CN105079814B - A kind of realgar of modified with folic acid-mesoporous monox nanometer combination drug - Google Patents
A kind of realgar of modified with folic acid-mesoporous monox nanometer combination drug Download PDFInfo
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Abstract
For nanometer-size realgar, to normal cell, there is also this defects of certain toxic side effect, the present invention modifies folic acid in mesoporous monox nanometer particle surface, realgar is loaded again, it is intended to improve its active targeting in vivo, and in particular to a kind of realgar mesoporous monox nanometer combination drug of modified with folic acid and preparation method thereof.The volume ratio that the present invention passes through investigation ethylenediamine and water, the concentration of realgar ethylenediamine solution, carrier amount and load time are found, the mesoporous monox nanometer particle of modified with folic acid has realgar certain load capacity, form the realgar mesoporous monox nanometer combination drug of modified with folic acid, and its pattern and structure do not occur significantly to change, but it targets characteristic and need to also be verified further across In vitro cell experiment.
Description
Technical field
The invention patent relates to mesoporous material preparation and technical field of medicine, and in particular to a kind of hero of modified with folic acid
Huang-mesoporous monox nanometer combination drug and preparation method thereof.
Background technology
Mineral drug realgar (Realgar) is the Chinese medicine that applicating history is long in traditional Chinese medicine, is loaded in earliest《Legendary god of farming's book on Chinese herbal medicine
Through》, main component is Red Arsenic Glass (As4S4), and it is mingled with a small amount of arsenic (As2O3) and other heavy metallic salts, for solving poisoning
Worm, eliminating dampness remove phlegm, preventing malaria etc..Since the 1950s, domestic many scholars by containing realgar compound preparation or single it is male
Huang achieves fine curative effect for the tumour of clinical treatment hematological system and the tumour at other positions of human body.And due to its poison
Property be less than arsenic injection, realgar be proposed as treatment acute promyelocytic leukemia (APL) second-line chemotherapy medicine (Wu J
Z, Shao Y B, Liu J L, et al.The medicinal use of realgar (As4S4)and its recent
Development as ananticancer agent [J] .Journal ofEthnopharmacology, 2011,135 (3)：
595-602).Research at present has shown that the mechanism of realgar antitumor action is inducing cell apoptosis, Cell differentiation inducing activity, inhibits nucleic acid
It synthesizes, as (progress [J] of the quick realgars of Liu Rong, Pu moral such as vascular endothelial cell inhibitor and direct cytotoxicity
When treasure's traditional Chinese medical science traditional Chinese medicines, 2007,18 (4)：982-984).But realgar is sulfide-based mineral, is insoluble in water and major part is organic
Solvent always exists the problems such as oral dose is big, genotoxic potential is big in current clinical application.
Realgar grain size is reduced to that micro-, nano-scale dimension is horizontal by the micronization technologies such as generally use air-flow and ball milling at present,
Its bioavilability is improved, but these existing methods still have many disadvantages, such as：Grain size is difficult to control, stability is poor, water
Dissolubility is poor, oxidation easily occurs and reunites etc..(Yang X L, Xu H B, Ye H Q, the et al.Nanometer such as Yang Xiangliang
realgar solid dispersion and its preparation method：China, CN1478486 [P] .2004-
03-03) using nanometer-size realgar as active constituent, using high molecular polymer as carrier, antioxidant and surfactant is added, is passed through
Fusion method and solvent evaporation method are prepared for nanometer realgar solid dispersion, solve oxidation and the agglomeration traits of nanometer-size realgar.Shen
Bright equal (Shen X C, Liang H, Chen Y, et al.Method for preparing the nanometer realgar of star
gel and nanometer realgar with biomacromolecule template to regulate shape
and particle thereof：China, CN100374463C [P] .2008-03-12) chemical method is used, with large biological molecule
Regulate and control the nanometer-size realgar of pattern and grain size obtained different-shape and grain size for template.However nanometer-size realgar prepared by the above method exists
Also there is certain toxic side effect to normal cell while killing tumour cell.
All there is overexpression (Morelli C, Maris P, Sisci on most of human body tumour cell in folacin receptor
D, et al.PEG-templated mesoporous silica nanoparticles exclusively target
Cancer cells [J] .Nanoscale, 2011,3 (8)：3198-3207), therefore, usually by leaf in drug formulation design
Acid is used as active targeting recognition ligand.And mesoporous monox nanometer particle surface meets Zhi Weidian with abundant, is easy to folic acid
Modification, while the carrier has many advantages, such as high load capacity, morphology controllable and low system toxicity (Tang F Q, Li L
L, Chen D.Mesoporous silica nanoparticles：Synthesis, biocompatibility and drug
Delivery [J] .Advanced Materials, 2012,24 (12)：1504-1534), and enable realgar in nanometer level
It is uniformly dispersed in mesoporous chamber, therefore be selected as realgar targeting delivery vehicles there is good feasibility.
Invention content
The invention discloses a kind of mesoporous monox nanometer particles of modified with folic acid, it has bigger serface and hole body
Product, pore-size distribution is narrow, uniform particle sizes and monodispersed spherical morphology, is suitable as pharmaceutical carrier, has in drug delivery field
There is good application prospect.
The mesoporous monox nanometer particle of the modified with folic acid of the present invention can load realgar by physical absorption, form folic acid
The realgar of modification-mesoporous monox nanometer combination drug, it is expected that special by the folacin receptor with tumor cell surface after its intravenous
The opposite sex combines, and selectively accumulates and is phagocytized by cells in tumor locus, reduces toxic side effect of the realgar to normal cell, and real
Now effective therapeutic effect.
To achieve the above object, the technical solution adopted by the present invention is：Using tetraethyl orthosilicate as silicon source, cetyl three
Methyl bromide ammonium is template, and ethyl alcohol is cosolvent, and triethanolamine is that chelating agent under alkaline condition receive by synthesizing mesoporous monox
Rice corpuscles, grafting is in its surface bond aminopropyl after passing through after solvent extraction removes template, then passes through coupling reaction
Folic acid is modified to get to the mesoporous monox nanometer particle of modified with folic acid.Then it is molten realgar to be dissolved in anhydrous ethylenediamine formation cluster
Liquid (As4S4-NH2C2H4NH2), other insoluble mineralogical compositions are centrifuged off, then diluted with deionized water, are configured to a certain concentration
Realgar ethylenediamine solution, high speed vibrate by way of be carried on modified with folic acid mesoporous monox nanometer particle duct
In to get modified with folic acid realgar-mesoporous monox nanometer combination drug.
The building-up process of the realgar of modified with folic acid-mesoporous monox nanometer combination drug is as follows：
Tetraethyl orthosilicate in above-mentioned preparation method: cetyl trimethylammonium bromide: triethanolamine: water: ethyl alcohol rubs
You are than being 1: 0.2~0.3: 0.8~1.0: 130~150: 7.0~13.0.Within this range, by changing tetraethyl orthosilicate
The mesoporous monox nanometer grain of different-grain diameter size can be obtained with the ratio of triethanolamine or tetraethyl orthosilicate and ethyl alcohol
Son.
In the preparation method of realgar-mesoporous monox nanometer compound：Ethylenediamine: the volume ratio of water is 1: 0.33~1: 3,
A concentration of 2~20mg/mL of realgar, carrier amount are 5~20mg, and load time is 0~4 hour.
More preferably preparation method is as follows：
A. at room temperature, appropriate cationic surfactant is weighed to be placed in round-bottomed flask, be added after deionized water in 40~
80 DEG C of heating stirrings, absolute ethyl alcohol and triethanolamine are sequentially added after dissolving, and tetraethyl orthosilicate is added dropwise after stirring evenly,
It is kept for 40~80 DEG C and continues stirring 1~3 hour；
B. reaction mixture is centrifuged, is washed with deionized water to neutrality, then done in 60 DEG C of vacuum after being washed with absolute ethyl alcohol
It is dry；
C. template is removed with hydrochloric ethanol solution, 60 DEG C of vacuum drying obtain mesoporous monox nanometer particle；
D. at room temperature, weigh appropriate mesoporous monox nanometer particle to be placed in round-bottomed flask, absolute ethyl alcohol and stirring point is added
It dissipates, measures after appropriate 3- aminopropyl triethoxysilanes are dissolved in absolute ethyl alcohol and above-mentioned round-bottomed flask is added, it is stirred at room temperature 40~
60 hours；
E. reaction mixture is centrifuged, washs 60 DEG C of vacuum drying of postposition with absolute ethyl alcohol, obtains amidized mesoporous oxygen
SiClx nano-particle；
F. at room temperature, appropriate folic acid is weighed in round-bottomed flask, and dimethyl sulfoxide ultrasonic dissolution is added, sequentially adds N- hydroxyls
Succimide and 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, room temperature are added suitable after being protected from light stirring 1 hour
Amidized mesoporous monox nanometer particle is measured, continues to be protected from light stirring 10~30 hours；
G. reaction mixture is centrifuged, is dried in vacuo after being washed with phosphate buffer, obtain the mesoporous oxygen of modified with folic acid
SiClx nano-particle.
H. realgar is dissolved in anhydrous ethylenediamine, insoluble mineralogical composition is centrifuged off after dissolving, then diluted with deionized water,
Make ethylenediamine: the volume ratio of water is 1: 0.33~1: 3, and the realgar ethylenediamine for being configured to a concentration of 2~20mg/mL of realgar is molten
Liquid；
I. 5~20mg mesoporous monox nanometer particles are weighed to be placed in plastic centrifuge tube, it is molten that above-mentioned realgar ethylenediamine is added
Liquid is placed in high-speed oscillator and vibrates 0~4 hour at room temperature；
J. it centrifuges, is washed with deionized, merge supernatant and be transferred in conical flask and carry out wet digestion, use atom
Fluorescence Spectrometer measures the variation of the front and back arsenic in sample concentration of load, and realgar load capacity is calculated according to standard curve.
K. the mesoporous monox nanometer particle of modified with folic acid is used to replace the mesoporous monox nanometer particle in i, with optimizing
To condition investigate its load capacity to realgar.
The creativeness of the present invention is：
1. silicon species are complexed using triethanolamine in the preparation of the meso pore silicon oxide material in the present invention, the preparation method with
Weak solution method and micro emulsion method are simple compared to building-up process, and yield is high, convenient post-treatment.
2. the spherical morphology of mesoporous monox nanometer particle prepared by the present invention with vermiform duct, uniform particle diameter, about
For 80~100nm, see that Fig. 1, specific surface area and pore volume are respectively 973m2/ g and 1.01cm3/ g has orderly meso-hole structure,
Narrow pore-size distribution is shown in Fig. 2 to Fig. 4, which has more active site, is easy to be modified, while having high
The advantages that load capacity, morphology controllable and low system toxicity, it is suitable as pharmaceutical carrier.
3. mesoporous monox nanometer particle is usually all that load passes as the research hotspot that pharmaceutical carrier is nearly ten years
Molecules like pharmaceuticals are passed, the research of load mineral drug realgar yet there are no document report.The body that the present invention passes through investigation ethylenediamine and water
Product ratio, the concentration of realgar ethylenediamine solution, carrier amount and duration of oscillation find that mesoporous monox nanometer particle has one to realgar
Fixed load capacity is shown in Fig. 6 to Fig. 9, and its pattern and structure do not occur significantly to change, and sees that Figure 10, load capacity are about 8%,
Figure 11 is the energy spectrum analysis figure of realgar-mesoporous monox nanometer compound, and furtherly lucid realgar is carried on Jie in nanometer level
In the silicon oxide nanoparticle of hole, realgar-mesoporous monox nanometer composite medicine of modified with folic acid is formed after its surface modification folic acid
Object, but it targets characteristic and need to also be verified further across In vitro cell experiment.
Description of the drawings
Fig. 1 is transmission electron microscope (TEM) photo for the mesoporous monox nanometer particle that embodiment 1 synthesizes；
Fig. 2 is small angle X-ray diffraction (XRD) collection of illustrative plates for the mesoporous monox nanometer particle that embodiment 1 synthesizes；
Fig. 3 is the nitrogen adsorption-desorption isotherm curve for the mesoporous monox nanometer particle that embodiment 1 synthesizes；
Fig. 4 is the pore size distribution curve for the mesoporous monox nanometer particle that embodiment 1 synthesizes；
Fig. 5 is the infrared spectrogram of the mesoporous monox nanometer particle for the modified with folic acid that embodiment 3 synthesizes；
Fig. 6 is the relation curve of ethylenediamine and water volume ratio and carrying drug ratio in embodiment 4；
Fig. 7 is the relation curve of realgar concentration and carrying drug ratio in embodiment 5；
Fig. 8 is the amount of carrier and the relation curve of carrying drug ratio in embodiment 6；
Fig. 9 is the relation curve of duration of oscillation and carrying drug ratio in embodiment 7；
Figure 10 is transmission electron microscope (TEM) photo of realgar-mesoporous monox nanometer combination drug in embodiment 8；
Figure 11 is energy spectrum analysis (EDX) collection of illustrative plates of realgar-mesoporous monox nanometer combination drug in embodiment 8
Specific implementation mode
Embodiment 1
The synthesis of mesoporous monox nanometer particle
At room temperature, it weighs cetyl trimethylammonium bromide 0.7g to be placed in 50mL round-bottomed flasks, deionized water is added
17.50mL sequentially adds absolute ethyl alcohol 4.00mL and triethanolamine 1.00g, after stirring evenly in 60 DEG C of heating stirrings after dissolving
Tetraethyl orthosilicate 1.50mL is added dropwise, is kept for 60 DEG C continue stirring 2 hours, reaction mixture is centrifuged, deionized water is used
It is washed till neutrality, then washs 60 DEG C of postposition three times with absolute ethyl alcohol and is dried in vacuum overnight.Above-mentioned product 1.0g is weighed in acidic ethanol
In (containing 36% concentrated hydrochloric acid 20mL) 200mL, is centrifuged after flowing back 12 hours in 60 DEG C, 60 DEG C of postposition three times are washed with absolute ethyl alcohol
It is dried in vacuum overnight, obtains mesoporous monox nanometer particle.The nano-particle has the spherical shape of uniform grain size and dispersion
Looks, transmission electron microscope picture are shown in Fig. 1, it is seen that particle diameter distribution is uniform, about 90nm or so.Its small angle X-ray diffraction collection of illustrative plates is shown in Fig. 2,
There is (100) crystal face characteristic diffraction peak in 2 θ=1.91 ° or so, being illustrated with reference to Fig. 1 the nano-particle has orderly mesoporous knot
Structure.Its nitrogen adsorption-desorption collection of illustrative plates is shown in Fig. 3, has typical IV types thermoisopleth.The aperture point being calculated according to BJH models
Cloth curve is shown in that Fig. 4, desorption aperture are 2.37nm.BET and BJH formula are respectively adopted, mesoporous monox nanometer particle is calculated
Specific surface area and pore volume are 973m2/ g and 1.01cm3/g。
Embodiment 2
The synthesis of amidized mesoporous monox nanometer particle
At room temperature, mesoporous monox nanometer particle 0.7g is weighed in 10mL round-bottomed flasks, and absolute ethyl alcohol 2.50mL is added
It is dispersed with stirring, measures 3- aminopropyl triethoxysilanes 1.50mL and be dissolved in 3.00mL absolute ethyl alcohols, above-mentioned round-bottomed flask, room is added
Temperature stirring centrifuges after 48 hours, and washing 60 DEG C of postposition three times with absolute ethyl alcohol is dried in vacuum overnight, and obtains Jie of aminopropyl modification
Hole silicon oxide nanoparticle.The nano-particle elemental analysis result is shown：N, 2.47%；C, 10.70%；H, 3.04%, with Jie
For hole silicon oxide nanoparticle compared to there is nitrogen, infrared spectrogram is shown in Fig. 5,2936cm-1(vC-H) and 1473cm-1(δC-H) inhale
The presence that peak demonstrates propyl is received, further illustrates and aminopropyl has been successfully introduced by rear grafting.
Embodiment 3
The synthesis of the mesoporous monox nanometer particle of modified with folic acid
At room temperature, folic acid 0.2g is weighed in round-bottomed flask, and dimethyl sulfoxide 15.00mL ultrasonic dissolutions are added, sequentially add
N- hydroxysuccinimides 0.1g and 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochloride 0.5g, room temperature, which is protected from light, to be stirred
The amidized mesoporous monox nanometer particles of 50mg are added after mixing 1 hour, continue to be protected from light stirring 20 hours, by reaction mixture from
The heart is washed with the pH phosphate buffers for being 7.00 and is dried in vacuo afterwards three times, obtains the mesoporous monox nanometer grain of modified with folic acid
Son.Its infrared spectrogram is shown in that Fig. 5, curve a are the infrared spectrogram of the mesoporous monox nanometer particle of aminopropyl modification, and b is leaf
The infrared spectrogram of the mesoporous monox nanometer particle of acid modification, c are the infrared spectrogram of folic acid, wherein 1697cm-1(vC=O)
Absorption peak is speculated as the absorption peak of carboxylic acid in folic acid；In 1646cm-1(vC=O)、1424cm-1(vC-N) at newly increased amide respectively
The absorption peak of group；1608cm-1(6N-H) absorption peak speculate may be folic acid in primary amine absorption peak；Between 1508~1608cm-1(vC=C) absorption peak be phenyl ring characteristic absorption peak, further illustrate folic acid be successfully coupled to aminopropyl modification Jie
On the silicon oxide nanoparticle of hole.
Embodiment 4
Investigate the volume ratio of ethylenediamine and water
At room temperature, precision weighs a certain amount of realgar and is dissolved in ethylenediamine, be configured to a concentration of 2.50 respectively, 3.00,4.00,
6.00, the realgar ethylenediamine mother liquor of 8.00mg/mL centrifuges 10 minutes for 12000 revs/min after shaking up, dense from above-mentioned difference respectively
Take 1.50 in the mother liquor of degree, 1.30,1.00,0.70,0.50mL supernatants set in 5mL plastic centrifuge tubes, then be separately added into 0.50,
0.70,1.00,1.30,1.50mL deionized waters so that liquor capacity is 2.00mL in each centrifuge tube, and realgar is final concentration of
2mg/mL.The volume ratio of ethylenediamine and deionized water is respectively 3: 1,2: 1,1: 1,1: 2,1: 3 in five groups of experiments, and every group of experiment is flat
Three parts of row operation.
Precision weighs in 10mg mesoporous monox nanometers particle to above-mentioned centrifuge tube respectively, is placed in high speed at room temperature and vibrates
Device vibrates 30 minutes under the conditions of 1800 revs/min, is then centrifuged 10 minutes at 12000 revs/min, deionization is used in combination respectively
Three times, merging supernatant is transferred in 50mL conical flasks carries out wet digestion to water washing, is transferred to 0.6mol/L hydrochloric acid
It in 100mL measuring bottles, then dilutes step by step, is separately added into 10% thiocarbamide and 10% ascorbic acid mixed solution 10mL, is placed at room temperature for 30
It is measured with Atomic Fluorescence Spectrometer after minute, the concentration c of arsenic in supernatant is calculated according to standard curvet, according to sample before and after load
The variation of product concentration, by equation Qt=(c0-ct) × v/m calculates the load capacity Q of carrier, investigates result and sees Fig. 6.
Embodiment 5
When the volume ratio of ethylenediamine and water is 2: 1, realgar concentration is investigated
At room temperature, precision weighs a certain amount of realgar and is dissolved in ethylenediamine, be configured to a concentration of 3 respectively, 9,15,24,30mg/
The realgar ethylenediamine mother liquor of mL is centrifuged 10 minutes for 12000 revs/min after shaking up, is taken from the mother liquor of above-mentioned various concentration respectively
1.30mL supernatants are set in 5mL plastic centrifuge tubes, then are separately added into 0.70mL deionized waters and are made solution body in each centrifuge tube
Product is 2.00mL, realgar final concentration is respectively 2,6,10,16,20mg/mL, each concentration point is parallel to investigate three parts.
Precision weighs in 10mg mesoporous monox nanometers particle to above-mentioned centrifuge tube respectively, and experiment process is examined with embodiment 4
It examines result and sees Fig. 7.
Embodiment 6
The volume ratio of ethylenediamine and water is 2: 1, when a concentration of 16mg/mL of realgar, investigates carrier amount
At room temperature, precision weighs a certain amount of realgar and is dissolved in ethylenediamine, is configured to the realgar ethylenediamine of a concentration of 24mg/mL
Mother liquor centrifuges 10 minutes for 12000 revs/min after shaking up, therefrom takes 1.30mL supernatants to set in 5mL plastic centrifuge tubes, add
0.70mL deionized waters so that liquor capacity is 2.00mL in each centrifuge tube, and realgar final concentration is respectively 16mg/mL.
Respectively precision weigh 5,10,15, tetra- groups of 20mg (every group of three parts of experiment operation repetitive) mesoporous monox nanometer particle
To in above-mentioned centrifuge tube, experiment process investigates result and sees Fig. 8 with embodiment 4.
Embodiment 7
The volume ratio of ethylenediamine and water is 2: 1, a concentration of 16mg/mL of realgar, when carrier amount is 10mg, investigates load time
At room temperature, precision weighs a certain amount of realgar and is dissolved in ethylenediamine, is configured to the realgar ethylenediamine of a concentration of 24mg/mL
Mother liquor centrifuges 10 minutes for 12000 revs/min after shaking up, therefrom takes 1.30mL supernatants to set in 5mL plastic centrifuge tubes, then distinguish
0.70mL deionized waters are added and so that liquor capacity is 2.00mL in each centrifuge tube, realgar final concentration is respectively 16mg/mL.
Precision weighs in 10mg mesoporous monox nanometers particle to above-mentioned centrifuge tube respectively, is placed in high speed at room temperature and vibrates
Device vibrates 0,0.2,0.5,2,4 hour (three parts of each time point operation repetitive), subsequently respectively under the conditions of 1800 revs/min
Experiment process investigates result and sees Fig. 9 with embodiment 4.
Embodiment 8
At room temperature, precision weighs a certain amount of realgar and is dissolved in ethylenediamine, is configured to the realgar ethylenediamine of a concentration of 24mg/mL
Mother liquor centrifuges 10 minutes for 12000 revs/min after shaking up, therefrom takes 1.30mL supernatants to set in 5mL plastic centrifuge tubes, then distinguish
0.70mL deionized waters are added and so that liquor capacity is 2.00mL in each centrifuge tube, realgar final concentration is respectively 16mg/mL.
Precision weighs in 10mg mesoporous monox nanometers particle to above-mentioned centrifuge tube (three parts of operation repetitive) respectively, tests
Journey is the same as embodiment 4.It finds that its pattern and structure do not occur significantly to change after transmission electron microscope characterization, sees that Figure 10, load capacity are about
8.0%, Figure 11 are the energy spectrum analysis figures of realgar-mesoporous monox nanometer combination drug, and furtherly lucid realgar is in nanometer level
It is carried in the mesoporous monox nanometer particle of modified with folic acid.
Embodiment 9
At room temperature, precision weighs a certain amount of realgar and is dissolved in ethylenediamine, is configured to the realgar ethylenediamine of a concentration of 24mg/mL
Mother liquor centrifuges 10 minutes for 12000 revs/min after shaking up, therefrom takes 1.30mL supernatants to set in 5mL plastic centrifuge tubes, then distinguish
0.70mL deionized waters are added and so that liquor capacity is 2.00mL in each centrifuge tube, realgar final concentration is respectively 16mg/mL.
(operation repetitive three in the accurate mesoporous monox nanometer particle to above-mentioned centrifuge tube for weighing 10mg modified with folic acid respectively
Part), for experiment process with embodiment 4, load capacity is about 7.5%.
Claims (6)
1. a kind of preparation method of the realgar of modified with folic acid-mesoporous monox nanometer particle, which is characterized in that including following step
Suddenly：
Realgar is dissolved in anhydrous ethylenediamine, insoluble mineralogical composition is centrifuged off after dissolving, then dilute with deionized water by step 1
It releases so that ethylenediamine: the volume ratio of water is 1: 0.33~1: 3, is configured to the realgar ethylenediamine of a concentration of 2~20mg/mL of realgar
Solution；
Step 2, the mesoporous monox nanometer particle for weighing 5~20mg modified with folic acid are placed in plastic centrifuge tube, and step 1 is added
The realgar ethylenediamine solution of preparation, be placed at room temperature high-speed oscillator vibrate 0~4 hour it is mesoporous to get the realgar-of modified with folic acid
Silicon oxide nanoparticle.
2. the preparation method of the realgar of modified with folic acid according to claim 1-mesoporous monox nanometer particle, feature exist
In in step 2, the mesoporous monox nanometer particle of the modified with folic acid prepares gained by following methods：With tetraethyl orthosilicate
For silicon source, cetyl trimethylammonium bromide is template, and ethyl alcohol is cosolvent, triethanolamine be chelating agent under alkaline condition
Synthesizing mesoporous monox nanometer particle, grafting is in its surface bond ammonia third after passing through after solvent extraction removes template
Base, then folic acid is modified to get to the mesoporous monox nanometer particle of modified with folic acid by coupling reaction.
3. preparation method according to claim 2, which is characterized in that in the preparation method, tetraethyl orthosilicate: 16
Alkyl trimethyl ammonium bromide: triethanolamine: water: the molar ratio of ethyl alcohol be 1: 0.2~0.3: 0.8~1.0: 130~150: 7.0~
13.0。
4. preparation method according to claim 2, which is characterized in that the mesoporous monox nanometer particle of the modified with folic acid
Preparation method include the following steps：
(1) at room temperature, cationic surfactant cetyl trimethylammonium bromide is weighed to be placed in round-bottomed flask, addition go from
In 40~80 DEG C of heating stirrings after sub- water, absolute ethyl alcohol and triethanolamine are sequentially added after dissolving, is added dropwise after stirring evenly
Tetraethyl orthosilicate is kept for 40~80 DEG C and continues stirring 1~3 hour；
(2) step (1) reaction mixture is centrifuged, is washed with deionized water to neutrality, then after being washed with absolute ethyl alcohol it is true in 60 DEG C
Sky is dry；
(3) template is removed with hydrochloric ethanol solution, 60 DEG C of vacuum drying obtain mesoporous monox nanometer particle；
(4) at room temperature, it weighs mesoporous monox nanometer particle obtained by step (3) to be placed in round-bottomed flask, absolute ethyl alcohol is added and stirs
Dispersion is mixed, measures after appropriate 3- aminopropyl triethoxysilanes are dissolved in absolute ethyl alcohol and above-mentioned round-bottomed flask is added, be stirred at room temperature
40~60 hours；
(5) reaction mixture is centrifuged, washs 60 DEG C of vacuum drying of postposition with absolute ethyl alcohol, obtains amidized mesopore silicon oxide
Nano-particle；
(6) at room temperature, folic acid is weighed in round-bottomed flask, and dimethyl sulfoxide ultrasonic dissolution is added, sequentially adds N- maloyls
Appropriate step is added after being protected from light stirring 1 hour in imines and 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, room temperature
(5) the amidized mesoporous monox nanometer particle of gained, continues to be protected from light stirring 10~30 hours；
(7) reaction mixture is centrifuged, is dried in vacuo after being washed with phosphate buffer, obtain the mesopore silicon oxide of modified with folic acid
Nano-particle.
5. preparation method according to claim 4, which is characterized in that in step (3), prepare gained mesoporous monox nanometer
Particle exists in the form of colloidal suspension liquid in water；Its grain size is from 50nm to 150nm.
6. any preparation method prepares realgar-mesoporous monox nanometer particle of gained modified with folic acid in claim 1-5.
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|---|---|---|---|---|
| CN1478486A (en) * | 2003-07-08 | 2004-03-03 | 华中科技大学 | Nanometer realgar solid dispersion and its preparation method |
| CN1827118A (en) * | 2005-03-05 | 2006-09-06 | 广西师范大学 | Method for preparing nanometer realgar gel and nanometer realgar with biomacromolecule template to regulate shape and particle thereof |
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2014
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1478486A (en) * | 2003-07-08 | 2004-03-03 | 华中科技大学 | Nanometer realgar solid dispersion and its preparation method |
| CN1827118A (en) * | 2005-03-05 | 2006-09-06 | 广西师范大学 | Method for preparing nanometer realgar gel and nanometer realgar with biomacromolecule template to regulate shape and particle thereof |
Non-Patent Citations (5)
| Title |
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| "Arsenic(II) Sulfide Quantum Dots Prepared by a Wet Process from its Bulk;Junzhong Wang et al;《JACS》;20080812;第130卷;第11596页左栏第2段、流程图1 * |
| Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals;Jie Lu et al;《SMALL》;20100707;第6卷(第7期);第1794-1805页 * |
| Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery;Fangqiong Tang et al;《Adv. Mater.》;20070126;第24卷;第1504-1534页 * |
| 介孔二氧化硅纳米粒介导的药物传递***及其生物安全性的研究进展;肖正林等;《中国医药工业杂志》;20130110;第44卷(第1期);摘要、第82页第1.1节、第84页第1.3节 * |
| 基于介孔二氧化硅的多功能纳米药物输送体系研究进展;郝晓红等;《生物化学与生物物理进展》;20131231;第40卷(第10期);第1014-1022页 * |
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