CN102805869A - Folic acid functionalized drug-loaded mesoporous silica and preparation method thereof - Google Patents
Folic acid functionalized drug-loaded mesoporous silica and preparation method thereof Download PDFInfo
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- CN102805869A CN102805869A CN2011101421095A CN201110142109A CN102805869A CN 102805869 A CN102805869 A CN 102805869A CN 2011101421095 A CN2011101421095 A CN 2011101421095A CN 201110142109 A CN201110142109 A CN 201110142109A CN 102805869 A CN102805869 A CN 102805869A
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Abstract
The invention discloses folic acid-functionalized drug-loaded mesoporous silica and a preparation method thereof. The folic acid-functionalized drug-loaded mesoporous silica of the present invention is prepared according to the following steps: 1) adopting orthosilicate as a silicon source, adopting an n-hexadecyl quaternary ammonium salt as a template agent, adopting mercaptopropyl trimethoxysilane as a functionalization reagent, and adopting a method of copolycondensation, synthesis and grafting to prepare thiol-functionalized mesoporous silica; 2) carrying out a reaction of the thiol-functionalized mesoporous silica and 2-(pyridindithio)ethyl ammonium chloride to obtain amino-functionalized mesoporous silica adopting a disulfide bond as a linker; 3) adopting a physical adsorption method to assemble a drug into pore channels of the mesoporous silica; and 4) linking folic acid to the mesoporous silica through the disulfide bond with a covalence effect to obtain the folic acid-functionalized drug-loaded mesoporous silica. The product of the present invention has characteristics of folic acid targeting effect, large specific surface area, high thermal stability, no toxicity, high drug loading rate, and effective prevention from drug leakage.
Description
Technical field
The present invention relates to a kind of pharmaceutical carrier and preparation method thereof, relate in particular to mesopore silicon oxide of a kind of folic acid functionalization and preparation method thereof.
Background technology
Pharmaceutical carrier is the principal element that influences drug effect.Pharmaceutical carrier of different nature has the different drug release behavior.Ideal pharmaceutical carrier should have excellent biological compatibility, biodegradability, physics and chemistry and biological stability and extremely low toxicity, and suitable drug loading is arranged.
Mesoporous material has adjustable mesoporous (2-50nm) duct of homogeneous, high specific surface area, stable framing structure and the surface that is easy to functionalization.Since using the self-assembling technique of nanostructured to prepare mesopore silicon oxide first from the scientist of U.S. Mobil company in 1992, meso pore silicon oxide material is a research focus of material science always.Mesopore silicon oxide has the pore passage structure and the chemical homogeneity of rule, and heat stability is high, active, the avirulence of inanimate object, can degrade through the low toxicity approach at organism, thereby possess the primary condition as pharmaceutical carrier.Mesopore silicon oxide mainly is to take the method for physical absorption that medicine is written into the duct at present, and then studies its release behavior as the research of pharmaceutical carrier.Yet a ubiquitous problem is: because the duct both ends open, early stage leakage will take place in medicine before arriving ad-hoc location.
Summary of the invention
Technical problem to be solved by this invention provides medicine carrying mesopore silicon oxide of a kind of folic acid functionalization and preparation method thereof.
The medicine carrying mesopore silicon oxide of folic acid functionalization provided by the present invention is to prepare according to the method that comprises the steps:
1) with the alkyl quaternary ammonium salts is template, under alkali condition, makes positive esters of silicon acis and mercaptopropyl trimethoxysilane carry out copolycondensation, obtain mercapto-functionalized mesopore silicon oxide;
2) adopt synthetic back grafting, make the mercapto-functionalized mesopore silicon oxide reaction of mercaptopropyl trimethoxysilane and step 1) preparation, obtain the mercapto-functionalized mesopore silicon oxide of secondary;
3) under lucifuge and oxygen free condition, make step 2) mercapto-functionalized mesopore silicon oxide and 2-(2-amino-ethyl dithio) the pyridine hydrochloride reaction of preparation, obtain amino functional mesopore silicon oxide with the disulfide bond connection; Remove template wherein then, the amino functional mesopore silicon oxide template that is removed, that disulfide bond connects;
4) adopt physisorphtion, drug group is installed in the duct of removing amino functional mesopore silicon oxide template, that disulfide bond connects of step 3) preparation, obtain the amino functional mesopore silicon oxide of the disulfide bond connection of medicine carrying;
5) under the catalytic action of 1-ethyl-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCHCl), make folic acid and the amino functional mesopore silicon oxide reaction that the disulfide bond of the medicine carrying of step 4) preparation is connected, obtain the medicine carrying mesopore silicon oxide of folic acid functionalization.
Wherein, copolycondensation described in the step 1) can carry out in water; The reaction temperature of said copolycondensation can be 50～90 ℃, and the response time can be 2～12 hours; The pH value of said alkali condition is 8～13.
In the said copolycondensation of step 1), the mol ratio of alkyl quaternary ammonium salts, positive esters of silicon acis, mercaptopropyl trimethoxysilane, water can be followed successively by (2-4): (20-25): (4-6): (20000-30000), be preferably 2.8: 22.4: 5.2: 26700.
The alkyl quaternary ammonium salts of template described in the step 1) specifically can be DTAC, DTAB, tetradecyl trimethyl ammonium chloride, TTAB, hexadecyltrimethylammonium chloride, cetyl trimethyl ammonium bromide, OTAC, octadecyl trimethylammonium bromide etc., and said positive esters of silicon acis can be methyl silicate, ethyl orthosilicate etc.
Step 2) reaction dissolvent of reaction can be dry toluene, anhydrous cyclohexane or absolute methanol etc. described in; Said being reflected at carried out under the reflux state 24～48 hours.
Step 2) in the said reaction, the mol ratio of mercaptopropyl trimethoxysilane and mercapto-functionalized mesopore silicon oxide can be (0.9-1.3): (0.8-1.1), be preferably 1.2: 1.
In the said reaction of step 3), step 2) the mercapto-functionalized mesopore silicon oxide of preparation and the mass ratio of 2-(2-amino-ethyl dithio) pyridine hydrochloride are (1-2): (0.8-1.4), be preferably 1.5: 1.
In the step 3), the method for removing template can be solvent extraction; The solvent that is adopted in the said solvent extraction is that mass concentration is the mixed liquor that 35%-37% hydrochloric acid solution and absolute methanol form according to volume ratio at 1: 20.
Be reflected at described in the step 5) in the dimethyl sulfoxide and carry out.The reaction temperature of said reaction is 20-35 ℃, and the response time is 12-36 hour.
In the said reaction of step 5), the amino functional mesopore silicon oxide mass ratio that folic acid, EDCHCl are connected with the disulfide bond of medicine carrying is (2-4): (6-12): (7-13).Be preferably (3.5: 10.5: 10)
In order to solve with the mesopore silicon oxide is the early stage medicine leakage problem that carrier produces, and inventor of the present invention takes the method for chemical bonding first, with folic acid and load the mesopore silicon oxide of model drug covalently bound, efficiently solve the problem of early stage leakage.Under specific reducing condition, connect the disulfide bonds of folic acid and mesopore silicon oxide, thereby the model drug of load is discharged with the first order kinetics process.The medicine carrying mesopore silicon oxide of the folic acid functionalization of the inventive method preparation not only has the folic acid targeting, and specific surface area is big, and heat stability is high, avirulence, and carrying drug ratio is high, especially can effectively prevent the advantage that medicine is revealed.This nano material is suitable for those and has more short-decayed medicine, has potential application prospect as a kind of new nanometer transport agent at biomedicine field.
The present invention compared with prior art has the following advantages: (1) reaction condition is gentle, need not HTHP, and the response time is short, need not crystallization or ageing process, thereby more simply saves time easy operating.(2) the cheap and environmental friendliness of the template that is adopted, preparation cost is low.(3) folic acid is being adsorbed on the mesopore silicon oxide carrier surface of model drug with covalent bonding, avoiding the early stage leakage in the medicament transport process.(4) prepared nano-medicament carrier material discharges model drug under reducing condition with the one-level release dynamics, meet the release rule of controlled release and slow releasing pharmaceutical carrier.
Description of drawings
Fig. 1 is that the medicine carrying mesoporous monox nanometer drug carrier material of folic acid functionalization of embodiment 1 preparation is at external release profiles.
The specific embodiment
The present invention will be described through specific embodiment below, but the present invention is not limited thereto.Experimental technique described in the following embodiment like no specified otherwise, is conventional method; Said reagent and material like no specified otherwise, all can obtain from commercial sources.
The medicine carrying mesoporous monox nanometer drug carrier material of embodiment 1, preparation folic acid functionalization
One, the method for following copolycondensation of employing and synthetic back grafting prepares the mesopore silicon oxide of sulfydryl modification:
A) copolycondensation method: 1g n-hexadecyl ammonium bromide (2.8mmol) is placed round-bottomed flask, add deionized water (480mL, 26.7mol) and vigorous stirring, with 2M sodium hydroxide (3.5mL, 0.175mmol) adjusting pH to 11.The mixture that under 80 ℃ of temperature, adds 5mL ethyl orthosilicate (22.4mmol) and 0.97mL mercaptopropyl trimethoxysilane (5.24mmol), nitrogen protection continue down to stir 2 hours.After the cooling that reactant liquor is centrifugal, white jelly, with deionized water and washing with alcohol number time, vacuum drying, obtain the mesopore silicon oxide of sulfydryl modification.
B) synthesize the back grafting: the mesopore silicon oxide of the synthetic sulfydryl modification that obtains of 0.9g copolycondensation method is placed round-bottomed flask, add dry toluene, add 1mL mercaptopropyl trimethoxysilane (5.4mmol), back flow reaction 24 hours under stirring.Washing with alcohol, vacuum drying obtains the mesopore silicon oxide of secondary sulfydryl modification.
Two, 2-(2-amino-ethyl dithio) pyridine hydrochloride is synthetic: 1g two thiopyridines are dissolved in the 5.5mL methanol, add 0.2mL acetic acid.0.26g 2-sulfydryl ethylammonium chloride is dissolved in 2.27mL methanol, it is added in the above-mentioned solution.Stirring at normal temperature, lucifuge, nitrogen protection is stirred after 48 hours product vacuum rotary steam to butter shape, wears away with ether, filtration under diminished pressure, product vacuum drying 24 hours is for use.
1H?NMR(DMSO-d
6)δ＝3.11(m，4H，CH
2-CH
2)，7.31(m，1H，py)，7.76(d，1H，py)，7.85(m，1H，py)，8.29(s，3H，NH
3)，8.52(d，1H，py)。ESI-MS，m/z：187[M
+]。
Three, the mercapto-functionalized mesopore silicon oxide of the above-mentioned 0.8g that obtains being placed round-bottomed flask, is solvent with the absolute methanol, and (0.5g, 2.67mmol), the lucifuge nitrogen protection was reacted 24 hours down to add 2-(2-amino-ethyl dithio) pyridine hydrochloride.Centrifugal supernatant discarded, washing with alcohol, vacuum drying obtains the amino functional mesopore silicon oxide that connects with disulfide bond.Use mixed liquor (volume ratio 1: 20) the extraction template n-hexadecyl trimethylammonium bromide of concentration as 37%HCl and absolute methanol; Use washing with alcohol, centrifugal several then; Vacuum drying, the amino functional mesopore silicon oxide template that is removed, that disulfide bond connects (is designated as MS-NH
2).
Four, under the room temperature, 0.008mol model drug fluorescein sodium is dissolved in the 100mL phosphate buffer (PBS) (0.08M), adds 0.2g mesopore silicon oxide MS-NH
2, lucifuge stirred 36 hours.Centrifugal supernatant discarded, PBS washing, vacuum drying has obtained adsorbing the mesopore silicon oxide (F-MS-NH of the amino functional that the disulfide bond of model drug connects
2).
Five, under the room temperature; (0.18mmol) is dissolved among the DMSO with 80mg folic acid; Under stirring condition, add 240mg 1-ethyl-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCHCl) (1.25mmol), add the F-MS-NH that 0.22g has adsorbed model drug after 0.5 hour
2, nitrogen protection was reacted 24 hours down.Product is with the washing of DMSO and ethanol gradient centrifugation, and vacuum drying has promptly obtained the medicine carrying mesoporous monox nanometer drug carrier material (being designated as F-MS-F) of folic acid functionalization.
Embodiment 2 medicine extracorporeal releasing tests:
Under 37 ℃, the 1.5mg F-MS-F that embodiment 1 is obtained is scattered in the 3mL PBS buffer solution, adds 3.0mg DTT (6.5mM), uses the fluorescence intensity at F-2500 type spectrofluorophotometer (HITACHI, Japan) monitoring 515nm place.Excitation wavelength: 504nm, slit: 2.5nm.
Matched group solution does not add Reducing agent DTT, and experimental group solution adds the Reducing agent DTT of variable concentrations.With time is abscissa, and cumulative release concentration is that vertical coordinate is drawn release profiles.As can be seen from Figure 1, matched group is not owing to add DTT, and disulfide bond does not rupture, and the duct is by the folic acid shutoff, and model drug does not almost discharge; And in the experimental group owing to added DTT, the fracture of disulfide bond causes drug release rate all faster than matched group, and rate of release accelerates with the increase of Reducing agent DTT concentration in the experimental group.
To DTT concentration is the experimental group of 6.5mM, and 0-15 hour accumulative total release profiles carries out linear fit with the kinetic model equation.The result shows that the release of fluorescein sodium meets one-level release dynamics process, and regression equation is: y=-797.651*exp (x/1.9432)+764.464.
Can reach a conclusion thus: can effectively solve the early stage problem of revealing of mesopore silicon oxide medicine carrying Chinese medicine with disulfide bond mesoporous monox nanometer drug carrier material that connect, the folic acid functionalization.
The above is merely the preferred embodiments of the present invention, only is illustrative for the purpose of the present invention, and nonrestrictive; Those of ordinary skills understand, and in spirit that claim of the present invention limited and scope, can carry out many changes to it, revise, even equivalence change, but all will fall in protection scope of the present invention.
Claims (10)
1. a method for preparing the medicine carrying mesopore silicon oxide of folic acid functionalization comprises the steps:
1) with the alkyl quaternary ammonium salts is template, under alkali condition, makes positive esters of silicon acis and mercaptopropyl trimethoxysilane carry out copolycondensation, obtain mercapto-functionalized mesopore silicon oxide;
2) adopt synthetic back grafting, make the mercapto-functionalized mesopore silicon oxide reaction of mercaptopropyl trimethoxysilane and step 1) preparation, obtain the mercapto-functionalized mesopore silicon oxide of secondary;
3) under lucifuge and oxygen free condition, make step 2) mercapto-functionalized mesopore silicon oxide and 2-(2-amino-ethyl dithio) the pyridine hydrochloride reaction of preparation, obtain amino functional mesopore silicon oxide with the disulfide bond connection; Remove template wherein then, the amino functional mesopore silicon oxide template that is removed, that disulfide bond connects;
4) adopt physisorphtion, drug group is installed in the duct of removing amino functional mesopore silicon oxide template, that disulfide bond connects of step 3) preparation, obtain the amino functional mesopore silicon oxide of the disulfide bond connection of medicine carrying;
5) under the catalytic action of 1-ethyl-(3-dimethylamino-propyl) carbodiimide hydrochloride, make folic acid and the amino functional mesopore silicon oxide reaction that the disulfide bond of the medicine carrying of step 4) preparation is connected, obtain the medicine carrying mesopore silicon oxide of folic acid functionalization.
2. method according to claim 1 is characterized in that: copolycondensation described in the step 1) carries out in water; The reaction temperature of said copolycondensation is 50-90 ℃, and the response time is 2-12 hour; The pH value of said alkali condition is 8-13.
3. method according to claim 1 and 2; It is characterized in that: in the said copolycondensation of step 1); The mol ratio of alkyl quaternary ammonium salts, positive esters of silicon acis, mercaptopropyl trimethoxysilane, water is (2-4): (20-25): (4-6): (20000-30000), be preferably 2.8: 22.4: 5.2: 26700.
4. method according to claim 1 is characterized in that: step 2) described in the reaction reaction dissolvent be that dry toluene, anhydrous cyclohexane or absolute methanol are wherein at least a; Said being reflected at carried out under the reflux state 24-48 hour.
5. according to claim 1 or 4 described methods, it is characterized in that: step 2) in the said reaction, the mass ratio of mercaptopropyl trimethoxysilane and mercapto-functionalized mesopore silicon oxide is (0.9-1.3): (0.8-1.1), be preferably 1.2: 1.
6. method according to claim 1; It is characterized in that: in the said reaction of step 3); Step 2) the mercapto-functionalized mesopore silicon oxide of preparation and the mass ratio of 2-(2-amino-ethyl dithio) pyridine hydrochloride are (1-2): (0.8-1.4), be preferably 1.5: 1.
7. according to claim 1 or 6 described methods, it is characterized in that: in the step 3), the method for removing template is a solvent extraction; The solvent that is adopted in the said solvent extraction is that mass concentration is the mixed liquor that 35%-37% hydrochloric acid solution and absolute methanol form according to volume ratio at 1: 20.
8. method according to claim 1 is characterized in that: be reflected at described in the step 5) in the dimethyl sulfoxide and carry out; The reaction temperature of said reaction is 20-35 ℃, and the response time is 12-36 hour.
9. according to claim 1 or 8 described methods; It is characterized in that: in the said reaction of step 5); Folic acid, the amino functional mesopore silicon oxide mass ratio that the 1-ethyl-(3-dimethylamino-propyl) carbodiimide hydrochloride is connected with the disulfide bond of medicine carrying are (2-4): (6-12): (7-13), be preferably 3.5: 10.5: 10.
10. the medicine carrying mesopore silicon oxide of the folic acid functionalization that arbitrary said method prepares among the claim 1-9.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103990125A (en) * | 2014-05-30 | 2014-08-20 | 东华大学 | Coupled folic acid-targeted hollow mesoporous silicon dioxide/copper sulphide nano compound and preparation method and application thereof |
| CN105004626A (en) * | 2015-07-22 | 2015-10-28 | 中国科学院上海微系统与信息技术研究所 | High-sensitivity ammonia class gas sensor and preparation method thereof |
| CN105905912A (en) * | 2016-04-05 | 2016-08-31 | 天津大学 | High-yield mesoporous silica nano-particle and folic acid targeting modification method thereof |
| CN110217801A (en) * | 2019-05-23 | 2019-09-10 | 首都医科大学 | The mesoporous silicon oxide nanomaterial and the preparation method and application thereof of lipoic acid functionalization |
| CN110507634A (en) * | 2019-09-16 | 2019-11-29 | 湖北大学 | A kind of hollow mesoporous silicon based medicine carrier system of charge flip type and preparation method thereof |
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2011
- 2011-05-30 CN CN201110142109.5A patent/CN102805869B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103990125A (en) * | 2014-05-30 | 2014-08-20 | 东华大学 | Coupled folic acid-targeted hollow mesoporous silicon dioxide/copper sulphide nano compound and preparation method and application thereof |
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| CN110507634A (en) * | 2019-09-16 | 2019-11-29 | 湖北大学 | A kind of hollow mesoporous silicon based medicine carrier system of charge flip type and preparation method thereof |
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