CN106806897A - A kind of magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted and preparation method thereof - Google Patents
A kind of magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted and preparation method thereof Download PDFInfo
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Abstract
The invention discloses magnetic/functionalized tungsten disulfide pharmaceutical carrier of a kind of folate-targeted and preparation method thereof.The present invention passes through chemical coprecipitation by MFe first2O4(M=Fe, Co and Ni) magnetic nano-particle modification on tungsten disulfide nano slices surface, then magnetic tungsten disulfide nano slices are carried out with amino functional to be modified, then targeting modification is carried out to it using the reaction that carboxyl and amino form amido link by targeting biological molecules of folic acid, final load antineoplastic is prepared from, the present invention has operating process controllable, reaction condition is gently easy to the advantage of large-scale production, invention significantly improves the drugloading rate of antineoplastic, blood halflife and mean residence time, the drug delivery system based on the nano composite material can be targeted to up to and be enriched in lesions position simultaneously, medicine slowly discharges and intelligence is controllable, antineoplastic toxic and side effect is reduced so as to reach, improve the drug concentration of diseased region and the purpose of enhancing antitumor curative effect.
Description
Technical field
The present invention relates to new drug carrier field, more particularly to a kind of folate-targeted is magnetic/functionalized
Tungsten disulfide pharmaceutical carrier and preparation method thereof.
Background technology
Cancer is just increasingly becoming the major disease of harm human health most serious.According to world health group
(WHO) report is knitted, whole world new cancer cases in 2012 and death respectively reach 1400
Ten thousand and 8,200,000, wherein the new diagnosis cases of cancer of China is 3,070,000, the 21.8% of global sum is accounted for,
Number of cancer deaths about 2,200,000, account for the 26.9% of global number of cancer deaths.Basic research
With the key link and effective means that effectively treatment is considered as healing cancer.Put with traditional
Treat, chemotherapy is compared with operative treatment, target medicine carrier has high selectivity to tumour cell,
Toxic and side effect over the course for the treatment of to normal cell is small, it is considered to be fight cancer is maximally effective
One of method.
From Andre Geim and Konstantin Novoselov grinding because of Graphene in 2010
Since studying carefully acquisition Nobel Prize in physics, class Graphene transient metal sulfide MS2(M=Mo,
W, Nb and Ta etc.) extensive concern of people is received because of its unique physicochemical properties.Its
In, individual layer tungsten disulfide has unique lamellar structure, big specific surface area and significant electronics
Characteristic, shows wide application in terms of catalyst, field-effect transistor and lithium ion battery
Space, but it is also more rare in the research report of biomedical sector.Tungsten disulfide has and stone
Close-packed hexagonal structure as black alkenes, layer is connected with interlayer by weak Van der Waals force, and can
Prepared with by simple liquid phase stripping method, ultrasonic wave added stripping method or lithium ion intercalation stripping method
Go out the individual layer of stabilization or the tungsten disulfide dispersion liquid of few layer, this is applied to for tungsten disulfide nano slices
Biomedical sector has established important foundation.Additionally, Teo et al. uses WST-8 methods and MTT
Method have studied toxic effect of the tungsten disulfide nano slices to people's alveolar epithelial cells (A549).As a result
Show, A549 cells still keep 80% after cultivating 24h in 400 μ g/mL of sample Cmax
Cell survival rate above, it was demonstrated that individual layer tungsten disulfide is under sample concentration high to A549 cells
Still show low cytotoxicity.Importantly, tungsten disulfide has big specific surface area, knot
Close good aqueous dispersion and low cytotoxicity makes it be in terms of high potency drugs carrier
Reveal good application prospect, this viewpoint is by the Advanced Materials phases in 2014
The polyethylene glycol functionalization tungsten disulfide nano slices that Kan Shangliu village seminar reports first are applied to
The phototherapy of tumour and the research work of chemotherapy are confirmed.
Although current pharmaceutical carrier is improving drug solubility and extension blood circulation time etc.
Aspect achieves important progress, but targets inefficiency, drugloading rate deficiency, bio-compatible
Property not enough and lack controlled release significantly limit target medicine carrier in field of cancer treatment
Further apply.It is contemplated that passing through chemical coprecipitation by MFe2O4(M=Fe, Co
And Ni) magnetic nano-particle modification on tungsten disulfide nano slices surface, then to magnetic curing
Tungsten nanometer sheet carries out amino functional and is modified, and then utilizes carboxyl by targeting biological molecules of folic acid
The reaction for forming amido link with amino carries out targeting modification, the functionalization tungsten disulfide of preparation to it
Nanometer sheet not only has targeting efficiency and antineoplastic load capacity high high, and can be real
When follow the trail of the treatment effect of medicine transport in vivo and distribution and assessment medicine to disease, this
There is important theory significance and clinical valency for effective treatment of cancer and other major diseases
Value.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of magnetic/functionalized two sulphur of folate-targeted
Change tungsten pharmaceutical carrier and preparation method thereof, it is intended to by equal on individual layer tungsten disulfide nano slices surface
Even modification particle diameter is the MFe of 4-15nm2O4(M=Fe, Co and Ni) magnetic nano-particle,
Then magnetic tungsten disulfide nano slices are carried out with amino functional to be modified, then using carboxyl and ammonia
Folic acid is connected to magnetic/functionalized tungsten disulfide nano slices by the reaction that base forms amido link, is finally born
Carrying anti-tumor model drug is prepared from, and preparation technology is controllable, reaction condition is gentle and beneficial to rule
Modelling is produced, and the obtained magnetic/functionalized tungsten disulfide medicament carrier system of folate-targeted has good
Aqueous dispersion, excellent structural stability and antineoplastic load capacity high, the target
Antibody-antigene phase strong between folic acid and cancer-cell surface receptors is utilized to medicament carrier system
Interaction, the functionalization tungsten disulfide that will load antineoplastic is special by endocytosis
Property be transported in the middle of cancer cell, so as to realize that lower drug targeting release and treatment is instructed in magnetic resonance imaging
Effect real-time assessment.
In order to solve the above technical problems, the technical solution used in the present invention is：A kind of folic acid target
To magnetic/functionalized tungsten disulfide pharmaceutical carrier, it is characterised in that：Including tungsten disulfide nano slices,
MFe of the uniform modification on tungsten disulfide nano slices surface2O4Magnetic nano-particle, by acid amides into
Key is acted on and by MFe2O4Magnetic/functionalized tungsten disulfide nano slices after magnetic nano-particle modification
Surface connection folate-targeted molecule, and company is supported on by physical absorption and hydrogen bond action
It is connected to antitumor on the magnetic/functionalized tungsten disulfide nano slices of the folate-targeted of folate-targeted molecule
Model drug, wherein MFe2O4The M of magnetic nano-particle is in Fe, Co, Ni element
Kind.
Further technical scheme is that the tungsten disulfide nano slices thickness is 0.3-1.5nm,
Its size is 0.5-5 μm, the MFe2O4A diameter of 4-15nm of nano-particle, its shape
It is spherical or hexahedron shape.
Further technical scheme is that described antitumor model medicine is cis-platinum, carboplatin,
PTX, taxol, camptothecine, 5 FU 5 fluorouracil, epirubicin, gemcitabine, the third kappa
Hydrazine, endoxan, daunorubicin, mitomycin, plicamycin, daunomycin, hydrochloric acid Ah
One or more in mycin.
Further technical scheme is, a kind of described magnetic/functionalized tungsten disulfide of folate-targeted
The preparation method of pharmaceutical carrier, it is characterised in that：Comprise the following steps：
(1) preparation of magnetic/functionalized tungsten disulfide nano slices
By in tungsten disulphide powder addition deionized water, sonic oscillation 0.5-12h will be proportional
The trivalent iron salt and divalence M salt of metering are dissolved completely in deionized water, will with nitrogen bubbling law
It is warming up to 60 DEG C after stirring, alkaline conditioner is gradually added dropwise makes the pH value of reaction system be
10-14,90 DEG C are heated to after reaction 0.5-2h, continue to react 1-4h, are added and curing
Amino modified dose of the proportional metering of tungsten nanometer sheet, mechanical agitation or sonic oscillation 1-4h, its
Product absolute ethyl alcohol alcohol is washed three times, centrifugation, is placed in vacuum drying chamber and is dried
24h, obtains magnetic/functionalized tungsten disulfide nano slices；
(2) preparation of the magnetic/functionalized tungsten disulfide nano slices of folate-targeted
Magnetic/functionalized tungsten disulfide nano slices are scattered in 2- (N- morpholines) ethyl sulfonic acid cushioning liquid
In, add mechanical agitation after the catalyst of metering proportional to magnetic/functionalized tungsten disulfide nano slices
Or sonic oscillation 0.5-1h, it is subsequently added into meter proportional to magnetic/functionalized tungsten disulfide nano slices
The folic acid of amount, mechanical agitation or sonic oscillation 6-24h in nitrogen atmosphere at 30 DEG C, its reaction
Product absolute ethyl alcohol alcohol is washed three times, centrifugation, and vacuum drying 24h obtains final product folate-targeted magnetic
Functionalization tungsten disulfide nano slices；
(3) preparation of the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted
By the magnetic/functionalized tungsten disulfide nano slices of the folate-targeted of proportional metering and antineoplastic
Thing is scattered in PBS, mechanical agitation or ultrasound in nitrogen atmosphere at 30 DEG C
Vibration 4-24h, its product is flushed three times with PBS, centrifugation, very
Sky dries 24h and obtains final product the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted.
Further technical scheme is, the folate-targeted molecule and magnetic/functionalized tungsten disulfide
The mass ratio of nanometer sheet is 1:2-1:6, the antineoplastic and folate-targeted magnetic/functionalized two
The mass ratio of tungsten sulfide nanometer sheet is 1:1-1:5.
Further technical scheme is that amino modified dose used in the step (1) is
γ aminopropyltriethoxy silane, γ-aminoethylaminopropyl trimethoxy silane, the Guangs of L- half
One kind in propylhomoserin, polymethylene acid amides, poly- ethyleneimine or poly-asparagine, wherein tungsten disulfide
Nanometer sheet and amino modified dose of mass ratio are 1:1-20:1.
Further technical scheme is that the trivalent iron salt used in the step (1) is iron
Nitrate, chloride, sulfate, oxalates, acetate, nitrate hydrate, chlorination
One kind in thing hydrate, sulfate hydrate, oxalic acid salt hydrate, acetic acid salt hydrate,
The divalence M salt for being used is the nitrate of M, chloride, sulfate, oxalates, acetate,
Nitrate hydrate, chloride hydrates, sulfate hydrate, oxalic acid salt hydrate, acetic acid
One or more in salt hydrate, the mol ratio of wherein trivalent iron salt and divalence M salt is
1:0.5-1:1.9。
Further technical scheme is also resided in, and the catalyst used in the step (2) is N,
N'- Dicyclohexylcarbodiimides, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
/ N- hydroxysuccinimides, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
The mass ratio of the one kind in/DMAP, wherein tungsten disulfide nano slices and catalyst
It is 1:1-10:1.
It is using the beneficial effect produced by above-mentioned technical proposal：The present invention has operating process
Controllable, reaction condition is gently easy to the advantage of large-scale production；The present invention is common by chemistry first
The precipitation method are by MFe2O4The modification of (M=Fe, Co and Ni) magnetic nano-particle is received in tungsten disulfide
Magnetic tungsten disulfide nano slices are then carried out amino functional and are modified by rice piece surface, then with
Folic acid is that targeting biological molecules carry out target using the reaction that carboxyl and amino form amido link to it
To modification, final load antitumor model medicine preparation is formed；Invention significantly improves nanometer
The drugloading rate of piece, blood halflife and mean residence time, while being based on the nano composite material
Drug delivery system can be targeted to up to and be enriched in lesions position, medicine slowly discharges and intelligence
Can be controllable, so as to reach reduce antineoplastic toxic and side effect, the medicine that improves diseased region it is dense
The purpose of degree and improvement treatment effect.
Brief description of the drawings
The present invention is further detailed explanation with reference to the accompanying drawings and detailed description.
Fig. 1 is the transmission electron microscope picture of the magnetic/functionalized tungsten disulfide of folate-targeted prepared by the present invention；
Fig. 2 is the X-ray diffraction of the magnetic/functionalized tungsten disulfide of folate-targeted prepared by the present invention
Figure；
Fig. 3 is the hysteresis curve of the magnetic/functionalized tungsten disulfide of folate-targeted prepared by the present invention；
Fig. 4-a are the drugloading rates of the magnetic/functionalized tungsten disulfide of folate-targeted prepared by the present invention；
Fig. 4-b are the insoluble drug releases of the magnetic/functionalized tungsten disulfide of folate-targeted prepared by the present invention
Curve map；
Fig. 5 is the cytotoxicity number of the magnetic/functionalized tungsten disulfide of folate-targeted prepared by the present invention
According to figure.
Specific embodiment
With reference to the accompanying drawing in the embodiment of the present invention, to the technical scheme in the embodiment of the present invention
It is clearly and completely described, it is clear that described embodiment is only one of the invention
Divide embodiment, rather than whole embodiments.Based on the embodiment in the present invention, this area is general
The every other embodiment that logical technical staff is obtained under the premise of creative work is not made,
Belong to the scope of protection of the invention.
Many details are elaborated in the following description in order to fully understand the present invention, but
It is that the present invention can also be different from other manner described here to implement using other, this area
Technical staff can be similar popularization, therefore the present invention in the case of without prejudice to intension of the present invention
Do not limited by following public specific embodiment.
The present invention includes tungsten disulfide nano slices, uniformly modifies on tungsten disulfide nano slices surface
MFe2O4Magnetic nano-particle, is acted on and by MFe by acid amides bonding2O4Magnetic nano-particle is repaiied
The folate-targeted molecule of the surface connection of the magnetic/functionalized tungsten disulfide nano slices after decorations, Yi Jitong
Cross physical absorption and hydrogen bond action is supported on the folate-targeted magnetic work(for being connected with folate-targeted molecule
The antitumor model medicine on tungsten disulfide nano slices, wherein MFe can be changed2O4Magnetic nano-particle
M be the one kind in Fe, Co, Ni element.
Wherein, tungsten disulfide nano slices thickness is 0.3-1.5nm, and its size is 0.5-5 μm,
MFe2O4A diameter of 4-15nm of magnetic nano-particle, it is shaped as spherical or hexahedron shape.
Its preparation method comprises the following steps：
(1) preparation of magnetic/functionalized tungsten disulfide nano slices
By in tungsten disulphide powder addition deionized water, sonic oscillation 0.5-12h will be proportional
The trivalent iron salt and divalence M salt of metering are dissolved completely in deionized water, will with nitrogen bubbling law
It is warming up to 60 DEG C after stirring, alkaline conditioner is gradually added dropwise makes the pH value of reaction system be
10-14, is heated to 90 DEG C after reaction 0.5-2h, continuation reaction 1-4h is made tungsten disulfide and receives
Rice piece, adds amino modified dose of proportional to tungsten disulfide nano slices metering, mechanical agitation or
Sonic oscillation 1-4h, its product absolute ethyl alcohol alcohol is washed three times, and centrifugation is placed in
24h is dried in vacuum drying chamber, magnetic/functionalized tungsten disulfide nano slices are obtained；
Wherein, trivalent iron salt is nitrate, chloride, sulfate, oxalates, the acetic acid of iron
Salt, nitrate hydrate, chloride hydrates, sulfate hydrate, oxalic acid salt hydrate,
One kind in acetic acid salt hydrate, the divalence M salt for being used is the nitrate of M, chloride,
Sulfate, oxalates, acetate, nitrate hydrate, chloride hydrates, sulfuric acid salt solution
One or more in compound, oxalic acid salt hydrate, acetic acid salt hydrate, wherein trivalent iron salt
It is 1 with the mol ratio of divalence M salt:0.5-1:1.9.
Amino modified dose is γ aminopropyltriethoxy silane, γ-aminoethylaminopropyl front three
In TMOS, Cys, polymethylene acid amides, poly- ethyleneimine or poly-asparagine one
Kind, wherein tungsten disulfide nano slices and amino modified dose of mass ratio are 1:1-20:1.
(2) preparation of the magnetic/functionalized tungsten disulfide nano slices of folate-targeted
The magnetic/functionalized tungsten disulfide nano slices and folic acid of proportional metering are scattered in 2- (N-
Quinoline) in ethyl sulfonic acid cushioning liquid, add the catalyst of metering proportional to tungsten disulfide nano slices
Mechanical agitation or sonic oscillation 0.5-1h, are subsequently added into proportional to tungsten disulfide nano slices afterwards
The folic acid of metering (please determine material and the quantity for this time being added, if with addition for the first time
Amount it is the same, which kind of relation both have), mechanical agitation or ultrasound in nitrogen atmosphere at 30 DEG C
Vibration 6-24h, its product absolute ethyl alcohol alcohol is washed three times, centrifugation, vacuum drying
24h obtains final product the magnetic/functionalized tungsten disulfide nano slices of folate-targeted；
Wherein, folic acid and the mass ratio of magnetic/functionalized tungsten disulfide nano slices are 1:2-1:6,
(3) preparation of the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted
By the magnetic/functionalized tungsten disulfide nano slices of the folic acid of proportional metering and antineoplastic point
Dissipate in PBS, mechanical agitation or sonic oscillation in nitrogen atmosphere at 30 DEG C
4-24h, its product is flushed three times with PBS, centrifugation, and vacuum is done
Dry 24h obtains final product the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted.
Wherein, the mass ratio of antineoplastic and the magnetic/functionalized tungsten disulfide nano slices of folate-targeted
It is 1:1-1:5.
Antitumor model medicine is cis-platinum, carboplatin, PTX, taxol, camptothecine, 5- fluorine urine
Pyrimidine, epirubicin, gemcitabine, procarbazine, endoxan, daunorubicin, mitogen
One or more in mycin, plicamycin, daunomycin, ADMh.
Embodiment 1
(1) preparation of magnetic/functionalized tungsten disulfide nano slices
By in 5.0g commercialization tungsten disulphide powder addition 500mL deionized waters, low-power is placed in
In ultrasonic tank, sonic oscillation 0.5-12h；Add 8.0g FeCl3·6H2O and 2.94g FeCl2·
4H2O, 60 DEG C are warming up to after being stirred for uniformly with nitrogen bubbling law, and 2.5M hydrogen is gradually added dropwise
Sodium hydroxide solution makes pH value of reaction system for 10-14, and 90 DEG C are heated to after reaction 0.5-2h,
Continue to react 1-4h；Add 0.25g γ aminopropyltriethoxy silanes, mechanical agitation or
Sonic oscillation 4-12h, reaction solution is turned with after phosphate buffer ultrasonic disperse in 4000r/min
The lower centrifugation of speed, its product absolute ethyl alcohol alcohol is washed three times, is placed in vacuum drying chamber
24h is dried, magnetic/functionalized tungsten disulfide nano slices are obtained；
(2) preparation of the magnetic/functionalized tungsten disulfide nano slices of folate-targeted
The magnetic/functionalized tungsten disulfide nano slices of 0.5g are scattered in into 2- (N- morpholines) ethyl sulfonic acid to delay
Rush in solution, mechanical agitation or ultrasound are shaken after addition 0.5g N, N'- Dicyclohexylcarbodiimides
0.5-1h is swung, 0.1g folic acid is subsequently added into, the mechanical agitation or super in nitrogen atmosphere at 30 DEG C
Sound oscillation 6-24h, reaction solution is turned with after PBS ultrasonic disperse in 4000r/min
The lower centrifugation of speed, its product absolute ethyl alcohol alcohol is washed three times, and vacuum drying 24h is obtained final product
The magnetic/functionalized tungsten disulfide nano slices of folate-targeted.
(3) preparation of the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted
By the magnetic/functionalized tungsten disulfide nano slices of 250mg folate-targeteds and 2.5mg antineoplastics
ADMh is scattered in PBS, and machinery is stirred in nitrogen atmosphere at 30 DEG C
Mix or sonic oscillation 4-24h, reaction solution with after phosphate buffer ultrasonic disperse
Centrifugation under 4000r/min rotating speeds, its product is flushed three times with PBS,
Vacuum drying 24h obtains final product the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted.
Embodiment 2
(1) preparation of magnetic/functionalized tungsten disulfide nano slices
By in 5.0g commercialization tungsten disulphide powder addition 500mL deionized waters, low-power is placed in
In ultrasonic tank, sonic oscillation 0.5-12h；Add 8.0g FeCl3·6H2O and 4.85g C DEG C l2·
6H2O, 60 DEG C are warming up to after being stirred for uniformly with nitrogen bubbling law, and 2.5M hydrogen is gradually added dropwise
Sodium hydroxide solution makes pH value of reaction system for 10-14, and 90 DEG C are heated to after reaction 0.5-2h,
Continue to react 1-4h；Add 0.25g γ aminopropyltriethoxy silanes, mechanical agitation or
Sonic oscillation 4-12h, reaction solution is turned with after phosphate buffer ultrasonic disperse in 4000r/min
The lower centrifugation of speed, its product absolute ethyl alcohol alcohol is washed three times, is placed in vacuum drying chamber
24h is dried, magnetic/functionalized tungsten disulfide nano slices are obtained.
(2) preparation of the magnetic/functionalized tungsten disulfide nano slices of folate-targeted
The magnetic/functionalized tungsten disulfide nano slices of 0.5g are scattered in into 2- (N- morpholines) ethyl sulfonic acid to delay
Rush in solution, mechanical agitation or ultrasound are shaken after addition 0.5g N, N'- Dicyclohexylcarbodiimides
0.5-1h is swung, 0.1g folic acid is subsequently added into, the mechanical agitation or super in nitrogen atmosphere at 30 DEG C
Sound oscillation 6-24h, reaction solution with after phosphate buffer ultrasonic disperse in 4000r/min rotating speeds
Lower centrifugation, its product absolute ethyl alcohol alcohol is washed three times, and vacuum drying 24h obtains final product leaf
The magnetic/functionalized tungsten disulfide nano slices of acid targeting.
(3) preparation of the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted
By the magnetic/functionalized tungsten disulfide nano slices of 250mg folate-targeteds and 2.5mg antineoplastics
ADMh is scattered in PBS, and machinery is stirred in nitrogen atmosphere at 30 DEG C
Mix or sonic oscillation 4-24h, then reaction solution with after phosphate buffer ultrasonic disperse
Centrifugation under 4000r/min rotating speeds, its product is flushed three times with PBS,
Vacuum drying 24h obtains final product the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted.
Embodiment 3
(1) preparation of magnetic/functionalized tungsten disulfide nano slices
By in 5.0g commercialization tungsten disulphide powder addition 500mL deionized waters, low-power is placed in
In ultrasonic tank, sonic oscillation 0.5-12h；Add 8.0g FeCl3·6H2O and 3.52g NiCl2·
6H2O, 60 DEG C are warming up to after being stirred for uniformly with nitrogen bubbling law, and 2.5M hydrogen is gradually added dropwise
Sodium hydroxide solution makes pH value of reaction system for 10-14, and 90 DEG C are heated to after reaction 0.5-2h,
Continue to react 1-4h；Add 0.25g γ aminopropyltriethoxy silanes, mechanical agitation or
Sonic oscillation 4-12h, reaction solution is turned with after phosphate buffer ultrasonic disperse in 4000r/min
The lower centrifugation of speed, its product absolute ethyl alcohol alcohol is washed three times, is placed in vacuum drying chamber
24h is dried, magnetic/functionalized tungsten disulfide nano slices are obtained；
(2) preparation of the magnetic/functionalized tungsten disulfide of folate-targeted
The magnetic/functionalized tungsten disulfide nano slices of 0.5g are scattered in into 2- (N- morpholines) ethyl sulfonic acid to delay
Rush in solution, mechanical agitation or ultrasound are shaken after addition 0.5g N, N'- Dicyclohexylcarbodiimides
0.5-1h is swung, 0.1g folic acid is subsequently added into, the mechanical agitation or super in nitrogen atmosphere at 30 DEG C
Sound oscillation 6-24h, reaction solution with after phosphate buffer ultrasonic disperse in 4000r/min rotating speeds
Lower centrifugation, its product absolute ethyl alcohol alcohol is washed three times, and vacuum drying 24h obtains final product leaf
The magnetic/functionalized tungsten disulfide nano slices of acid targeting.
(3) preparation of the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted
By the magnetic/functionalized tungsten disulfide nano slices of 250mg folate-targeteds and 2.5mg antineoplastics
ADMh is scattered in PBS, and machinery is stirred in nitrogen atmosphere at 30 DEG C
Mix or sonic oscillation 4-24h, reaction solution with after phosphate buffer ultrasonic disperse
Centrifugation under 4000r/min rotating speeds, its product is flushed three times with PBS,
Vacuum drying 24h obtains final product the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted.
The performance characterization of the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted：
Fig. 1 is the transmission electron microscope picture that the Folic Acid of embodiment 1 targets magnetic/functionalized tungsten disulfide.From
Visible in figure, the tungsten disulfide nano slices of several near-transparents are completely exfoliated, and do not pile up freely and layer
The generation of folded phenomenon.The average-size of ferriferrous oxide nano-particle is received between 4-15nm
Rice corpuscles is equably modified on the surface of tungsten disulfide nano slices, has not seen serious agglomeration and freedom
Be scattered particle.
Fig. 2 is the x-ray diffraction pattern that the Folic Acid of embodiment 1 targets magnetic/functionalized tungsten disulfide
Spectrum.Can be observed from figure, 2 θ=29.7 °, 35.4 °, 42.8 °, 53.4 °,
Occur strong and sharp characteristic diffraction peak at 56.8 ° and 62.3 °, four oxidations are corresponded to respectively
(220), (311), (400), (422), (511) and (440) crystal face in three-iron standard card
(JCPDS No.22-1086).Additionally, the magnetic/functionalized tungsten disulfide of folate-targeted manifests substantially
Go out ferroso-ferric oxide characteristic diffraction peak and do not observe tungsten disulfide diffraction maximum, this is mainly
Because during chemical reaction, ferriferrous oxide nano-particle is in tungsten disulfide nano slices table
The attachment and growth in face destroy the ordered stacks of tungsten disulfide nano slices layer, cause tungsten disulfide
Nanometer sheet is in unordered exfoliated state in compound system.
Fig. 3 is the hysteresis curve figure that the Folic Acid of embodiment 1 targets magnetic/functionalized tungsten disulfide.
It can be seen that not occurring on the magnetization curve of the folate-targeted magnetic tungsten disulfide for preparing substantially
Hysteresis curve, remanent magnetism and coercivity be substantially zeroed, shows that the folate-targeted for obtaining is magnetic/functionalized
Tungsten disulfide has superparamagnetism at room temperature, and saturation magnetization is 62.7emu/g.
Fig. 4-a and 4-b be embodiment 1 in ADMh DOX be model drug folic acid target
To the drugloading rate and drug release patterns figure of magnetic/functionalized tungsten disulfide.It can be seen that preparing
The drugloading rate of the magnetic/functionalized tungsten disulfide of folate-targeted there is concentration dependent, saturation drugloading rate
Reach 0.71mg/mg.Additionally, the insoluble drug release behavior of the nano composite material for preparing is presented prominent
Two stages are released and are sustained, there is different cumulative release amounts under different pH environments,
Typical pH sensitivities release characteristics are showed, shows magnetic/functionalized two sulphur of folate-targeted for preparing
It is a kind of good intellectual drug carrier to change tungsten.
Fig. 5 is the MTT cytotoxicities that the Folic Acid of case study on implementation 1 targets magnetic/functionalized tungsten disulfide
Datagram.It can be seen that MG-63 cells are in the sample that Cmax is 150 μ g/mL point
After being incubated 24h in dispersion liquid, its cell survival rate drops to 15%, it was demonstrated that the folic acid target of preparation
To magnetic/functionalized tungsten disulfide there is obvious cancer cell to kill effect, this is further clinic
Early diagnosis of tumor and treatment provide theoretical reference.
Claims (8)
1. the magnetic/functionalized tungsten disulfide pharmaceutical carrier of a kind of folate-targeted, it is characterised in that：Bag
Tungsten disulfide nano slices are included, MFe of the uniform modification on tungsten disulfide nano slices surface2O4Magnetic is received
Rice corpuscles, is acted on and by MFe by acid amides bonding2O4Magnetic function after magnetic nano-particle modification
Change the folate-targeted molecule of the surface connection of tungsten disulfide nano slices, and by physical absorption and
Hydrogen bond action is supported on the magnetic/functionalized tungsten disulfide of folate-targeted for being connected with folate-targeted molecule
Antitumor model medicine in nanometer sheet, wherein MFe2O4The M of magnetic nano-particle be Fe, Co,
One kind in Ni elements.
2. the magnetic/functionalized tungsten disulfide medicine of a kind of folate-targeted according to claim 1
Carrier, it is characterised in that：The tungsten disulfide nano slices thickness is 0.3-1.5nm, its size
It is 0.5-5 μm, the MFe2O4A diameter of 4-15nm of magnetic nano-particle, it is shaped as
Spherical or hexahedron shape.
3. the magnetic/functionalized tungsten disulfide medicine of a kind of folate-targeted according to claim 1
Carrier, it is characterised in that：Described antitumor model medicine is cis-platinum, carboplatin, PTX, purple
China fir alcohol, camptothecine, 5 FU 5 fluorouracil, epirubicin, gemcitabine, procarbazine, ring phosphorus
In acid amides, daunorubicin, mitomycin, plicamycin, daunomycin, ADMh
One or more.
4. a kind of folate-targeted magnetic work(according to claim 1-3 any one claims
The preparation method of tungsten disulfide pharmaceutical carrier can be changed, it is characterised in that：Comprise the following steps：
(1) preparation of magnetic/functionalized tungsten disulfide nano slices
By in tungsten disulphide powder addition deionized water, sonic oscillation 0.5-12h will be proportional
The trivalent iron salt and divalence M salt of metering are dissolved completely in deionized water, will with nitrogen bubbling law
It is warming up to 60 DEG C after stirring, alkaline conditioner is gradually added dropwise makes the pH value of reaction system be
10-14,90 DEG C are heated to after reaction 0.5-2h, continue to react 1-4h, are added and curing
Amino modified dose of the proportional metering of tungsten nanometer sheet, mechanical agitation or sonic oscillation 1-4h, its
Product absolute ethyl alcohol alcohol is washed three times, centrifugation, is placed in vacuum drying chamber and is dried
24h, obtains magnetic/functionalized tungsten disulfide nano slices；
(2) preparation of the magnetic/functionalized tungsten disulfide nano slices of folate-targeted
Magnetic/functionalized tungsten disulfide nano slices are scattered in 2- (N- morpholines) ethyl sulfonic acid cushioning liquid
In, add mechanical agitation after the catalyst of metering proportional to magnetic/functionalized tungsten disulfide nano slices
Or sonic oscillation 0.5-1h, it is subsequently added into meter proportional to magnetic/functionalized tungsten disulfide nano slices
The folic acid of amount, mechanical agitation or sonic oscillation 6-24h in nitrogen atmosphere at 30 DEG C, its reaction
Product absolute ethyl alcohol alcohol is washed three times, centrifugation, and vacuum drying 24h obtains final product folate-targeted magnetic
Functionalization tungsten disulfide nano slices；
(3) preparation of the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted
By the magnetic/functionalized tungsten disulfide nano slices of the folate-targeted of proportional metering and antineoplastic
Thing is scattered in PBS, mechanical agitation or ultrasound in nitrogen atmosphere at 30 DEG C
Vibration 4-24h, its product is flushed three times with PBS, centrifugation, very
Sky dries 24h and obtains final product the magnetic/functionalized tungsten disulfide pharmaceutical carrier of folate-targeted.
5. the magnetic/functionalized tungsten disulfide medicine of a kind of folate-targeted according to claim 4
Carrier, it is characterised in that：The folic acid is with the mass ratio of magnetic/functionalized tungsten disulfide nano slices
1:2-1:6, the matter of the antineoplastic and the magnetic/functionalized tungsten disulfide nano slices of folate-targeted
Amount is than being 1:1-1:5.
6. the magnetic/functionalized tungsten disulfide medicine of a kind of folate-targeted according to claim 4
The preparation method of carrier, it is characterised in that：Amino modified dose used in the step (1)
It is γ aminopropyltriethoxy silane, γ-aminoethylaminopropyl trimethoxy silane, L-
One kind in cysteine, polymethylene acid amides, poly- ethyleneimine or poly-asparagine, wherein two sulphur
It is 1 to change tungsten nanometer sheet and amino modified dose of mass ratio:1-20:1.
7. the magnetic/functionalized tungsten disulfide medicine of a kind of folate-targeted according to claim 4
The preparation method of carrier, it is characterised in that：Trivalent iron salt used in the step (1) is
The nitrate of iron, chloride, sulfate, oxalates, acetate, nitrate hydrate, chlorine
One kind in compound hydrate, sulfate hydrate, oxalic acid salt hydrate, acetic acid salt hydrate,
The divalence M salt for being used is the nitrate of M, chloride, sulfate, oxalates, acetate,
Nitrate hydrate, chloride hydrates, sulfate hydrate, oxalic acid salt hydrate, acetic acid
One or more in salt hydrate, the mol ratio of wherein trivalent iron salt and divalence M salt is
1:0.5-1:1.9。
8. the magnetic/functionalized tungsten disulfide medicine of a kind of folate-targeted according to claim 4
The preparation method of carrier, it is characterised in that：Catalyst used in the step (2) is N,
N'- Dicyclohexylcarbodiimides, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
/ N- hydroxysuccinimides, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
One kind in/DMAP, wherein magnetic/functionalized tungsten disulfide nano slices and catalyst
Mass ratio be 1:1-10:1.
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Citations (3)
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|---|---|---|---|---|
| CN101940791A (en) * | 2010-08-27 | 2011-01-12 | 天津医科大学 | Dually-targeted pH-sensitive antineoplastic drug carrier material as well as preparation and application thereof |
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2015
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|---|---|---|---|---|
| CN101940791A (en) * | 2010-08-27 | 2011-01-12 | 天津医科大学 | Dually-targeted pH-sensitive antineoplastic drug carrier material as well as preparation and application thereof |
| CN103705928A (en) * | 2013-12-27 | 2014-04-09 | 中国科学院高能物理研究所 | Single-layer MoS2 nano-chip, preparation method and nano-drug carrier |
| CN104587495A (en) * | 2014-12-30 | 2015-05-06 | 东华大学 | MRI (magnetic resonance imaging)-guided targeted photo-thermal agent and preparation method of chemotherapeutic system of MRI-guided targeted photo-thermal agent |
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