CN104940958B - A kind of fluorescence magnetic nano target medicine and preparation method thereof - Google Patents
A kind of fluorescence magnetic nano target medicine and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of fluorescence magnetic nano target medicine, by magnetic Fe3O4The ZnSe ZnS core shell quantum dot self assemblies of chitosan Chelerythrine drug-carrying nanometer particle and functionalized modification, wherein magnetic Fe3O4Chitosan Chelerythrine drug-carrying nanometer particle is with Fe3O4Be framework material carrier for magnetic core, chitosan, Chelerythrine be targeted drug；The ZnSe ZnS core shell quantum dots of wherein functionalized modification refer to that using ZnSe be kernel, ZnS for shell, the ZnSe ZnS core shell quantum dots after mercaptocarboxylic acids are modified.The inventive method is easy, cost is cheap, green；Fluorescence magnetic nano target medicine fluorescence property prepared by the present invention is stablized, biological safety is good, while has the advantage of magnetic material and fluorescent material, can realize that Magnetic Isolation, targets identification, fluorescence imaging and magnetic resonance imaging etc. are multi-functional simultaneously.
Description
Technical field
The present invention relates to targeted drug field, more particularly to a kind of fluorescence magnetic nano target medicine and preparation method thereof.
Background technology
Nano-carrier constructively possesses the physics and chemical characteristic of uniqueness due to the size with 1-100nm.They
High surface-to-volume ratio and possibility that their performance is adjusted, make nano-carrier turn into imaging, diagnosis and
The powerful for the treatment of.Although nano-carrier promotes the development of medical science, still its some applications face the challenge, such as to body
The real-time monitoring of inner cell activity, effective transmission for the special targeting of target site or medicine in target cell etc..More work(
Energy nano-carrier is designed to be obviously improved existing nano-carrier characteristic and helps to overcome these deficiencies.Especially with receiving
What rice corpuscles was combined with treating malignant tumor deepens continuously, and increasing nano-particle will be applied to diagnosis of malignant tumor
And Therapy study, nano particle can be achieved to tumor patient personalized treatment.The lossless diagnosis in place of tumour and treatment are to be related to
The important scientific problems of human life and health.Therefore, develop collect targeting mark, drug delivery and result report etc. it is multi-functional in
The degradable nano medicine of one, while realize lossless diagnosis in place, treat and monitor this serial procedures in real time, it is medicine
The target that worker dreams of.To prepare this intelligent multifunctional drug nano-carrier.And magnetic nano-particle and quantum
The development and application of point assembling is expected to improve lesion detection mode, need to assemble various chemical moleculars simultaneously for high-performance targeting diagnosis
Development to same nanoparticle surface and treatment Nano medication provides new opportunity.
Drug targeting technology is the study hotspot and Disciplinary Frontiers of chemotherapy, radiotherapy and gene therapy tumour.2004
Reported in Science magazines, drug targeting technology has become the main flow of oncotherapy, in existing numerous targeted drug
In system, the magnetic and medicated of magnetic field guiding has clear advantage：Directly intravenous injection medication can be realized, passes through magnetic fields
Target site is enriched in, mitigates the toxic side effect to human body, thus is widely used.
Magnetic and medicated is a kind of new drug targeting system, mainly by magnetic material, framework material and anticarcinogen
Thing three parts are formed, and cancer therapy drug and appropriate magnetic material are wrapped up or adsorbed in carrier by method physically or chemically
The drug system of the stabilization with magnetic responsiveness is made on material, is gathered in tumor target in the presence of magnetic field in vitro, improves
The concentration of target area medicine, reduce the Side effect that medicine is knitted to non-target district's groups.Medicine passes through the side of controlled delayed release in vivo
Formula discharges from carrier material, medicine effect is played in the cell or subcellsular level of tumor tissues, to reach high-efficiency low-toxicity
Purpose.At present, the most frequently used magnetic material is ferrite class material, Fe of the particle diameter in 1-100nm3O4With biological safety
High, the features such as magnetic responsiveness is high, therefore it is usually used in Magnetic Bio-materials.
Chitosan and its derivative have excellent physicochemical properties and biological nature：Can wire drawing, film forming, system
Grain, can be combined, cytotoxic is extremely low, has with many kinds of substance (heavy metal, fat, protein, cholesterol and tumour cell etc.)
Good biocompatibility and biodegradable, and the excellent novel chitosan of feature can be obtained by chemical modification and is spread out
Biology, the chitosan derivatives after improvement have broad application prospects in anti-tumor drugs targeting field.
As the development in biologic medical field progressively strengthens for the dependence of material, it is necessary to prepare a kind of multi-functional micron
Targeting vector is set to obtain in addition to accurate targeting positioning to nano level material, it is necessary to which integration is more suitable for targeted drug treatment
New function, i.e., targeting lesions position drug controlled-releasing function and target location and course of conveying in imaging function.Class
It is exactly that investigation of materials person is especially interested at present like the composite intelligent carrier with targeting positioning, imaging tracer and therapeutic reagent
Research direction.Quantum dot (quantum dot, QDs) has fluorescence efficiency as a kind of new namo fluorescence probe
The features such as high, luminous wide coverage and optical property stabilization, in vital movement monitoring and long-time vivo tracking etc.
Advantage with uniqueness.
Chelerythrine (CHE) belongs to benzo coffee pyridine class quaternary ammonium base alkaloid, has notable physiologically active and anti-inflammatory, sterilization
Etc. multiple pharmacological effect.Meanwhile Chelerythrine is a kind of potential inhibitors of protein kinase C with clinical practice application,
It is the target of oncotherapy and protein kinase C is promoting cell propagation, suppressing to play an important role in apoptotic signal transductive process
Point, therefore Chelerythrine (CHE) is a good cancer therapy drug.But because CHE has stronger cytotoxicity；CHE is in blood
Middle metabolism is very fast, t1/2It is shorter, it is necessary to frequent drug administration, waste big；CHE mouthfeel is very poor, is unfavorable for directly being administered orally, therefore
Limit the applications of CHE clinically.
Therefore finding and developing suitable formulation has turned into the key of Chelerythrine clinical drug application.It there is no text both at home and abroad
Offer and nanoparticle is made in CHE to realize that its orientation conveys, reduce the report of dosage and toxic side effect, therefore, how to develop collection
The multi-functional degradable nano Chelerythrine cancer therapy drugs in one such as targeting mark, drug delivery and result report, this
It is directly the technical barrier that those skilled in the art face for a long time.
The content of the invention
The technical problems to be solved by the invention are to overcome the shortcomings of to mention in background above technology and defect, there is provided one
It kind can realize that Magnetic Isolation, targets identification, fluorescence imaging, magnetic resonance imaging and the good fluorescence magnetic of Release Performance are received simultaneously
Rice targeted drug, correspondingly provide a kind of method simplicity, cheap, green, efficiency high the fluorescence magnetic nano target of cost
The preparation method of medicine.
In order to solve the above technical problems, technical scheme proposed by the present invention is a kind of fluorescence magnetic nano target medicine, by
Magnetic Fe3O4- chitosan-Chelerythrine（Fe3O4/CTS -CHE）The ZnSe-ZnS nucleocapsids of drug-carrying nanometer particle and functionalized modification
Quantum dot self assembly, the magnetic Fe3O4- chitosan-Chelerythrine drug-carrying nanometer particle is with Fe3O4For magnetic core, chitosan
（CTS）For framework material carrier, Chelerythrine（CHE）For targeted drug；The ZnSe-ZnS nucleocapsid quantum of the functionalized modification
Point refers to that using ZnSe be kernel, ZnS for shell, the ZnSe-ZnS core-shell quanta dots after mercaptocarboxylic acids are modified.（Adopt
The ZnSe-ZnS core-shell quanta dots of functionalized modification have been synthesized with aqueous phase synthesis method, have been marked by electrostatic self-assembled, have been prepared for having
There is the multifunctional nano drug bearing microsphere of good fluorescence performance and magnetic）.
The technical concept total as one, the present invention also provide a kind of preparation of above-mentioned fluorescence magnetic nano target medicine
Method, comprise the following steps：
Step（1）Fe3O4The preparation of-chitosan-Chelerythrine drug-carrying nanometer particle：With cushioning liquid by magnetic Fe3O4-
Chitin nanometer is fully swelled, washed, and then adds chelerythrine aqueous alkali, shaken at room temperature hatching, is separated with magnet,
Obtain carrying medicine compound and upper solution, washing, dry, grinding obtains Fe3O4- chitosan-Chelerythrine drug-carrying nanometer particle；
Step（2）The preparation of the ZnSe-ZnS core-shell quanta dots of functionalized modification：ZnSe-ZnS core-shell quanta dots are dissolved in chlorine
In imitative, then add the carboxylic acid compound containing sulfydryl, be stirred overnight, be centrifuged off it is unnecessary contain mercaptocarboxylic acids,
By remaining washing of precipitate（At least 3 times）, dry, that is, obtain the ZnSe-ZnS core-shell quanta dots of the functionalized modification；
Step（3）Self assembly：Prepare Fe3O4- chitosan-Chelerythrine drug-carrying nanometer particle solution, functionalized modification
ZnSe-ZnS core-shell quanta dots solution, then the ZnSe-ZnS core-shell quanta dots solution of functionalized modification is added dropwise to substantially isometric
Fe3O4Self assembly is carried out in-chitosan-Chelerythrine drug-carrying nanometer particle solution, is stirred overnight（Mixing speed is preferably
600r/min）, precipitation filtering, washing, vacuum drying, that is, obtain the fluorescence magnetic nano target medicine.Can by experiment detection
Know, the fluorescence efficiency of fluorescence magnetic nano target medicine that the present invention is prepared is more than 12% and has a ferromagnetism.
In above-mentioned preparation method, it is preferred that the magnetic Fe3O4The preparation of-chitin nanometer includes following step
Suddenly：By magnetic Fe3O4Nano particle is added in the acetic acid solution dissolved with chitosan, adds atoleine, Si Pan -80（span-
80）, ultrasonic disperse（General at least 20min）, add glutaraldehyde solution（25%）, stirring reaction（At least 4h）, filtering, use oil
Ether wash, and use acetone washing dehydration, drying, be ground into flowing powder, that is, obtain the magnetic Fe3O4- chitosan nano
Son；The magnetic Fe3O4The mass ratio of nano particle and chitosan is 1:0.5~2.
In above-mentioned preparation method, it is preferred that the magnetic Fe3O4The preparation of nano particle comprises the following steps：By seven water
Ferrous sulfate is dissolved in deionized water, is added Aqueous Solutions of Polyethylene Glycol, is stirred and evenly mixed, the water bath with thermostatic control under normal temperature（Such as 30
℃）, ammonia spirit is added dropwise under agitation, is 9 ~ 10 to pH value of solution, then adds hydrogen peroxide solution, make part Fe (OH)2
It is oxidized to trivalent iron salt to solution and black is presented, mixed solution is transferred in autoclave, the constant temperature at 150 ~ 170 DEG C
Reaction, then with water washing is distilled, centrifuge, and washed with absolute ethyl alcohol, dry, grind to obtain the magnetic Fe3O4Nanometer
Grain.
In above-mentioned preparation method, it is preferred that the preparation of the ZnSe-ZnS core-shell quanta dots comprises the following steps：Will be hard
Resin acid zinc is dissolved in toluene, is led to nitrogen, heating, is subsequently cooled to room temperature, obtains Zn precursor solutions；Sulphur powder is dissolved in three n-octyls
In phosphine (TOP), lead to nitrogen, heating, S precursor solutions are made；
Under nitrogen protection, by ZnSe quantum dots（QDs）Solution, normal heptane, TOPO (TOPO) and 16
Alkylamine (HDA) mix, and control ZnSe: ZnS mass ratio be 1:（0.5~3）, heating stirring, until normal heptane volatilizees completely
Untill, then stir while be slowly added to the Zn precursor solutions and S precursor solutions, react keeping temperature, then use first
Alcohol washing purifying, the ZnSe-ZnS core-shell quanta dots are obtained after precipitation, vacuum drying.
In above-mentioned preparation method, it is preferred that the parts by weight of the zinc stearate are 320~420 parts, the weight of the sulphur powder
It is 16 ~ 24 parts to measure part；The zinc stearate is dissolved in toluene, logical nitrogen, is heated to 50 ~ 70 DEG C；The sulphur powder is dissolved in three
In n-octyl phosphine, lead to nitrogen, be heated to 80 ~ 100 DEG C；The temperature of the heating stirring is 180 ~ 200 DEG C；The reaction keeps temperature
Spend for 180 ~ 200 degrees Celsius, time at least 1h.
In above-mentioned preparation method, it is preferred that the preparation of the ZnSe quantum dot solutions comprises the following steps：Will
ZnAc2·2H2O is dissolved in deionized water, stirs lower addition TGA (TGA), is 9~10 with NaOH solution regulation pH, is led to
N2Deoxygenation；In N2Under protection and stirring, NaHSe solution is added, makes HSe in reaction system-With Zn2+The ratio between the amount of material be 1: 2
~8（More preferably 1: 4~6）, after stirring reaction at least 10min, 100 DEG C of backflow at least 15min, obtain the ZnSe quantum
Point solution.
In above-mentioned preparation method, it is preferred that the preparation of the NaHSe solution comprises the following steps：By 37~56 weight
The NaBH of part4It is dissolved in deoxygenation deionized water, ice-water bath cooling, under nitrogen atmosphere, adds the selenium powder of 39~60 parts by weight,
It is well mixed, at least 0.5h is reacted under confined conditions, is usually no more than 2 h, until the selenium powder of black is wholly absent, while bottom of bottle
There is white crystal, supernatant is the NaHSe solution.
In above-mentioned preparation method, it is preferred that the cushioning liquid is glutaraldehyde solution（5%）, pH is 6 ~ 8；It is described abundant
The time of swelling is more than 10h；It is 2 ~ 4h the times that the time of the vibration hatching, which is,；The carboxylic acid compound containing sulfydryl is 3-
Mercaptopropionic acid, dimercaptosuccinic acid, TGA, cysteine, 2 mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, sulfydryl acid,
Any one in sulfydryl enanthic acid；The step（2）Solution used in washing of precipitate is dimethylformamide.
In above-mentioned preparation method, it is preferred that the Fe3O4- chitosan-Chelerythrine drug-carrying nanometer particle solution be by
The Fe3O4- chitosan-Chelerythrine drug-carrying nanometer particle, which is dissolved in preparing in acetic acid-sodium acetate solution that pH is 4 ~ 5, to be obtained；Institute
The ZnSe-ZnS core-shell quanta dots solution for stating functionalized modification is to be dissolved in pH by the ZnSe-ZnS core-shell quanta dots of the functionalized modification
For 2 ~ 6（More preferably pH is 3 ~ 5, and most preferably pH is 4 ~ 5）Acetic acid-sodium acetate solution in prepare and obtain.Acetic acid-the acetic acid
Sodium solution can add 84ml glacial acetic acids after being dissolved in water with 164g sodium acetates again, and be obtained after being finally diluted to 1L.
Compared with prior art, the advantage of the invention is that：
（1）Method is easy, cost is cheap, green；The quantum dot of early stage is to prepare in organic solvent, and it prepares bar
Part is harsher, and material toxicity is big, and reactions steps are also more complicated, and cost is higher.By contrast, the inventive method is in aqueous phase
Middle progress, is a kind of green aqueous phase synthesis method of cheap environmental protection, and a kind of environment-friendly, simple precipitation polymerization method of method.
（2）The present invention is prepared for the electronegative ZnSe/ZnS core-shell type quantum points of mercaptocarboxylic acids modification, leads to
A kind of layer upon layer electrostatic self-assembly method for being directly based upon charge effect is crossed, makes electronegative ZnSe-ZnS core-shell quanta dots and positively charged
Magnetic Fe3O4- chitin nanometer（Derivative polymer microsphere）It is self-assembled into the Fe of magnetic fluorescence3O4- chitosan-
CHE-ZnSe/ZnS multifunctional nano drug materials, method is easy, cost is cheap, green.
（3）Fluorescence magnetic nano target medicine fluorescence property prepared by the present invention is stablized, biological safety is good, by with hard
Resin acid zinc and sodium hydrogen selenide are presoma, using mercaptopropionic acid as stabilizer, the synthesis in water ZnSe-ZnS nucleocapsid amounts of high quality
Sub- point.After quantum dot row surface chemical modification or special molecular connection, the fluorescence property of ZnSe-ZnS core-shell quanta dots is stable,
Cytotoxicity is small, good biocompatibility, can be widely used for biological living mark and detection.
（4）Compared with the fluorescent material or magnetic material of simple function, the Fe of the invention prepared3O4- chitosan-CHE-
ZnSe/ZnS fluorescence magnetics nano target medicine has the advantage of magnetic material and fluorescent material simultaneously, can realize magnetic point simultaneously
From, targets identification, fluorescence imaging and magnetic resonance imaging etc. it is multi-functional.
Brief description of the drawings
In order to illustrate more clearly about the embodiment of the present invention or technical scheme of the prior art, below will be to embodiment or existing
There is the required accompanying drawing used in technology description to be briefly described, it should be apparent that, drawings in the following description are the present invention
Some embodiments, for those of ordinary skill in the art, on the premise of not paying creative work, can also basis
These accompanying drawings obtain other accompanying drawings.
Fig. 1 is the stereoscan photograph of fluorescence magnetic nano target drug bearing microsphere in the embodiment of the present invention 1.
Fig. 2 is the release profiles of fluorescence magnetic nano target Nano medication CHE in different medium in the embodiment of the present invention 1
（37℃）.
Inhibitory action effects of the Fig. 3 for fluorescence magnetic nano target Nano medication in the embodiment of the present invention 1 to liver cancer cells
Figure.
Fig. 4 is the aspect graph that Hoechst dyes liver cancer cells after 24h in the embodiment of the present invention 1.
Embodiment
For the ease of understanding the present invention, the present invention is made below in conjunction with Figure of description and preferred embodiment more complete
Face, meticulously describe, but protection scope of the present invention is not limited to embodiment in detail below.
Unless otherwise defined, the implication that all technical terms used hereinafter are generally understood that with those skilled in the art
It is identical.Technical term used herein is intended merely to describe the purpose of specific embodiment, is not intended to the limitation present invention
Protection domain.
Unless otherwise specified, various raw material, reagent, the instrument and equipment etc. used in the present invention can pass through city
Field is commercially available or can be prepared by existing method.
Embodiment 1：
A kind of fluorescence magnetic nano target medicine of the invention, by positively charged magnetic Fe3O4- chitosan-chelerythrine
The ZnSe-ZnS core-shell quanta dots self assemblies of alkali drug-carrying nanometer particle and negatively charged functionalized modification, magnetic Fe3O4- chitosan-is white
The red alkali drug-carrying nanometer particle of dish is bent with Fe3O4Be framework material carrier for magnetic core, chitosan, Chelerythrine be targeted drug；Function
The ZnSe-ZnS core-shell quanta dots of modification refer to that using ZnSe be kernel, ZnS for shell, after mercaptocarboxylic acids are modified
ZnSe-ZnS core-shell quanta dots.Its stereoscan photograph is as shown in Figure 1.
The preparation method of the present embodiment, comprises the following steps：
2.502 g ferrous sulfate heptahydrates are dissolved in 30mL deionized water, 10 mL concentration of addition are 50 g × L-1
The PEG-20000 aqueous solution after, be sufficiently stirred in 30 DEG C of waters bath with thermostatic control, a certain amount of dilute ammonia solution 30mL be added dropwise, to solution
PH value is 10, then adds a certain amount of hydrogen peroxide solution stirring 20min.Finally, it is fully transferred in autoclave, in
Isothermal reaction 5h, obtains magnetic Fe at 160 DEG C3O4Nano particle.
By 0.2g magnetic Fes obtained above3O4Nano particle adds 5% acetic acid solution 20 dissolved with 0.2g chitosans
Ml, after adding atoleine 40 mL, span-80 0.5 mL, ultrasonic disperse 20min, add 3 mL 25% glutaraldehyde
Solution, mechanic whirl-nett reaction 4h, filtering, with petroleum ether, and acetone washing dehydration is used, drying, be ground into flowing powder, i.e.,
Obtain magnetic Fe3O4- chitin nanometer（Fe3O4- CTS complex microspheres）.
Standard but weighs 50mg magnetic Fes3O4- chitosan microball is put into 100ml conical flasks, with the glutaraldehydes of 20.0 ml 5%
Phosphate buffer（pH6.8）Nanoparticle is fully swelled（>10h）, then pour out buffer solution.By the magnetic Fe after swelling3O4- shell
Glycan microballoon is washed 2 times with buffer solution.Add certain density CHE hydrochloric acid saline solution 40.0ml, shaken at room temperature hatching 2.5h.
Separated with magnet, obtain carrying medicine compound and upper solution.Medicine compound is carried with 2.0 ml milli-Q waters 2 times.Medicine will be carried to answer
Compound is dried in vacuo 10h in 60 DEG C, and Fe is produced after grinding3O4- chitosan-CHE drug-carrying nanometer particles.
By 0.426g（10mmol）NaBH4Add in the small flasks of 20mL, add 2.0mL deoxygenation deionized waters, frozen water
Bath cooling, under nitrogen atmosphere, add 0.3948g（5mmol）Selenium powder, it is well mixed, is produced after reacting 1h under confined conditions
NaHSe solution.
By 2.195g（10mmol）ZnAc2·2H2For O in 150mL three-necked bottles, adding 100mL deionized waters makes its molten
Solution, is stirred vigorously lower addition 0.18ml（24mmol）TGA, the pH value that solution is adjusted with 1.0 mol/L NaOH solution are
9.5, lead to N2Deoxygenation 1h；In N2Under protection and stirring, the NaHSe solution 1.0mL for drawing preparation is added in mixed liquor, stirring reaction
After 10min, 100 DEG C of backflow 15min, ZnSe quantum dot solutions are obtained.
0.36 g zinc stearates are dissolved in 2.5 mL toluene, leads to nitrogen, is heated to 60 DEG C, is subsequently cooled to room temperature, obtain
To Zn precursor solutions；16 mg S powder is dissolved in 2.5 mL TOP, is led to nitrogen, is heated to 90 DEG C, and S precursor solutions are made.In nitrogen
Under gas shielded, the ZnSe quantum dot solutions being already prepared to are added into three-neck flask（Containing 20 mg ZnSe）, while add 4
ML normal heptanes, 2.5 g TOPO and 1.5 g hexadecylamines.Then stir while by obtained Zn precursor solutions
It is slowly added to S precursor solutions in three-neck flask, the addition time is 1 h, maintains the temperature at 190 DEG C~200 DEG C；Solution adds
React 1 h again afterwards, produce ZnSe-ZnS core-shell quanta dots.
20 mg ZnSe-ZnS core-shell quanta dots are dissolved in 1.0 mL chloroforms, then add 100 μ L 0.1M sulfydryl
Propionic acid, it is stirred overnight, produces the ZnSe-ZnS core-shell quanta dots of mercaptopropionic acid modification.
By magnetic Fe3O4/ CTS-CHE Nano medications are dissolved in the ethyl sodium solution of pH=4.5 (164g sodium acetates
Water is dissolved in, adds 84ml glacial acetic acids, is diluted to 1L), it is configured to 1mg/mL Nano medication solution.By mercaptopropionic acid modification
ZnSe-ZnS quantum dots are dissolved in the ethyl sodium solution of PH=4.5, are equally configured to 1mg/mL quantum dot solution.It is past
50ml nano-medicament carrier solution is added in three-neck flask, 50ml quantum dot solutions (1mg/mL) is taken, is slowly dropped to a nanometer medicine
In thing carrier solution, 600r/min, it is stirred overnight.After precipitation filtering, washing, vacuum drying, produce with fluorescence and strong magnetic
The Fe of property3O4/ CTS-CHE-ZnSe/ZnS fluorescence magnetic nano target medicines.
Fig. 2 is fluorescence magnetic nano target medicine CHE under the environment of different medium pH 1.0 and 7.4 in the present embodiment
Release profiles（37℃）.As seen from the figure, the release of CHE medicines, which shows as dashing forward, releases gentle On The Drug Release two benches pattern, rate of release
Increase with time lengthening, but last rate of release tends to be constant.After 1h, Fe3O4/ CTS-CHE-ZnSe/ZnS fluorescence magnetics
Nano target medicine releases 47.2 % and 20.6% CHE medicines in pH 1.0 and 7.4.After 120 h, fluorescence magnetic is received
Rice targeted drug discharges 69.2 % and 45.8% CHE medicines in pH 1.0 and 7.4.Illustrate made fluorescence magnetic nanometer
Targeted drug has obvious slow releasing function, and its rate of release in acid medium is greater than alkaline medium.This for
The treatment that made fluorescence magnetic nano target medicine microballoon is used for cancer is highly useful, because micro- residing for tumour cell
Environment pH is less than the microenvironment pH of normal cell.
Inhibitory action design sketch of the Fig. 3 for fluorescence magnetic nano target medicine in the present embodiment to liver cancer cells.Can by figure
Know, when acting on 24h, 36h, 48h, 60h and 72h, Fe3O4Each concentration group of/CTS-CHE-ZnSe/ZnS Nano medications is thin to liver cancer
Born of the same parents HepG2 propagation has obvious inhibiting effect, and the inhibitory action of high dose is it is obvious that and be in dosage and time dependence.
Fig. 4 is the aspect graph that Hoechst dyes liver cancer cells after 24h in the present embodiment.As seen from the figure, Hoechst
33258 Coloration experiments illustrate Fe3O4/ CTS-CHE-ZnSe/ZnS fluorescence magnetics nano target medicine can induce HepG2 cells to wither
Die.
Embodiment 2：
A kind of fluorescence magnetic nano target medicine of the invention, by positively charged magnetic Fe3O4- chitosan-chelerythrine
The ZnSe-ZnS core-shell quanta dots self assemblies of alkali drug-carrying nanometer particle and negatively charged functionalized modification, magnetic Fe3O4- chitosan-is white
The red alkali drug-carrying nanometer particle of dish is bent with Fe3O4Be framework material carrier for magnetic core, chitosan, Chelerythrine be targeted drug；Function
The ZnSe-ZnS core-shell quanta dots of modification refer to that using ZnSe be kernel, ZnS for shell, after mercaptocarboxylic acids are modified
ZnSe-ZnS core-shell quanta dots.
The preparation method of the present embodiment, comprises the following steps：
2.502 g ferrous sulfate heptahydrates are dissolved in 30mL deionized water, 10 mL concentration of addition are 50 g × L-1
The PEG-20000 aqueous solution after, be sufficiently stirred in 30 DEG C of waters bath with thermostatic control, a certain amount of dilute ammonia solution 30mL be added dropwise, to solution
PH value is 10, then adds a certain amount of hydrogen peroxide solution stirring 20min.Finally, it is fully transferred in autoclave, in
Isothermal reaction 5h, obtains magnetic Fe at 160 DEG C3O4Nano particle.
By 0.25g magnetic Fes obtained above3O4Nano particle adds 5% acetic acid solution 20 dissolved with 0.3g chitosans
Ml, after adding atoleine 40 mL, span-80 0.5 mL, ultrasonic disperse 20min, add 3 mL 25% glutaraldehyde
Solution, mechanic whirl-nett reaction 4h, filtering, with petroleum ether, and acetone washing dehydration is used, drying, be ground into flowing powder, i.e.,
Obtain magnetic Fe3O4- chitin nanometer（Fe3O4- CTS complex microspheres）.
Standard but weighs 50mg magnetic Fes3O4- chitosan microball is put into 100ml conical flasks, with the glutaraldehydes of 20.0 ml 5%
Phosphate buffer（pH6.8）Nanoparticle is fully swelled（>10h）, then pour out buffer solution.By the magnetic Fe after swelling3O4- shell
Glycan microballoon is washed 2 times with buffer solution.Add certain density CHE hydrochloric acid saline solution 40.0ml, shaken at room temperature hatching 2.5h.
Separated with magnet, obtain carrying medicine compound and upper solution.Medicine compound is carried with 2.0 ml milli-Q waters 2 times.Medicine will be carried to answer
Compound is dried in vacuo 10h in 60 DEG C, and Fe is produced after grinding3O4- chitosan-CHE drug-carrying nanometer particles.
By 0.3785g（10mmol）NaBH4Add in the small flasks of 20mL, add 2.0mL deoxygenation deionized waters, ice
Water-bath cooling, under nitrogen atmosphere, add 0.3948g（5mmol）Selenium powder, it is well mixed, is after reacting 1h under confined conditions
Obtain NaHSe solution.
By 2.195g（10mmol）ZnAc2·2H2For O in 150mL three-necked bottles, adding 100mL deionized waters makes its molten
Solution, is stirred vigorously lower addition 0.18ml（24mmol）TGA, the pH value that solution is adjusted with 1.0 mol/L NaOH solution are
9.5, lead to N2Deoxygenation 1h；In N2Under protection and stirring, the NaHSe solution 1.0mL for drawing preparation is added in mixed liquor, stirring reaction
After 10min, 100 DEG C of backflow 15min, ZnSe quantum dot solutions are obtained.
0.36 g zinc stearates are dissolved in 2.5 mL toluene, leads to nitrogen, is heated to 60 DEG C, is subsequently cooled to room temperature, obtain
To Zn precursor solutions；20 mg S powder is dissolved in 2.5 mL TOP, leads to nitrogen, is heated to 90 DEG C, S precursor solutions are made.
Under nitrogen protection, the ZnSe quantum dot solutions being already prepared to are added into three-neck flask（Containing 20 mg ZnSe）, add simultaneously
4 mL normal heptanes, 2.5 g TOPO and 1.5 g hexadecylamines.Then stir while obtained Zn precursors is molten
Liquid and S precursor solutions are slowly added in three-neck flask, and the addition time is 1 h, maintains the temperature at 190 DEG C~200 DEG C；Solution adds
1 h is reacted after entering again, produces ZnSe-ZnS core-shell quanta dots.
20 mg ZnSe-ZnS core-shell quanta dots are dissolved in 1.0 mL chloroforms, then add 100 μ L 0.1M sulfydryl
Propionic acid, it is stirred overnight, produces the ZnSe-ZnS core-shell quanta dots of mercaptopropionic acid modification.
By magnetic Fe3O4/ CTS-CHE Nano medications are dissolved in the ethyl sodium solution of pH=4.5 (164g sodium acetates
Water is dissolved in, adds 84ml glacial acetic acids, is diluted to 1L), it is configured to 1mg/mL Nano medication solution.By mercaptopropionic acid modification
ZnSe-ZnS quantum dots are dissolved in the ethyl sodium solution of PH=4.5, are equally configured to 1mg/mL quantum dot solution.It is past
50ml nano-medicament carrier solution is added in three-neck flask, 50ml quantum dot solutions (1mg/mL) is taken, is slowly dropped to a nanometer medicine
In thing carrier solution, 600r/min, it is stirred overnight.After precipitation filtering, washing, vacuum drying, produce with fluorescence and strong magnetic
The Fe of property3O4/ CTS-CHE-ZnSe/ZnS fluorescence magnetic nano target medicines.
Embodiment 3：
A kind of fluorescence magnetic nano target medicine of the invention, by positively charged magnetic Fe3O4- chitosan-chelerythrine
The ZnSe-ZnS core-shell quanta dots self assemblies of alkali drug-carrying nanometer particle and negatively charged functionalized modification, magnetic Fe3O4- chitosan-is white
The red alkali drug-carrying nanometer particle of dish is bent with Fe3O4Be framework material carrier for magnetic core, chitosan, Chelerythrine be targeted drug；Function
The ZnSe-ZnS core-shell quanta dots of modification refer to that using ZnSe be kernel, ZnS for shell, after mercaptocarboxylic acids are modified
ZnSe-ZnS core-shell quanta dots.
The preparation method of the present embodiment, comprises the following steps：
2.528 g ferrous sulfate heptahydrates are dissolved in 30mL deionized water, 10 mL concentration of addition are 50 g × L-1
The PEG-20000 aqueous solution after, be sufficiently stirred in 30 DEG C of waters bath with thermostatic control, a certain amount of dilute ammonia solution 30mL be added dropwise, to solution
PH value is 10, then adds a certain amount of hydrogen peroxide solution stirring 20min.Finally, it is fully transferred in autoclave, in
Isothermal reaction 5h, obtains magnetic Fe at 160 DEG C3O4Nano particle.
By 0.22g magnetic Fes obtained above3O4Nano particle adds 5% acetic acid solution 20 dissolved with 0.32g chitosans
Ml, after adding atoleine 40 mL, span-80 0.5 mL, ultrasonic disperse 20min, add 3 mL 25% glutaraldehyde
Solution, mechanic whirl-nett reaction 4h, filtering, with petroleum ether, and acetone washing dehydration is used, drying, be ground into flowing powder, i.e.,
Obtain magnetic Fe3O4- chitin nanometer（Fe3O4- CTS complex microspheres）.
Standard but weighs 50mg magnetic Fes3O4- chitosan microball is put into 100ml conical flasks, with the glutaraldehydes of 20.0 ml 5%
Phosphate buffer（pH6.8）Nanoparticle is fully swelled（>10h）, then pour out buffer solution.By the magnetic Fe after swelling3O4- shell
Glycan microballoon is washed 2 times with buffer solution.Add certain density CHE hydrochloric acid saline solution 40.0ml, shaken at room temperature hatching 2.5h.
Separated with magnet, obtain carrying medicine compound and upper solution.Medicine compound is carried with 2.0 ml milli-Q waters 2 times.Medicine will be carried to answer
Compound is dried in vacuo 10h in 60 DEG C, and Fe is produced after grinding3O4- chitosan-CHE drug-carrying nanometer particles.
By 0.3785g（10mmol）NaBH4Add in the small flasks of 20mL, add 2.0mL deoxygenation deionized waters, ice
Water-bath cooling, under nitrogen atmosphere, add 0.3948g（5mmol）Selenium powder, it is well mixed, is after reacting 1h under confined conditions
Obtain NaHSe solution.
By 2.9g（10mmol）ZnAc2·2H2For O in 150mL three-necked bottles, adding 100mL deionized waters makes its dissolving,
It is stirred vigorously lower addition 0.18ml（24mmol）TGA, the pH value that solution is adjusted with 1.0 mol/L NaOH solution is 9.5, is led to
N2Deoxygenation 1h；In N2Under protection and stirring, the NaHSe solution 1.0mL for drawing preparation is added in mixed liquor, stirring reaction 10min
Afterwards, 100 DEG C of backflow 15min, obtain ZnSe quantum dot solutions.
0.32 g zinc stearates are dissolved in 2.5 mL toluene, leads to nitrogen, is heated to 60 DEG C, is subsequently cooled to room temperature, obtain
To Zn precursor solutions；30 mg S powder is dissolved in 2.5 mL TOP, leads to nitrogen, is heated to 90 DEG C, S precursor solutions are made.
Under nitrogen protection, the ZnSe QDs solution being already prepared to is added into three-neck flask（Containing 20 mg ZnSe）, while add 4
ML normal heptanes, 2.5 g TOPO and 1.5 g hexadecylamines.Then stir while by obtained Zn precursor solutions
It is slowly added to S precursor solutions in three-neck flask, the addition time is 1 h, maintains the temperature at 190 DEG C~200 DEG C；Solution adds
React 1 h again afterwards, produce ZnSe-ZnS core-shell quanta dots.
By magnetic Fe3O4/ CTS-CHE Nano medications are dissolved in the ethyl sodium solution of pH=4.5 (164g sodium acetates
Water is dissolved in, adds 84ml glacial acetic acids, is diluted to 1L), it is configured to 1mg/mL Nano medication solution.By mercaptopropionic acid modification
ZnSe-ZnS quantum dots are dissolved in the ethyl sodium solution of PH=4.5, are equally configured to 1mg/mL quantum dot solution.It is past
50ml nano-medicament carrier solution is added in three-neck flask, 50ml quantum dot solutions (1mg/mL) is taken, is slowly dropped to a nanometer medicine
In thing carrier solution, 600r/min, it is stirred overnight.After precipitation filtering, washing, vacuum drying, produce with fluorescence and strong magnetic
The Fe of property3O4/ CTS-CHE-ZnSe/ZnS fluorescence magnetic nano target medicines.
Claims (10)
1. a kind of fluorescence magnetic nano target medicine, it is characterised in that by magnetic Fe3O4- chitosan-Chelerythrine carries medicine and received
The ZnSe-ZnS core-shell quanta dots self assemblies of the grain of rice and functionalized modification, the magnetic Fe3O4- chitosan-Chelerythrine carries medicine and received
The grain of rice is with Fe3O4Be framework material carrier for magnetic core, chitosan, Chelerythrine be targeted drug；The functionalized modification
ZnSe-ZnS core-shell quanta dots refer to that using ZnSe be kernel, ZnS for shell, the ZnSe- after mercaptocarboxylic acids are modified
ZnS core shell quantum dot.
2. a kind of preparation method of fluorescence magnetic nano target medicine as claimed in claim 1, it is characterised in that including following
Step：
Step（1）Fe3O4The preparation of-chitosan-Chelerythrine drug-carrying nanometer particle：With cushioning liquid by magnetic Fe3O4- chitosan
Nano-particle is fully swelled, washed, and then adds chelerythrine aqueous alkali, shaken at room temperature hatching, is separated, carried with magnet
Medicine compound and upper solution, washing, dry, grinding obtains Fe3O4- chitosan-Chelerythrine drug-carrying nanometer particle；
Step（2）The preparation of the ZnSe-ZnS core-shell quanta dots of functionalized modification：ZnSe-ZnS core-shell quanta dots are dissolved in chloroform,
Then add the carboxylic acid compound containing sulfydryl, be stirred overnight, be centrifuged off it is unnecessary contain mercaptocarboxylic acids, by residue
Washing of precipitate, drying, that is, obtain the ZnSe-ZnS core-shell quanta dots of the functionalized modification；
Step（3）Self assembly：Prepare Fe3O4- chitosan-Chelerythrine drug-carrying nanometer particle solution, the ZnSe-ZnS of functionalized modification
Core-shell quanta dots solution, the ZnSe-ZnS core-shell quanta dots solution of functionalized modification is then added dropwise to Fe3O4- chitosan-greater celandine
In red alkali drug-carrying nanometer particle solution, it is stirred overnight, precipitates filtering, washing, vacuum drying, that is, obtains the fluorescence magnetic nanometer target
To medicine.
3. preparation method according to claim 2, it is characterised in that the magnetic Fe3O4The system of-chitin nanometer
It is standby to comprise the following steps：By magnetic Fe3O4Nano particle is added in the acetic acid solution dissolved with chitosan, addition atoleine,
Span-80, ultrasonic disperse add glutaraldehyde solution, stirring reaction, filtering, with petroleum ether, and with acetone washing dehydration,
Dry, be ground into flowing powder, that is, obtain the magnetic Fe3O4- chitin nanometer；The magnetic Fe3O4Nano particle with
The mass ratio of chitosan is 1:0.5~2.
4. preparation method according to claim 3, it is characterised in that the magnetic Fe3O4The preparation of nano particle include with
Lower step：Ferrous sulfate heptahydrate is dissolved in deionized water, Aqueous Solutions of Polyethylene Glycol is added, stirs and evenly mixs, the constant temperature under normal temperature
Water-bath, ammonia spirit is added dropwise under agitation, is 9 ~ 10 to pH value of solution, then adds hydrogen peroxide solution, mixed solution is turned
Move in autoclave, the isothermal reaction at 150 ~ 170 DEG C, then with water washing is distilled, centrifuge, and washed with absolute ethyl alcohol
Wash, dry, grind to obtain the magnetic Fe3O4Nano particle.
5. preparation method according to claim 2, it is characterised in that the preparation of the ZnSe-ZnS core-shell quanta dots includes
Following steps：Zinc stearate is dissolved in toluene, leads to nitrogen, heating, is subsequently cooled to room temperature, obtains Zn precursor solutions；By sulphur
Powder is dissolved in tri-n-octyl phosphine, is led to nitrogen, heating, S precursor solutions is made；
Under nitrogen protection, ZnSe quantum dot solutions, normal heptane, TOPO and hexadecylamine are mixed, and controlled
Processed ZnSe: ZnS mass ratio is 1:（0.5~3）, heating stirring, untill normal heptane completely volatilization, then while stirring one
While being slowly added to the Zn precursor solutions and S precursor solutions, keeping temperature is reacted, then washs purifying, precipitation, vacuum with methanol
The ZnSe-ZnS core-shell quanta dots are obtained after drying.
6. preparation method according to claim 5, it is characterised in that the parts by weight of the zinc stearate are 320~420
Part, the parts by weight of the sulphur powder are 16 ~ 24 parts；The zinc stearate is dissolved in toluene, logical nitrogen, is heated to 50 ~ 70 DEG C；Will
The sulphur powder is dissolved in tri-n-octyl phosphine, is led to nitrogen, is heated to 80 ~ 100 DEG C；The temperature of the heating stirring is 180 ~ 200 DEG C；
The reaction keeping temperature is 180 ~ 200 degrees Celsius, time at least 1h.
7. preparation method according to claim 5, it is characterised in that the preparation of the ZnSe quantum dot solutions includes following
Step：Zinc diacetate dihydrate is dissolved in deionized water, stir it is lower add TGA, with NaOH solution regulation pH be 9~
10, lead to N2Deoxygenation；In N2Under protection and stirring, NaHSe solution is added, makes HSe in reaction system-With Zn2+The ratio between the amount of material
For 1: 2~8, after stirring reaction at least 10min, backflow, the ZnSe quantum dot solutions are obtained.
8. preparation method according to claim 7, it is characterised in that the preparation of the NaHSe solution comprises the following steps：
By the NaBH of 37~56 parts by weight4It is dissolved in deoxygenation deionized water, ice-water bath cooling, under nitrogen atmosphere, adds 39~60 weights
The selenium powder of part is measured, is well mixed, reacts at least 0.5h under confined conditions, until the selenium powder of black is wholly absent, while bottom of bottle goes out
Existing white crystal, supernatant is the NaHSe solution.
9. preparation method according to claim 2, it is characterised in that the cushioning liquid is glutaraldehyde solution, pH is 6 ~
8；The time being fully swelled is more than 10h；The time of the vibration hatching is 2 ~ 4h；The carboxylic acid compound containing sulfydryl
For 3- mercaptopropionic acids, dimercaptosuccinic acid, TGA, cysteine, 2 mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, sulfydryl
Acid, any one in sulfydryl enanthic acid；The step（2）Solution used in washing of precipitate is dimethylformamide.
10. the preparation method according to any one in claim 2 ~ 9, it is characterised in that the Fe3O4- chitosan-is white
It is by the Fe to bend the red alkali drug-carrying nanometer particle solution of dish3O4- chitosan-Chelerythrine drug-carrying nanometer particle is dissolved in the second that pH is 4 ~ 5
Prepare and obtain in acid-sodium acetate solution, concentration is 1 ~ 2mg/mL；The ZnSe-ZnS core-shell quanta dots solution of the functionalized modification is
It is dissolved in preparing in acetic acid-sodium acetate solution that pH is 2 ~ 6 by the ZnSe-ZnS core-shell quanta dots of the functionalized modification and is obtained, concentration
For 1 ~ 3 mg/mL.
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