CN109847062A - A kind of Quercetin metal nano drug and its preparation method and application - Google Patents
A kind of Quercetin metal nano drug and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of Quercetin metal nano drugs and its preparation method and application.The present invention provides a kind of Quercetin metal nano drug, Quercetin and transition metal element are coordinated by coordinate bond, and by the surface modification containing carbonyl or the high molecular polymer of hydroxyl, form Quercetin metal nano drug.The Nano medication is the multi-functional nanometer material with cancer target, can inhibit growth, invasion, transfer and recurrence of tumour cell etc., even is eliminated tumour cell, has the effect of that the various modes such as photo-thermal therapy, optical dynamic therapy and radiotherapy are antitumor.In addition, when the Nano medication degradation in vivo and metabolism, the quercetin molecule of generation can be more efficient performance antitumor action, its aggregation, distribution and metabolic condition in vivo also has traceability, excellent diagnosis and treatment integration nano platform can be formed, is had a good application prospect and wide development space in field of medicaments.
Description
Technical field
The invention belongs to anti-tumor drug technical field, more particularly, to a kind of Quercetin metal nano drug and its
Preparation method and application.
Background technique
The shortcomings that there are poorly water-solubles for classic chemotherapy drug, and blood circulation time is short, lack tumor-selective.And organism
Inside the pH of especially tumor locus is lower, the higher feature of content of hydrogen peroxide.Due to nano material have in vivo it is good
Good high-permeability and retention effect has excellent cancer target ability, visits people constantly in terms of nano material
Rope, especially Nano medication, it has also become research hotspot.
Quercetin is the aglycon of aurantiin, belongs to flavanone kind composition, has anti-inflammatory, antibacterial, removes free radical, resists
The effects of oxidation, antitumor, inhibition coagulating platelets and antiatherosclerosis.Studies have shown that Quercetin can significantly inhibit rush
The effect of cancer agent inhibits DNA, RNA and the protein synthesis of ehrlich ascites cell.Quercetin is as main nutrient for plants
One of, there are a variety of benefits to human health, be mainly derived from the fruit of the plants such as cherry, tealeaves, red onion, raspberry and cowberry
In real and leaf.Therefore, Quercetin has good biocompatibility and biological safety.
It is required to there are many organism in transition metal element (such as iron, copper, zinc, manganese, vanadium, cobalt, ruthenium, osmium, iridium, tungsten, gadolinium)
Microelement, iron be synthesize hemoglobin raw material, zinc be the key that constitute organism in zinc ester gp.Transition metal element
It can be coordinated with the hydroxyl on Quercetin, form the complex of different four-coordinations, hexa-coordinate and two coordinations, these cooperations
Object has different optical physics and spectrochemical property, such as photo-thermal, light power according to the difference of metal.
Polyvinylpyrrolidone is a kind of water-soluble macromolecule, studies have shown that polyvinylpyrrolidone is with excellent
Physiological inertia is not involved in human metabolism, and has excellent biocompatibility, is not formed and is appointed to skin, mucous membrane and eyes
What is stimulated.The polyvinylpyrrolidone of pharmaceutical grade is international one of the three big medicinal new accessories advocated, and can be used as tablet, granule
Binder, the cosolvent of injection, the glidant of capsule and coating film forming agent, the dispersing agent and enzyme and temperature-sensitive medicine of liquid preparation
The stabilizer of object can also do cryopreservative.For contact lenses, its hydrophily and lubricity can be increased.Currently, polyethylene pyrrole
Pyrrolidone 30 has obtained the approval listing of national medical administrative department.
Photo-thermal therapy (photothermal therapy, PTT) is rapid by advantages such as its part, efficient, Small side effects
Hot spot as therapeutic field of tumor.Its principle is to utilize the photothermal reagent for being enriched in tumor locus under near infrared light excitation,
Heat is generated using its photothermal conversion effect, tumor by local temperature can be made to increase to realize the effect of killing tumor cell.By
In water-soluble very poor (the 7 μ g/mL of <) of Quercetin, it is lower (< 3.6%) that pharmacokinetic property results in bioavilability, institute
It is greatly limited with the use of Quercetin clinically.And Quercetin is the good chelatingligand of metal ion, it can
The metal complex of plurality of stable is formed with many metal ions, therefore structure is carried out to it as lead compound using Quercetin and is repaired
Decorations synthesize water-soluble enhancing, the Quercetin metal nano complex that pharmacokinetic property improves, for the clinic of Quercetin
Using being extremely important.
Existing patent CN101220014A discloses Quercetin class with Apoptosis effect and its glycoside compounds
Metal complex, it was demonstrated that the complex that compounds like quercetol and bivalent metal ion, trivalent metal ion are formed can induce swollen
Apoptosis of tumor inhibits survivin protein expression, activates the activity of caspase-3, can be used to prepare as cell induction agent
The drug for treating tumour.But photo-thermal therapy is carried out to tumour currently without any application nanoscale Quercetin Metal Drugs
Report.
Summary of the invention
The technical problem to be solved by the present invention is to make up the blank of the prior art, a kind of Quercetin metal nano drug is provided
Preparation method and its low-temperature tumor photo-thermal therapy.
The first purpose of the invention is to provide a kind of Quercetin metal nano drugs.
A second object of the present invention is to provide a kind of preparation methods of Quercetin metal nano drug.
Third object of the present invention is to provide the Quercetin metal nano drugs that the above method is prepared.
Fourth object of the present invention is to provide the application of above-mentioned Quercetin metal nano drug.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
The present invention provides a kind of Quercetin metal nano drug, Quercetin and transition metal element are carried out by coordinate bond
Coordination, and by the surface modification containing carbonyl or the high molecular polymer of hydroxyl, form Quercetin metal nano drug.
The enrichment retention effect of Quercetin metal nano drug utilization nano particle of the invention, is selectively enriched to swollen
Tumor region has biological target tropism and specificity；Using the electron transition generated between Quercetin and transition-metal coordination, carry out
Photo-thermal therapy；By Quercetin to the inhibiting effect of heat shock protein, realizes low temperature photo-thermal therapy, inhibit the activity of tumour cell
It even is eliminated tumour cell, while again without any side effects to normal histocyte.
The present invention also provides the preparation methods of the Quercetin metal nano drug, by Quercetin solution, transition metal
Salting liquid is mixed containing the high molecular polymer of carbonyl or hydroxyl, is stirred, and Quercetin metal nano drug can be obtained in dialysis.
Preferably, the Quercetin, transition metal salt, high molecular polymer containing carbonyl or hydroxyl mass ratio be
0.5~1.5:2~6:10~24.
It is highly preferred that the mass ratio of the Quercetin, transition metal salt, high molecular polymer containing carbonyl or hydroxyl is
0.8~1.2:3~5:10~14.
It is further preferred that the matter of the Quercetin, transition metal salt, high molecular polymer containing carbonyl or hydroxyl
Amount is than being 1:4:12.
Preferably, the transition metal salt is in the soluble-salt of iron, copper, zinc, manganese, vanadium, cobalt, ruthenium, osmium, iridium, tungsten or gadolinium
Any one or a few.
Preferably, the molecular weight of the high molecular polymer containing carbonyl or hydroxyl is more than or equal to 10000.
It is highly preferred that the molecular weight of the high molecular polymer containing carbonyl or hydroxyl is 55000.
Preferably, the high molecular polymer containing carbonyl or hydroxyl is polyvinylpyrrolidone and/or polyaminoacid.
It is highly preferred that polyaminoacid is poly arginine and/or polylysine.
It is further preferred that the high molecular polymer containing carbonyl or hydroxyl is polyvinylpyrrolidone.
Preferably, the speed of the stirring is 500~1000r/min.
It is highly preferred that the speed of the stirring is 800r/min.
Preferably, the time of the stirring is 10~48h.
It is highly preferred that the time of the stirring is 12h.
If mixing speed too small (being less than 500r/min), mixing time are too short (being less than 10h), can reaction system be formed
Precipitating, the partial size of the Nano medication of formation is excessive (being greater than 400nm), is unfavorable for Nano medication in the circulation of living body and in tumor area
The enrichment in domain；If mixing speed excessive (being greater than 1000r/min), mixing time are too long (being greater than 48h), the Nano medication formed
Partial size it is too small (be less than 50nm), be unfavorable for the aggregation tracked the Nano medication in vivo, distribution and metabolism.
The Quercetin solution is that Quercetin is dissolved in solution obtained in solvent.
Preferably, the solvent is any one or a few in methanol, ethyl alcohol or dimethylformamide.
It is highly preferred that the solvent is ethyl alcohol.
Preferably, the mixed method are as follows: ultrasonic treatment.
Preferably, the frequency of the ultrasound is 35~40KHZ.
It is highly preferred that the frequency of the ultrasound is 40KHZ.
Preferably, the power of the ultrasound is 40~60W.
It is highly preferred that the power of the ultrasound is 60W.
Preferably, the time of the ultrasound is 8~12min.
It is highly preferred that the time of the ultrasound is 10min.
Preferably, the method for the dialysis are as follows: reaction solution is added in cellulose dialysis bag and is dialysed.
Preferably, the molecular cut off of the cellulose dialysis bag is 8~100,000.
It is highly preferred that the molecular cut off of the cellulose dialysis bag is 100,000.
Preferably, the time of the dialysis is 70~75h.
It is highly preferred that the time of the dialysis is 72h.
In addition, the Quercetin metal nano drug that the above method is prepared, it also should be within protection scope of the present invention.
Above-mentioned Nano medication as and/or prepare application in anti-tumor drug, also should be in protection scope of the present invention
Within.
Preferably, the anti-tumor drug is the antineoplastic of low temperature photo-thermal therapy, optical dynamic therapy and/or radiotherapy
Object.
The tumour is benign tumour or malignant tumour.
Compared with prior art, the invention has the following advantages:
(1) present invention mixes Quercetin with transition metal element, hydroxyl and mistake in Quercetin using Quercetin as carrier
It crosses metallic element and forms coordinate bond, carry out Coordinate self-assembly, and be added and carry out table containing the high molecular polymer of carbonyl or hydroxyl
Face modification, is successfully prepared Quercetin metal nano drug；Wherein, the addition of high molecular polymer, increase it is water-soluble and
Stability advantageously forms stable nanostructure；
(2) present invention using the pH of especially tumor locus in organism lower, the higher feature of content of hydrogen peroxide, solution
The weaker problem of the coordination ability of the hydroxyl and transition metal element determined in Quercetin, the above particular surroundings meeting of tumor locus
So that Nano medication disintegrates, facilitates Nano medication and degrade and be metabolized in vivo；After Nano medication degradation, the Mongolian oak of formation
Skin element molecule can further play itself antitumor action of Quercetin, the growth of inhibition tumour cell that can be more efficient,
Invasion, transfer and recurrence etc.；Meanwhile the transition metal element of generation can be applied to the diagnostic work of clinical imaging means；In addition,
The dispersibility and water solubility of the Nano medication are preferable, and substantially in 50~400nm, which is conducive to the partial size of nano particle
Circulation of the Nano medication in living body and the enrichment in tumor region, are suitably applied in viviperception and clinical treatment tumour；
(3) Quercetin is coordinated from different transition metal elements, can generate different Photophysical Behaviors, have photo-thermal therapy,
The antitumous effect of the various modes such as optical dynamic therapy and radiotherapy, while there is the energy of Magnetic resonance imaging and photoacoustic imaging
Power can track aggregation, distribution and the metabolic condition of the Nano medication in vivo by different imaging means；Therefore, of the invention
Quercetin metal nano drug be the multi-functional nanometer material with cancer target, excellent diagnosis and treatment integration nanometer can be formed
Platform.
Detailed description of the invention
Fig. 1 is the synthetic route chart of Quercetin metal nano drug；Wherein, (1) represents polyvinylpyrrolidone, (2) generation
Table transition metal salt, (3) represent Quercetin, and (4) represent Quercetin metal nano drug.
Fig. 2 is the photo-thermal curve and thermograph of Quercetin metal nano drug；Wherein, figure a) is Quercetin metal nano
The uv absorption spectra of drug；Figure b) be Quercetin metal nano drug photo-thermal heating curve figure；Figure c) is Quercetin gold
Belong to the hydration grain-size graph of Nano medication；Figure d) is the Quercetin of different quality ratio and the photo-thermal efficiency that transition metal element iron mixes
Figure；Figure e) be Quercetin metal nano drug aqueous solution figure.
Fig. 3 is the antitumor the performance test results figure of low temperature of quercitrin plain sheet Nano medication.
Fig. 4 is the living imaging figure of quercitrin plain sheet Nano medication；Wherein, figure (a) is the tumour of quercitrin plain sheet Nano medication
Photoacoustic imaging figure；Scheme the NMR imaging figure for the tumour that (b) is quercitrin plain sheet Nano medication.
Fig. 5 is the living body low temperature antitumous effect figure of quercitrin plain sheet Nano medication；Wherein, figure a) be living body photothermal imaging
Figure；Figure b) be quercitrin plain sheet Nano medication tumor suppression curve graph；Figure c) be the tumour cell taken out from living body form
Figure；Figure d) be living body changes of weight curve graph.
Specific embodiment
Further illustrate the present invention below in conjunction with specific embodiment, but embodiment the present invention is not done it is any type of
It limits.Unless stated otherwise, the present invention uses reagent, method and apparatus is the art conventional reagents, method and apparatus.
Unless stated otherwise, following embodiment agents useful for same and material are commercially available.
The synthetic route of Quercetin metal nano drug is as shown in Figure 1 in following example 1~11.
The synthesis of 1 quercitrin plain sheet Nano medication of embodiment
Under the ultrasound condition of 35KHZ 40W, the Quercetin of 20mg is dissolved in the ethanol-water solution (body of ethyl alcohol and water
Product is than being 1:1) in, obtain Quercetin solution；The green vitriol of 80mg is dissolved in the ultrapure water of 10mL, is added
240mg molecular weight be 55000 polyvinylpyrrolidone, altogether ultrasound 8min, then by stirring 0.5h be uniformly mixed, addition with
On obtained Quercetin solution, continue to stir 12h obtaining reaction solution under 500r/min revolving speed；Reaction solution is added to retention point
In the cellulose dialysis bag that son amount is 100,000, after ultrapure water dialysis 72h, it is freeze-dried, is obtained black with freeze drier
Color powder；Quantifying for iron content is carried out using ICP, 4 DEG C save for use.
The synthesis of 2 Quercetin ruthenium Nano medication of embodiment
Under the ultrasound condition of 40KHZ 40W, the Quercetin of 10mg is dissolved in the methanol-water solution (body of methanol and water
Product is than being 1:1) in, obtain Quercetin solution；80mg ruthenium trichloride is dissolved in the ultrapure water of 10mL, 240mg molecule is added
The poly arginine that amount is 55000, ultrasound 9min, is then uniformly mixed by stirring 0.5h, Quercetin derived above is added altogether
Solution continues stirring 36h under 600r/min revolving speed and obtains reaction solution；Reaction solution is added to the fibre that molecular cut off is 80,000
It ties up in plain bag filter, after ultrapure water dialysis 70h, is freeze-dried with freeze drier, obtains brown-black powder；Using
ICP carries out quantifying for ruthenium content, and 4 DEG C save for use.
The synthesis of 3 Quercetin tungsten Nano medication of embodiment
Under the ultrasound condition of 35KHZ 60W, the Quercetin of 30mg is dissolved in dimethyl formamide solution (dimethyl methyl
The volume ratio of amide and water is 1:1) in, obtain Quercetin solution；The tungsten hexachloride of 80mg is dissolved in two that volume ratio is 1:1
In methylformamide aqueous solution, the polylysine that 240mg molecular weight is 55000 is added, ultrasound 10min, then passes through stirring altogether
1h is uniformly mixed, and Quercetin solution derived above is added, and is continued stirring under 800r/min revolving speed and is obtained reaction solution for 24 hours；It crosses
Precipitating is filtered out, supernatant is added in the cellulose dialysis bag that molecular weight is 90,000, dialyses after 75h, is carried out with freeze drier
It is dry, obtain black powder；Quantifying for W content is carried out using ICP, 4 DEG C save for use.
The synthesis of 4 Quercetin osmium Nano medication of embodiment
Under the ultrasound condition of 40KHZ 60W, the Quercetin of 16mg is dissolved in the methanol-water solution (body of methanol and water
Product is than being 1:1) in, obtain Quercetin solution；The osmium trichloride of 80mg is dissolved in the ultrapure water of 5mL, is added super with 20mL
The polyvinylpyrrolidone that the 240mg molecular weight of pure water dissolution is 55000, ultrasound 12min, then equal by stirring 1h mixing altogether
It is even, Quercetin solution derived above is added, continues stirring under 1000r/min revolving speed and obtains reaction solution for 24 hours；It is heavy to filter out
It forms sediment, supernatant is added in the cellulose dialysis bag that molecular cut off is 100,000, dialyse 73h, is carried out with freeze drier cold
It is lyophilized dry, obtains brown-black powder；Quantifying for osmium content is carried out using ICP, 4 DEG C save for use.
The synthesis of 5 Quercetin-Cu Nano medication of embodiment
Under the ultrasound condition of 38KHZ 60W, the Quercetin of 24mg is dissolved in the ethanol-water solution (body of ethyl alcohol and water
Product is than being 1:1) in, obtain Quercetin solution；The copper chloride of 80mg is dissolved in the ultrapure water of 2mL, it is super that 25mL is then added
The poly arginine that the 240mg molecular weight of pure water dissolution is 55000, ultrasound 11min, is then uniformly mixed by stirring 0.5h altogether,
Quercetin solution derived above is added, continues stirring under 1000r/min revolving speed and obtains reaction solution for 24 hours；Reaction solution is added
In bag filter to molecular cut off for 100,000 cellulose, dialyse 74h, is freeze-dried with freeze drier, obtains indigo plant
Color powder；Quantifying for content of copper ion is carried out using ICP, 4 DEG C save for use.
The synthesis of 6 Quercetin zinc Nano medication of embodiment
Under the ultrasound condition of 38KHZ 40W, the Quercetin of 20mg is dissolved in dimethyl formamide solution (dimethyl methyl
The volume ratio of amide and water is 1:1) in, obtain Quercetin solution；The zinc chloride of 40mg is dissolved in the ultrapure water of 2mL, so
The polylysine that the 240mg molecular weight of 25mL ultrapure water dissolution is 55000 is added afterwards, altogether ultrasound 8min, then passes through stirring 1h
It is uniformly mixed, Quercetin solution derived above is added, continue stirring 48h under 600r/min revolving speed and obtain reaction solution；Anti-
Liquid is answered to be added in the bag filter for the cellulose that molecular cut off is 90,000, dialyse 72h, it is freeze-dried with freeze drier,
Obtain yellow powder；Quantifying for zinc ion content is carried out using ICP, is placed in hollow drier and saves for use.
The synthesis of 7 Quercetin manganese Nano medication of embodiment
Under the ultrasound condition of 40KHZ 50W, the Quercetin of 20mg is dissolved in the methanol-water solution (body of methanol and water
Product is than being 1:1) in, obtain Quercetin solution；The manganese chloride of 60mg is dissolved in the ultrapure water of 4mL, it is super that 20mL is then added
The polyvinylpyrrolidone that the 240mg molecular weight of pure water dissolution is 55000, ultrasound 10min, then equal by stirring 2h mixing altogether
It is even, Quercetin solution derived above is added, continues stirring 48h under 800r/min revolving speed and obtains reaction solution；Reaction solution plus
In the bag filter for entering the cellulose for being 100,000 to molecular cut off, dialyse 70h, is freeze-dried, is obtained with freeze drier
Brownish-yellow powder；Quantifying for manganese ion content is carried out using ICP, 4 DEG C save for use.
The synthesis of 8 Quercetin vanadium Nano medication of embodiment
Under the ultrasound condition of 35KHZ 50W, the Quercetin of 20mg is dissolved in the methanol-water solution (body of methanol and water
Product is than being 1:1) in, obtain Quercetin solution；The vanadium tetrachloride of 100mg is dissolved in the ultrapure water of 4mL, 20mL is then added
The poly arginine that the 240mg molecular weight of ultrapure water dissolution is 55000, ultrasound 12min, is then uniformly mixed by stirring 2h altogether,
Quercetin solution derived above is added, continues stirring 48h under 1000r/min revolving speed and obtains reaction solution；Reaction solution is added
In bag filter to molecular cut off for 100,000 cellulose, dialyse 75h, is freeze-dried with freeze drier, obtains palm fibre
Yellow powder；Quantifying for vanadium ion content is carried out using ICP, 4 DEG C save for use.
The synthesis of 9 Quercetin cobalt Nano medication of embodiment
Under the ultrasound condition of 38KHZ 50W, the Quercetin of 20mg is dissolved in the ethanol-water solution (body of ethyl alcohol and water
Product is than being 1:1) in, obtain Quercetin solution；The cobaltic chloride of 120mg is dissolved in the ultrapure water of 4mL and the dimethyl methyl of 2mL
In amide, the polyvinylpyrrolidone that the 280mg molecular weight of 20mL ultrapure water dissolution is 55000 is then added, altogether ultrasound
Then 10min is uniformly mixed by stirring 0.5h, Quercetin solution derived above is added, continues under 800r/min revolving speed
Stirring 48h obtains reaction solution；Reaction solution is added in the bag filter for the cellulose that molecular cut off is 100,000, dialyse 70h, uses
Freeze drier is freeze-dried, and yellow powder is obtained；Quantifying for cobalt ions content is carried out using ICP, 4 DEG C save for use.
The synthesis of 10 Quercetin gadolinium Nano medication of embodiment
Under the ultrasound condition of 35KHZ 55W, the Quercetin of 20mg is dissolved in the methanol-water solution (body of methanol and water
Product is than being 1:1) in, obtain Quercetin solution；The dichloride gadolinium of 80mg is dissolved in the ultrapure water of 4mL and the dimethyl methyl of 2mL
In amide, the polyvinylpyrrolidone that the 200mg molecular weight of 20mL ultrapure water dissolution is 55000 is then added, altogether ultrasound 8min,
Then it is uniformly mixed by stirring 2h, Quercetin solution derived above is added, continued stirring 48h under 600r/min revolving speed and obtain
To reaction solution；Reaction solution is added in the bag filter for the cellulose that molecular cut off is 100,000, dialyse 73h, with freeze-drying
Machine is freeze-dried, and yellow powder is obtained, and carries out quantifying for gadolinium ion content using ICP, 4 DEG C save for use.
The synthesis of 11 Quercetin iridium Nano medication of embodiment
Under the ultrasound condition of 35KHZ 45W, the Quercetin of 20mg is dissolved in dimethyl formamide solution (dimethyl methyl
The volume ratio of amide and water is 1:1) in, obtain Quercetin solution；The iridous chloride of 80mg is dissolved in the ultrapure water of 4mL,
Then the polyvinylpyrrolidone that the 480mg molecular weight of 20mL ultrapure water dissolution is 55000 is added, ultrasound 12min, then leads to altogether
It crosses stirring 1h to be uniformly mixed, Quercetin solution derived above is added, continue stirring 48h under 1000r/min revolving speed and obtain instead
Answer liquid；Reaction solution be added to molecular cut off be 100,000 cellulose bag filter in, dialyse 72h, with freeze drier into
Row freeze-drying, obtains yellow powder, carries out quantifying for iridium ion content using ICP, 4 DEG C save for use.
The light thermal property of 12 Quercetin metal nano drug of embodiment is tested
1, light thermal property test experiments
(1) the UV absorption experiment of Quercetin metal nano drug
1) experimental method
Quercitrin plain sheet, ruthenium, tungsten, osmium, copper, zinc, manganese, cobalt, gadolinium and the iridium nanometer medicine that embodiment 1~11 is prepared respectively
Object is diluted, be made into 3mL concentration be 50 μ g/mL drug solution, tested in ultraviolet absorption spectrum instrument, starting point from
300nm, terminal measure 900nm, and using wavelength as abscissa, absorbance is ordinate mapping, and Quercetin metal nano can be obtained
The ultra-violet absorption spectrum of drug.
2) experimental result
The ultra-violet absorption spectrum of Quercetin metal nano drug is as shown in figure a) in Fig. 2, it can be seen that Quercetin and gold
After belonging to coordination, new absorption peak is had between 400~500nm and is generated, this is because the electron transition on metal is to Quercetin
Result, it was demonstrated that Quercetin and metal are coordinated；In addition, the Nano medication of quercitrin plain sheet, ruthenium and osmium has at 808nm
Very strong UV absorption, and the UV absorption at 808nm is to do the necessary condition of photo-thermal therapy.
(2) photo-thermal of Quercetin metal nano drug, which heats up, tests
1) experimental method
Quercitrin plain sheet, ruthenium, tungsten, osmium, copper, zinc, manganese, cobalt, gadolinium and the iridium Nano medication being prepared with embodiment 1~11,
With the content quantitative of metal, it is made into the test fluid that 2mL concentration is 50 μ g/mL；Then respectively with the near infrared laser of 808nm into
Row illumination is (with 1.3W/cm2Power), every 10s, with thermometer record 1 quercitrin plain sheet Nano medication temperature value, concurrent irradiation
10min is iteratively repeated 3 times, makees the time to the curve graph of temperature, the photo-thermal heating that Quercetin metal nano drug can be obtained is bent
Line.
2) experimental result
The photo-thermal heating curve of Quercetin metal nano drug is as shown in figure b) in Fig. 2, it can be seen that quercitrin plain sheet is received
Rice drug has good photo-thermal effect, and the degree that heats up is influenced by drug concentration；In addition, quercitrin plain sheet Nano medication is through light
15 DEG C can be at least improved according to rear temperature, this temperature difference can effectively kill tumour cell, therefore, quercitrin plain sheet nanometer medicine
Object has good photo-thermal toxicity.
(3) the hydration partial size experiment of Quercetin metal nano drug
1) experimental method
Quercitrin plain sheet, ruthenium, tungsten, osmium, copper, zinc, manganese, cobalt, gadolinium and the iridium Nano medication being prepared with embodiment 1~11,
With the content quantitative of metal, it is made into the test fluid that 2mL concentration is 50 μ g/mL；It is measured by Brooker dynamic light scattering,
The hydration partial size of Quercetin metal nano drug can be obtained.
2) experimental result
Shown in figure c) in the hydration partial size such as Fig. 2 of Quercetin metal nano drug, it can be seen that Quercetin and transition gold
Belong to iron, ruthenium, osmium, copper, zinc, manganese, cobalt, tungsten, gadolinium and iridium can form nano particle, during preparing Nano medication by control
Mixing speed and mixing time make partial size substantially in 50~400nm, the partial size is big come the partial size of the nano particle controlled
It is small to be conducive to circulation of the Nano medication in living body and the enrichment in tumor region, it is suitably applied viviperception and clinical treatment
In tumour.
(4) the photo-thermal efficiency experiment of the Quercetin of different quality ratio and the mixing of transition metal element iron
1) experimental method
The mass ratio that Quercetin and transition metal element iron is respectively set is 1:1,0.5:1 and 0.25:1, synthesizes Quercetin
Iron Nano medication measures the Quercetin of different quality ratio and the photo-thermal efficiency of transition metal element iron mixing.
2) experimental result
The photo-thermal efficiency of Quercetin and transition metal element iron mixing of different quality ratio, can as shown in the figure d) in Fig. 2
To find out, when the mass ratio of Quercetin and iron is 0.25:1, the photo-thermal effect of quercitrin plain sheet Nano medication is best, and heat up degree
Maximum, therefore, selecting the mass ratio of Quercetin and iron is 0.25:1, Quercetin when as synthesis Quercetin metal nano drug
With the mass ratio of metal.
(5) the aqueous solution experiment of Quercetin metal nano drug
1) experimental method
Quercitrin plain sheet, ruthenium, tungsten, osmium, copper, zinc, manganese, cobalt, gadolinium and the iridium Nano medication being prepared with embodiment 1~11,
With the content quantitative of metal, be made into the test fluid that 3mL concentration is 50 μ g/mL, be put into transparent reagent bottle, using camera into
Row is taken pictures.
2) experimental result
The aqueous solution of Quercetin metal nano drug is as shown in figure e) in Fig. 2, it can be seen that Quercetin metal is received
The water solubility of rice drug is all relatively good, can satisfy the drug of clinical application；And the Nano medication of quercitrin plain sheet, ruthenium and osmium is presented
The solution of black out, this also just corresponds to ultra-violet absorption spectrum, has very strong near infrared absorption at 808nm, mention to photo-thermal therapy
Having supplied may.
The antitumor performance test of low temperature of 13 Quercetin metal nano drug of embodiment
1, low temperature antitumor activity energy test experiments
(1) using human breast cancer cell as research object, the quercitrin plain sheet Nano medication that embodiment 1 is prepared is configured to
Various concentration, concentration are respectively as follows: 3.13 μ g/mL, 6.25 μ g/mL, 12.5 μ g/mL, 25 μ g/mL, 50 μ g/mL and 100 μ g/mL；
(2) respectively under 37 DEG C, 45 DEG C and sunshine condition, after being incubated for human breast cancer cell 12h, with the near-infrared of 808nm
Laser illumination is (with 0.5W/cm2Power) 20min；It is incubated for 12h again, is incubated in total for 24 hours, then carries out cell using mtt assay
Survival rate statistics.
2, experimental result
The antitumor performance test of low temperature of quercitrin plain sheet Nano medication is fig. 3, it is shown that at 37 DEG C, 45 DEG C
It is incubated for human breast cancer cell to compare, when the human breast cancer cell for being incubated for 20min with daylight, and the quercitrin of each various concentration is added
When plain sheet Nano medication, human breast cancer cell survival rate is minimum, illustrates that quercitrin plain sheet Nano medication has low temperature antitumor activity
Energy.
The NMR imaging and photoacoustic imaging performance of 14 quercitrin plain sheet Nano medication of embodiment are tested
1, NMR imaging and photoacoustic imaging performance test experiments
Using nude mice as animal model, human breast cancer cell is planted by way of subcutaneously planting tumor, grows to 60cm to tumour3
When, 4 nude mices are taken, are divided into 2 groups, every group 2；Wherein for doing NMR imaging, the nude mice of another set is used for one group of nude mice
Do photoacoustic imaging；The quercitrin plain sheet nanometer medicine that tail vein injection embodiment 1 is prepared is carried out to 1 nude mice in every group respectively
Object (120 μ L, 0.8mg/kg), then anaesthetizes 2 groups of nude mices with chloraldurate, respectively with toy NMR imaging instrument and small
Animal photoacoustic imager tests tumor locus, and every 1h measurement is primary, measures 4h in total；Then it maps, can obtain
To the photoacoustic imaging and NMR imaging effect of tumor locus, for instructing low temperature photo-thermal therapy.
2, experimental result
The living imaging of quercitrin plain sheet Nano medication is as shown in Figure 4, it can be seen that Quercetin iron Nano medication is in tumour portion
Position enrichment accumulate at any time, after drug 2h is added, quercitrin plain sheet Nano medication tumor locus enrichment highest, this
When can be irradiated with the near infrared laser of 808nm, photo-thermal therapy, therefore, quercitrin are instructed by optoacoustic and the double imagings of magnetic resonance
Plain sheet Nano medication has the ability of good photo-thermal effect and NMR imaging.
The antitumor performance test of living body low temperature of 15 quercitrin plain sheet Nano medication of embodiment
Using the quercitrin plain sheet Nano medication that embodiment 1 is prepared as experimental drug, experiment is divided into 4 groups below: Mongolian oak
Skin plain sheet Nano medication group, Quercetin group, control buffer solution (PBS) group, quercitrin plain sheet Nano medication+daylight group, pass through tail
Vein is added to corresponding Nano medication in nude mouse, after drug 2h is added, with the near infrared laser of 808nm to Quercetin
Metal nano drug+daylight group is irradiated.
(1) the photothermal imaging experiment of living body
1) experimental method
By quercitrin plain sheet Nano medication group and PBS group, Nano medication and PBS are added in nude mouse by tail vein,
After drug 2h is added, it is irradiated that (power is to quercitrin plain sheet Nano medication group and PBS group with the near infrared laser of 808nm
0.5W/cm2), it is taken pictures with toy thermal imaging system every 4min, total concurrent irradiation 20min.
2) experimental result
The photothermal imaging of living body is as shown in figure a) in Fig. 5, it can be seen that the temperature at nude mouse tumor position is with irradiation time
Increase, the temperature of PBS group tumor locus has increased slightly, and the temperature of quercitrin plain sheet Nano medication group tumor locus is increased more
Obviously, temperature can be increased up to 44~45 DEG C, this temperature, which is fit into, carries out low temperature photo-thermal therapy, therefore, using power
For 0.5W/cm2, irradiation 20min progress low temperature anti-tumor experiment.
(2) the tumor suppression curve experiments of quercitrin plain sheet Nano medication
1) experimental method
Using nude mice as animal model, human breast cancer cell is planted by way of subcutaneously planting tumor, grows to 60cm to tumour3
When, pass through corresponding drug in above-mentioned 4 groups of tail vein injection；Then to quercitrin plain sheet Nano medication group, with the near-infrared of 808nm
Laser illumination is (with 0.5W/cm2Power), every 2d is measured with size of the vernier caliper to tumour, obtains the body of tumour
Product, observes 20d altogether；Then it is mapped with the relationship for observing number of days and gross tumor volume, obtains tumor suppression curve.
2) experimental result
The tumor suppression curve of quercitrin plain sheet Nano medication is as shown in figure b) in Fig. 5, it can be seen that PBS group nude mice
The increase of tumour at any time is gradually grown up；Compared with PBS group, Quercetin group and quercitrin plain sheet Nano medication group tumour growth are
Slow down, but still increase obviously, illustrates that the chemotherapeutic toxicity of Quercetin group or quercitrin plain sheet Nano medication group itself is very low, it is insufficient
For antitumor；And quercitrin plain sheet Nano medication+daylight group tumour is almost without growth, and gradually melts, until disappearing
It loses, illustrates that Quercetin metal nano drug has good tumor inhibitory effect under conditions of illumination.
(3) form of the tumour cell taken out in living body
1) experimental method
After tumor suppression curve experiments to quercitrin plain sheet Nano medication, experiment nude mice is put to death, tumour is taken out and carries out
It takes pictures.
2) experimental result
The form of the tumour cell taken out in living body is as shown in figure c) in Fig. 5, it can be seen that the tumour growth of PBS group
It is huge；Compared with PBS group, the tumour of quercitrin plain sheet Nano medication group and Quercetin group is relatively small, but difference is little；And Mongolian oak
Skin plain sheet Nano medication+daylight group tumour has disappeared close to 2/3rds, and the tumour of one third reduces clearly,
Show that quercitrin plain sheet Nano medication has good photo-thermal toxicity, can be good at antitumor.
(4) the changes of weight curve graph of living body
1) experimental method
Using nude mice as animal model, human breast cancer cell is planted by way of subcutaneously planting tumor, grows to 60cm to tumour3
When, pass through corresponding drug in above-mentioned 4 groups of tail vein injection；Then to quercitrin plain sheet Nano medication group, with the near-infrared of 808nm
Laser illumination is (with 0.5W/cm2Power), every 2d, with scale to experiment nude mice weight measure, observe 20d altogether；
Then it is mapped with the relationship for observing number of days and nude mice weight, obtains the variation of nude mice weight in experimentation.
2) experimental result
Shown in figure d) in the changes of weight curve such as Fig. 5 of living body, it can be seen that PBS group, Quercetin group, quercitrin plain sheet
Nano medication group and quercitrin plain sheet Nano medication+daylight group nude mice weight, increase at any time all increased, and illustrate quercitrin
The toxic side effect of plain metal nano drug is smaller, smaller to the organ damage of nude mice.
In conclusion Quercetin metal nano drug has water-soluble and good photo-thermal effect, and partial size well
Size is suitable, antitumor suitable for living body, is conducive to circulation of the Nano medication in living body and the enrichment in tumor region；The drug
For when treating tumour, to there is good photo-thermal toxicity, good low temperature photo-thermal therapy effect and the work for completely eliminating tumour
With.
The preferred embodiment that the above specific embodiment is of the invention for ease of understanding and illustrates, but the invention is not limited to
Above-described embodiment does not mean that the present invention must rely on above-described embodiment and could implement.Person of ordinary skill in the field
It is the addition of equivalence replacement and auxiliary element to raw material selected by the present invention, specific it will be clearly understood that any improvement in the present invention
The selection etc. of mode, all of which fall within the scope of protection and disclosure of the present invention.
Claims (10)
1. a kind of Quercetin metal nano drug, which is characterized in that Quercetin and transition metal element are matched by coordinate bond
Position, and by the surface modification containing carbonyl or the high molecular polymer of hydroxyl, form Quercetin metal nano drug.
2. the preparation method of Quercetin metal nano drug described in claim 1, which is characterized in that by Quercetin solution, transition
Metal salt solution is mixed containing the high molecular polymer of carbonyl or hydroxyl, is stirred, and Quercetin metal nano can be obtained in dialysis
Drug.
3. preparation method according to claim 2, which is characterized in that the Quercetin, transition metal salt, containing carbonyl or
The mass ratio of the high molecular polymer of hydroxyl is 0.5~1.5:2~6:10~24.
4. preparation method according to claim 2, which is characterized in that the transition metal salt be iron, copper, zinc, manganese, vanadium,
Cobalt, ruthenium, osmium, iridium, tungsten or gadolinium soluble-salt in any one or a few.
5. preparation method according to claim 2, which is characterized in that the high molecular polymer containing carbonyl or hydroxyl
Molecular weight be more than or equal to 10000.
6. preparation method according to claim 2, which is characterized in that the high molecular polymer containing carbonyl or hydroxyl
For polyvinylpyrrolidone and/or polyaminoacid.
7. preparation method according to claim 2, which is characterized in that the speed of the stirring is 500~1000r/min,
Time is 10~48h.
8. preparation method according to claim 2, which is characterized in that the solvent of the Quercetin solution is methanol, ethyl alcohol
Or any one or a few in dimethylformamide.
9. the Quercetin metal nano drug that any the method for claim 2~8 is prepared.
10. the Nano medication of claim 1 or 9 as and/or prepare application in anti-tumor drug.
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| CN117084981A (en) * | 2023-09-21 | 2023-11-21 | 河南中医药大学 | Preparation method and application of iron ion synergistic artemisinin-quercetin synergistic treatment nano system |
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