CN104940958A - Fluorescent magnetic nano targeted medicine and preparation method thereof - Google Patents
Fluorescent magnetic nano targeted medicine and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a fluorescent magnetic nano targeted medicine which is prepared by self-assembling magnetic Fe3O4-chitosan-chelerythrine drug-loaded nano-particles and functional modified ZnSe-ZnS core-shell quantum dots, wherein the magnetic Fe3O4-chitosan-chelerythrine drug-loaded nano-particles take Fe3O4 as a magnetic core, chitosan as a skeleton material carrier and chelerythrine as a garget medicine; and the functional modified ZnSe-ZnS core-shell quantum dots are ZnSe-ZnS core-shell quantum dots which take ZnSe as inner cores and ZnS as shells, and are modified by a mercaptan carboxylic acid compound. A method disclosed by the invention is simple and convenient, is low in cost, and is green and environment-friendly; and the fluorescent magnetic nano targeted medicine prepared by the method is stable in fluorescent property and good in biological safety, has the advantages of a magnetic material and a fluorescent material at the same time, and can simultaneously realize multiple functions of magnetic separation, targeted recognition, fluorescent imaging and magnetic resonance imaging.
Description
Technical field
The present invention relates to targeted drug field, particularly relate to a kind of fluorescence magnetic nano target medicine and preparation method thereof.
Background technology
Nano-carrier constructively has unique physics and chemistry characteristic owing to having the size of 1-100nm.Their high surface and volume ratio and the probability regulated their performance, make nano-carrier become the powerful of imaging, Diagnosis and Treat.Although nano-carrier facilitates the development of medical science, still its some application face the challenge, such as to the real-time monitoring of cells in vivo activity, for target site Special Targets to or the effective transmission etc. of medicine in target cell.The design of multifunctional nano-carrier obviously can improve existing nano-carrier characteristic and help to overcome these deficiencies.What be especially combined with treating malignant tumor along with nanoparticle deepens continuously, and increasing nanoparticle will be applied to diagnosis of malignant tumor and Therapy study, and nano-particle can realize tumor patient personalized treatment.It is the important scientific problems being related to human life's health that tumor can't harm Diagnosis and Treat in place.Therefore, development integrates the multi-functional degradable nano medicine such as targeting labelling, drug conveying and report the test, and realize harmless diagnosis in place, treatment also this serial procedures of Real-Time Monitoring, be the target that medical personal dreams of simultaneously.For preparing the multifunctional drug nano-carrier of this intelligence.And the development and application that magnetic nano-particle and quantum dot are assembled is expected to improve lesion detection mode, the development that various chemical molecular need be assembled into simultaneously same nanoparticle surface and treatment Nano medication for high-performance targeting diagnosis provides new opportunity.
Drug targeting technology is chemotherapy, the study hotspot of radiotherapy and gene therapy tumor and Disciplinary Frontiers.Report in Science magazines in 2004, drug targeting technology has become the main flow of oncotherapy, in existing numerous drug targeting system, the magnetic and medicated of magnetic field guiding has obvious advantage: can realize direct intravenous injection medication, target site is enriched in by the action of a magnetic field, alleviate the toxic and side effects to human body, be thus widely used.
Magnetic and medicated is a kind of novel drug targeting system, mainly by magnetic material, framework material and cancer therapy drug three part form, cancer therapy drug and suitable magnetic material are undertaken wrapping up or adsorb the stable drug system made on a support material and have magnetic responsiveness by the method for physics or chemistry, tumor target is gathered under the effect in magnetic field in vitro, improve the concentration of target area medicine, reduce the Side effect that medicine is organized non-target area.Medicine is discharged from carrier material by the mode of controlled delayed release in vivo, at cell or the subcellsular level performance drug effect of tumor tissues, to reach the object of high-efficiency low-toxicity.At present, the most frequently used magnetic material is ferrite class material, the Fe of particle diameter in 1-100nm
3o
4have that biological safety is high, magnetic responsiveness high, be therefore usually used in Magnetic Bio-materials.
Chitosan and its derivant have excellent physicochemical properties and biological nature: energy wire drawing, film forming, granulation, can combine with many kinds of substance (heavy metal, fat, protein, cholesterol and tumor cell etc.), cytotoxic is extremely low, there are good biocompatibility and biodegradable, and obtain the excellent chitosan derivative of feature by chemical modification, the chitosan derivatives after improvement has broad application prospects in anti-tumor drugs targeting field.
Along with the development in biologic medical field progressively strengthens for the dependency of material, a kind of multi-functional micron of preparation is needed to make targeting vector obtain except accurate targeting location to nano level material, also must integrate the new function being more applicable to targeted drug treatment, the imaging function namely in the drug controlled-releasing function of targeting lesions position and target location and course of conveying.The similar composite intelligent carrier with targeting location, imaging spike and treatment reagent, the interested especially research direction of investigation of materials person just at present.Quantum dot (quantum dot, QDs) as the namo fluorescence probe that a class is novel, there is the features such as high, the luminous wide coverage of fluorescence efficiency and optical property are stable, in vital movement monitoring and long-time vivo tracking etc., there is unique advantage.
Chelerythrine (CHE) belongs to benzo coffee pyridine class quaternary ammonium base alkaloid, has remarkable physiologically active and the multiple pharmacological effect such as antiinflammatory, sterilization.Simultaneously, chelerythrine is a kind of potential inhibitors of protein kinase C with clinical practice application, and Protein kinase C plays an important role in promotion cell proliferation, apoptosis inhibit signal transduction process, be the target spot of oncotherapy, therefore chelerythrine (CHE) is a good cancer therapy drug.But because CHE has stronger cytotoxicity; CHE in blood metabolism is very fast, t
1/2shorter, need frequent drug administration, waste is large; The mouthfeel of CHE is very poor, is unfavorable for direct oral administration, because which limit CHE application clinically.
Therefore find and develop the key that suitable dosage form has become the application of chelerythrine clinical drug.There is no document both at home and abroad and CHE is made nanoparticle to realize its directed conveying, reduce the report of dosage and toxic and side effects, therefore, how to develop and integrate the multi-functional degradable nano chelerythrine cancer therapy drug such as targeting labelling, drug conveying and report the test, this is the technical barrier that those skilled in the art face for a long time always.
Summary of the invention
Technical problem to be solved by this invention is, overcome the deficiency and defect mentioned in above background technology, there is provided a kind of and can realize the good fluorescence magnetic nano target medicine of Magnetic Isolation, targets identification, fluorescence imaging, nuclear magnetic resonance and Release Performance simultaneously, also correspondingly provide that a kind of method is easy, with low cost, environmental protection, fluorescence magnetic nano target medicine that efficiency is high preparation method.
For solving the problems of the technologies described above, the technical scheme that the present invention proposes is a kind of fluorescence magnetic nano target medicine, by magnetic Fe
3o
4-chitosan-chelerythrine (Fe
3o
4/ CTS-CHE) the ZnSe-ZnS core-shell quanta dots self assembly of drug-carrying nanometer particle and functionalized modification, described magnetic Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle is with Fe
3o
4for magnetic core, chitosan (CTS) be framework material carrier, chelerythrine (CHE) is targeted drug; The ZnSe-ZnS core-shell quanta dots of described functionalized modification refers to ZnSe to be kernel, ZnS is shell, the ZnSe-ZnS core-shell quanta dots after mercaptocarboxylic acids is modified.(adopt aqueous phase synthesis method to synthesize the ZnSe-ZnS core-shell quanta dots of functionalized modification, by electrostatic self-assembled labelling, prepared the multifunctional nano medicine carrying microballoons with good fluorescence performance and magnetic).
As a total technical conceive, the present invention also provides a kind of preparation method of above-mentioned fluorescence magnetic nano target medicine, comprises the following steps:
Step (1) Fe
3o
4the preparation of-chitosan-chelerythrine drug-carrying nanometer particle: with buffer solution by magnetic Fe
3o
4-chitin nanometer is fully swelling, washing, and then add chelerythrine aqueous alkali, shaken at room temperature is hatched, and is separated, obtains medicine carrying complex and upper solution with Magnet, and washing, drying, grinding obtains Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle;
The preparation of the ZnSe-ZnS core-shell quanta dots of step (2) functionalized modification: ZnSe-ZnS core-shell quanta dots is dissolved in chloroform, then the carboxylic acid compound containing sulfydryl is added, stirring is spent the night, what centrifugal removing was unnecessary contains mercaptocarboxylic acids, by remaining washing of precipitate (at least 3 times), drying, namely obtain the ZnSe-ZnS core-shell quanta dots of described functionalized modification;
Step (3) self assembly: preparation Fe
3o
4the ZnSe-ZnS core-shell quanta dots solution of-chitosan-chelerythrine drug-carrying nanometer particle solution, functionalized modification, then drops to substantially isopyknic Fe by the ZnSe-ZnS core-shell quanta dots solution of functionalized modification
3o
4carry out self assembly in-chitosan-chelerythrine drug-carrying nanometer particle solution, stir spend the night (mixing speed is preferably 600r/min), sedimentation and filtration, washing, vacuum drying, namely obtain described fluorescence magnetic nano target medicine.Detected from experiment, the fluorescence efficiency of the fluorescence magnetic nano target medicine that the present invention prepares is more than 12% and have ferromagnetism.
In above-mentioned preparation method, preferably, described magnetic Fe
3o
4the preparation of-chitin nanometer comprises the following steps: by magnetic Fe
3o
4nano-particle adds and is dissolved with in the acetic acid solution of chitosan, add liquid paraffin, Si Pan-80(span-80), ultrasonic disperse (generally at least 20min), adds glutaraldehyde solution (25%), stirring reaction (at least 4h), filter, by petroleum ether, and with washing with acetone dehydration, dry, grind to form flowing powder, namely obtain described magnetic Fe
3o
4-chitin nanometer; Described magnetic Fe
3o
4the mass ratio of nano-particle and chitosan is 1:0.5 ~ 2.
In above-mentioned preparation method, preferably, described magnetic Fe
3o
4the preparation of nano-particle comprises the following steps: be dissolved in by ferrous sulfate heptahydrate in deionized water, add Aqueous Solutions of Polyethylene Glycol, stirring and evenly mixing, water bath with thermostatic control under room temperature (such as 30 DEG C), drip ammonia spirit under agitation, be 9 ~ 10 to pH value of solution, then add hydrogen peroxide solution, make part Fe (OH)
2be oxidized to trivalent iron salt and present black to solution, mixed solution is transferred in autoclave, isothermal reaction at 150 ~ 170 DEG C, then use distilled water wash, centrifugalize, and with absolute ethanol washing, dry, grind to obtain described magnetic Fe
3o
4nano-particle.
In above-mentioned preparation method, preferably, the preparation of described ZnSe-ZnS core-shell quanta dots comprises the following steps: be dissolved in by zinc stearate in toluene, and logical nitrogen, heating, be then cooled to room temperature, obtain Zn precursor solution; Sulfur powder is dissolved in tri-n-octyl phosphine (TOP), logical nitrogen, heating, obtained S precursor solution;
Under nitrogen protection; ZnSe quantum dot (QDs) solution, normal heptane, TOPO (TOPO) and hexadecylamine (HDA) are mixed; and the mass ratio of control ZnSe: ZnS is 1: (0.5 ~ 3); heated and stirred; till normal heptane volatilizees completely; then stir while slowly add described Zn precursor solution and S precursor solution; reaction keeps temperature; then purify by methanol wash, after precipitation, vacuum drying, obtain described ZnSe-ZnS core-shell quanta dots.
In above-mentioned preparation method, preferably, the weight portion of described zinc stearate is 320 ~ 420 parts, and the weight portion of described sulfur powder is 16 ~ 24 parts; Described zinc stearate is dissolved in toluene, leads to nitrogen, be heated to 50 ~ 70 DEG C; Be dissolved in tri-n-octyl phosphine by described sulfur powder, logical nitrogen, is heated to 80 ~ 100 DEG C; The temperature of described heated and stirred is 180 ~ 200 DEG C; Described reaction keeps temperature to be 180 ~ 200 degrees Celsius, and the time is 1h at least.
In above-mentioned preparation method, preferably, the preparation of described ZnSe quantum dot solution comprises the following steps: by ZnAc
22H
2o is dissolved in deionized water, adds TGA (TGA) under stirring, regulates pH to be 9 ~ 10 by NaOH solution, logical N
2deoxygenation; At N
2protect and under stirring, add NaHSe solution, make HSe in reaction system
-with Zn
2+the ratio of amount of substance be that 1: 2 ~ 8(is more preferably 1: 4 ~ 6), stirring reaction is at least after 10min, and 100 DEG C of at least 15min that reflux, obtain described ZnSe quantum dot solution.
In above-mentioned preparation method, preferably, the preparation of described NaHSe solution comprises the following steps: by the NaBH of 37 ~ 56 weight portions
4be dissolved in deoxygenation deionized water, ice-water bath cools, under nitrogen atmosphere, add the selenium powder of 39 ~ 60 weight portions, mix homogeneously, under airtight condition, react at least 0.5h, generally be no more than 2 h, until the selenium powder of black disappears completely, occur white crystal at the bottom of bottle, supernatant is described NaHSe solution simultaneously.
In above-mentioned preparation method, preferably, described buffer solution is glutaraldehyde solution (5%), and pH is 6 ~ 8; The described fully swelling time is greater than 10h; The time of described vibration hatching is the time is 2 ~ 4h; The described carboxylic acid compound containing sulfydryl is any one in acid, sulfydryl enanthic acid of 3-mercaptopropionic acid, dimercaptosuccinic acid, TGA, cysteine, 2 mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, sulfydryl; Described step (2) washing of precipitate solution used is dimethyl formamide.
In above-mentioned preparation method, preferably, described Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle solution is by described Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle is dissolved in pH and prepares in the acetic acid-sodium acetate solution of 4 ~ 5 to obtain; The ZnSe-ZnS core-shell quanta dots solution of described functionalized modification is that to be dissolved in pH by the ZnSe-ZnS core-shell quanta dots of described functionalized modification be that to be more preferably pH be 3 ~ 5 to 2 ~ 6(, and most preferably pH is 4 ~ 5) acetic acid-sodium acetate solution in prepare and obtain.Described acetic acid-sodium acetate solution can be water-soluble with 164g sodium acetate after add 84ml glacial acetic acid again, and to obtain after being finally diluted to 1L.
Compared with prior art, the invention has the advantages that:
(1) easy, with low cost, the environmental protection of method; Early stage quantum dot prepares in organic solvent, and its preparation condition is harsher, and material toxicity is large, and reactions steps is more complicated also, and cost is higher.By contrast, the inventive method is carried out in aqueous phase, is a kind of Green Water phase synthesi of cheap environmental protection, is also a kind of environmental friendliness, the simple precipitation polymerization method of method.
(2) the present invention has prepared the electronegative ZnSe/ZnS core-shell type quantum point that mercaptocarboxylic acids is modified, and by a kind of directly based on the layer upon layer electrostatic self-assembly method of charge effect, makes the magnetic Fe of electronegative ZnSe-ZnS core-shell quanta dots and positively charged
3o
4-chitin nanometer (derivant polymer microsphere) is self-assembled into the Fe of magnetic fluorescence
3o
4-chitosan-CHE-ZnSe/ZnS multifunctional nano drug material, method is easy, with low cost, environmental protection.
(3) the fluorescence magnetic nano target medicine fluorescence property prepared of the present invention is stable, biological safety is good, by with zinc stearate and sodium hydrogen selenide for presoma, take mercaptopropionic acid as stabilizing agent, the high-quality ZnSe-ZnS core-shell quanta dots of synthesis in water.After connecting the capable surface chemical modification of quantum dot or special molecular, the fluorescence property of ZnSe-ZnS core-shell quanta dots is stablized, and cytotoxicity is little, good biocompatibility, can be widely used in biological living labelling and detection.
(4) compared with the fluorescent material of simple function or magnetic material, Fe prepared by the present invention
3o
4-chitosan-CHE-ZnSe/ZnS fluorescence magnetic nano target medicine has the advantage of magnetic material and fluorescent material simultaneously, can realize Magnetic Isolation, targets identification, fluorescence imaging and nuclear magnetic resonance etc. multi-functional simultaneously.
Accompanying drawing explanation
In order to be illustrated more clearly in the embodiment of the present invention or technical scheme of the prior art, be briefly described to the accompanying drawing used required in embodiment or description of the prior art below, apparently, accompanying drawing in the following describes is some embodiments of the present invention, for those of ordinary skill in the art, under the prerequisite not paying creative work, other accompanying drawing can also be obtained according to these accompanying drawings.
Fig. 1 is the stereoscan photograph of fluorescence magnetic nano target medicine carrying microballoons in the embodiment of the present invention 1.
Fig. 2 is the release profiles (37 DEG C) of fluorescence magnetic nano target Nano medication CHE in different medium in the embodiment of the present invention 1.
Fig. 3 be in the embodiment of the present invention 1 fluorescence magnetic nano target Nano medication to the inhibitory action design sketch of hepatoma carcinoma cell.
Fig. 4 is the aspect graph of hepatoma carcinoma cell after Hoechst dyeing 24h in the embodiment of the present invention 1.
Detailed description of the invention
For the ease of understanding the present invention, hereafter will do to describe more comprehensively, meticulously to the present invention in conjunction with Figure of description and preferred embodiment, but protection scope of the present invention is not limited to following specific embodiment.
Unless otherwise defined, hereinafter used all technical term is identical with the implication that those skilled in the art understand usually.The object of technical term used herein just in order to describe specific embodiment is not be intended to limit the scope of the invention.
Unless otherwise specified, the various raw materials, reagent, instrument and equipment etc. used in the present invention are all bought by market and are obtained or prepare by existing method.
embodiment 1:
A kind of fluorescence magnetic nano target medicine of the present invention, by positively charged magnetic Fe
3o
4the ZnSe-ZnS core-shell quanta dots self assembly of-chitosan-chelerythrine drug-carrying nanometer particle and electronegative functionalized modification, magnetic Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle is with Fe
3o
4for magnetic core, chitosan be framework material carrier, chelerythrine is targeted drug; The ZnSe-ZnS core-shell quanta dots of functionalized modification refers to ZnSe to be kernel, ZnS is shell, the ZnSe-ZnS core-shell quanta dots after mercaptocarboxylic acids is modified.Its stereoscan photograph as shown in Figure 1.
The preparation method of the present embodiment, comprises the following steps:
Be dissolved in the deionized water of 30mL by 2.502 g ferrous sulfate heptahydrates, adding 10 mL concentration is 50 g × L
-1pEG-20000 aqueous solution after, fully stirring in 30 DEG C of waters bath with thermostatic control, drip a certain amount of dilute ammonia solution 30mL, is 10 to solution ph, then add a certain amount of hydrogen peroxide solution stir 20min.Finally, be all transferred in autoclave, at 160 DEG C, isothermal reaction 5h, obtains magnetic Fe
3o
4nano-particle.
By above-mentioned for 0.2g obtained magnetic Fe
3o
4nano-particle adds 5% acetic acid solution 20 ml being dissolved with 0.2g chitosan, add liquid paraffin 40 mL again, span-80 0.5 mL, after ultrasonic disperse 20min, add the glutaraldehyde solution of 3 mL 25% again, mechanic whirl-nett reaction 4h, filters, by petroleum ether, and dewater with washing with acetone, drying, grinds to form flowing powder, obtains magnetic Fe
3o
4-chitin nanometer (Fe
3o
4-CTS complex microsphere).
Standard but takes 50mg magnetic Fe
3o
4-chitosan microball puts into 100ml conical flask, with 20.0 ml 5% glutaraldehydes phosphate buffer (pH6.8) by fully swelling for nanoparticle (>10h), then pours out buffer.By the magnetic Fe after swelling
3o
4-chitosan microball buffer solution 2 times.Add certain density CHE hydrochlorate aqueous solution 40.0ml, shaken at room temperature hatching 2.5h.Be separated with Magnet, obtain medicine carrying complex and upper solution.With 2.0 ml milli-Q water medicine carrying complex 2 times.By medicine carrying complex in 60 DEG C of vacuum drying 10h, after grinding, namely obtain Fe
3o
4-chitosan-CHE drug-carrying nanometer particle.
By 0.426g(10mmol) NaBH
4add in the little flask of 20mL, then add 2.0mL deoxygenation deionized water, ice-water bath cools, and under nitrogen atmosphere, adds 0.3948g(5mmol) selenium powder, mix homogeneously, namely obtains NaHSe solution after reacting 1h under airtight condition.
By 2.195g(10mmol) ZnAc
22H
2o, in 150mL three-necked bottle, adds 100mL deionized water and makes it dissolve, add 0.18ml(24mmol under vigorous stirring) TGA, regulate the pH value of solution to be 9.5 by the NaOH solution of 1.0 mol/L, logical N
2deoxygenation 1h; At N
2protect and under stirring, draw the NaHSe solution 1.0mL prepared and add in mixed liquor, after stirring reaction 10min, 100 DEG C of backflow 15min, obtain ZnSe quantum dot solution.
Be dissolved in by 0.36 g zinc stearate in 2.5 mL toluene, logical nitrogen, is heated to 60 DEG C, is then cooled to room temperature, obtain Zn precursor solution; The S powder of 16 mg is dissolved in 2.5 mL TOP, and logical nitrogen, is heated to 90 DEG C, obtained S precursor solution.Under nitrogen protection, in three-neck flask, add ready ZnSe quantum dot solution (containing 20 mg ZnSe), add 4 mL normal heptane, 2.5 g TOPO and 1.5 g hexadecylamines simultaneously.Then stir while obtained Zn precursor solution and S precursor solution are slowly added in three-neck flask, the joining day is 1 h, maintains the temperature at 190 DEG C ~ 200 DEG C; React 1 h again after solution adds, obtain ZnSe-ZnS core-shell quanta dots.
Be dissolved in 1.0 mL chloroforms by 20 mg ZnSe-ZnS core-shell quanta dots, then add the mercaptopropionic acid of 100 μ L 0.1M, stirring is spent the night, and obtains the ZnSe-ZnS core-shell quanta dots that mercaptopropionic acid is modified.
By magnetic Fe
3o
4/ CTS-CHE Nano medication is dissolved in (164g sodium acetate is water-soluble, adds 84ml glacial acetic acid, is diluted to 1L) in the ethyl sodium solution of pH=4.5, is mixed with the Nano medication solution of 1mg/mL.The ZnSe-ZnS quantum dot that mercaptopropionic acid is modified is dissolved in the ethyl sodium solution of PH=4.5, is mixed with the quantum dot solution of 1mg/mL equally.In three-neck flask, add 50ml nano-medicament carrier solution, get 50ml quantum dot solution (1mg/mL), be slowly added drop-wise in nano-medicament carrier solution, 600r/min, stirring is spent the night.After sedimentation and filtration, washing, vacuum drying, fluorescence and ferromagnetic Fe must be had
3o
4/ CTS-CHE-ZnSe/ZnS fluorescence magnetic nano target medicine.
Fig. 2 is the release profiles (37 DEG C) of fluorescence magnetic nano target medicine CHE under different medium pH 1.0 and 7.4 environment in the present embodiment.As seen from the figure, the release of CHE medicine shows as prominent releasing and slow releasing two benches pattern, and rate of release extends in time and increases, but last rate of release is tending towards constant.After 1h, Fe
3o
4/ CTS-CHE-ZnSe/ZnS fluorescence magnetic nano target medicine releases 47.2 % and 20.6% CHE medicine in pH 1.0 and 7.4.After 120 h, fluorescence magnetic nano target medicine discharges 69.2 % and 45.8% CHE medicine in pH 1.0 and 7.4.Illustrate that made fluorescence magnetic nano target medicine has obvious slow releasing function, and its rate of release in acid medium is greater than alkaline medium.This treatment being used for cancer for made fluorescence magnetic nano target medicine microsphere is very useful, because the microenvironment pH residing for tumor cell is lower than Normocellular microenvironment pH.
Fig. 3 be in the present embodiment fluorescence magnetic nano target medicine to the inhibitory action design sketch of hepatoma carcinoma cell.As seen from the figure, when effect 24h, 36h, 48h, 60h and 72h, Fe
3o
4/ CTS-CHE-ZnSe/ZnS Nano medication each concentration group has obvious inhibitory action to hepatocellular carcinoma H22 propagation, and the inhibitory action of high dose clearly, and is dosage and time dependence.
Fig. 4 is the aspect graph of hepatoma carcinoma cell after Hoechst dyeing 24h in the present embodiment.As seen from the figure, Hoechst 33258 Coloration experiment illustrates Fe
3o
4/ CTS-CHE-ZnSe/ZnS fluorescence magnetic nano target medicine can induce HepG2 apoptosis.
embodiment 2:
A kind of fluorescence magnetic nano target medicine of the present invention, by positively charged magnetic Fe
3o
4the ZnSe-ZnS core-shell quanta dots self assembly of-chitosan-chelerythrine drug-carrying nanometer particle and electronegative functionalized modification, magnetic Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle is with Fe
3o
4for magnetic core, chitosan be framework material carrier, chelerythrine is targeted drug; The ZnSe-ZnS core-shell quanta dots of functionalized modification refers to ZnSe to be kernel, ZnS is shell, the ZnSe-ZnS core-shell quanta dots after mercaptocarboxylic acids is modified.
The preparation method of the present embodiment, comprises the following steps:
Be dissolved in the deionized water of 30mL by 2.502 g ferrous sulfate heptahydrates, adding 10 mL concentration is 50 g × L
-1pEG-20000 aqueous solution after, fully stirring in 30 DEG C of waters bath with thermostatic control, drip a certain amount of dilute ammonia solution 30mL, is 10 to solution ph, then add a certain amount of hydrogen peroxide solution stir 20min.Finally, be all transferred in autoclave, at 160 DEG C, isothermal reaction 5h, obtains magnetic Fe
3o
4nano-particle.
By above-mentioned for 0.25g obtained magnetic Fe
3o
4nano-particle adds 5% acetic acid solution 20 ml being dissolved with 0.3g chitosan, add liquid paraffin 40 mL again, span-80 0.5 mL, after ultrasonic disperse 20min, add the glutaraldehyde solution of 3 mL 25% again, mechanic whirl-nett reaction 4h, filters, by petroleum ether, and dewater with washing with acetone, drying, grinds to form flowing powder, obtains magnetic Fe
3o
4-chitin nanometer (Fe
3o
4-CTS complex microsphere).
Standard but takes 50mg magnetic Fe
3o
4-chitosan microball puts into 100ml conical flask, with 20.0 ml 5% glutaraldehydes phosphate buffer (pH6.8) by fully swelling for nanoparticle (>10h), then pours out buffer.By the magnetic Fe after swelling
3o
4-chitosan microball buffer solution 2 times.Add certain density CHE hydrochlorate aqueous solution 40.0ml, shaken at room temperature hatching 2.5h.Be separated with Magnet, obtain medicine carrying complex and upper solution.With 2.0 ml milli-Q water medicine carrying complex 2 times.By medicine carrying complex in 60 DEG C of vacuum drying 10h, after grinding, namely obtain Fe
3o
4-chitosan-CHE drug-carrying nanometer particle.
By 0.3785g(10mmol) NaBH
4add in the little flask of 20mL, then add 2.0mL deoxygenation deionized water, ice-water bath cools, and under nitrogen atmosphere, adds 0.3948g(5mmol) selenium powder, mix homogeneously, namely obtains NaHSe solution after reacting 1h under airtight condition.
By 2.195g(10mmol) ZnAc
22H
2o, in 150mL three-necked bottle, adds 100mL deionized water and makes it dissolve, add 0.18ml(24mmol under vigorous stirring) TGA, regulate the pH value of solution to be 9.5 by the NaOH solution of 1.0 mol/L, logical N
2deoxygenation 1h; At N
2protect and under stirring, draw the NaHSe solution 1.0mL prepared and add in mixed liquor, after stirring reaction 10min, 100 DEG C of backflow 15min, obtain ZnSe quantum dot solution.
Be dissolved in by 0.36 g zinc stearate in 2.5 mL toluene, logical nitrogen, is heated to 60 DEG C, is then cooled to room temperature, obtain Zn precursor solution; Be dissolved in by the S powder of 20 mg in 2.5 mL TOP, logical nitrogen, is heated to 90 DEG C, obtained S precursor solution.Under nitrogen protection, in three-neck flask, add ready ZnSe quantum dot solution (containing 20 mg ZnSe), add 4 mL normal heptane, 2.5 g TOPO and 1.5 g hexadecylamines simultaneously.Then stir while obtained Zn precursor solution and S precursor solution are slowly added in three-neck flask, the joining day is 1 h, maintains the temperature at 190 DEG C ~ 200 DEG C; React 1 h again after solution adds, obtain ZnSe-ZnS core-shell quanta dots.
Be dissolved in 1.0 mL chloroforms by 20 mg ZnSe-ZnS core-shell quanta dots, then add the mercaptopropionic acid of 100 μ L 0.1M, stirring is spent the night, and obtains the ZnSe-ZnS core-shell quanta dots that mercaptopropionic acid is modified.
By magnetic Fe
3o
4/ CTS-CHE Nano medication is dissolved in (164g sodium acetate is water-soluble, adds 84ml glacial acetic acid, is diluted to 1L) in the ethyl sodium solution of pH=4.5, is mixed with the Nano medication solution of 1mg/mL.The ZnSe-ZnS quantum dot that mercaptopropionic acid is modified is dissolved in the ethyl sodium solution of PH=4.5, is mixed with the quantum dot solution of 1mg/mL equally.In three-neck flask, add 50ml nano-medicament carrier solution, get 50ml quantum dot solution (1mg/mL), be slowly added drop-wise in nano-medicament carrier solution, 600r/min, stirring is spent the night.After sedimentation and filtration, washing, vacuum drying, fluorescence and ferromagnetic Fe must be had
3o
4/ CTS-CHE-ZnSe/ZnS fluorescence magnetic nano target medicine.
embodiment 3:
A kind of fluorescence magnetic nano target medicine of the present invention, by positively charged magnetic Fe
3o
4the ZnSe-ZnS core-shell quanta dots self assembly of-chitosan-chelerythrine drug-carrying nanometer particle and electronegative functionalized modification, magnetic Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle is with Fe
3o
4for magnetic core, chitosan be framework material carrier, chelerythrine is targeted drug; The ZnSe-ZnS core-shell quanta dots of functionalized modification refers to ZnSe to be kernel, ZnS is shell, the ZnSe-ZnS core-shell quanta dots after mercaptocarboxylic acids is modified.
The preparation method of the present embodiment, comprises the following steps:
Be dissolved in the deionized water of 30mL by 2.528 g ferrous sulfate heptahydrates, adding 10 mL concentration is 50 g × L
-1pEG-20000 aqueous solution after, fully stirring in 30 DEG C of waters bath with thermostatic control, drip a certain amount of dilute ammonia solution 30mL, is 10 to solution ph, then add a certain amount of hydrogen peroxide solution stir 20min.Finally, be all transferred in autoclave, at 160 DEG C, isothermal reaction 5h, obtains magnetic Fe
3o
4nano-particle.
By above-mentioned for 0.22g obtained magnetic Fe
3o
4nano-particle adds 5% acetic acid solution 20 ml being dissolved with 0.32g chitosan, add liquid paraffin 40 mL again, span-80 0.5 mL, after ultrasonic disperse 20min, add the glutaraldehyde solution of 3 mL 25% again, mechanic whirl-nett reaction 4h, filters, by petroleum ether, and dewater with washing with acetone, drying, grinds to form flowing powder, obtains magnetic Fe
3o
4-chitin nanometer (Fe
3o
4-CTS complex microsphere).
Standard but takes 50mg magnetic Fe
3o
4-chitosan microball puts into 100ml conical flask, with 20.0 ml 5% glutaraldehydes phosphate buffer (pH6.8) by fully swelling for nanoparticle (>10h), then pours out buffer.By the magnetic Fe after swelling
3o
4-chitosan microball buffer solution 2 times.Add certain density CHE hydrochlorate aqueous solution 40.0ml, shaken at room temperature hatching 2.5h.Be separated with Magnet, obtain medicine carrying complex and upper solution.With 2.0 ml milli-Q water medicine carrying complex 2 times.By medicine carrying complex in 60 DEG C of vacuum drying 10h, after grinding, namely obtain Fe
3o
4-chitosan-CHE drug-carrying nanometer particle.
By 0.3785g(10mmol) NaBH
4add in the little flask of 20mL, then add 2.0mL deoxygenation deionized water, ice-water bath cools, and under nitrogen atmosphere, adds 0.3948g(5mmol) selenium powder, mix homogeneously, namely obtains NaHSe solution after reacting 1h under airtight condition.
By 2.9g(10mmol) ZnAc
22H
2o, in 150mL three-necked bottle, adds 100mL deionized water and makes it dissolve, add 0.18ml(24mmol under vigorous stirring) TGA, regulate the pH value of solution to be 9.5 by the NaOH solution of 1.0 mol/L, logical N
2deoxygenation 1h; At N
2protect and under stirring, draw the NaHSe solution 1.0mL prepared and add in mixed liquor, after stirring reaction 10min, 100 DEG C of backflow 15min, obtain ZnSe quantum dot solution.
Be dissolved in by 0.32 g zinc stearate in 2.5 mL toluene, logical nitrogen, is heated to 60 DEG C, is then cooled to room temperature, obtain Zn precursor solution; Be dissolved in by the S powder of 30 mg in 2.5 mL TOP, logical nitrogen, is heated to 90 DEG C, obtained S precursor solution.Under nitrogen protection, in three-neck flask, add ready ZnSe QDs solution (containing 20 mg ZnSe), add 4 mL normal heptane, 2.5 g TOPO and 1.5 g hexadecylamines simultaneously.Then stir while obtained Zn precursor solution and S precursor solution are slowly added in three-neck flask, the joining day is 1 h, maintains the temperature at 190 DEG C ~ 200 DEG C; React 1 h again after solution adds, obtain ZnSe-ZnS core-shell quanta dots.
By magnetic Fe
3o
4/ CTS-CHE Nano medication is dissolved in (164g sodium acetate is water-soluble, adds 84ml glacial acetic acid, is diluted to 1L) in the ethyl sodium solution of pH=4.5, is mixed with the Nano medication solution of 1mg/mL.The ZnSe-ZnS quantum dot that mercaptopropionic acid is modified is dissolved in the ethyl sodium solution of PH=4.5, is mixed with the quantum dot solution of 1mg/mL equally.In three-neck flask, add 50ml nano-medicament carrier solution, get 50ml quantum dot solution (1mg/mL), be slowly added drop-wise in nano-medicament carrier solution, 600r/min, stirring is spent the night.After sedimentation and filtration, washing, vacuum drying, fluorescence and ferromagnetic Fe must be had
3o
4/ CTS-CHE-ZnSe/ZnS fluorescence magnetic nano target medicine.
Claims (10)
1. a fluorescence magnetic nano target medicine, is characterized in that, by magnetic Fe
3o
4the ZnSe-ZnS core-shell quanta dots self assembly of-chitosan-chelerythrine drug-carrying nanometer particle and functionalized modification, described magnetic Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle is with Fe
3o
4for magnetic core, chitosan be framework material carrier, chelerythrine is targeted drug; The ZnSe-ZnS core-shell quanta dots of described functionalized modification refers to ZnSe to be kernel, ZnS is shell, the ZnSe-ZnS core-shell quanta dots after mercaptocarboxylic acids is modified.
2. a preparation method for fluorescence magnetic nano target medicine as claimed in claim 1, is characterized in that, comprise the following steps:
Step (1) Fe
3o
4the preparation of-chitosan-chelerythrine drug-carrying nanometer particle: with buffer solution by magnetic Fe
3o
4-chitin nanometer is fully swelling, washing, and then add chelerythrine aqueous alkali, shaken at room temperature is hatched, and is separated, obtains medicine carrying complex and upper solution with Magnet, and washing, drying, grinding obtains Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle;
The preparation of the ZnSe-ZnS core-shell quanta dots of step (2) functionalized modification: ZnSe-ZnS core-shell quanta dots is dissolved in chloroform, then the carboxylic acid compound containing sulfydryl is added, stirring is spent the night, what centrifugal removing was unnecessary contains mercaptocarboxylic acids, by remaining washing of precipitate, drying, namely obtain the ZnSe-ZnS core-shell quanta dots of described functionalized modification;
Step (3) self assembly: preparation Fe
3o
4the ZnSe-ZnS core-shell quanta dots solution of-chitosan-chelerythrine drug-carrying nanometer particle solution, functionalized modification, then drops to Fe by the ZnSe-ZnS core-shell quanta dots solution of functionalized modification
3o
4in-chitosan-chelerythrine drug-carrying nanometer particle solution, stir spend the night, sedimentation and filtration, washing, vacuum drying, namely obtain described fluorescence magnetic nano target medicine.
3. preparation method according to claim 2, is characterized in that, described magnetic Fe
3o
4the preparation of-chitin nanometer comprises the following steps: by magnetic Fe
3o
4nano-particle adds and is dissolved with in the acetic acid solution of chitosan, adds liquid paraffin, Si Pan-80, ultrasonic disperse, adds glutaraldehyde solution, stirring reaction, filters, by petroleum ether, and dewaters with washing with acetone, drying, grinds to form flowing powder, namely obtains described magnetic Fe
3o
4-chitin nanometer; Described magnetic Fe
3o
4the mass ratio of nano-particle and chitosan is 1:0.5 ~ 2.
4. preparation method according to claim 3, is characterized in that, described magnetic Fe
3o
4the preparation of nano-particle comprises the following steps: be dissolved in by ferrous sulfate heptahydrate in deionized water, add Aqueous Solutions of Polyethylene Glycol, stirring and evenly mixing, water bath with thermostatic control under room temperature, drips ammonia spirit under agitation, is 9 ~ 10 to pH value of solution, then hydrogen peroxide solution is added, mixed solution is transferred in autoclave, isothermal reaction at 150 ~ 170 DEG C, then uses distilled water wash, centrifugalize, and with absolute ethanol washing, dry, grind to obtain described magnetic Fe
3o
4nano-particle.
5. preparation method according to claim 2, is characterized in that, the preparation of described ZnSe-ZnS core-shell quanta dots comprises the following steps: be dissolved in by zinc stearate in toluene, and logical nitrogen, heating, be then cooled to room temperature, obtain Zn precursor solution; Sulfur powder is dissolved in tri-n-octyl phosphine, logical nitrogen, heating, obtained S precursor solution;
Under nitrogen protection; ZnSe quantum dot solution, normal heptane, TOPO and hexadecylamine are mixed; and the mass ratio of control ZnSe: ZnS is 1: (0.5 ~ 3); heated and stirred; till normal heptane volatilizees completely, then stir and slowly add described Zn precursor solution and S precursor solution, reaction keeps temperature; then purify by methanol wash, after precipitation, vacuum drying, obtain described ZnSe-ZnS core-shell quanta dots.
6. preparation method according to claim 5, is characterized in that, the weight portion of described zinc stearate is 320 ~ 420 parts, and the weight portion of described sulfur powder is 16 ~ 24 parts; Described zinc stearate is dissolved in toluene, leads to nitrogen, be heated to 50 ~ 70 DEG C; Be dissolved in tri-n-octyl phosphine by described sulfur powder, logical nitrogen, is heated to 80 ~ 100 DEG C; The temperature of described heated and stirred is 180 ~ 200 DEG C; Described reaction keeps temperature to be 180 ~ 200 degrees Celsius, and the time is 1h at least.
7. preparation method according to claim 5, is characterized in that, the preparation of described ZnSe quantum dot solution comprises the following steps: be dissolved in by Zinc diacetate dihydrate in deionized water, adds TGA under stirring, regulates pH to be 9 ~ 10 by NaOH solution, logical N
2deoxygenation; At N
2protect and under stirring, add NaHSe solution, make HSe in reaction system
-with Zn
2+the ratio of amount of substance be 1: 2 ~ 8, stirring reaction is at least after 10min, and backflow, obtains described ZnSe quantum dot solution.
8. preparation method according to claim 7, is characterized in that, the preparation of described NaHSe solution comprises the following steps: by the NaBH of 37 ~ 56 weight portions
4be dissolved in deoxygenation deionized water, ice-water bath cools, under nitrogen atmosphere, add the selenium powder of 39 ~ 60 weight portions, mix homogeneously, under airtight condition, react at least 0.5h, until the selenium powder of black disappears completely, occur white crystal at the bottom of bottle, supernatant is described NaHSe solution simultaneously.
9. preparation method according to claim 2, is characterized in that, described buffer solution is glutaraldehyde solution, and pH is 6 ~ 8; The described fully swelling time is greater than 10h; The time of described vibration hatching is 2 ~ 4h; The described carboxylic acid compound containing sulfydryl is any one in acid, sulfydryl enanthic acid of 3-mercaptopropionic acid, dimercaptosuccinic acid, TGA, cysteine, 2 mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, sulfydryl; Described step (2) washing of precipitate solution used is dimethyl formamide.
10. according to the preparation method in claim 2 ~ 9 described in any one, it is characterized in that, described Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle solution is by described Fe
3o
4-chitosan-chelerythrine drug-carrying nanometer particle is dissolved in pH and prepares in the acetic acid-sodium acetate solution of 4 ~ 5 to obtain, and concentration is 1 ~ 2mg/mL; The ZnSe-ZnS core-shell quanta dots solution of described functionalized modification is dissolved in pH by the ZnSe-ZnS core-shell quanta dots of described functionalized modification to prepare in the acetic acid-sodium acetate solution of 2 ~ 6 to obtain, and concentration is 1 ~ 3 mg/mL.
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Cited By (5)
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| CN105838703A (en) * | 2016-06-07 | 2016-08-10 | 华中农业大学 | Method for removing patulin in orange juice by utilizing immobilized inactivated yeast cells of magnetic microspheres and application of method |
| CN112439063A (en) * | 2019-08-12 | 2021-03-05 | 湖南早晨纳米机器人有限公司 | Preparation method of far infrared magnetic therapy body nano robot |
| CN114272201A (en) * | 2021-12-13 | 2022-04-05 | 贵州中医药大学 | Chelerythrine mPEG-PLGA nano gel composite preparation and detection methods and application thereof |
| WO2022143343A1 (en) * | 2020-12-28 | 2022-07-07 | Tcl科技集团股份有限公司 | Quantum dot dispersion solution and quantum dot storage method |
| CN114939068A (en) * | 2022-06-28 | 2022-08-26 | 四川大学 | Amorphous calcium phosphate composite material, preparation method thereof and application thereof in oral cavity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105838703A (en) * | 2016-06-07 | 2016-08-10 | 华中农业大学 | Method for removing patulin in orange juice by utilizing immobilized inactivated yeast cells of magnetic microspheres and application of method |
| CN105838703B (en) * | 2016-06-07 | 2018-02-16 | 华中农业大学 | A kind of method and its application that patulin in orange blossom is removed using magnetic microsphere immobilized inactivation yeast cells |
| CN112439063A (en) * | 2019-08-12 | 2021-03-05 | 湖南早晨纳米机器人有限公司 | Preparation method of far infrared magnetic therapy body nano robot |
| WO2022143343A1 (en) * | 2020-12-28 | 2022-07-07 | Tcl科技集团股份有限公司 | Quantum dot dispersion solution and quantum dot storage method |
| CN114272201A (en) * | 2021-12-13 | 2022-04-05 | 贵州中医药大学 | Chelerythrine mPEG-PLGA nano gel composite preparation and detection methods and application thereof |
| CN114272201B (en) * | 2021-12-13 | 2024-01-26 | 贵州中医药大学 | Chelidonine mPEG-PLGA nano gel composite preparation, and preparation method, detection method and application thereof |
| CN114939068A (en) * | 2022-06-28 | 2022-08-26 | 四川大学 | Amorphous calcium phosphate composite material, preparation method thereof and application thereof in oral cavity |
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