CN104840977A - Method for preparing magnetic fluorescence composite nano drug carrier - Google Patents
Method for preparing magnetic fluorescence composite nano drug carrier Download PDFInfo
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- CN104840977A CN104840977A CN201510124945.9A CN201510124945A CN104840977A CN 104840977 A CN104840977 A CN 104840977A CN 201510124945 A CN201510124945 A CN 201510124945A CN 104840977 A CN104840977 A CN 104840977A
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Abstract
The invention relates to a method for preparing a magnetic fluorescence composite nano drug carrier. The method selects a beta-cyclodextrin derivative-wrapped hydrophobic medicine having an inner core molecular structure, and encapsulating effect is greatly improved. The carrier structure takes negative charge-carried carboxymethyl chitosan or carboxymethyl-beta-cyclodextrin-modified magnetic nanoparticles as a core, then under effect of poly diallyldimethylammonium chloride (PDDA), an ion cross-linking agent and a medicine-loaded anionic high-molecular organic matter, and the magnetic fluorescence composite nano particles can be obtained by connecting water-soluble quantum dot through an ion crosslinking method. According to the invention, fluorescence quantum dots are uniformly distributed on the surface of the magnetic nano particles, wherein the particle size of the magnetic nano particles is 10-200nm, and the quantum point particle size is 1.5-10nm. The reaction method has the advantages of mild condition and simple operation method, the composite nano drug carrier has good biology compatibility and hydrophilcity, controllable packaging and release can be realized on tumor medicines, the nano drug carrier has magnetic targeting and fluorescence tracer functions, and has important research and application value in the fields relative to the drug carrier, biology imaging, and biomolecule monitoring and separating.
Description
Technical field
The present invention relates to a kind of preparation method of multi-functional, hydrophobic pharmaceutical carrier, be specifically related to a kind of preparation method of magnetic fluorescence composite Nano pharmaceutical carrier, this composite Nano pharmaceutical carrier has possessed the fluorescence property of quantum dot and the magnetic property of magnetic nanoparticle simultaneously, can be used as targeting location and bioluminescence imaging aspect in organism.
Background technology
Tumor is one of major disease threatening human health at present, treat the commonsense method actinotherapy of tumor, chemical medicinal treatment, heating therapy and excision etc. and have certain limitation, if radiation and chemotherapy is while killing tumor cell, also normal human cell can be damaged.Therefore, people expect chemotherapy and radiation medicine direction and location to be transported to specific lesion tissue and organ for a long time, realize the object of local patholoic change topical therapeutic.Given this, develop a kind of multi-functional drug carriers, by designing cleverly, multiple functional supports material is integrated in single and stable system, to reach specific purpose, as extended blood circulation time, targeting, drug controlled release, the therapeutic agent of load simultaneously, developer or contrast agent etc.Unique medicine control system is formed by the form of chemical bonding, physical absorption or parcel and drug molecule, the nanometer medicine of synthesis carries characteristics such as having both drug loading is high, targeting good, toxicity is low, controllable release, can timing, location, quantitative performance drug effect.
Quantum dot and magnetics nanoparticle go out obvious advantage in a lot of field especially biomedical fields.But they often only have single function, as the fluorescent labeling of quantum dot, the Magnetic Isolation etc. of magnetic particle, if two kinds of function-separation and mark function to be dissolved in one, novel magnetic fluorescence nano composite material is prepared by certain physical and chemical process, make it as while fluorescent probe, also there is good magnetic response characteristic.Therefore, magnetic fluorescence nano particle has Magneto separate and fluorescent tracing dual-use function, and its performance and application scope, all considerably beyond the nanoparticle of simple function, not only can be carried out detection on bio-molecular level and be separated; Also achieve various modes imaging, i.e. fluorescence imaging, nuclear magnetic resonance (MRI) and Laser scanning confocal microscopy.Going deep at present along with composite nanometer particle research, this composite particles has clear superiority in drug targeting transportation, because composite nanometer particle can while realizing targeted, utilize fluorescent marker imaging technique, to the course of conveying of medicine and and the mechanism of cell monitor in real time, the antitumor machanism of further drugs molecule while drug targeting release, therefore at biomedical sector, speed and the accuracy rate of bioanalysis and medical diagnosis is significantly improved.
There is research surface, beta-schardinger dextrin-is as a kind of supramolecular materials, and it has the structure that outer rim is hydrophilic and inner chamber is hydrophobic, and thus it can provide a hydrophobic binding site as the enzyme, as the various suitable object of main body enclose, as organic molecule, inorganic ions and drug molecule etc.Meanwhile, as pharmaceutical carrier, not only can form clathrate with the material of poorly water-soluble, and the encapsulating of some water-soluble substances can be promoted.Carboxymethyl-beta-cyclodextrin and Sulfobutyl ether β _ cyclodextrin are as the derivant of cyclodextrin, self-contained negative charge can form composite nanometer particle with the diallyl dimethyl ammoniumchloride (PDDA) with positive charge by electrostatical binding, its distinctive inner chamber hydrophobic structure can form clathrate with some hydrophobic drugs, and the encapsulating successful of this type of material is improved.Medicine is after cyclodextrin inclusion compound, and its chemical stability, solubility property, bioavailability significantly improve.
Summary of the invention
A kind of ionic cross-linking is the object of the present invention is to provide to prepare the method integrating the preparation of the multifunctional nano pharmaceutical carrier of magnetic, fluorescence and drug loading, composite Nano pharmaceutical carrier prepared by the method has that magnetic responsiveness is strong, light stability is high, drug loading high preparation technology is simple, good dispersion and the advantages such as size uniform, has apply widely in field of nano biotechnology.
The present invention is achieved by the following measures:
A preparation method for magnetic fluorescence composite Nano pharmaceutical carrier, adopts following steps:
A () adopts blended investment to prepare electronegative magnetic nanocomposites:
1. take 50-500mg magnetic nanoparticle and be dissolved in 30 mL pH=7.4, concentration is in the PBS buffer solution of 0.01mol/L, and logical nitrogen deoxidation, utilizes ultrasonic washing unit to be uniformly dispersed by magnetic particle; 2. take 10-800 mg carboxymethyl chitosan or carboxymethyl-beta-cyclodextrin is dissolved in the buffer solution of 20 mL PBS=7.4, add the group that 0.1-0.5 g 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC) activates carboxymethyl chitosan or carboxymethyl-beta-cyclodextrin surface simultaneously; 3. incite somebody to action 1. and 2. two solution mixing, 25 DEG C of vibration 2-6 h in water bath with thermostatic control agitator, then use distilled water and PBS (pH=7.4) buffer solution fully to wash successively, namely obtain electronegative magnetic nanocomposites;
B () adopts ionic cross-linking to prepare magnetic fluorescence composite Nano pharmaceutical carrier:
The concentrated aqueous phase quantum point getting preparation is dissolved in distilled water, adds ion crosslinking agent, obtains reaction solution A; Mixed with anionic macromolecule organic by the alcoholic solution of hydrophobic drug, oscillating reactions 2-10 h under room temperature, obtains the clathrate B comprising medicine; The electronegative magnetic nanocomposites getting preparation in 0.005-0.05g step (a) is dissolved in distilled water, and ultrasonic 20-60 min, makes magnetic nanometer particles be uniformly dispersed, and adds diallyl dimethyl ammoniumchloride and obtain reaction solution C; Dropwise joined by reaction solution A and B in reaction solution C, oscillating reactions 2-10 h under room temperature, centrifugalize, distilled water wash, namely obtains magnetic fluorescence composite Nano pharmaceutical carrier.
Magnetic fluorescence composite Nano pharmaceutical carrier preparation of the present invention, the particle diameter of composite Nano pharmaceutical carrier is 10-220 nm; Magnetic nanoparticle (MNPs) is superparamagnetic, paramagnetic or ferromagnetic metal and metal-oxide, is selected from Fe
3o
4, Fe
2o
3, MeFe
2o
4(Me=Co, Mn, Ni), compound neodymium iron boron, SmCo etc., metal Fe, Co, Ni and alloy Fe
2co, Ni
2one in the nano-particle of the metal-oxide of Fe; The preparation method of magnetic nanoparticle comprises coprecipitation, hydro-thermal method; Magnetic nanoparticle surface is containing at least one in hydroxyl, amino, carboxyl.
Quantum dot of the present invention be surface with the water-soluble quantum dot of hydrophilic group, quantum dot is II-VI group semi-conducting material, or is the composite of II-VI group semi-conducting material formation, and described quantum point grain diameter is 1.5-10 nm; Preferred quantum dot is ZnSe, CdSe, CdTe, CdS, ZnSe/ZnS, CdS/ZnS, CdSe/ZnS, CdTe/ZnS, Zn
xcd
1-Xse, CdSe
1-Xs
x, CdSe
1-Xte
x, CdSe/ZnSe, CdS/ZnSe, CdTe/ZnSe, CdSe/CdS, CdTe/CdS, CdS/Zn
xcd
1-Xs, ZnSe/Zn
xcd
1-Xs, CdSe/Zn
xcd
1-Xs or CdTe/Zn
xcd
1-Xone in S, wherein 0 < X < 1.
Ion crosslinking agent of the present invention comprises one or more in tripolyphosphate, four Quadrafos, hexametaphosphate, pyrophosphate, molybdate, hyaluronic acid or gamma-polyglutamic acid-; Anionic macromolecule organic carboxymethyl-beta-cyclodextrin or Sulfobutyl ether β _ cyclodextrin; Carboxymethyl chitosan can select O-CMC or CMC; Molecular weight and the mass concentration of diallyl dimethyl ammoniumchloride are respectively 1 × 10
5-2 × 10
5with 0.51-5.1 mg/mL.
Hydrophobic drug of the present invention comprises at least one in ibuprofen, 5-fluorouracil, Docetaxel, camptothecine or paclitaxel.
The preparation of a kind of magnetic fluorescence composite Nano pharmaceutical carrier of the present invention, in step (a), carboxymethyl chitosan or the thickness of carboxymethyl-beta-cyclodextrin on magnetic nanoparticle surface are 3-10 nm; In step (b), the mol ratio of hydrophobic drug and anionic macromolecule organic is 1:10-1:60, electronegative magnetic nanocomposites and the mol ratio of quantum dot are 1:1-1:20, diallyl dimethyl ammoniumchloride: anionic macromolecule organic: the mass ratio of ion crosslinking agent is 1:0.1-2:0.01-0.5.
Quantum dot surface of the present invention contains at least one in sulfydryl, carboxyl, amino; The hydrophilic group part used in semiconductor-quantum-point synthesis comprises one or more in 3-mercaptopropionic acid, TGA, Cys, 2 mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, mercaptohexanoic acid, dimercaptosuccinic acid, mercaptoethanol, glutathion, mercaprol or mercaptoethylmaine.
beneficial effect of the present invention:
(1) the present invention utilizes the polyelectrolyte effect between opposite charges material to be assembled into magnetic fluorescence composite Nano pharmaceutical carrier by ionic cross-linking, and without the need to an organic solvent, reaction condition is gentle, can protect the activity of drug molecule to greatest extent;
(2) the present invention selects diallyl dimethyl ammoniumchloride (PDDA) as cationic polyelectrolyte, it has safe, nontoxic, the soluble in water and characteristic such as hydrolytic stability is good, cohesiveness is strong, avoids the bio-toxicity using other organic polyelectrolyte to cause;
(3) the present invention selects with the carboxymethyl-beta-cyclodextrin of inner chamber molecular structure or Sulfobutyl ether β _ cyclodextrin embedding hydrophobic drug, to hydrophobic active, there is good encapsulating effect, improve the dissolubility of medicine, increase medicine stability, reduce the untoward reaction of medicine;
(4) the Multifunctional composite nanometer pharmaceutical carrier prepared of the present invention, while can targeted drug delivery being realized, utilize fluorescent labelling techniques, the course of conveying of medicine and the mechanism of cell are monitored in real time, significantly improve speed and the accuracy rate of bioanalysis and medical diagnosis.
Accompanying drawing explanation
The abosrption spectrogram of Fig. 1 magnetic fluorescence composite Nano pharmaceutical carrier drug release
The TEM photo of Fig. 2 magnetic fluorescence composite Nano pharmaceutical carrier
The hysteresis curve of Fig. 3 magnetic fluorescence composite Nano pharmaceutical carrier
The Absorption and fluorescence spectrum of Fig. 4 magnetic fluorescence composite Nano pharmaceutical carrier
The digital photograph of Fig. 5 magnetic fluorescence composite Nano pharmaceutical carrier when uviol lamp and externally-applied magnetic field.
Detailed description of the invention
Below by specific embodiment, technical scheme of the present invention is described, but technical scheme of the present invention is not limited with specific embodiment.
Embodiment 1:
1.1 aqueous phases prepare CdTe quantum.Under nitrogen protection, by 0.0945g NaBH
4be dissolved in 5 mL distilled water with 0.0063g Te powder, be heated to 40 DEG C, after dissolving completely, obtain NaHTe solution; Get 0.293 g Cd (Ac)
2dissolve in 100 mL distilled water, after it dissolves completely, add 2.0 mmol TGAs, regulate pH=11 by the NaOH solution of 1mol/L, obtain the precursor solution of Cd; Proceed in there-necked flask by the presoma of Cd, inject NaHTe solution rapidly under nitrogen protection, oil bath 100 DEG C backflow, after magnetic agitation 2h, taking-up is put into refrigerator and is quickly cooled to room temperature, obtains red, transparent solution, is the CdTe QDs solution prepared.
1.2 adopt hydro-thermal method to prepare Fe
3o
4nano-particle.Take 3 g FeCl
3be dissolved in 80 mL ethylene glycol and stir ultrasonic dissolution, add Polyethylene Glycol 2 g that molecular weight is 2000, sodium acetate 7 g, stir ultrasonic making it to dissolve, precursor solution is proceeded in hydrothermal reaction kettle, at 200 DEG C of reaction 4 h, after having reacted, gained solution with water and dehydrated alcohol are alternately washed, through vacuum drying, obtain dry Fe
3o
4magnetic nanoparticle.
1.3 adopt blended investment to prepare electronegative magnetic nanocomposites.Take 0.08 g Fe
3o
4magnetic nanoparticle is dissolved in 30 mL pH=7.4, and concentration is in the PBS buffer solution of 0.01mol/L, and logical nitrogen deoxidation, utilizes ultrasonic washing unit to be uniformly dispersed by magnetic particle, obtain finely dispersed Fe
3o
4nanoparticles solution; Take 0.2 g carboxymethyl chitosan to be dissolved in the PBS buffer solution of 20 mL pH=7.4, add the group that 0.1 g 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC) activates carboxymethyl chitosan surface simultaneously; Afterwards carboxymethyl chitosan solution is added Fe
3o
4nanoparticles solution, 25 DEG C of vibration 2 h in water bath with thermostatic control agitator, reaction terminates rear Magnet and collects product, then uses distilled water and PBS (pH=7.4) buffer solution fully to wash successively, namely obtains carboxymethyl chitosan magnetic nanocomposites.
1.4 adopt ionic cross-linking to prepare magnetic fluorescence composite Nano pharmaceutical carrier.Get the concentrated aqueous phase CdTe quantum of 1.1 preparations, be dissolved in after isopropyl alcohol separating-purifying in 5mL distilled water, and add sodium polyphosphate, wherein the concentration of sodium polyphosphate and CdTe quantum is respectively 1 mg/mL and 0.04 mol/L, obtains reaction solution A; Mixed with 2g carboxymethyl-beta-cyclodextrin by the methanol solution of 20 mg hydrophobic drug 5-fluorouracil, oscillating reactions 2 h under room temperature, obtains the clathrate B comprising 5-fluorouracil; The magnetic nanocomposites getting in 0.01g step 1.3 carboxymethyl chitosan of preparation sugar-modified is dissolved in 10 mL distilled water, and ultrasonic 30 min, make magnetic nanometer particles be uniformly dispersed, and to add mass concentration be 1 mg/mL PDDA, obtains reaction solution C; A and B solution are dropwise added in C solution, vibrate 4h in the water bath with thermostatic control agitator of 25 DEG C, Magnet collecting reaction product, with distilled water cleaning reaction product, obtains magnetic fluorescence composite Nano pharmaceutical carrier.Fig. 1 is the abosrption spectrogram of the magnetic fluorescence composite Nano pharmaceutical carrier drug release of preparation, and Fig. 2 is the TEM photo of the magnetic fluorescence composite Nano pharmaceutical carrier of preparation.
Embodiment 2:
2.1 adopt Aqueous phase to prepare CdTe/ZnS quantum dot. and first adopt chemical coprecipitation to prepare CdTe quantum, preparation method is as described in above-described embodiment 1, and difference is the response time is 4h.Getting the CdTe quantum prepared is dissolved in 30 mL distilled water, and wherein the concentration of CdTe quantum is 1.67 × 10
-3mol/L, adds 0.0329 g Zn (Ac)
2, 0.0921 g reductive glutathione, be 1 mol/L NaOH solution adjust ph by the concentration configured be 8, under magnetic stirring, oil bath 100 DEG C backflow, magnetic agitation is put into refrigerator after reacting 2 h and is quickly cooled to room temperature, obtains the CdTe/ZnS quantum dot of water solublity high-luminous-efficiency.
2.2 adopt hydro-thermal method to prepare Fe
3o
4nano-particle.Get 2.78 g FeSO
47H
2o, 4.32 g FeCl
36H
2o is dissolved in 30 mL distilled water; after magnetic agitation is dissolved; add 30 mL ethylene glycol again; after stirring under nitrogen protection; add in there-necked flask, regulate pH to 9-11 by the NaOH solution that the concentration configured is 2 mol/L, add surfactant polyvinylpyrrolidone 0.15 g; 30 min are reacted, obtained Fe after abundant stirring
3o
4the presoma of magnetic nanoparticle.By Fe
3o
4the presoma of magnetic nanoparticle proceeds in hydrothermal reaction kettle, at 160 DEG C, react 6h.After having reacted, gained solution with water and dehydrated alcohol are alternately washed, through vacuum drying, obtain dry Fe
3o
4magnetic nanoparticle.
2.3 adopt blended investment to prepare carboxymethyl-beta-cyclodextrin magnetic nanocomposites.Take 0.2 g Fe
3o
4magnetic nanoparticle is dissolved in 30 mL pH=7.4, and concentration is in the PBS buffer solution of 0.01mol/L, and logical nitrogen deoxidation, utilizes ultrasonic washing unit to be uniformly dispersed by magnetic particle, obtain finely dispersed Fe
3o
4nanoparticles solution; Take 0.5 g carboxymethyl-beta-cyclodextrin to be dissolved in the PBS buffer solution of 20 mL pH=7.4, add the group that 0.3 g 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC) activates carboxymethyl-beta-cyclodextrin surface simultaneously; Afterwards carboxymethyl-beta-cyclodextrin solution is added Fe
3o
4nanoparticles solution, 25 DEG C of vibration 4 h in water bath with thermostatic control agitator, reaction terminates rear Magnet and collects product, then uses distilled water and PBS (pH=7.4) buffer solution fully to wash successively, namely obtains carboxymethyl-beta-cyclodextrin magnetic nanocomposites.
2.4 adopt ionic cross-linking to prepare magnetic fluorescence composite Nano pharmaceutical carrier.Get the concentrated aqueous phase CdTe/ZnS quantum dot of 2.1 preparations, be dissolved in 5mL distilled water after isopropyl alcohol separating-purifying, and add sodium tetrapolyphosphate, wherein the concentration of sodium tetrapolyphosphate and CdTe/ZnS quantum dot is respectively 1.5 mg/mL and 0.05 mol/L, obtains reaction solution A; Mixed with 4g carboxymethyl-beta-cyclodextrin by the alcoholic solution of 60mg hydrophobic drug Docetaxel, oscillating reactions 4 h under room temperature, obtains the clathrate B comprising Docetaxel; The magnetic nanocomposites that the carboxymethyl-beta-cyclodextrin getting preparation in 0.02 g step 2.3 is modified is dissolved in 10 mL distilled water, ultrasonic 30 min, magnetic nanometer particles is uniformly dispersed, and to add mass concentration be 2 mg/mL diallyl dimethyl ammoniumchloride, obtain reaction solution C; A and B solution are dropwise added in C solution, vibrate 6h in the water bath with thermostatic control agitator of 25 DEG C, Magnet collecting reaction product, with distilled water cleaning reaction product, obtains magnetic fluorescence composite Nano pharmaceutical carrier.Fig. 3 is the hysteresis curve of the magnetic fluorescence composite Nano pharmaceutical carrier of preparation.
Embodiment 3:
The preparation of 3.1 ZnSe/ZnS quantum dot solutions.First chemical coprecipitation is adopted to prepare ZnSe quantum dot, under nitrogen protection, by 0.01g NaBH
4be dissolved in 2 mL distilled water with 0.0061g Se powder, be heated to 40 DEG C, after dissolving completely, obtain NaHSe solution; Get 0.0439 g Zn (Ac)
2dissolve in 20 mL distilled water, after it dissolves completely, add reduced glutathion 0.0737g, regulate pH=11.5 by the NaOH solution of 1mol/L, obtain the precursor solution of Zn; Proceed in there-necked flask by the presoma of Zn, inject NaHSe solution rapidly under nitrogen protection, oil bath 100 DEG C backflow, after magnetic agitation 1h, taking-up is put into refrigerator and is quickly cooled to room temperature, obtains colourless transparent solution, is the ZnSe QDs solution prepared.Get ZnSe quantum dot 15 mL prepared, wherein the concentration of ZnSe quantum dot is 2.7 × 10
-3mol/L, adds 0.0138 g Zn (Ac)
2, 0.0277 g reductive glutathione and 0.01 g thiourea, be 1 mol/L NaOH solution adjust ph by the concentration configured be 10.5, under magnetic stirring, oil bath 100 DEG C backflow, magnetic agitation is put into refrigerator after reacting 2 h and is quickly cooled to room temperature, obtains the ZnSe/ZnS quantum dot of faint yellow water solublity high-luminous-efficiency.
The preparation of 3.2 magnetic nanoparticles.Employing patent publication No. is that the method for CN101597495A prepares Fe
3o
4/ CoO core-shell structure magnetic nano-particle.
3.3 adopt blended investment to prepare carboxymethyl chitosan magnetic nanocomposites.Take 0.35 g Fe
3o
4/ CoO magnetic nanoparticle is dissolved in 30 mL pH=7.4, and concentration is in the PBS buffer solution of 0.01mol/L, and logical nitrogen deoxidation, utilizes ultrasonic washing unit to be uniformly dispersed by magnetic particle, obtain finely dispersed Fe
3o
4/ CoO nanoparticles solution; Take 0.65 g carboxymethyl chitosan to be dissolved in the PBS buffer solution of 20 mL pH=7.4, add the group that 0.3 g 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC) activates carboxymethyl chitosan surface simultaneously; Afterwards carboxymethyl chitosan solution is added Fe
3o
4/ CoO nanoparticles solution, 25 DEG C of vibration 5 h in water bath with thermostatic control agitator, reaction terminates rear Magnet and collects product, then uses distilled water and PBS (pH=7.4) buffer solution fully to wash successively, namely obtains carboxymethyl chitosan magnetic nanocomposites.
3.4 adopt ionic cross-linking to prepare magnetic fluorescence composite nanometer particle.Get the concentrated aqueous phase ZnSe/ZnS quantum dot of 3.1 preparations, be dissolved in after isopropyl alcohol separating-purifying in 5mL distilled water, and add tetrasodium pyrophosphate, wherein the concentration of tetrasodium pyrophosphate and ZnSe/ZnS quantum dot is respectively 2 mg/mL and 0.1 mol/L, obtains reaction solution A; The alcoholic solution of 30 mg hydrophobic drug paclitaxels is mixed with 1.42g Sulfobutyl ether β _ cyclodextrin, obtains the clathrate B comprising paclitaxel; The magnetic nanocomposites getting in 0.035 g step 3.3 carboxymethyl chitosan of preparation sugar-modified is dissolved in 10 mL distilled water, ultrasonic 30 min, magnetic nanometer particles is uniformly dispersed, and to add mass concentration be 2 mg/mL diallyl dimethyl ammoniumchloride, obtain reaction solution C; A and B solution are dropwise added in C solution, vibrate 6h in the water bath with thermostatic control agitator of 25 DEG C, Magnet collecting reaction product, with distilled water cleaning reaction product, obtains magnetic fluorescence composite Nano pharmaceutical carrier.Fig. 4 is the Absorption and fluorescence spectrum of the magnetic fluorescence composite Nano pharmaceutical carrier of preparation.
Embodiment 4:
4.1 adopt Aqueous phase to prepare CdSe quantum dot. under nitrogen protection, by 0.0106 g NaBH
4be dissolved in 2 mL distilled water with 0.0063 g Se powder, be heated to 40 DEG C, after dissolving completely, obtain NaHSe solution; Get 0.0533 g Cd (Ac)
2dissolve in 20 mL distilled water, after it dissolves completely, add 1.0 mmol mercaptopropionic acids, regulate pH=11.5 by the NaOH solution of 1mol/L, obtain the precursor solution of Cd; Proceed in there-necked flask by the presoma of Cd, inject NaHSe solution rapidly under nitrogen protection, oil bath 100 DEG C backflow, after magnetic agitation 1h, taking-up is put into refrigerator and is quickly cooled to room temperature, is the CdSe QDs solution prepared.
The preparation of 4.2 magnetic nanoparticles.Employing patent publication No. is that the method for CN 101928043 A prepares α-Fe
2o
3magnetic nanoparticle.
4.3 adopt blended investment to prepare carboxymethyl-beta-cyclodextrin magnetic nanocomposites.Take 0.5 g α-Fe
2o
3magnetic nanoparticle is dissolved in 30 mL pH=7.4, and concentration is in the PBS buffer solution of 0.01mol/L, and logical nitrogen deoxidation, utilizes ultrasonic washing unit to be uniformly dispersed by magnetic particle, obtain finely dispersed α-Fe
2o
3nanoparticles solution; Take 0.8 g carboxymethyl-beta-cyclodextrin to be dissolved in the buffer solution of 20 mL PBS=7.4, add the group that 0.5 g 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC) activates carboxymethyl-beta-cyclodextrin surface simultaneously; Afterwards carboxymethyl-beta-cyclodextrin solution is added α-Fe
2o
3nanoparticles solution, 25 DEG C of vibration 6 h in water bath with thermostatic control agitator, reaction terminates rear Magnet and collects product, then uses distilled water and PBS (pH=7.4) buffer solution fully to wash successively, namely obtains carboxymethyl-beta-cyclodextrin magnetic nanocomposites.
4.4 adopt ionic cross-linking to prepare magnetic fluorescence composite Nano pharmaceutical carrier.Get the concentrated aqueous phase CdSe quantum dot of 4.1 preparations, be dissolved in after isopropyl alcohol separating-purifying in 5 mL distilled water, and add sodium molybdate, wherein the concentration of sodium molybdate and CdSe quantum dot is respectively 2.5 mg/mL and 0.25 mol/L, obtains reaction solution A; The methanol solution of 50mg hydrophobic drug camptothecine is mixed with 3.9g Sulfobutyl ether β _ cyclodextrin, obtains the clathrate B comprising camptothecine; The magnetic nanocomposites that the carboxymethyl-beta-cyclodextrin getting preparation in 0.05 g step 4.3 is modified is dissolved in 10 mL distilled water, ultrasonic 30 min, magnetic nanometer particles is uniformly dispersed, and to add mass concentration be 5 mg/mL diallyl dimethyl ammoniumchloride, obtain reaction solution C; A and B solution are dropwise added in C solution, vibrate 10 h in the water bath with thermostatic control agitator of 25 DEG C, Magnet collecting reaction product, with distilled water cleaning reaction product, obtains magnetic fluorescence composite Nano pharmaceutical carrier.Fig. 5 is the digital photograph of magnetic fluorescence composite Nano pharmaceutical carrier when uviol lamp and externally-applied magnetic field of preparation.
Claims (8)
1. the preparation method of a magnetic fluorescence composite Nano pharmaceutical carrier, it is characterized in that: the magnetic nano-particle modified with electronegative carboxymethyl chitosan or carboxymethyl-beta-cyclodextrin, diallyl dimethyl ammoniumchloride (PDDA), ion crosslinking agent are connected water-soluble quantum dot with the anionic macromolecule organic of carrying medicament by ionic cross-linking and obtain, described fluorescence quantum is evenly distributed on the surface of magnetic nanoparticle with single dispersing form, wherein the size of magnetic nanoparticle is at 10-200 nm, and the particle diameter of quantum dot is at 1.5-10 nm.
2. the preparation of a kind of magnetic fluorescence composite Nano pharmaceutical carrier according to claim 1, it is characterized in that, described preparation method comprises the following steps:
A () adopts blended investment to prepare electronegative magnetic nanocomposites: 1. take 50-500mg magnetic nanoparticle and be dissolved in 30 mL pH=7.4, concentration is in the PBS buffer solution of 0.01mol/L, logical nitrogen deoxidation, utilizes ultrasonic washing unit to be uniformly dispersed by magnetic particle; 2. take 10-800 mg carboxymethyl chitosan or carboxymethyl-beta-cyclodextrin is dissolved in the buffer solution of 20 mL PBS=7.4, add the group that 0.1-0.5 g 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC) activates carboxymethyl chitosan or carboxymethyl-beta-cyclodextrin surface simultaneously; 3. incite somebody to action 1. and 2. two solution mixing, 25 DEG C of vibration 2-6 h in water bath with thermostatic control agitator, then use distilled water and PBS (pH=7.4) buffer solution fully to wash successively, namely obtain electronegative magnetic nanocomposites;
B () adopts ionic cross-linking to prepare magnetic fluorescence composite Nano pharmaceutical carrier:
The concentrated aqueous phase quantum point getting preparation is dissolved in distilled water, and adds ion crosslinking agent, obtains reaction solution A; The methanol of hydrophobic drug or alcoholic solution are mixed with anionic macromolecule organic, oscillating reactions 2-10 h under room temperature, obtains the clathrate B comprising medicine; The electronegative magnetic nanocomposites getting preparation in 0.005-0.05g step (a) is dissolved in distilled water, and ultrasonic 20-60 min, makes magnetic nanometer particles be uniformly dispersed, and adds diallyl dimethyl ammoniumchloride and obtain reaction solution C; Dropwise joined by reaction solution A and B in reaction solution C, oscillating reactions 2-10 h under room temperature, centrifugalize, distilled water wash, namely obtains magnetic fluorescence composite Nano pharmaceutical carrier.
3. a kind of magnetic fluorescence composite Nano pharmaceutical carrier according to claim 1 and 2, is characterized in that, the particle diameter of described magnetic fluorescence composite Nano pharmaceutical carrier is 10-220 nm; Described magnetic nanoparticle (MNPs) is superparamagnetic, paramagnetic or ferromagnetic metal and metal-oxide, is selected from Fe
3o
4, Fe
2o
3, MeFe
2o
4(Me=Co, Mn, Ni), compound neodymium iron boron, SmCo etc., metal Fe, Co, Ni and alloy Fe
2co, Ni
2one in the nano-particle of the metal-oxide of Fe; The preparation method of magnetic nanoparticle comprises coprecipitation, hydro-thermal method; Magnetic nanoparticle surface is containing at least one in hydroxyl, amino, carboxyl.
4. a kind of magnetic fluorescence composite Nano pharmaceutical carrier according to claim 1 and 2, it is characterized in that, described quantum dot is the water-soluble quantum dot of surface with hydrophilic group, quantum dot is II-VI group semi-conducting material, or be the composite that II-VI semi-conducting material is formed, described quantum point grain diameter is 1.5-10 nm; Preferred quantum dot is ZnSe, CdSe, CdTe, CdS, ZnSe/ZnS, CdS/ZnS, CdSe/ZnS, CdTe/ZnS, Zn
xcd
1-Xse, CdSe
1-Xs
x, CdSe
1-Xte
x, CdSe/ZnSe, CdS/ZnSe, CdTe/ZnSe, CdSe/CdS, CdTe/CdS, CdS/Zn
xcd
1-Xs, ZnSe/Zn
xcd
1-Xs, CdSe/Zn
xcd
1-Xs or CdTe/Zn
xcd
1-Xone in S, wherein 0 < X < 1.
5. a kind of magnetic fluorescence composite Nano pharmaceutical carrier according to claim 1 and 2, it is characterized in that, described ion crosslinking agent comprises one or more in tripolyphosphate, four Quadrafos, hexametaphosphate, pyrophosphate, molybdate, hyaluronic acid or gamma-polyglutamic acid-; Anionic macromolecule organic comprises carboxymethyl-beta-cyclodextrin or Sulfobutyl ether β _ cyclodextrin; Described carboxymethyl chitosan can select O-CMC or CMC; Molecular weight and the mass concentration of diallyl dimethyl ammoniumchloride are respectively 1 × 10
5-2 × 10
5with 0.51-5.1 mg/mL.
6. a kind of magnetic fluorescence composite Nano pharmaceutical carrier according to claim 1 and 2, it is characterized in that, described hydrophobic drug comprises at least one in ibuprofen, 5-fluorouracil, Docetaxel, camptothecine or paclitaxel.
7. a kind of magnetic fluorescence composite Nano pharmaceutical carrier according to claim 2, is characterized in that, in step (a), carboxymethyl chitosan or the thickness of carboxymethyl-beta-cyclodextrin on magnetic nanoparticle surface are 3-10 nm; In step (b), the mol ratio of hydrophobic drug and anionic macromolecule organic is 1:10-1:60, electronegative magnetic nanocomposites and the mol ratio of quantum dot are 1:1-1:20, diallyl dimethyl ammoniumchloride: anionic macromolecule organic: the mass ratio of ion crosslinking agent is 1:0.1-2:0.01-0.5.
8. the preparation of water-soluble quantum dot according to claim 4, is characterized in that: described quantum dot surface contains at least one in sulfydryl, carboxyl, amino; The hydrophilic group part used in semiconductor-quantum-point synthesis comprises one or more in 3-mercaptopropionic acid, TGA, Cys, 2 mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, mercaptohexanoic acid, dimercaptosuccinic acid, mercaptoethanol, glutathion, mercaprol or mercaptoethylmaine.
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