CN108785673A - A kind of Prussian blue similar object nanometer photo-thermal therapy agent of load medicine and preparation method thereof that sodium nitroprussiate is conjugated - Google Patents
A kind of Prussian blue similar object nanometer photo-thermal therapy agent of load medicine and preparation method thereof that sodium nitroprussiate is conjugated Download PDFInfo
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- BQMKAHQKDSZAIQ-UHFFFAOYSA-N tetrasodium;iron(3+);nitroxyl anion;pentacyanide Chemical compound [Na+].[Na+].[Na+].[Na+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=[N-] BQMKAHQKDSZAIQ-UHFFFAOYSA-N 0.000 title claims abstract description 50
- DCYOBGZUOMKFPA-UHFFFAOYSA-N iron(2+);iron(3+);octadecacyanide Chemical compound [Fe+2].[Fe+2].[Fe+2].[Fe+3].[Fe+3].[Fe+3].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCYOBGZUOMKFPA-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960003351 prussian blue Drugs 0.000 title claims abstract description 44
- 239000013225 prussian blue Substances 0.000 title claims abstract description 44
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 238000007626 photothermal therapy Methods 0.000 title claims abstract description 33
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000002105 nanoparticle Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- -1 potassium ferricyanide Chemical compound 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000001556 precipitation Methods 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims 2
- 241001062009 Indigofera Species 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 29
- 230000000694 effects Effects 0.000 abstract description 12
- 238000011282 treatment Methods 0.000 abstract description 9
- 210000004881 tumor cell Anatomy 0.000 abstract description 7
- 238000002512 chemotherapy Methods 0.000 abstract description 6
- 206010061309 Neoplasm progression Diseases 0.000 abstract description 5
- 230000033115 angiogenesis Effects 0.000 abstract description 5
- 230000006907 apoptotic process Effects 0.000 abstract description 5
- 230000001939 inductive effect Effects 0.000 abstract description 4
- 230000036457 multidrug resistance Effects 0.000 abstract description 4
- 230000002441 reversible effect Effects 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 238000001027 hydrothermal synthesis Methods 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 238000002601 radiography Methods 0.000 abstract description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 72
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 40
- 229960003668 docetaxel Drugs 0.000 description 40
- 210000004027 cell Anatomy 0.000 description 24
- 239000000243 solution Substances 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 230000004083 survival effect Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 6
- 235000013339 cereals Nutrition 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 239000012980 RPMI-1640 medium Substances 0.000 description 5
- 239000012894 fetal calf serum Substances 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
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- 238000005516 engineering process Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
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- 238000001514 detection method Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 210000004216 mammary stem cell Anatomy 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- 238000000015 thermotherapy Methods 0.000 description 2
- 206010063081 Acute left ventricular failure Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002185 docetaxel anhydrous group Chemical group 0.000 description 1
- YTMAHSMXCDBBJP-XKIQGVRMSA-N docetaxel ethanol Chemical compound CCO.O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YTMAHSMXCDBBJP-XKIQGVRMSA-N 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
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- 208000021760 high fever Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- YKHQSWIVNHQJSW-UHFFFAOYSA-N iron;oxalonitrile Chemical compound [Fe].N#CC#N YKHQSWIVNHQJSW-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000002647 laser therapy Methods 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229960003753 nitric oxide Drugs 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001507 sample dispersion Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
- 210000003462 vein Anatomy 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
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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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- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Acoustics & Sound (AREA)
- Radiology & Medical Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses the Prussian blue similar object nanometer photo-thermal therapy agents of load medicine and preparation method thereof that a kind of sodium nitroprussiate is conjugated.The Prussian blue similar object nanometer photo-thermal therapy agent grain size of load medicine that the sodium nitroprussiate prepared by hydro-thermal reaction method is conjugated is about 205.4nm, can pass through tumor locus EPR effects and realize passive target.Under the irradiation of near-infrared laser, this nanometer of photo-thermal therapy agent not only can induce photo-thermal ablated tumor cell by excellent photothermal conversion efficiency, can also control NO releases, so as to improve EPR effects, increase nanoparticle intra-tumor delivery.Meanwhile NO can also prevent angiogenesis, reverse multidrug resistance etc. from inhibiting tumour progression by inducing apoptosis of tumour cell.On the other hand, due to the architectural difference of sodium nitroprussiate and the potassium ferricyanide, lead to nanoparticle lattice defect, to increase the drugloading rate of this nanometer of photo-thermal therapy agent.Therefore, after carrying chemotherapeutics, under the irradiation of near infrared light, the controllable NO releases of dosage, the combination tumor treatment of photo-thermal therapy and chemotherapy may be implemented.In addition, the Prussian blue similar object nanometer photo-thermal therapy agent of load medicine that the sodium nitroprussiate of the present invention is conjugated also has good photo and thermal stability and certain optoacoustic radiography performance.
Description
Technical field
The present invention relates to medical medicine fields, and in particular to the conjugated Prussian blue similar object nanometer photo-thermal of load medicine of sodium nitroprussiate
Therapeutic agent and preparation method thereof.
Background technology
Nitric oxide (NO) is the signal of interest molecule generated by nitricoxide synthase endogenous.It is in angiocarpy, nerve,
Vital effect is played in breathing, stomach and intestine and the various biosystems such as immune.In recent years, NO is to tumor proliferation, apoptosis
Influence with transfer gradually causes the concern of people.It is worth noting that, the antitumor action of NO is strongly depend on it in target spot
Concentration.For example, picomole NO promotes tumour progression by Tumor Cell Growth Stimulated and enhancing angiogenesis, and micromole
NO prevents angiogenesis by inducing apoptosis of tumour cell, and reverse multidrug resistance inhibits tumour progression.Therefore, when accurate
Sky releases of the control NO in physiological environment simultaneously improves the strategy of its bioavilability for optimizing the therapeutic effect of NO to closing weight
It wants.Most common method is light excitation inactive precursor release NO, realizes that the controllable NO of dosage is released by adjusting light excitation signal
Specific physiological targets are put into, and to non-target spot tissue effect very little.Compared with Uv and visible light, light of the near infrared light in NO
There is unique advantage in terms of generation, be because it is with larger penetration depth and relatively mild to organizing.
Photo-thermal therapy is a kind of promising oncotherapy technology developed recently.It utilizes photothermal conversion materiat by photon
Energy is converted to thermal energy, carrys out ablated tumor cell to quickly improve tissue temperature.Apply minimally invasive near infrared light by part to shine
It penetrates, the high fever caused by photo-thermal therapy can be controlled to minimize the damage to non-targeted tissue.However, due in tumor tissues
The uneven distribution of heat is used alone photo-thermal therapy and is difficult to completely eliminate tumour, this necessarily leads to tumor recurrence and transfer.With
Photo-thermal therapy is used alone to compare, combined chemotherapy strategy can play significant synergistic effect, and greatly improve therapeutic effect.
Prussian blue for antidote that therapeutic radiation the exposes and widely people as Food and Drug Adminstration of the US's approval
Know, shows good biocompatibility and biological safety.Recently, it is shown near infrared light window due to Prussian blue
The feature for going out high absorbance, caused photo-thermal therapy agent that the attention of many researchers drives as near infrared light it
One.However, the inhomogeneities and penetrability due to tumour are poor, nano particle is caused to be accumulated in tumor tissues less.
Sodium nitroprussiate generates NO by the metabolism in vascular smooth muscle and plays its powerful vasorelaxation action, and is to use
In the common drug for the treatment of hypertension emergency and acute left ventricular failure.It is worth noting that, sodium nitroprussiate is a kind of NO donors, and
It is similar to the raw material potassium ferricyanide structure in mesoporous Prussian blue building-up process.Therefore, in mesoporous Prussian blue synthesis
Cheng Zhong, sodium nitroprussiate, which is added, makes it be embedded in crystal structure, prepares the conjugated Prussian blue similar object of sodium nitroprussiate.
The Prussian blue similar object nanometer light of load medicine for using the sodium nitroprussiate prepared by hydrothermal synthesis method conjugated in the present invention
Heat cure agent grain size is smaller and is uniformly dispersed, and can realize passive target by tumor locus EPR effects.In the photograph of near-infrared laser
It penetrates down, this nanometer of photo-thermal therapy agent not only can induce photo-thermal ablated tumor cell by excellent photothermal conversion efficiency, may be used also
To control NO releases, so as to improve EPR effects, increase nanoparticle intra-tumor delivery.Meanwhile NO can also be by inducing tumour thin
Born of the same parents' apoptosis prevents angiogenesis, reverse multidrug resistance etc. from inhibiting tumour progression.On the other hand, due to sodium nitroprussiate and iron cyanogen
The architectural difference for changing potassium, leads to nanoparticle lattice defect, to increase the drugloading rate of this nanometer of photo-thermal therapy agent.Therefore, it carries
After chemotherapeutics, under the irradiation of near infrared light, the controllable NO releases of dosage, the combination tumor of photo-thermal therapy and chemotherapy are realized
Treatment.However the Prussian blue similar object nanometer photo-thermal therapy agent of load medicine and preparation method thereof being conjugated about sodium nitroprussiate, at present also
Do not report.
Invention content
In view of the problems of the existing technology, the purpose of the present invention is to provide the Prussias Zai Yao that a kind of sodium nitroprussiate is conjugated
Blue analog nanometer photo-thermal therapy agent and preparation method thereof.The novel nano photo-thermal therapy agent grain size is smaller and is uniformly dispersed, can
Passive target is realized by tumor locus EPR effects.Under the irradiation of near-infrared laser, this nanometer of photo-thermal therapy agent not only can be with
Photo-thermal ablated tumor cell is induced by excellent photothermal conversion efficiency, NO releases can also be controlled, so as to improve EPR effects,
Increase nanoparticle intra-tumor delivery.Meanwhile NO can also prevent angiogenesis, reverse multidrug by inducing apoptosis of tumour cell
Drug resistance etc. inhibits tumour progression.On the other hand, due to the architectural difference of sodium nitroprussiate and the potassium ferricyanide, lead to nanoparticle lattice
Defect, to increase the drugloading rate of this nanometer of photo-thermal therapy agent.Therefore, after carrying chemotherapeutics, in the irradiation of near infrared light
Under, realize the controllable NO releases of dosage, the combination tumor treatment of photo-thermal therapy and chemotherapy.The advantages of combination therapy, will not only damage
Lose monotherapy effect, but also can significant raising therapeutic effect, shorten treatment cycle, reduce adverse side effect.In addition,
The nanometer photo-thermal therapy agent of the present invention also has good photo and thermal stability and certain optoacoustic radiography performance.It is closed using hydro-thermal
The conjugated Prussian blue similar object nanometer photo-thermal therapy agent of load medicine of sodium nitroprussiate, convenience simple for process, used material are prepared at method
Expect economical and practical and good biocompatibility, has broad application prospects.
The purpose of the present invention can be achieved through the following technical solutions：
Step 1：Suitable potassium ferricyanide, sodium nitroprussiate and polyvinylpyrrolidone are weighed in a certain amount of hydrochloric acid solution,
Certain time is stirred under magnetic stirring apparatus makes it be uniformly dispersed, and obtains mixed solution.
Step 2：The mixed solution that step 1 obtains is placed in water-bath, is stirred to react at 60 DEG C~80 DEG C certain small
When.
Step 3：Precipitation is collected in the product obtained from step 2.Sewed for several times to get to sodium nitroprussiate with water supersound washing precipitation
The Prussian blue similar object nanoparticle closed.
Step 4：The conjugated Prussian blue similar object nanoparticle of the sodium nitroprussiate that step 3 obtains is dispersed in a certain amount of water
In, the ethanol solution of a certain amount of fat-soluble medicine is added, is stirred to react at room temperature 12 hours.By the mixed solution of reaction gained
In flinging to alcohol solvent on Rotary Evaporators, centrifuge, collect precipitate and be washed with water remove for several times the drug of unentrapped to get
The Prussian blue similar object nanometer photo-thermal therapy agent of load medicine being conjugated to sodium nitroprussiate.
Present invention application hydrothermal synthesis method is successfully prepared the conjugated Prussian blue similar object nanoparticle of load medicine of sodium nitroprussiate, should
Synthetic method low in raw material price is easy to get, and preparation process is simple, it is few to take, and is easy to large-scale mass production, prepares receiving for gained
Grain of rice uniform particle diameter and steady with good biocompatibility and biological safety and excellent photothermal conversion performance and photo-thermal
It is fixed, while under the irradiation of near infrared light, can realize the control release to NO, may be implemented to control the photo-thermal of tumour after carrying medicine
It treats, the synergistic treatment of chemotherapy and NO treatment threes.
Description of the drawings
Fig. 1 is the Prussian blue similar object nanoparticle transmission electron microscope picture that sodium nitroprussiate is conjugated in the embodiment of the present invention 1.
Fig. 2 is the Prussian blue similar object nanoparticle grain size distribution that sodium nitroprussiate is conjugated in the embodiment of the present invention 1.
Fig. 3 is the Prussian blue similar object nanoparticle FTIR spectrum figure that sodium nitroprussiate is conjugated in the embodiment of the present invention 1.
Fig. 4 is the conjugated Prussian blue similar object nanoparticle of 0.2mg/mL sodium nitroprussiates in the embodiment of the present invention 2 in different work(
10 minutes heating curves of 808nm laser irradiations of rate density.
Fig. 5 is in the embodiment of the present invention 3 in 0.8W/cm2, the sodium nitroprussiate of various concentration is conjugated under 808nm laser irradiations
Prussian blue similar object nanoparticle heating curve.
Fig. 6 is the conjugated Prussian blue similar object nanoparticle of sodium nitroprussiate in the embodiment of the present invention 4 in different capacity density
The release conditions of NO under 808nm laser irradiations.
Fig. 7 is the conjugated Prussian blue similar object nanoparticle of sodium nitroprussiate in the embodiment of the present invention 5 in pulsed 808nm laser
The release conditions of the lower NO of irradiation.
Fig. 8 is the cumulative release row for the load Prussian blue similar object nanoparticle of medicine that sodium nitroprussiate is conjugated in the embodiment of the present invention 6
For.
Fig. 9 is that the conjugated Prussian blue similar object nanoparticle of the sodium nitroprussiate of various concentration in the embodiment of the present invention 7 is thin to 4T1
The toxicity of born of the same parents.
Figure 10 is using the conjugated Prussian blue similar object nanoparticle of sodium nitroprussiate as carrier in the embodiment of the present invention 8, in cell
Level realizes the collaboration oncotherapy of thermotherapy, chemotherapy and NO treatment threes.
Figure 11 is that the sodium nitroprussiate of various concentration in the embodiment of the present invention 9 conjugated Prussian blue similar object nanoparticle and nitre are general
The conjugated Prussian blue similar object nanoparticle of load medicine of sodium is under different laser irradiation times to the toxicity of 4T1 cells.
Figure 12 is the tumor volume growth curve of mouse in the embodiment of the present invention 10.
Specific implementation mode
Below in conjunction with attached drawing embodiment, the present invention will be described in detail, but the present invention is not limited in following embodiments.
Embodiment 1
1. the preparation of the conjugated Prussian blue similar object nanoparticle (m-PB-NO) of sodium nitroprussiate
The 60mg potassium ferricyanides are weighed, 488.7mg sodium nitroprussiates and 3g polyvinylpyrrolidones (PVP) are in the salt of 40mL 0.1M
In acid solution, stirring makes it be uniformly dispersed in 20 minutes.And transfer them in water-bath, it is stirred to react in 80 DEG C 12 hours.From
The heart collects precipitation, water supersound washing is used in combination 3 times to get the Prussian blue similar object nanoparticle being conjugated to sodium nitroprussiate.
2. the preparation (DTX m-PB-NO) of the conjugated load Prussian blue similar object nanoparticle of medicine of sodium nitroprussiate
With docetaxel (DTX) for model drug, the Prussian blue similar object nanoparticle that 10mg sodium nitroprussiates are conjugated is disperseed
In 10mL water, 1mL 1.5mg/mL docetaxel ethanol solutions are added, are stirred to react 12 hours.The mixing of reaction gained is molten
Liquid is centrifuged in flinging to alcohol solvent on Rotary Evaporators, is collected and is precipitated and the drug for removing unentrapped for several times is washed with water, i.e.,
Obtain the conjugated Prussian blue similar object nanometer photo-thermal therapy agent of load medicine of sodium nitroprussiate.
The m-PB-NO being prepared into is diluted to certain multiple, with its form of transmission electron microscope observing, as shown in Figure 1, m-PB-
NO is class cube structure.Its grain size is measured using Malvern laser particle size analyzer, particle diameter distribution result is shown in Fig. 2, m-PB-NO
Average grain diameter be 205 ± 10.25nm.The success that Fourier's infrared analysis verifies sodium nitroprussiate is conjugated, as shown in figure 3, from mesoporous
Prussian blue (m-PB) and m-PB-NO observe cyano group in 2086cm-1The strong stretching vibration at place.From sodium nitroprussiate and m-PB-
NO observes 1944cm-1The nitroso absorption peak at place, the results showed that SNP can be embedded in m-PB skeleton structures to form m-
PB-NO
Embodiment 2
The m-PB-NO prepared in Example 1 is dispersed in water to form 0.2mg/mL suspensions, take the suspension of 1mL in
In quartz colorimetric utensil.The use of power density is 0.8W/cm2、1.0W/cm2、1.5W/cm2、2.0W/cm2、2.5W/cm2808nm
Laser irradiates 10 minutes respectively, using thermocouple probe thermometer record different time points temperature variations as shown in figure 4,
As the irradiation time increases, solution temperature gradually rises, while as laser power increases, and solution heating rate increases, when
Laser power is 2.5W/cm2When, the temperature of solution has been increased to 63.4 DEG C, illustrates that there is m-PB-NO excellent photothermal conversion to imitate
Rate.
Embodiment 3
The m-PB-NO prepared in Example 1 is dispersed in water, take 0.05mg/mL, 0.1mg/mL, 0.2mg/mL,
The m-PB-NO suspensions 1mL of 0.5mg/mL, 1mg/mL are in quartz colorimetric utensil, using water as blank control.Use power density
For 0.8W/cm2808nm laser irradiate respectively 10 minutes, use thermocouple probe thermometer record different time points temperature
Situation of change is as shown in figure 5, as the irradiation time increases, solution temperature gradually rises, while with the increasing of m-PB-NO concentration
Add, solution heating rate is faster, and as a concentration of 1mg/mL of m-PB-NO, the temperature of solution has been increased to 47.5 DEG C, illustrates m-
PB-NO has excellent photothermal conversion efficiency.
Embodiment 4
The m-PB-NO prepared in Example 1 is scattered in PBS, takes the m-PB-NO suspension of 1mL 1mg/mL that stone is added
The use of power density is 1.5W/cm in English cuvette2、2.0W/cm2、2.5W/cm2808nm laser irradiate respectively 20 minutes,
Using non-irradiated as blank control.Using the burst size of NO in NO detection kit determination samples as shown in fig. 6, with irradiation
The burst size of the extension of time, NO gradually increases, while as laser power increases, and the rate of release of NO also increases, as a result table
Bright m-PB-NO can discharge a certain amount of NO under the irradiation of near infrared light laser.
Embodiment 5
The m-PB-NO prepared in Example 1 is scattered in PBS, takes the m-PB-NO suspension of 1mL 1mg/mL that stone is added
The use of using power density is first 2.5W/cm in English cuvette2808nm laser irradiations 5 minutes, be then shut off laser 5 and divide
Then clock carries out the laser period twice again, in selected time interval, use the release of NO in NO detection kit determination samples
For amount as shown in fig. 7, when laser is opened, m-PB-NO discharges rapidly out NO, and with laser shutdown after, the burst size of NO is almost
Do not increase, the results showed that m-PB-NO can stimuli responsive near-infrared laser signal, by adjust laser signal, but realize
Control release to NO.
Embodiment 6
The DTX@m-PB-NO and free DTX sample dispersions prepared in Example 1 is placed in PBS in bag filter, will
It is immersed in the PBS solution containing 0.5% (v/v) Tween 80.It is shaken in the shaking table that rotary speed is 120 revs/min at 37 DEG C.
The solution for taking out 2mL in different time points, is then added same amount of fresh PBS, and using high effective liquid chromatography for measuring, it is tired
Count the DTX of release.Test results are shown in figure 8, due to the poorly water-soluble of DTX, preparation of the DTX suspension at 36 hours
Only 50.65%, show relatively slow rate of release.And in DTX@m-PB-NO, since the dispersibility of DTX increases, 12
Hour accumulative release rate is 69.92%, and 24 hours are 81.45%, have comparatively faster rate of release.
Embodiment 7
The m-PB-NO prepared in Example 1 is prepared with the RPMI-1640 cell culture mediums containing 10% fetal calf serum
It is dense at 0.0063mg/mL, 0.0125mg/mL, 0.025mg/mL, 0.05mg/mL, 0.1mg/mL, 0.2mg/mL, 0.5mg/mL
Degree, toxicity of the different m-PB-NO carrier concns to 4T1 cells is evaluated with tetrazolium bromide (MTT) method.The results are shown in Figure 9, as a result table
It is bright, even if m-PB-NO, when at concentrations up to 0.5mg/mL, the survival rate of 4T1 cells is still up to 90% or more, it was demonstrated that m-PB-NO
To cell be do not have it is virose.
Embodiment 8
M-PB-NO the and DTX@m-PB-NO and free DTX prepared in Example 1, with containing 10% fetal calf serum
RPMI-1640 cell culture mediums are configured to the various concentration containing identical DTX amounts, and different treatments are evaluated with tetrazolium bromide (MTT) method
Toxicity of the method to 4T1 cells.4T1 Mouse mammary cells are being contained into 10% (v/v) fetal calf serum and 1% penicillin/strepto-
In 37 DEG C in the RPMI-1640 culture mediums of element, 5%CO2It is cultivated under atmosphere.By cell (per hole 5 × 103It is a) it is seeded in the training of 96 holes
It supports in plate and incubates 24 hours with attached cell.Culture medium is removed, DTX, m- that various concentration contains identical DTX amounts is then added
PB-NO and [email protected] is 1.5W/cm with power density after 24 hours2808nm laser irradiations contain m-PB-NO and
The cell of DTX m-PB-NO 5 minutes.After being incubated 24 hours again, 10 μ LMTT solution are added after being washed twice with PBS buffer solution
(5mg/mL) and 90 μ L fresh cultures simultaneously incubate cell 4 hours again.Then it is replaced often with 150 μ L dimethyl sulfoxide (DMSO)s (DMSO)
Culture medium in hole measures absorbance at 490nm after gently shaking and calculates its corresponding cell survival rate.Experimental result is such as
Shown in Figure 10, with the increase of contained DTX concentration, DTX@m-PB-NO cell survival rates continuously decrease, after laser irradiation, phase
Corresponding cell survival rate further decreases, and is further enhanced to the lethality of cell.
Embodiment 9
M-PB-NO the and DTX@m-PB-NO and free DTX prepared in Example 1, with containing 10% fetal calf serum
RPMI-1640 cell culture mediums are configured to the various concentration containing identical DTX amounts, and different laser are evaluated with tetrazolium bromide (MTT) method
Toxicity of the irradiation time to 4T1 cells.By 4T1 Mouse mammary cells containing 10% (v/v) fetal calf serum and 1% penicillin/
In 37 DEG C in the RPMI-1640 culture mediums of streptomysin, 5%CO2It is cultivated under atmosphere.By cell (per hole 5 × 103It is a) it is seeded in 96
In well culture plate and 24 hours are incubated with attached cell.Culture medium is removed, various concentration is then added and contains identical DTX amounts
DTX, m-PB-NO and [email protected] is 1.5W/cm with power density after 24 hours2808nm laser irradiate 0 point respectively
Clock, 3 minutes, 5 minutes and 10 minutes, then after being incubated 24 hours, 10 μ LMTT solution are added after being washed twice with PBS buffer solution
(5mg/mL) and 90 μ L fresh cultures simultaneously incubate cell 4 hours again.Then it is replaced often with 150 μ L dimethyl sulfoxide (DMSO)s (DMSO)
Culture medium in hole measures absorbance at 490nm after gently shaking and calculates its corresponding cell survival rate.Experimental result is such as
Shown in Figure 11, for free DTX and blank group, with the increase of laser irradiation time, cell survival rate does not have much
Change, shows that laser does not have an impact the cell of dissociate DTX and blank group, and for m-PB-NO and DTX m-PB-NO groups,
With the increase of irradiation time, cell survival rate is decreased obviously, and shows that m-PB-NO and DTX@m-PB-NO have apparent photo-thermal to control
Therapeutic effect can play apparent synergistic effect after carrying DTX chemotherapeutics, be further increased to the killing rate of cell.
Embodiment 10
4T1 lotus knurls female BAl BIc/c mouse are randomly divided into six groups：(a) physiological saline；(b) physiological saline+laser；(c)
DTX；(d)DTX@m-PB-NO；(e) m-PB-NO+ laser；(f) DTX@m-PB-NO+ laser (every group of n=5).It is big in mouse tumor
It is small to reach about 130mm3Afterwards, it is injected intravenously physiological saline respectively within every two days, dissociate DTX, m-PB-NO and DTX m-PB-NO.Vein
After injection 24 hours, the mouse from group b, e and f receives 808nm laser (1.5W/cm-2) irradiate 5 minutes.Every 2 days record mouse
Gross tumor volume, according to following equation calculate gross tumor volume：Volume=0.5 × L × W2, wherein L and W are the length of tumour respectively
And width.It at the 16th day, is autopsied to mouse, collects tumour and weighs to tumour.Experimental result is as shown in figure 12, right
In with physiological saline and physiological saline+laser therapy group, tumour continues to increase daily.Compared with free DTX groups, with DTX@m-
The mouse of PB-NO processing shows better antitumor effect.This shows the EPR effects due to tumor tissues, DTX@m-PB-NO
Intra-tumor delivery increase, lead to the high drug concentration in tumor tissues, to play better antitumous effect.It is shone in NIR
It penetrates down, the NO discharged from DTX m-PB-NO can reduce multidrug resistance, to enhance the tumor suppression ability of DTX.Meanwhile m-
The thermotherapy of PB-NO inductions can increase Intracellular drug accumulation and cell to the sensibility of drug.This shows DTX@m-PB-NO
+ laser group, which plays apparent synergistic effect, can significantly inhibit the growth of in-vivo tumour.
Claims (5)
1. a kind of conjugated Prussian blue similar object nanometer photo-thermal therapy agent of load medicine of sodium nitroprussiate, it is characterised in that each component in preparation
Weight percent is：10~20 parts of the potassium ferricyanide, 1~3 part of drug, 10~150 parts of sodium nitroprussiate, polyvinylpyrrolidone 500~
600 parts, 36% 8~80 parts of concentrated hydrochloric acid, 1000~2000 parts of ethyl alcohol, 8000~20000 parts of water.
2. the preparation side of the conjugated load Prussian blue similar object nanometer photo-thermal therapy agent of medicine of sodium nitroprussiate as described in claim 1
Method, it is characterised in that this approach includes the following steps：(1) potassium ferricyanide, sodium nitroprussiate and polyvinylpyrrolidine of recipe quantity are weighed
Ketone stirs evenly in a certain amount of hydrochloric acid solution, and obtained mixed liquor is placed in water-bath, is stirred at 60 DEG C~80 DEG C anti-
Certain time is answered, precipitation is collected from obtained product, with water supersound washing precipitation for several times to get the Pu Lu being conjugated to sodium nitroprussiate
Scholar's indigo plant analog nanoparticle；(2) the conjugated Prussian blue similar object nanoparticle of the sodium nitroprussiate that step (1) obtains is dispersed in prescription
In the water of amount, the ethanol solution of recipe quantity fat-soluble medicine is added, reaction 12 hours is then stirred at room temperature, by the mixed of reaction gained
Solution is closed in flinging to solvent on Rotary Evaporators, is centrifuged, is collected and precipitate and the drug for removing unentrapped for several times is washed with water, i.e.,
Obtain the conjugated Prussian blue similar object nanometer photo-thermal therapy agent of load medicine of sodium nitroprussiate.
3. such as claim 1, the Prussian blue similar object nanometer photo-thermal therapy agent of load medicine that the sodium nitroprussiate described in 2 is conjugated, feature
It is the concentration of hydrochloric acid solution within the scope of 0.01M~1M.
4. such as claim 1, the Prussian blue similar object nanometer photo-thermal therapy agent of load medicine that the sodium nitroprussiate described in 2 is conjugated, feature
It is the molar ratio of the potassium ferricyanide and sodium nitroprussiate 0.1：9.9~9.9：In 0.1 range.
5. such as claim 1, the Prussian blue similar object nanometer photo-thermal therapy agent of load medicine that the sodium nitroprussiate described in 2 is conjugated, feature
It is that the conjugated Prussian blue similar object nanometer photo-thermal therapy agent particle size range of load medicine of the sodium nitroprussiate is 50~1000nm.
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