O4、Co0.95Fe2.05O4At least one of (1).
6. The process for the preparation of a tumor targeting drug according to any of the claims 1 to 5, characterized in that the process at least comprises:
the tumor targeting drug can be obtained by reacting a mixture containing an active targeting unit, a condensing agent and/or a chelating agent and an anti-tumor drug molecule.
7. The method according to claim 6, wherein the reaction conditions are as follows: the reaction temperature is 0-80 ℃; the reaction time is 5 minutes to 48 hours.
8. The preparation method according to claim 6, wherein the molar ratio of the active targeting unit to the condensing agent and/or chelating agent to the antitumor drug molecule is 1-10:3-30: 1-10.
9. The method according to claim 6, wherein the condensing agent is selected from the group consisting of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, N-hydroxysuccinimide, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 4-pyrrolidinopyridine, 4-dimethylaminopyridine, 1-hydroxy-7-azobenzotriazol, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxycyclophthalimide, 2-hydroxy-3 a,4,4,7 a-tetrahydro-1H-4, 7-methylisoindole-1, 3(2H) -dione, pentafluorophenol, 2- (7-azobenzotriazol) -N, n ', N ' -tetramethyluronium hexafluorophosphate, benzotriazol-N, N, N ', N ' -tetramethyluronium hexafluorophosphate, 6-chlorobenzotriazole-1, 1,3, 3-tetramethyluronium hexafluorophosphate, 1- (1-pyrrolidinyl-1H-1, 2, 3-triazolo [4,5b ] pyridin-1-ylmethylene) -pyrrolidinyl-hexafluorophosphate N-oxide, O- (benzotriazol-1-yl) -N, N, N ', N ' -bis (tetramethylene) urea hexafluorophosphate, benzotriazol-N, N, N ', N ' -tetramethyluronium hexafluorophosphate, O- (N-succinimidyl) -bis (dimethylamino) carbenium tetrafluoroborate, salts of N, N ' -tetramethyluronium hexafluorophosphate, salts of N, N-butanediamine and N- (N-butanediamine-1-yl) -bis (dimethylamino) carbenium tetrafluoroborate, O- (5-norbornenyl-2, 3-dicarboximide) -N, N, N ', N' -tetramethyluronium tetrafluoroborate, 7-azabenzotriazol-1-yloxytris (dimethylamino) phosphine hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, (3H-1,2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tris-1-pyrrolidinylphosphonium hexafluorophosphate, diphenylphosphinic chloride, diethyl cyanophosphate, diphenyl phosphorazide, thiodimethylphosphorylazide, bis (2-oxo-3-oxazolidinyl) phosphoryl chloride, sodium chloride, potassium chloride, magnesium chloride, benzotriazole-1-yloxy-N, N dimethyl-azomethine hexachloroantimonate, 5- (1H-benzotriazole-1-yloxy) -3, 4-dihydro-1-methyl-2H-pyrroline hexachloroantimonate, 1- (1H-benzotriazole-1-yloxy) benzyl-methylene-pyrrole hexachloroantimonate, 2-bromo-1-methylpyrrole hexachloroantimonate, 5- (3',4' -dihydro-4 ' -oxy-1 ',2', 3' -benzotriazin-3 ' -yloxy) -3, 4-dihydro-1-methyl-2H-pyrroline, 5- (7-azobenzotriazole-1-yloxy) -3, 4-dihydro-1-methyl-2H-pyrroline hexachloroantimonate, 5- (pentafluorobenzyloxy) 3, 4-dihydro-1-methyl-2H-pyrroline hexachloroantimonate, 5- (succinimidyloxy) -3, 4-dihydro-1-methyl-2H-pyrroline hexachlorophosphate, 2-bromo-1-ethylpyridine tetrafluoroborate, 2-fluoro-1-methylpyridine tetrafluoroborate, 2-bromo-1-ethylpyridine hexachloroantimonate, 2-fluoro-1-ethylpyridine hexachloroantimonate, 2-bromo-3-ethyl-4-methylthiazole hexafluoroborate, 2-chloro-1, 3-dimethyl-1H-benzimidazole hexafluorophosphate, sodium hexafluoroantimonate, sodium hexafluoro-1, sodium hexafluoro-3-dimethyl-1H-benzimidazole, sodium hexafluoro-phosphate, sodium hexafluoro-bis (sodium hexafluoro-sodium, At least one of chloro-tris (pyrrolidinyl) phosphine hexafluorophosphate and 2,4, 6-trimorpholinyl-s-triazine;
the chelating agent is selected from 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetracarboxylic acid, 2, 4-di-tert-amylphenol, tetracarboxylic acid ethylene diamine tetraacetic acid, aminotrimethylene phosphonic acid, ethylene diamine tetramethylene sodium phosphonate, 1-hydroxyethylidene-1, 1-diphosphonic acid, diethylenetriamine pentamethylene phosphonic acid, sodium polyacrylate, ethylenediamine dipentyl sodium acetate, 2-phosphonobutane-1, 2, 4-tricarboxylic acid, 2-hydroxyphosphonoacetic acid, hexamethylenediamine tetramethylidene phosphonic acid, bis-1, 6-ethylenetriamine pentamethylene phosphonic acid, polyaspartic acid, polyepoxysuccinic acid, maleic acid-acrylic acid copolymer, nitrilotriacetic acid, iminodiacetic acid, dimethyloxyethylglycine, N-hydroxyethylethylamine triacetic acid, N-hydroxyethylamine triacetic acid, At least one of sodium tripolyphosphate, sodium pyrophosphate, trisodium phosphate, sodium citrate, sodium gluconate, potassium sodium tartrate and sodium silicate;
preferably, the mixture further comprises a solvent;
the solvent is at least one selected from water, methanol, ethanol, propanol, ethylene glycol, glycerol, N-dimethylformamide, acetonitrile, tetrahydrofuran and pyridine;
preferably, the reaction is carried out in a microwave reactor.
10. Use of a tumor-targeted pharmaceutical according to any one of claims 1 to 5 or prepared according to any one of claims 6 to 9 for the preparation of a medicament for the treatment of tumors, wherein said tumors comprise at least one of esophageal cancer, breast cancer, renal cancer, ovarian cancer, lung cancer, colorectal cancer, leukemia with high expression of the neuropeptide YY3 receptor.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN108210506A (en) * 2017-12-22 2018-06-29 上海交通大学 PH is responded and the Nano medication delivery vector of polypeptide targeting and its preparation and application
CN108578708A (en) * 2018-04-25 2018-09-28 中国科学院化学研究所 A kind of double target polypeptide-drug conjugates and preparation method thereof and antitumor application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108210506A (en) * 2017-12-22 2018-06-29 上海交通大学 PH is responded and the Nano medication delivery vector of polypeptide targeting and its preparation and application
CN108578708A (en) * 2018-04-25 2018-09-28 中国科学院化学研究所 A kind of double target polypeptide-drug conjugates and preparation method thereof and antitumor application thereof

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Application publication date: 20211207