CN110237275A - A kind of nanometer of diagnosis and treatment agent and preparation method thereof, application - Google Patents
A kind of nanometer of diagnosis and treatment agent and preparation method thereof, application Download PDFInfo
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- CN110237275A CN110237275A CN201910436014.0A CN201910436014A CN110237275A CN 110237275 A CN110237275 A CN 110237275A CN 201910436014 A CN201910436014 A CN 201910436014A CN 110237275 A CN110237275 A CN 110237275A
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- 238000011282 treatment Methods 0.000 title claims abstract description 81
- 238000003745 diagnosis Methods 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 claims abstract description 76
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims abstract description 72
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 53
- 108010015776 Glucose oxidase Proteins 0.000 claims abstract description 27
- 239000004366 Glucose oxidase Substances 0.000 claims abstract description 27
- 229940116332 glucose oxidase Drugs 0.000 claims abstract description 27
- 235000019420 glucose oxidase Nutrition 0.000 claims abstract description 27
- 239000002055 nanoplate Substances 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000001179 sorption measurement Methods 0.000 claims abstract description 12
- 230000008878 coupling Effects 0.000 claims abstract description 8
- 238000010168 coupling process Methods 0.000 claims abstract description 8
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 229910052748 manganese Inorganic materials 0.000 claims description 8
- 239000011572 manganese Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 6
- 239000012670 alkaline solution Substances 0.000 claims description 6
- 239000007822 coupling agent Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000002872 contrast media Substances 0.000 claims description 5
- 239000012266 salt solution Substances 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 235000007164 Oryza sativa Nutrition 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 235000009566 rice Nutrition 0.000 claims description 4
- HYZQBNDRDQEWAN-LNTINUHCSA-N (z)-4-hydroxypent-3-en-2-one;manganese(3+) Chemical compound [Mn+3].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O HYZQBNDRDQEWAN-LNTINUHCSA-N 0.000 claims description 3
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 3
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 3
- 108090000854 Oxidoreductases Proteins 0.000 claims description 3
- 102000004316 Oxidoreductases Human genes 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000000908 ammonium hydroxide Substances 0.000 claims description 3
- 229940034982 antineoplastic agent Drugs 0.000 claims description 3
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- 239000007788 liquid Substances 0.000 claims description 3
- 239000011565 manganese chloride Substances 0.000 claims description 3
- 229940099607 manganese chloride Drugs 0.000 claims description 3
- 235000002867 manganese chloride Nutrition 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- -1 3- dimethylamino-propyl Chemical group 0.000 claims description 2
- 229940071125 manganese acetate Drugs 0.000 claims description 2
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 claims description 2
- 240000007594 Oryza sativa Species 0.000 claims 1
- 240000006365 Vitis vinifera Species 0.000 claims 1
- BYOBIQOEWYNTMM-UHFFFAOYSA-N manganese;nitric acid Chemical compound [Mn].O[N+]([O-])=O BYOBIQOEWYNTMM-UHFFFAOYSA-N 0.000 claims 1
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 43
- 238000007626 photothermal therapy Methods 0.000 abstract description 12
- 235000003642 hunger Nutrition 0.000 abstract description 10
- 230000037351 starvation Effects 0.000 abstract description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 abstract description 9
- 238000003384 imaging method Methods 0.000 abstract description 9
- 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 abstract description 6
- 239000008103 glucose Substances 0.000 abstract description 6
- 238000002595 magnetic resonance imaging Methods 0.000 abstract description 6
- 230000003834 intracellular effect Effects 0.000 abstract description 4
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- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 abstract 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 abstract description 2
- 231100000433 cytotoxic Toxicity 0.000 abstract description 2
- 230000001472 cytotoxic effect Effects 0.000 abstract description 2
- 239000000174 gluconic acid Substances 0.000 abstract description 2
- 235000012208 gluconic acid Nutrition 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 21
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical class CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 101710128063 Carbohydrate oxidase Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
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- 229910001437 manganese ion Inorganic materials 0.000 description 2
- MIVBAHRSNUNMPP-UHFFFAOYSA-N manganese(2+);dinitrate Chemical compound [Mn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MIVBAHRSNUNMPP-UHFFFAOYSA-N 0.000 description 2
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
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- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
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- VQWQYXBWRCCZGX-UHFFFAOYSA-N acetic acid;manganese Chemical compound [Mn].CC(O)=O.CC(O)=O VQWQYXBWRCCZGX-UHFFFAOYSA-N 0.000 description 1
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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- 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
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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
- A61K47/6923—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 an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/225—Microparticles, microcapsules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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)
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
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- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Inorganic Chemistry (AREA)
- Radiology & Medical Imaging (AREA)
- Genetics & Genomics (AREA)
- General Engineering & Computer Science (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of nanometer of diagnosis and treatment agent and preparation method thereof, application, the nanometer diagnosis and treatment agent include adsorption have melanin manganese dioxide nano-plates and with the manganese dioxide nano-plates covalent coupling glucose oxidase.Nanometer diagnosis and treatment agent of the present invention has good biocompatibility and degradability, the melanin on manganese dioxide nano-plates is adsorbed in the good photothermal conversion ability near infrared region, it can be brought rapidly up in tumor locus under laser irradiation, achieve the purpose that photo-thermal therapy, intracellular convert glucose can be gluconic acid and the cytotoxic hydrogen peroxide of tool by the glucose oxidase of manganese dioxide nano-plates surface coupling, consume intracellular energy source, achieve the purpose that class starvation treats tumour, nanometer diagnosis and treatment agent of the invention realizes the photoacoustic imaging of tumour and the photo-thermal therapy of magnetic resonance imaging monitoring tumour treats the synergistic treatment combined with class starvation, it has a good application prospect in the diagnosis and treatment field of tumour.
Description
Technical field
The present invention relates to technical field of biomedical materials, more particularly, to a kind of nanometer of diagnosis and treatment agent and preparation method thereof,
Using.
Background technique
Tumour cell be normal cell mutation after malignant cell, not only disease hair complicated mechanism it is changeable, but also almost with
Normal cell is very nearly the same, therefore any treatment means all inevitably cause to damage to normal cell, brings pain to patient.Black
Element is a kind of biochrome, is tyrosine or 3, the third ammonia of 4- dihydroxyphenyl is formed by a succession of chemical reaction, in animal, plant
And have this pigment in protist body.It has good photothermal conversion ability, and photo-thermal therapy will using photothermal converting agent
Near infrared light is converted into heat, kills tumour cell, the physiological function without influencing normal cell, however single photo-thermal therapy is simultaneously
Tumour growth cannot be completely inhibited, because photo-thermal also results in heat shock protein overexpression, to produce to this treatment method
It is raw immune.
The metabolism of tumor cell ratio normal cell is more vigorous, needs more nutritional ingredients, cuts off its source of nutrition, just
It can achieve the effect for inhibiting tumour growth, glucose is the energy source of tumour growth, consumes tumour with glucose oxidase
Position glucose is a type starvation treatment method, and the hydrogen peroxide generated after grape is glycoxidative, which also has, kills the latent of tumour cell
Power, photo-thermal therapy can promote cell to swallow diagnosis and treatment agent, enhance the therapeutic effect of glucose oxidase, and class starvation is treated and light
Heat cure combines, and can more thoroughly remove tumour cell.
The nanometer diagnosis and treatment agent of the prior art not can be implemented simultaneously to the hungry treatment of tumour progress and photo-thermal therapy, function list simultaneously
One, and existing nanometer diagnosis and treatment agent is usually and to be made in the corresponding nano material of deposited on substrates with silicon, Jin Dengwei substrate,
Such substrate can not degradation in vivo, to the bad adaptability of oncotherapy.
Therefore, the existing technology needs to be improved and developed.
Summary of the invention
In view of above-mentioned deficiencies of the prior art, the purpose of the present invention is to provide a kind of nanometer of diagnosis and treatment agent and its preparation sides
Method, application, it is intended to the technical issues of nanometer diagnosis and treatment agent for solving the prior art has a single function, and substrate can not degrade, bad adaptability.
Technical scheme is as follows:
A kind of nanometer of diagnosis and treatment agent, wherein the nanometer diagnosis and treatment agent include adsorption have the manganese dioxide nano-plates of melanin with
And with the manganese dioxide nano-plates covalent coupling glucose oxidase.
The nanometer diagnosis and treatment agent, wherein the thickness of the manganese dioxide nano-plates is less than 10 nm.
A kind of preparation method of nanometer of diagnosis and treatment agent, wherein comprising steps of
First melanin powder is dispersed in alkaline solution, obtains melanin solution；
Melanin solution is mixed with organic solvent later, and adjusts the pH value of melanin solution to scheduled model with acid solution
It encloses, is heated to scheduled reaction temperature later, manganese source stirring is added, reaction, which obtains adsorption, has the manganese dioxide of melanin to receive
Rice piece；
Then, glucose oxidase is dissolved in the water to obtain glucose oxidase solution, coupling agent is added and stirs the Portugal
It is molten to be added to the glucose oxidase after stirring by grape oxidase solution for the manganese dioxide nano-plates that adsorption has melanin
In liquid, continues to stir certain time, the nanometer diagnosis and treatment agent is made.
The preparation method, wherein the manganese source is potassium permanganate, manganese chloride, manganese nitrate, manganese acetylacetonate and acetic acid
Manganese it is one or more.
The preparation method, wherein the acid solution is the one or more of sulfuric acid solution and acetic acid solution.
The preparation method, wherein the alkaline solution is one kind of sodium hydroxide solution, amine salt solution and ammonium hydroxide
Or it is a variety of.
The preparation method, wherein the coupling agent includes 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide salt
Acid salt solution and n-hydroxysuccinimide solution, and the 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
The molar ratio of solution and n-hydroxysuccinimide solution is 1:1-1:2.
The preparation method, wherein the scheduled range is 7.0-8.0, and the scheduled reaction temperature is 90-
100℃。
The preparation method, wherein the organic solvent is the one or more of methanol, ethyl alcohol and acetone.
A kind of nanometer diagnosis and treatment agent described in any of the above embodiments as preparation treatment antineoplastic agents and as prepare optoacoustic or
The application of NMR contrast agent.
The utility model has the advantages that the invention discloses a kind of nanometer of diagnosis and treatment agent and preparation method thereof, application, wherein the nanometer is examined
Treat agent include adsorption have melanin manganese dioxide nano-plates and with the manganese dioxide nano-plates covalent coupling grape
Carbohydrate oxidase.The optoacoustic of tumour can be achieved at the same time in nanometer diagnosis and treatment agent of the invention and the class starvation of magnetic resonance imaging and tumour is controlled
The synergistic treatment combined with photo-thermal therapy is treated, is had a good application prospect in the Clinics and Practices field of tumour, meanwhile, this
The preparation process of the diagnosis and treatment agent of invention is simple, low in cost, it is easy to accomplish large-scale industrial production.
Detailed description of the invention
Fig. 1 is the synthetic route chart of nanometer diagnosis and treatment agent (MNS-GOx) of the present invention；
Fig. 2 is the corresponding TEM figure of MNS-GOx of the present invention；
Fig. 3 is the corresponding atomic force microscopy diagram of MNS-GOx of the present invention；
Fig. 4 is manganese element distribution map in MNS-GOx of the present invention；
Fig. 5 is oxygen element distribution map in MNS-GOx of the present invention；
Fig. 6 is photo-thermal curve graph of the various concentration MNS-GOx sample under the irradiation of same optical power；
Fig. 7 is photo-thermal curve graph of the MNS-GOx sample of 200 mcg/ml concentration under different laser irradiation power；
Fig. 8 is thermal infrared figure of the various concentration MNS-GOx sample solution under same smooth irradiation power；
Fig. 9 is the photo and thermal stability curve graph of the MNS-GOx sample of 200 mcg/ml concentration；
Figure 10 is different MNS sample sets and the cell survival rate figure that A375 cell is incubated for jointly；
Figure 11 is the magnetic resonance imaging signal variation diagram of A375 tumor-bearing mice before and after injecting MNS-GOx sample；
Figure 12 is the photoacoustic imaging signal intensity figure of A375 tumor-bearing mice before and after injecting MNS-GOx sample；
Figure 13 is that treatment phase difference treatment group tumors volume changes with time figure；
Figure 14 is treatment phase difference treatment group mouse survival cyclic curve figure；
Figure 15 is that treatment phase difference treatment group mouse weight changes with time figure.
Specific embodiment
The present invention provides a kind of nanometer of diagnosis and treatment agent and preparation method thereof, application, to make the purpose of the present invention, technical solution
And effect is clearer, clear, the present invention is described in more detail below.It should be appreciated that specific implementation described herein
Example is only used to explain the present invention, is not intended to limit the present invention.
The present invention provides a kind of nanometer of diagnosis and treatment agent, the nanometer diagnosis and treatment agent includes the titanium dioxide that adsorption has melanin
Manganese nanometer sheet and with the manganese dioxide nano-plates covalent coupling glucose oxidase.
Nanometer diagnosis and treatment agent of the invention using manganese dioxide nano-plates as substrate, can be by under tumour slightly acidic environment
It gradually degrades, until completely disappearing, manganese ion is released in decomposable process, as magnetic resonance imaging contrast, manganese dioxide nano
On piece is adsorbed with melanin, and melanin has good photothermal conversion ability, also with good near infrared region photoacoustic imaging
Radiography function, nanometer diagnosis and treatment agent of the invention pass through using melanin as template, on the one hand, melanin can control inorganic receive
The synthesis of rice material (manganese dioxide), instead of traditional polyethyleneglycol modified, it is possible to reduce immunogenicity, so that inorganic nano
Material has good biocompatibility.
Fig. 1 is that melanin manganese dioxide composite nano plate of the present invention loads glucose oxidase (MNS-GOx) nanometer diagnosis and treatment
The synthetic route chart of agent, the melanin in nanometer diagnosis and treatment agent of the invention have good photothermal conversion ability, and grape is glycoxidative
Enzyme (GOx) can consume tumor locus glucose, cut off the source of nutrition of tumour, and the hydrogen peroxide generated after grape is glycoxidative is same
Also there are the potentiality for killing tumour cell, realize and combine the treatment of class starvation and photo-thermal therapy, photo-thermal therapy simultaneously can be with
Promote cell to swallow diagnosis and treatment agent, further enhances the therapeutic effect of glucose oxidase, more thoroughly remove tumour cell.Specifically
For, the product dioxygen water energy after grape is glycoxidative is further reacted with other components in diagnosis and treatment agent, is decomposed into oxygen, on the one hand
The oxygen sources glycoxidative as grape, to consume more glucose, on the other hand, hydrogen peroxide can also make manganese dioxide
Nanometer sheet is accelerated to decompose, and generates manganese ion, as the contrast agent of NMR imaging, improves imaging effect.
In a preferred embodiment, the thickness of the manganese dioxide nano-plates is less than 10 nm.It is less than in thickness
Under conditions of 10nm, convenient for improving the dispersion degree of manganese dioxide nano-plates, while manganese dioxide nano-plates are also beneficial in tumour
Decomposition under environment, it is preferred that manganese dioxide nano-plates with a thickness of 5nm.
In addition, the present invention also provides the preparation methods of a kind of nanometer of diagnosis and treatment agent, comprising steps of
First melanin powder is dispersed in alkaline solution, obtains melanin solution；
Melanin solution is mixed with organic solvent later, and adjusts the pH value of melanin solution to scheduled model with acid solution
It encloses, is heated to scheduled reaction temperature later, manganese source stirring is added, reaction, which obtains adsorption, has the manganese dioxide of melanin to receive
Rice piece；
Then, glucose oxidase is dissolved in the water to obtain glucose oxidase solution, coupling agent is added and stirs the Portugal
It is molten to be added to the glucose oxidase after stirring by grape oxidase solution for the manganese dioxide nano-plates that adsorption has melanin
In liquid, continues to stir certain time, the nanometer diagnosis and treatment agent is made.
In a preferred embodiment, the manganese source be potassium permanganate, manganese chloride, manganese nitrate, manganese acetylacetonate and
Manganese acetate it is one or more.
In a preferred embodiment, the acid solution is the one or more of sulfuric acid, solution and acetic acid solution.
In a preferred embodiment, the alkaline solution is sodium hydroxide solution, amine salt solution and ammonium hydroxide
It is one or more.
In a preferred embodiment, the coupling agent includes that 1- (3- dimethylamino-propyl) -3- ethyl carbon two is sub-
Amide hydrochloride and n-hydroxysuccinimide solution, and the 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide salt
The molar ratio of acid salt solution and n-hydroxysuccinimide solution is 1:1-1:2.
In a preferred embodiment, the scheduled range is 7.0-8.0, and the scheduled reaction temperature is
80-100℃。
In a preferred embodiment, the organic solvent is the one or more of methanol, ethyl alcohol and acetone.
A kind of nanometer diagnosis and treatment agent described in any of the above embodiments as preparation treatment antineoplastic agents and as prepare optoacoustic or
The application of NMR contrast agent.
Embodiment 1: synthesis nanometer diagnosis and treatment agent (MNS-GOx)
28.5 mg melanin powder are scattered in 10 mL ultrapure waters and 0.5 mL ammonia water mixture first, are stirred by ultrasonic 5 minutes
The melanin solution being completely dissolved takes wherein 0.4 mL melanin solution, is added to the mixed of 48 mL water and 3.2 mL ethyl alcohol
It closes in solution, adjusting pH=7.0-8.0(with sulfuric acid solution is preferably 7.4), upper mixed liquor to be heated to 90 degree, is being stirred
Lower holding after five minutes, is slowly added to 0.32 mL liquor potassic permanganate, after reacting 30 min, after to obtain melanin manganese dioxide multiple
It closes nanometer sheet (MNS), is dispersed in water after centrifugation washing.10 mg1- (3- dimethylamino-propyl) -3- ethyl carbodiimide hydrochloride
It is ultrapure that salt (EDC), 20 mg n-hydroxysuccinimides (NHS) and a certain amount of glucose oxidase (GOx) are dissolved in 10 mL
It stirs 2 hours in water, melanin manganese dioxide composite nano plate solution is added and stirs 12 hours at room temperature, it is negative to obtain GOx
The diagnosis and treatment agent (MNS-GOx) being loaded on the surface MNS is centrifugated, and is dispersed in 2 mL ultrapure waters after milli-Q water.
Fig. 2 indicates the TEM shape appearance figure after nanometer diagnosis and treatment agent (MNS-GOx) synthesis, and uniform nanometer is presented in material in Fig. 2
Flake；Fig. 3 is MNS-GOx atomic force microscopy diagram, observes that nanometer sheet thickness is only 2 under the visible atomic force microscope of Fig. 3
Nm belongs to ultrathin nanometer piece；There is element manganese in discovery sample when Fig. 4 and Fig. 5 carries out constituency elemental analysis to MNS-GOx sample
And elemental oxygen, it is multiple that the above results show that the uniform ultra-thin manganese dioxide melanin of pattern can be prepared in synthetic method of the present invention
Close nanometer sheet material.
Embodiment 2: the light thermal property evaluation of nanometer diagnosis and treatment agent
Using the nanometer diagnosis and treatment agent of 808 nm laser illuminations, concentration is respectively as follows: 0,25,50,100,200 mcg/mls, shines
Penetrating power is 1 w/cm2, irradiation time is 3 minutes, and laser irradiation is monitored with thermal imaging system simultaneously；It is tested in optical power
In, it is respectively 0.5,1,1.5w/cm with the MNS-GOx illumination power of 200 mcg/ml concentration2, light application time 3 minutes；In light
In the evaluation test of thermal stability, with dense MNS illumination 3 minutes of 200 mcg/mls, no light 5 minutes, recycle 4 times.
Fig. 6 indicates photo-thermal effect curve graph of the various concentration MNS-GOx sample under the irradiation of same optical power；Fig. 7 is indicated
Photo-thermal effect curve graph of the MNS-GOx sample of 200 mcg/ml concentration under different laser irradiation power；Fig. 8 shows heat is red
Outer detection various concentration solution solution warming thermal infrared figure under same smooth irradiation power；Fig. 9 indicates 200 mcg/mls
The MNS-GOx sample photo and thermal stability curve graph of concentration.
Fig. 6,7,8 and 9 are used to evaluate the light thermal property of nanometer diagnosis and treatment agent (MNS-GOx), in Fig. 6 it can be seen that 808
Nm laser is with 1 w/cm2Power illumination under various concentration MNS-GOx material photo-thermal effect it is significantly different, 100 micrograms/milli
Rising concentration also can achieve 45 degree or more after illumination 3 minutes, it is sufficient to kill tumour cell.In Fig. 7 it can be seen that 200 micrograms/
Photothermal conversion of the milliliter MNS-GOx under different irradiation powers is different, wherein 1.5 w/cm2Photo-thermal effect be more than 60 degree.Fig. 8
In it can be seen that the solution temperature variation under the various concentration that monitors of thermal infrared instrument increases, Fig. 9 as solution concentration increases
In it can be seen that by taking 200 mcg/ml MNS-GOx as an example, in 1 w/cm2Illumination under measure solution photo and thermal stability, warp
4 circulation heating coolings are crossed, preferable photo-thermal effect can be kept.The above results all show the near-infrared of MNS-GOx material
Area's photothermal conversion effect is good, and photostability is strong.
Embodiment 3: using the mtt assay of standard, photo-thermal therapy/class starvation synergistic therapeutic action is evaluated to A375 cell survival
The influence of rate.
A375 cell is inoculated into 96 orifice plates with every 1 × 104 density of hole, is placed in 37 degree, is cultivated 24 under the conditions of 5%CO2
h.Then, the old culture medium in 96 orifice plates is sucked out, is separately added into containing 0,0.0625,0.125,0.25,0.5,1 mM
The DMEM culture medium of MNS solution, MNS-GOx solution.After continuing culture 24 hours, the old culture medium in 96 orifice plates is sucked out, every
The culture medium solution of 100 microlitres of MTT is added in a hole, continues to cultivate 4 h；Light group continues after cultivating 4 hours after solution is added,
Culture 20 hours is then proceeded to each hole illumination 5 minutes with the power of 1W/cm2 with 808 nm lasers.It is sucked out in 96 orifice plates
Residual media, in each hole be added 100 microlitres of DMSO solutions, after jiggling, in Synergy H1 type microplate reader
The OD value (Detection wavelength is 570 nm) for detecting every hole, calculates cell survival rate with following formula.Cell survival rate (cell
Viability) (%)=(the OD570 value of sample/blank OD570 value) × 100%.
Figure 10 indicates cell survival rate figure (reacting cells toxicity and the light that different MNS sample sets and A375 cell are incubated for altogether
Toxicity).It can be seen from fig. 10 that the cell dark toxicity of MNS is lower, there is good biological safety, load grape glycosyloxy
Change enzyme (GOx) and generate certain class starvation therapeutic effect later, A375 cell survival rate is declined, and MNS light group generates bright
Aobvious tumor-killing effect, the therapeutic effect of MNS-GOx are best.
Embodiment 4:
All experimental implementations are used according to China's clinical center animal health and using the animal that the committee passes through and health care
System.Female athymic nude mice (six weeks, 20-25 grams) is subcutaneously injected 2 × 10 in nude mice back leg6A375 tumour cell
PBS solution establishes mouse tumor model.When gross tumor volume is up to 60 mm3When, it is 1 mg/ml MNS-GOx by 50 microlitres of concentration
PBS solution be directly injected into A375 tumour by way of intratumor injection, utilize toy photoacoustic imaging system (Vevo
LAZR2100), the photoacoustic signal of tumor area, variation of the observation tumour photoacoustic signal after MNS-GOx injection in 24 hours are detected.
In addition, using the magnetic resonance signal at connection shadow uMR770 3.0T magnetic resonance imager observation mouse hind leg position, observation magnetic resonance letter
Number MNS-GOx injection after for 24 hours in variation.
Figure 11 is the magnetic resonance imaging signal variation of the A375 tumor-bearing mice before and after injecting MNS-GOx sample；Figure 12 be
Inject the photoacoustic imaging signal intensity of MNS-GOx sample front and back A375 tumor-bearing mice.It can be seen from figure 11 that MNS-GOx injects
The magnetic resonance signal contrast of tumor area significantly improves after 24 hours, in figure 12 it can be seen that tumour photoacoustic signal is in MNS-
It can be gradually decreased in 24 hours after GOx injection.
Embodiment 5:
Female athymic nude mice (six weeks, 20-25 grams) is subcutaneously injected 2 × 10 in nude mice foreleg6The PBS of A375 tumour cell
Solution establishes mouse tumor model.When gross tumor volume is up to 60 mm3When, carry out Experiment on therapy.A375 tumor-bearing mice is randomly divided into five
Group: (1) blank group (control)；(2) MNS group is injected；(3) MNS-GOx group is injected；(4) MNS irradiation group is injected；(5) MNS- is injected
GOx irradiation group.Vernier caliper measurement gross tumor volume is every other day used, and according to formula V=AB2/ 2 calculate gross tumor volume
(relative volume), wherein A is the major diameter of tumour, and B is the minor axis (mm) of tumour.Each measurement result passes through processing
Preceding starting tumor volume normalization, and observe the life cycle (survival) of every group of mouse.
Figure 13 indicates different treatment groups mouse tumor volume change during treatment, as can be seen from Figure 13 different treatment groups
The situation of change of gross tumor volume (relative volume) (Day) at any time, injection MNS-GOx irradiation group can make mouse swollen
Tumor melts completely, and no longer recurs, and the significant effect of injection MNS-GOx irradiation group is better than injection MNS group, injection MNS irradiation
Group, injection MNS-GOx group and blank group (control)；Figure 14 indicates different treatment group's mouse survival periods during treatment,
The situation of change of the life cycle (survival) of different treatment groups mouse (Day) at any time as can be seen from Figure 14, injection
MNS-GOx irradiation group significantly improves the life cycle of mouse, and the significant effect of injection MNS-GOx irradiation group is better than injection MNS-
GOx group, injection MNS irradiation group, injection MNS group and blank group (control)；Figure 15 indicates different treatments during treatment
Group mouse weight variation, weight of the different treatment groups mouse in treatment cycle does not have significant change as can be seen from Figure 15.
There is good near infrared region photothermal conversion ability and photo-thermal to control for nanometer sheet diagnosis and treatment agent (MNS-GOx) in the present invention
Therapeutic effect.With good biocompatibility, cell survival rate is greater than 90%, MNS-GOx and has after co-culturing 24 hours with cell
Good biodegradability, degradable complete in 24 hours, MNS-GOx can be used as photoacoustic contrast agent and magnetic resonance radiography
Agent is for tumor imaging monitoring treatment.
In conclusion the invention discloses a kind of nanometer of diagnosis and treatment agent and preparation method thereof, application, wherein the nanometer is examined
Treat agent include adsorption have melanin manganese dioxide nano-plates and with the manganese dioxide nano-plates covalent coupling grape
Carbohydrate oxidase.Manganese dioxide nano-plates in nanometer diagnosis and treatment agent of the invention have good biocompatibility and biodegradable
Property, the melanin on manganese dioxide nano-plates is adsorbed in the good photothermal conversion ability near infrared region, the energy under laser irradiation
It is enough to be brought rapidly up in tumor locus, achieve the purpose that photo-thermal therapy, the GOx of manganese dioxide nano-plates surface coupling can will be intracellular
Convert glucose be gluconic acid and have a cytotoxic hydrogen peroxide (H2O2), intracellular energy source is consumed, class is reached
The purpose of starvation treatment tumour, nanometer diagnosis and treatment agent of the invention realize that the photoacoustic imaging of tumour and magnetic resonance imaging monitoring are swollen simultaneously
The photo-thermal therapy of tumor treats the synergistic treatment combined with class starvation, has a good application prospect in the diagnosis and treatment field of tumour.
It should be understood that the application of the present invention is not limited to the above for those of ordinary skills can
With improvement or transformation based on the above description, all these modifications and variations all should belong to the guarantor of appended claims of the present invention
Protect range.
Claims (10)
1. a kind of nanometer of diagnosis and treatment agent, which is characterized in that the nanometer diagnosis and treatment agent includes the manganese dioxide that adsorption has melanin
Nanometer sheet and with the manganese dioxide nano-plates covalent coupling glucose oxidase.
2. according to claim 1 nanometer of diagnosis and treatment agent, which is characterized in that the thickness of the manganese dioxide nano-plates is less than 10
nm。
3. the preparation method of a kind of nanometer of diagnosis and treatment agent, which is characterized in that comprising steps of
First melanin powder is dispersed in alkaline solution, obtains melanin solution；
Melanin solution is mixed with organic solvent later, and adjusts the pH value of melanin solution to scheduled model with acid solution
It encloses, is heated to scheduled reaction temperature later, manganese source stirring is added, reaction, which obtains adsorption, has the manganese dioxide of melanin to receive
Rice piece；
Then, glucose oxidase is dissolved in the water to obtain glucose oxidase solution, coupling agent is added and stirs the Portugal
It is molten to be added to the glucose oxidase after stirring by grape oxidase solution for the manganese dioxide nano-plates that adsorption has melanin
In liquid, continues to stir certain time, the nanometer diagnosis and treatment agent is made.
4. preparation method according to claim 3, which is characterized in that the manganese source is potassium permanganate, manganese chloride, nitric acid
Manganese, manganese acetylacetonate and manganese acetate it is one or more.
5. preparation method according to claim 3, which is characterized in that the acid solution is sulfuric acid solution and acetic acid solution
It is one or more.
6. preparation method according to claim 3, which is characterized in that the alkaline solution is sodium hydroxide solution, amine salt
Solution and ammonium hydroxide it is one or more.
7. preparation method according to claim 6, which is characterized in that the coupling agent includes 1- (3- dimethylamino third
Base) -3- ethyl-carbodiimide hydrochloride solution and n-hydroxysuccinimide solution, and the 1- (3- dimethylamino-propyl) -
The molar ratio of 3- ethyl-carbodiimide hydrochloride solution and n-hydroxysuccinimide solution is 1:1-1:2.
8. preparation method according to claim 3, which is characterized in that the scheduled range is 7.0-8.0, described predetermined
Reaction temperature be 80-100 DEG C.
9. preparation method according to claim 3, which is characterized in that the organic solvent is methanol, ethyl alcohol and acetone
It is one or more.
10. a kind of if described in any item nanometers of diagnosis and treatment agent of claims 1 or 2 are as preparation treatment antineoplastic agents and as system
The application of standby optoacoustic or NMR contrast agent.
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Application publication date: 20190917 |