CN113144175A - Tumor microenvironment response CO gas therapeutic agent and preparation method and application thereof - Google Patents
Tumor microenvironment response CO gas therapeutic agent and preparation method and application thereof Download PDFInfo
- Publication number
- CN113144175A CN113144175A CN202110345675.XA CN202110345675A CN113144175A CN 113144175 A CN113144175 A CN 113144175A CN 202110345675 A CN202110345675 A CN 202110345675A CN 113144175 A CN113144175 A CN 113144175A
- Authority
- CN
- China
- Prior art keywords
- uio
- mnbr
- nano
- gas
- tumor microenvironment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 53
- 239000003814 drug Substances 0.000 title claims abstract description 39
- 229940124597 therapeutic agent Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title abstract description 17
- 230000004044 response Effects 0.000 title description 9
- 239000013208 UiO-67 Substances 0.000 claims abstract description 78
- 239000002105 nanoparticle Substances 0.000 claims abstract description 50
- 235000019420 glucose oxidase Nutrition 0.000 claims abstract description 35
- 108010015776 Glucose oxidase Proteins 0.000 claims abstract description 13
- 239000004366 Glucose oxidase Substances 0.000 claims abstract description 13
- 229940116332 glucose oxidase Drugs 0.000 claims abstract description 13
- 239000011148 porous material Substances 0.000 claims abstract description 11
- 230000000704 physical effect Effects 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- KVQMUHHSWICEIH-UHFFFAOYSA-N 6-(5-carboxypyridin-2-yl)pyridine-3-carboxylic acid Chemical compound N1=CC(C(=O)O)=CC=C1C1=CC=C(C(O)=O)C=N1 KVQMUHHSWICEIH-UHFFFAOYSA-N 0.000 claims description 5
- 238000004729 solvothermal method Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 claims description 4
- 238000001179 sorption measurement Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 abstract description 3
- 230000004043 responsiveness Effects 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000007789 gas Substances 0.000 description 41
- 210000004027 cell Anatomy 0.000 description 33
- 239000000243 solution Substances 0.000 description 26
- 239000002953 phosphate buffered saline Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000002560 therapeutic procedure Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000011068 loading method Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- -1 UiO-67@ MnBr (CO)5 Substances 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 4
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000000799 fluorescence microscopy Methods 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 108010054147 Hemoglobins Proteins 0.000 description 3
- 102000001554 Hemoglobins Human genes 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000000174 gluconic acid Substances 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 238000000703 high-speed centrifugation Methods 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- YRNWIFYIFSBPAU-UHFFFAOYSA-N 4-[4-(dimethylamino)phenyl]-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1C1=CC=C(N(C)C)C=C1 YRNWIFYIFSBPAU-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 108010003320 Carboxyhemoglobin Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229910001437 manganese ion Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 239000002114 nanocomposite Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- BJDYCCHRZIFCGN-UHFFFAOYSA-N pyridin-1-ium;iodide Chemical compound I.C1=CC=NC=C1 BJDYCCHRZIFCGN-UHFFFAOYSA-N 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000005316 response function Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
-
- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
- A61K47/6931—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
- A61K47/6935—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
- C12Y101/03—Oxidoreductases acting on the CH-OH group of donors (1.1) with a oxygen as acceptor (1.1.3)
- C12Y101/03004—Glucose oxidase (1.1.3.4)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Nanotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a CO gas therapeutic agent responding to a tumor microenvironment as well as a preparation method and application thereof, belonging to the technical field of pharmaceutical preparations. The CO gas therapeutic agent responding to the tumor microenvironment comprises UiO-67 nano particles, MnBr (CO)5And glucose oxidase GOx; wherein: MnBr (CO)5The glucose oxidase GOx is modified on the skeleton of the UiO-67 nano-particles through coordination bonds, and is adsorbed in the pores of the UiO-67 nano-particles through physical action. The CO gas therapeutic agent has the characteristic of tumor microenvironment responsiveness and is prepared by over-expressing H in a tumor microenvironment2O2To achieve a controlled release of CO gas.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a CO gas therapeutic agent responding to a tumor microenvironment, and a preparation method and application thereof.
Background
In recent years, gas therapy has been vigorously developed and has become cancerAn emerging field of therapy. Gas therapy is an emerging new strategy for tumor therapy with great application prospects. NO, H2The pharmacological activity of gaseous messenger molecules such as S and CO has attracted the interest of researchers, and these gaseous messenger molecules have been developed as new therapeutic approaches against certain cancers and cardiovascular diseases, and these endogenous gases have specific molecular targets, strong physiological function regulating functions, and high permeability across biological membranes, and thus have great advantages over traditional drugs. For example, the beneficial effects of low doses of CO (100->250 ppm) significantly induced pro-apoptosis in cancer cells but not normal cells. Although CO still shows a strong protective effect on normal cells, it has antiproliferative and pro-apoptotic effects on several cancer cells. However, the use of CO as a therapeutic agent presents significant challenges in controlling the delivery of appropriate CO concentrations to the diseased site and monitoring CO concentrations in real time to avoid unexpected systemic side effects on normal tissues and blood. Therefore, how to achieve tumor-targeted delivery of gas molecules, controllable gas release, and assistance of traditional tumor therapy methods for attenuation and synergy is still considered as a great challenge in clinical application of gas therapy.
The use of chemical drugs that are silenced in non-tumor tissues but are specifically activated under tumor-specific metabolic conditions is a promising approach, e.g. overexpressed enzymes, H2O2An overproduced active oxygen, a hypoxic microenvironment. According to the invention, the nano-carrier loaded CO gas prodrug is used as a CO gas therapeutic agent responding to a tumor microenvironment, so that accurate and controllable release of CO gas at a tumor part can be realized.
Disclosure of Invention
The invention aims to provide a CO therapeutic agent which has strong specificity, controllable release and simple synthesis method and can be released in response to a tumor microenvironment.
The invention also aims to provide a preparation method and application of the CO gas therapeutic agent.
In order to achieve the purpose, the invention adopts the following technical scheme:
a CO gas therapeutic agent for tumor microenvironment response comprises UiO-67 nanoparticles, MnBr (CO)5And glucose oxidase GOx;
said MnBr (CO)5The glucose oxidase GOx is modified on the skeleton of the UiO-67 nano-particles through coordination bonds, and is adsorbed in the pores of the UiO-67 nano-particles through physical action.
The glucose in the tumor cell generates gluconic acid and H under the catalysis of glucose oxidase GOx2O2(ii) a Gluconic acid will lower the pH of the tumor microenvironment to promote degradation of the UiO-67 nanoparticles, releasing MnBr (CO)5H overexpressed in the tumor microenvironment2O2Releasing CO; at the same time H2O2Can trigger MnBr (CO)5Decompose to release Mn2+And with H in tumor cells2O2A Fenton-like reaction (Fenton-like reaction) occurs to generate hydroxyl radicals (.oh).
Further, the diameter of the UiO-67 nano-particles is 70-100 nm.
The preparation method of the CO gas therapeutic agent comprises the following steps:
and 3, adsorbing glucose oxidase GOx into the pore channels of the nanoparticles obtained in the step 2 by adopting a pore channel adsorption method to obtain the nanoparticle.
Further, the specific process for preparing the UiO-67 nanoparticles by using the high-temperature solvothermal method in the step 1 is as follows: dissolving 2,2' -bipyridine-5, 5' -dicarboxylic acid in N, N ' -dimethylformamide, adding triethylamine under stirring, and continuously stirring until the solution is clear and transparent; dissolving zirconium chloride in N, N '-dimethylformamide, adding the two solutions into a tetrafluoroethylene high-pressure lining reaction kettle under the condition of stirring, reacting for 24 hours in an oven at 85 ℃, centrifugally collecting a product after the reaction is finished, and washing with the N, N' -dimethylformamide and absolute ethyl alcohol to obtain the UiO-67 nano particles.
Further, in step 2, MnBr (CO)5The specific process of modifying the UiO-67 nanoparticle skeleton is as follows: mixing MnBr (CO)5Adding into UiO-67 ethanol solution, stirring at 20-30 deg.C, transferring into 75 deg.C oil bath, heating and stirring for reaction, cooling to 20-30 deg.C after reaction, centrifuging to collect product, washing with anhydrous ethanol to obtain MnBr (CO)5Modified UiO-67 nanoparticles UiO-67@ MnBr (CO)5。
Further, the specific process of adsorbing glucose oxidase GOx into the pore channels of the nanoparticles obtained in step 2 in step 3 is as follows: dispersing the nanoparticles obtained in the step 2 in water, adding glucose oxidase GOx, stirring and reacting in the dark, centrifuging to collect a product, washing with water to obtain a CO gas therapeutic agent UiO-67@ MnBr (CO)5@GOx。
The application of the CO gas therapeutic agent in preparing a medicine for treating tumors.
Has the advantages that: the invention takes UiO-67 nano particles with mesopores as a carrier to efficiently carry CO gas release molecules MnBr (CO)5And constructing the tumor microenvironment responsive CO gas therapeutic agent. The therapeutic agents of the invention have the property of responsiveness to the tumor microenvironment through H overexpressed in the tumor microenvironment2O2To achieve a controlled release of CO gas. The adoption of the CO gas therapeutic agent is a non-invasive and green tumor treatment mode; the CO gas therapeutic agent can realize gas therapy, further enhances the therapeutic effect by combining with active oxygen generated by the decomposition of the therapeutic agent, and realizes more efficient anti-tumor therapy; in addition, the synthetic steps of the therapeutic agent are simpler, and the yield is higher; furthermore, the synthesis method is simple and low in cost, so that the method is suitable for large-scale production.
Drawings
FIG. 1 is SEM photograph (a) and TEM photograph (b) of UiO-67 nanoparticles in example 1.
FIG. 2 is a graph showing the particle size distribution (a) and the infrared spectrum (b) of UiO-67 nanoparticles of example 1.
FIG. 3 shows UiO-67@ Mn of example 1Br(CO)5At 40 mu M H2O2In PBS (a) and UiO-67@ MnBr (CO)5@ GOx in PBS solution of 40 mu M GO (c) in dark condition, and using an ultraviolet spectrum time change curve of a bovine serum albumin reduction method, UiO-67@ MnBr (CO)5At different concentrations of H2O2In PBS solution (b) and UiO-67@ MnBr (CO)5@ GOx CO release profile (d) in PBS solutions of different concentrations of GO.
Fig. 4H at pH = 4.5 for different concentrations of UiO-67 of example 12O2The color reaction between the PBS solution and Tetramethylbenzidine (TMB) shows a UV spectrum (a) with a peak at 652 nm and a color change mechanism (b).
FIG. 5 shows the cell activities (a) of Hela and MCF-7 cells in different concentrations of UiO-67, and of Hela and MCF-7 cells in different concentrations of UiO-67, UiO-67@ MnBr (CO)5、UiO-67@MnBr(CO)5@ GOx cytotoxicity (b).
FIG. 6 shows Hela cells in UiO-67, UiO-67@ MnBr (CO)5、UiO-67@MnBr(CO)5Confocal fluorescence imaging of intracellular CO Release under @ GOx culture (a), Hela cells in UiO-67, UiO-67@ MnBr (CO)5、UiO-67@MnBr(CO)5@ GOx Coconfocal fluorescence imaging of intracellular ROS in culture (b) Hela cells in UiO-67, UiO-67@ MnBr (CO), respectively5、UiO-67@MnBr(CO)5Fluorescence imaging of dead and alive staining of cells in culture with @ GOx (c).
Detailed Description
In order to explain the structural features and technical means of the present invention in detail and to achieve the object and effect thereof, the following detailed description is given with reference to the accompanying drawings in combination with the embodiments.
The invention provides a CO gas therapeutic agent with tumor microenvironment response, which comprises UiO-67 nano-particles with high porosity and a skeleton-modified CO precursor molecule MnBr (CO)5And to further increase intratumoral H2O2Concentration loaded GOx.
Specifically, the UO-67 nanoparticles are nanosphere structures having a diameter of about 85 nm.
The preparation method of the CO gas therapeutic agent comprises the following steps:
Dissolving 45 mg of 2,2' -bipyridine-5, 5' -dicarboxylic acid in 20 mL of N, N ' -Dimethylformamide (DMF), dropwise adding 360 mu L of triethylamine while stirring, and continuously stirring until the solution is clear and transparent; 45 mg of zirconium chloride was dissolved in 16 mL of DMF and the two solutions were added to a 50 mL tetrafluoroethylene autoclave with magnetic stirring and reacted in an oven at 85 ℃ for 24 hours. After the reaction was completed, the product was collected by high-speed centrifugation and washed 3 times with DMF and absolute ethanol. The resulting white product was finally dispersed in 10mL of absolute ethanol.
The DMF, the absolute ethyl alcohol, the zirconium chloride and the 2,2 '-bipyridyl-5, 5' -dicarboxylic acid are all chemical raw materials commonly used for preparation, and can be directly ordered from a reagent network.
The optimal temperature for the reaction is 85 ℃ and the reaction time is 24 h. The diameter of the obtained UiO-67 nano-particles is about 85 nm.
The UiO-67 was dispersed in the methanol solution and soaked for 1 day, and the methanol solution was changed three times in the middle. Weigh 30 mg of MnBr (CO)5The mixture was added to a 2 mg/mL 10mL solution of UiO-67 in ethanol, stirred at room temperature for 12 hours, and then transferred to a 75 ℃ oil bath and heated and stirred for 4 hours. After the reaction is finished, naturally cooling to room temperature, centrifuging at 6000 rpm for 5 min to collect a product, washing with absolute ethyl alcohol for 3 times, freeze-drying, and storing in dark place UiO-67@ MnBr (CO)5。
Step 3, absorbing GOx to the pore canal and the surface of the UiO-67 nano-particle with high porosity by adopting a physical adsorption method to obtain a final product UiO-67@ MnBr (CO) with the response function of the tumor microenvironment5@GOx。
Mixing the UiO-67@ MnBr (CO)5Dispersing 5mg in 10mL water, adding 2mg GOx, stirring at room temperature in dark place for 12h, centrifuging, collecting, washing with water for 3 times, and collecting the final productThe material was stored by freeze-drying in the dark.
The CO gas therapeutic agent prepared by the preparation method comprises nano-granular UiO-67 nano-particles and CO precursor molecules MnBr (CO)5And GOx.
The diameter of the UiO-67 nano particle is about 85 nm, and the skeleton is modified with MnBr (CO)5And GOx loading in the channels.
The CO gas release molecule is MnBr (CO)5。
The CO therapeutic agent has the function of tumor microenvironment response, and H in the tumor2O2Releasing CO gas under the environment. CO gas releasing molecule MnBr (CO) of the invention5H overexpressed in the tumor microenvironment2O2In response to (3) releasing CO gas. The CO therapeutic agent responds to the tumor microenvironment by MnBr (CO)5CO gas molecules released can be used for treating tumor gas, and simultaneously, the divalent manganese ions and the H overexpressed in the tumor are degraded2O2OH is used for ROS treatment. The killing effect of the CO gas therapeutic agent on the tumor is further improved by combining the mutual synergistic effect of the two. Thus, the CO therapeutic agent of the present invention achieves the controlled release of CO gas in tumors while achieving the treatment of starvation through Mn2+And H2O2The reaction generates hydroxyl free radicals, and the synergistic treatment of ROS is realized.
The prepared tumor microenvironment responsive CO gas release therapeutic agent can be applied as a preparation for treating tumors.
The preparation for treating the tumor releases CO gas to treat the tumor in response to the micro environment of the tumor.
It is understood that the ROS treatment and CO gas can inhibit the growth of tumor cells and kill cancer cells, therefore, the CO therapeutic agent of the invention is a noninvasive, efficient, low-toxicity and green tumor treatment mode.
The preparation method of the tumor CO therapeutic agent has the advantages of low price of synthetic raw materials, simple preparation process and easy large-scale production. In addition, the CO therapeutic agent prepared by the preparation method has good monodispersity and stability, good biocompatibility, high CO gas loading capacity and gas release with tumor microenvironment response.
The present invention will be further illustrated by the following specific examples.
Example 1
(1) And preparing UiO-67 nano particles.
Dissolving 45 mg of 2,2' -bipyridine-5, 5' -dicarboxylic acid in 20 mL of N, N ' -Dimethylformamide (DMF), dropwise adding 360 mu L of triethylamine while stirring, and continuously stirring until the solution is clear and transparent; 45 mg of zirconium chloride was dissolved in 16 mL of DMF and the two solutions were added to a 50 mL tetrafluoroethylene autoclave with magnetic stirring and reacted in an oven at 85 ℃ for 24 hours. After the reaction was completed, the product was collected by high-speed centrifugation and washed 3 times with DMF and absolute ethanol. The resulting white product was finally dispersed in 10mL of absolute ethanol.
(2) Preparation of MnBr (CO)5Modified UO-67 nanoparticles (UO-67 @ MnBr (CO)5)。
The UiO-67 was dispersed in the methanol solution and soaked for 1 day, and the methanol solution was changed three times in the middle. Weigh 30 mg of MnBr (CO)5The mixture was added to a 2 mg/mL 10mL solution of UiO-67 in ethanol, stirred at room temperature for 12 hours, and then transferred to a 75 ℃ oil bath and heated and stirred for 4 hours. After the reaction is finished, naturally cooling to room temperature, centrifuging the product at 6000 rpm for 5 min to collect the product, washing the product for 3 times by using absolute ethyl alcohol, and then freeze-drying and storing UiO-67@ MnBr (CO) in a dark place5。
(3) Preparation UiO-67@ MnBr (CO)5Channel loading GOx (UiO-67 @ MnBr (CO)5@GOx)。
Mixing the UiO-67@ MnBr (CO)5Dispersing 5mg in 10mL of water, adding 2mg of GOx, stirring for 12h at normal temperature in the dark, centrifuging, collecting, washing with water for 3 times, and freeze-drying and storing in the dark.
And (3) performance testing:
1. morphology determination of UiO-67 nanoparticles
FIG. 1 is SEM photographs (a) and (b) of UiO-67 nanoparticles prepared in example 1, the UiO-67 nanoparticles having a spherical shape.
2. UiO-67、UiO-67@MnBr(CO)5Measurement of Performance
In FIG. 2(a), it can be observed that the synthesized UiO-67 nanoparticles have a diameter of about 85 nm and are uniformly dispersed.
By the pair of MnBr (CO) in FIG. 2(b)5UiO-67 and UiO-67@ MnBr (CO)5Comparison of the Infrared Spectrum of the nanocomposites can be found in MnBr (CO)5After loading into UiO-67, MnBr (CO)5The three carbonyl peaks of (a) are reduced to two peaks (grey areas in fig. 2 b), indicating that the bipyridine is partially substituted with carbonyl groups on the inner/outer surface of UiO-67.
3. Determination of UiO-67@ MnBr (CO)5And UiO-67@ MnBr (CO)5Measurement of CO Release Performance of @ GOx
The carbon monoxide released in PBS was detected spectrophotometrically by measuring the conversion of hemoglobin (Hb) to carboxyhemoglobin (HbCO). First, UiO-67@ MnBr (CO) prepared in example 1 was added5Preparing PBS solution with concentration of 100 mug/mL, and completely dissolving hemoglobin (final concentration of 4.2 mM) from bovine red blood cells in PBS solution with different concentrations of H2O2In phosphate buffered saline (10 mM, pH = 7.4). Then, it was reduced by adding 1.6 mg of sodium dithionite under nitrogen atmosphere. The solution is then added to the freshly prepared hemoglobin solution. The entire reaction solution (4 mL) was immediately sealed in a 4mL ultraviolet quartz tube. The uv absorption spectra of the solutions (I = 350-. To eliminate the influencing factors and improve accuracy, two strong absorbing branches at I = 410 and 430nm, respectively, due to HbCO and Hb, were used to quantify the conversion of Hb to HbCO, resulting in fig. 3(a), which was then calculated by the formulaCalculating to obtain UiO-67@ MnBr (CO)5At different concentrations of H2O2Phosphate buffered saline CO Release Profile 3(b), where CCOAnd CHbSeparately express the released CO concentration and the initial Hb concentration (4.2. mu.M), I410 nmAnd I430 nmThe intensities of the collected spectra at L = 410 and 430nm are indicated, respectively. UiO-67@ MnB can be seenr(CO)5CO release amount of (2) is dependent on H2O2The concentration increased.
UiO-67@ MnBr (CO) can be obtained by the same method5@ GOx conversion of Hb to HbCO in GO solutions of varying concentrations FIG. 3(c), calculated to give UiO-67@ MnBr (CO)5@ GOx GO phosphate buffered saline CO release profile 3(d) at various concentrations. It can be seen that UiO-67@ MnBr (CO)5The CO release of @ GOx is dependent on H2O2The concentration increased.
4. UiO-67 Generation OH Performance determination
The measurements were performed in 3 mL of acetic acid (AcOH) buffer solution (0.1mL, pH 4.5) containing different concentrations of UiO-67 (5, 10, 20, 40, 80 μ g/mL), H prepared in example 12O2(10 mM) and TMB (1mM) at 37 ℃ for 5 minutes. TMB is oxidized by hydroxyl radical to ox-TMB, and the absorption spectrum is observed by an ultraviolet-visible spectrometer, and the ox-TMB has obvious absorption peak under the absorbance of 652 nm, as shown in figure 4 (a). Illustrating the better ability to generate hydroxyl radicals with increasing concentration of UiO-67 as prepared in example 1. TMB turns from colorless to blue after oxidation to ox-TMB by a hydroxyl radical, and FIG. 4(b) is a mechanism diagram of the oxidation of TMB to ox-TMB by a hydroxyl radical.
5. UiO-67、UiO-67@MnBr(CO)5、UiO-67@MnBr(CO)5Cytotoxicity of @ GOx
Hela and MCF-7 cells (1X 10)4One/well) were inoculated into a 96-well plate, 200 μ L DMEM medium was added per well, and placed at 37 ℃ with 5% CO2The incubator of (1) was incubated overnight. After the cells are completely attached to the wall, replacing a fresh DMEM medium, adding 50 mu L of DMEM solution containing Fe-Bpyd with different concentrations into each well, and continuously culturing for 48 h in an incubator. After the culture is completed, the cells are washed three times by PBS, redundant medicines are washed off, 100 muL of DMEM and 10 muL of thiazole blue (MTT) solution (5 mg/mL) prepared in advance are added into each well, the DMEM culture medium is sucked out after the cells are cultured in an incubator for 4 hours, 150 muL of dimethyl sulfoxide (DMSO) solvent is added into each well, the cells are slightly shaken for 10 min to completely dissolve blue-purple formazan, and the absorbance at 490 nm is measured by an enzyme labeling instrument. So as not to add UiO-67The treated cells were used as a control group, the cell activity was recorded as 100%, and the cell viability at each concentration was calculated. Each set of experiments was repeated three times and the average was calculated. As can be seen from FIGS. 5(a) and (b), UiO-67 of 160 μ g/mL had a cell activity of about 90%, UiO-67@ MnBr (CO)5@ GOx showed the best Hela inhibitory effect, UiO-67@ MnBr (CO)5The effect is the next time. Is due to the modification of GOx, increasing H in cancer cells2O2Increased CO release capacity while consuming intracellular GO, blocking the energy source, so UiO-67@ MnBr (CO)5@ GOx is the most cytotoxic.
6. UiO-67@MnBr(CO)5Production of @ GOx in Hela OH, CO Release Performance test.
Intracellular reactive oxygen species production was monitored using 2',7' -dichlorofluorescent yellow diacetate (DCFH-DA). Briefly, 100 μ g/mL of UiO-67, UiO-67@ MnBr (CO) for HeLa cells5、UiO-67@MnBr(CO)5@ GOx was incubated for 4 hours and then washed three times with PBS. Then, the cells at 37 ℃ with 2mM DCFH-DA incubation for 30 minutes. Finally, the distribution of reactive oxygen species was observed by CLSM at 488 nm excitation. FIG. 6(a) shows UiO-67@ MnBr (CO)5The group of @ GOx fluoresces most strongly, indicating UiO-67@ MnBr (CO)5The maximum amount of OH is produced at @ GOx.
FIG. 6(b) fluorescence imaging of CO in HeLa cells by CO probe (probe 1+ Palladium chloride, 1 μ M each, 15 μ L DMSO). The HeLa cells were treated with 100 μ g/m UiO-67, UiO-67@ MnBr (CO)5、UiO-67@MnBr(CO)5@ GOx was incubated for 4 hours and then washed three times with PBS. Then, the cells were incubated with 2mM CO probe for 30 minutes at 37 ℃ in an incubator with 5% CO. Finally, the distribution of CO was observed by CLSM at 520 nm excitation.
FIG. 6(c) UiO-67, UiO-67@ MnBr (CO)5、UiO-67@MnBr(CO)5Therapeutic effect of @ GOx on HeLa cells was visualized by live/dead cell staining for fluorescence imaging. HeLa cells were cultured at 1.0X 10 per dish5The density of individual cells was seeded on a glass-bottom culture dish (20 mm) for 24 hours. Then, after incubating the cells with the sample solution for 24 hours, the medium was aspirated off, and the cells were washed with PBSThe medium was removed 3 times. Then, the cells were stained with a PBS buffer solution of calcein-AM and Pyridine Iodide (PI) for 30 minutes. Finally, cells were washed 3 times with PBS and imaged by CLSM. The green fluorescence of calcein-AM was excited at 488 nm and detected with a 500-550 nm band pass filter. The red fluorescence of PI was excited at 633 nm and detected with a 660-710 nm bandpass filter. FIG. 6(c) shows UiO-67@ MnBr (CO)5The group @ GOx fluoresces the weakest green color and the most red color, indicating UiO-67@ MnBr (CO)5@ GOx killed the cells most effectively.
The CO therapeutic agent provided by the invention takes UiO-67 as a carrier and modifies MnBr (CO) on the skeleton5And GOx loading in the channels. The first-mentioned high porosity UiO-67 is prepared by high temperature solvothermal method, and has monodispersity and uniform size distribution. Then, by forming a coordinate bond, MnBr (CO)5The modified UiO-67 skeleton can be used as a carrier of CO gas. And further loading GOx in the multiple pore channels of the UiO-67, and finally realizing the function of the responsiveness of the tumor microenvironment. Again, use UiO-67@ MnBr (CO)5Degraded Mn of itself2+And H overexpressed in cells2O2OH is generated through reaction to realize ROS treatment, so the CO gas therapeutic agent can realize efficient anti-tumor treatment by combining the synergistic effect of CO gas, active oxygen and tumor hunger treatment.
Claims (7)
1. A tumor microenvironment-responsive CO gas therapeutic characterized by: comprises UiO-67 nano-particles, MnBr (CO)5And glucose oxidase GOx;
said MnBr (CO)5The glucose oxidase GOx is modified on the skeleton of the UiO-67 nano-particles through coordination bonds, and is adsorbed in the pores of the UiO-67 nano-particles through physical action.
2. The tumor microenvironment-responsive CO gas therapeutic of claim 1, wherein: the diameter of the UiO-67 nano-particles is 70-100 nm.
3. The method of preparing a tumor microenvironment-responsive CO gas therapeutic of claim 1, wherein: the method comprises the following steps:
step 1, preparing UiO-67 nano particles by adopting a high-temperature solvothermal method;
step 2, adopting a chemical bonding method to bond MnBr (CO)5Modifying to a UiO-67 nanoparticle skeleton;
and 3, adsorbing glucose oxidase GOx into the pore channels of the nanoparticles obtained in the step 2 by adopting a pore channel adsorption method to obtain the nanoparticle.
4. The production method according to claim 3, characterized in that: the specific process for preparing the UiO-67 nano particles by adopting the high-temperature solvothermal method in the step 1 is as follows: dissolving 2,2' -bipyridine-5, 5' -dicarboxylic acid in N, N ' -dimethylformamide, adding triethylamine under the condition of stirring, and continuously stirring until the solution is clear and transparent; dissolving zirconium chloride in N, N '-dimethylformamide, adding the two solutions into a tetrafluoroethylene high-pressure lining reaction kettle under the condition of stirring, reacting for 24 hours in an oven at 85 ℃, centrifugally collecting a product after the reaction is finished, and washing with the N, N' -dimethylformamide and absolute ethyl alcohol to obtain the UiO-67 nano particles.
5. The production method according to claim 3, characterized in that: in step 2, MnBr (CO)5The specific process of modifying the UiO-67 nanoparticle skeleton is as follows: mixing MnBr (CO)5Adding into UiO-67 ethanol solution, stirring at 20-30 deg.C, transferring into 75 deg.C oil bath, heating and stirring for reaction, cooling to 20-30 deg.C after reaction, centrifuging to collect product, washing with anhydrous ethanol to obtain MnBr (CO)5Modified UiO-67 nanoparticles.
6. The production method according to claim 3, characterized in that: the specific process of adsorbing glucose oxidase GOx into the nano-particle pore channel obtained in the step 2 in the step 3 is as follows: and (3) dispersing the nanoparticles obtained in the step (2) in water, adding glucose oxidase GOx, stirring and reacting in a dark place, centrifugally collecting a product, and washing with water to obtain the CO gas therapeutic agent.
7. Use of the tumor microenvironment responsive CO gas therapeutic of claim 1 in the manufacture of a medicament for the treatment of tumors.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110345675.XA CN113144175A (en) | 2021-03-31 | 2021-03-31 | Tumor microenvironment response CO gas therapeutic agent and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110345675.XA CN113144175A (en) | 2021-03-31 | 2021-03-31 | Tumor microenvironment response CO gas therapeutic agent and preparation method and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113144175A true CN113144175A (en) | 2021-07-23 |
Family
ID=76885710
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110345675.XA Pending CN113144175A (en) | 2021-03-31 | 2021-03-31 | Tumor microenvironment response CO gas therapeutic agent and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113144175A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113509559A (en) * | 2021-03-31 | 2021-10-19 | 南通大学 | CO and drug release synergistic therapeutic agent and preparation method and application thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111359672A (en) * | 2020-03-31 | 2020-07-03 | 上海应用技术大学 | UiO-67 loaded Rh-based catalyst, and preparation method and application thereof |
CN112121154A (en) * | 2020-10-20 | 2020-12-25 | 南通大学 | Tumor microenvironment response CO gas therapeutic agent and preparation and application thereof |
-
2021
- 2021-03-31 CN CN202110345675.XA patent/CN113144175A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111359672A (en) * | 2020-03-31 | 2020-07-03 | 上海应用技术大学 | UiO-67 loaded Rh-based catalyst, and preparation method and application thereof |
CN112121154A (en) * | 2020-10-20 | 2020-12-25 | 南通大学 | Tumor microenvironment response CO gas therapeutic agent and preparation and application thereof |
Non-Patent Citations (1)
Title |
---|
韩璐: "《导电纳米复合材料》", 科学技术文献出版社, pages: 131 - 132 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113509559A (en) * | 2021-03-31 | 2021-10-19 | 南通大学 | CO and drug release synergistic therapeutic agent and preparation method and application thereof |
CN113509559B (en) * | 2021-03-31 | 2024-03-15 | 南通大学 | CO and drug release synergistic therapeutic agent and preparation method and application thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112245579B (en) | Photodynamic therapeutic agent for relieving tumor hypoxia and preparation method and application thereof | |
CN109568578B (en) | Preparation method and application of natural biomass quantum dots and biomass quantum dot-copper nanocomposite | |
CN106139144A (en) | A kind of hyaluronic acid decorated golden Nano carbon balls with synergistic antitumor characteristic and preparation method and application | |
CN111297830B (en) | Hierarchical targeting nanoparticle for mediated phototherapy and preparation method and application thereof | |
Gu et al. | Dual catalytic cascaded nanoplatform for photo/chemodynamic/starvation synergistic therapy | |
CN111773245A (en) | Composite nano enzyme and preparation method and application thereof | |
Pang et al. | Aptamer modified MoS2 nanosheets application in targeted photothermal therapy for breast cancer | |
CN113150298B (en) | Covalent organic polymer based on porphyrin and preparation method and application thereof | |
CN112121154A (en) | Tumor microenvironment response CO gas therapeutic agent and preparation and application thereof | |
CN113144175A (en) | Tumor microenvironment response CO gas therapeutic agent and preparation method and application thereof | |
CN112274639B (en) | Fe2C @ Fe3O4 heterogeneous nano-particles, preparation method and application | |
CN114180621A (en) | Atom-dispersed vanadium-doped titanium dioxide and preparation method and application thereof | |
CN113230401A (en) | Core-shell up-conversion MOFs photosensitive composite material, preparation method and application thereof | |
Shi et al. | A small pore black TiO 2/-large pore Fe 3 O 4 cascade nanoreactor for chemodynamic/photothermal synergetic tumour therapy | |
CN110917349A (en) | Bowl-shaped ISP (internet service provider) composite functional nano particle as well as preparation method and application thereof | |
CN114344482B (en) | Multifunctional nanoparticle based on metal-organic framework and preparation method and application thereof | |
Li et al. | Photothermal/nitric oxide synergistic anti-tumour therapy based on MOF-derived carbon composite nanoparticles | |
CN115385861A (en) | Fluorescent probe and preparation method and application thereof | |
CN113509559B (en) | CO and drug release synergistic therapeutic agent and preparation method and application thereof | |
CN110642865B (en) | Application of high-charge cationic porphyrin in preparation of PDT nano photosensitizer | |
CN108421041B (en) | Photodynamic therapy compound and preparation method and application thereof | |
CN113230419A (en) | Novel targeted nano-particles based on phycocyanobilin and preparation method thereof | |
CN113679837A (en) | Narrow-band-gap inorganic nano enzyme therapeutic reagent and preparation method and application thereof | |
CN107857788B (en) | Glycosylated BODIPY derivative, surface sugar modified nano micelle and preparation method and application thereof | |
CN114933904B (en) | Ultrathin shell chiral cadmium selenide/cadmium sulfide material for optical diagnosis and treatment and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |