CN110507633A - Respond pH and the drug gene carrier of ultraviolet light and preparation method thereof - Google Patents
Respond pH and the drug gene carrier of ultraviolet light and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of response pH and the drug gene carrier of ultraviolet light and preparation method thereof.The drug gene carrier is using meso-porous nano silica as skeleton, surface grafting cationic block copolymers, and anticancer drug is loaded in mesopore orbit by the cumarin molecule of the chemistry key connection ultraviolet light photoresponse of acid-sensitive on the block by near surface.Cumarin on the surface of drug gene carrier of the invention can crosslink under ultraviolet lighting, so that the leakage in advance of anticancer drug is prevented, and the cumarin being crosslinked in acid condition hydrolyzes, and crosslinked action disappears, and anticancer drug is released；Another block has a large amount of tertiary amino, can be with Electrostatic Absorption gene.Drug gene carrier of the invention be able to respond pH variation controlled release anticancer drug, and can combined treatment gene, in drug targeting and gene target have application prospect.
Description
Technical field
The present invention relates to a kind of response pH and the drug gene carrier of ultraviolet light and preparation method thereof, belong to drug gene load
Body technique field.
Background technique
Mesoporous silica nano-particle have high-specific surface area, regulatable meso-hole structure, easy surface modification with
And good biofacies by property the advantages that, biomedicine field is applied to by extensive design.It can be set based on mesoporous silicon oxide
Diversified nano-carrier is counted, for delivering the healing potions such as drug or gene.Conventional nano carrier mainly passes through simply
Diffusion drug molecule is released, drug release behavior do not have controllability so that drug is sent out in the normal tissue
Raw leakage, thus drug can not high-efficiency delivery to target area, and cause serious toxic side effect.To Metaporous silicon dioxide material into
Row functional modification assigns its stimulus response performance, and utilizes mesopore orbit loading drug molecule, and the Functional Unit of surface modification
The shortcomings that part is capable of the release of control on demand drug, can overcome Conventional nano carrier.Stimuli responsive type common at present is mesoporous
Silicon pharmaceutical carrier surface modification is supermolecule nano valve i.e. rotaxane or pseudorotaxane structure, utilizes macrocycle molecule and chain molecule
Non-covalent binding realize closure to aperture, combine and be destroyed both under suitable stimulation, to release drug
Molecule.
The diversification of mesoporous silicon oxide surface modification is again such that load therapeutic gene is possibly realized.Traditional gene carries
Body is mainly cationic polymer or liposome, and since cationic charge density is big, the ability in conjunction with gene is strong, but companion
With serious cytotoxicity is generated, so that the practical application of this kind of genophore is restricted.In order to overcome cytotoxicity height
The shortcomings that keep high binding ability simultaneously, researcher by cationic polymer in conjunction with inorganic nano material, bio-compatible
Property significantly increased, the cationic polymer of inorganic material surface modification can effectively combine gene, for gene delivery.Its
In, mesoporous silica nano-particle is often used as the support material of cationic polymer due to its excellent characteristic.Jeffrey
I.Zink etc. has adsorbed layer of polyethylene imines by electrostatic interaction in the meso-porous titanium dioxide silicon face that elecrtonegativity phosphate is modified
(PEI), mesoporous silicon dioxide nano particle of PEI cladding can effectively combine Plasmid DNA and siRNA as the result is shown
(siRNA), high-efficiency delivery is to playing its bioactivity into the cell, and carrier itself it is substantially non-toxic (Song R, Zhang M,
Liu Y,et al.A multifunctional nanotheranostic for the intelligent MRI
diagnosis and synergistic treatment of hypoxic tumor[J].Biomaterials,2018,
175:123-133.).But utilize electrostatic interaction in the tactful in practice of elecrtonegativity surface cladding cationic polymer
Effect is not too much ideal, because the elecrtonegativity of material surface group is affected by environment very big, will subtract into internal rear electrostatic interaction
Weak, cationic polymer can be partially disengaged, and influence carrying efficiencies.The meso-porous titanium dioxide silicon face in large aperture such as Qiao Shizhang
It is coupled degradable polylysine (PLL), mesoporous silicon dioxide nano particle combines few core after polylysine cladding as the result is shown
The ability of thuja acid significantly improves, and the ability of passenger gene is better than amino functional mesoporous silicon oxide, and carrier has
Good biocompatibility (Hartono S B, Gu W, Kleitz F, et al.Poly-L-lysine functionalized
large pore cubic mesostructured silica nanoparticles as biocompatible
Carriers for gene delivery [J] .Acs Nano, 2012,6 (3): 2104-2117.) but the energy of delivery of gene
Power is not so good as other common cationic polymer such as polyethyleneimines, polyamide-amide etc., because its charge density is lower.
Summary of the invention
The purpose of the present invention is to provide a kind of response pH and the drug gene carrier of ultraviolet light and preparation method thereof.This hair
Bright by rationally designing, mesoporous silica nano-particle can load drug molecule and therapeutic gene simultaneously, i.e., orderly using it
Mesopore orbit be used to carrying medicament molecule, and the cationic polymer of surface modification be used to load therapeutic gene.
Realizing the technical solution of the object of the invention is:
The drug gene carrier of pH and ultraviolet light are responded, the carrier is using mesoporous silicon oxide as framework construction, surface
Grafted cation block polymer, chemical structure are as follows:
Wherein, A represents the anticancer drug of load, and B is represented mesoporous silica nano-particle (MSN), and C indicates block copolymerization
7- (along rhizome of Chinese monkshood amide ethyoxyl) the modified poly (glycidyl methacrylate) chain section of -4- methylcoumarin, D indicate embedding in object
Polymethylacrylic acid diformazan ammonia ethyl ester segment in section copolymer, E represent the therapeutic gene combined.
Heretofore described anticancer drug is selected from 5-fluor-uracil (5-FU), adriamycin (DOX), Chlorambucil
(Cbl), mitoxantrone (MX) etc..In the specific embodiment of the invention, the anticancer drug is 5-fluor-uracil (5-FU).
The preparation method of the drug gene carrier of above-mentioned response pH and ultraviolet light, the specific steps are as follows:
Step 1, by mesoporous silica nano-particle and bromo- 2- methyl-N-3 (trimethoxy silane) propionamide of 2- in nothing
It flows back in water-toluene, dealcoholization is carried out under nitrogen protection, obtains MSNs-Br；
Step 2, MSNs-Br is ground and be dried in vacuo, by monomer methacrylic acid glyceride, ligand pentamethyl diethyl
Alkenyl triamine and catalyst cuprous bromide dosage are respectively 1~3 μ L, 0.1~0.3 μ L of every milligram of mesoporous silica nano-particle
With 0.035~0.106mg, glyceral methacrylate, pentamethyldivinyltriamine and cuprous bromide is added in anhydrous N, N '-
It is reacted in dimethylformamide, the atom transition free radical polymerization reaction (SI- of first step surface initiation is carried out under oxygen free condition
ATRP), excessive cuprous bromide catalyst and residual monomer are removed through dialysis, vacuum drying obtains MSNs-g-PGMA；
Step 3, after MSNs-g-PGMA being ground, by monomer methacrylic acid diformazan ammonia ethyl ester, ligand pentamethyl divinyl
Base triamine and catalyst cuprous bromide dosage are respectively every milligram of mesoporous silica nano-particle 3-5 μ L, 0.16~0.26 μ L
With 0.053~0.089mg, dimethylaminoethyl acrylate methyl ammonia ethyl ester, pentamethyldivinyltriamine and cuprous bromide is added in methanol
It is reacted in the mixed solution of water, the atom transition free radical polymerization reaction of second step surface initiation, warp is carried out under oxygen free condition
Dialysis removes excessive cuprous bromide catalyst and residual monomer, and vacuum drying obtains MSNs-g-PGMA-b-PDMAEMA；
Step 4, second two is added in anhydrous tetrahydro furan in ultrasonic disperse after MSNs-g-PGMA-b-PDMAEMA being ground
Amine flows back into row ring-opening reaction under nitrogen atmosphere, is collected by centrifugation and washed product, vacuum drying obtain MSNs-g-PEDA-b-
PDMAEMA；
Step 5, ultrasonic disperse is in anhydrous N, N '-dimethyl formamide after MSNs-g-PEDA-b-PDMAEMA being ground,
And using 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and N- hydroxysuccinimide activation 7- (along crow
Head amide ethyoxyl) carboxyl on -4- methylcoumarin (CA-AMC), by 7- (along rhizome of Chinese monkshood amide ethyoxyl) -4- after activation
Methylcoumarin (CA-AMC) is added in above-mentioned dispersion liquid, carries out dehydration condensation, and simultaneously washed product, vacuum is collected by centrifugation
It is dry, obtain MSNs-g-PCAAMC-b-PDMAEMA；
Step 6, ultrasonic disperse is in the aqueous solution of anticancer drug after MSNs-g-PCAAMC-b-PDMAEMA being ground, room
Temperature is protected from light stirring to being uniformly mixed, and then uses the ultraviolet light dispersion liquid of 365nm, sends out the cumarin on block copolymer
After illumination, product is collected by centrifugation in third contact of a total solar or lunar eclipse dimerization reaction, and vacuum drying obtains MSNs-g-PCAAMC-b-PDMAEMA@5-
FU；
Step 7, it is dispersed in PBS buffer solution after MSNs-g-PCAAMC-b-PDMAEMA@5-FU grinding by vortex,
It mixes with gene (pDNA) with vortex, and is diluted with PBS buffer solution, is incubated at 37 DEG C, obtain the medicine of response pH and ultraviolet light
Object genophore MSNs-g-PCAAMC-b-PDMAEMA@5-FU/pDNA.
Preferably, in step 1, bromo- 2- methyl-N-3 (trimethoxy silane) propionamide of the 2- is by 3- aminopropyl three
Methoxy silane and 2- bromine isobutyl acylbromide occur nucleophilic substitution and are made.Bromo- 2- methyl-N-3 (the trimethoxy silicon of the 2-
Alkane) dosage of propionamide is that every milligram of mesoporous silica nano-particle uses 0.25~1 μ L, the reaction time is 12~for 24 hours.
Preferably, in step 2, the first step atom transition free radical polymerization reaction time is 5~15min.
Preferably, in step 3, the second step atom transition free radical polymerization reaction time is 3~5h, first alcohol and water
Volume ratio be 1:1.
Preferably, in step 4, the ring-opening reaction time is 24~36h.
Preferably, in step 5, the activated carboxylic time be 12~for 24 hours, reaction carry out at room temperature；Described is de-
Water condensation reaction time is 36~48h.
Preferably, in step 6, the concentration of the anticancer drug aqueous solution is 5~10mg/mL, ultraviolet light time
For 12-24h.
Preferably, in step 7, the mass ratio of the MSNs-g-PCAAMC-b-PDMAEMA@5-FU and gene is 10~
60:1.
The application that the present invention also provides the drug gene carriers of above-mentioned response pH and ultraviolet light in drug and gene controlled release.
Compared with prior art, the invention has the following advantages that
The drug gene carrier (1) of response pH and ultraviolet light of the invention are not needed using additional end-capping reagent, ultraviolet
Spontaneous crosslinking blocks drug molecule in meso-hole structure under illumination；(2) energy quick response pH stimulation, high sensitivity；(3) simultaneously
Gene delivery can be used for adsorbing therapy gene.
Detailed description of the invention
Fig. 1 is the action principle explanatory diagram of the drug gene carrier of response pH and ultraviolet light of the invention；
Fig. 2 be of the invention response pH and ultraviolet light drug gene carrier under acidity stimulation adriamycin release profiles；
Fig. 3 is the gel electrophoresis figure after the drug gene carrier adsorption gene of response pH and ultraviolet light of the invention.
Specific embodiment
The principle of the present invention is: under ultraviolet lighting of the wavelength greater than 310nm intermolecular ring can occur for cumarin molecule
Addition reaction, that is, so-called photodimerization phenomenon can be applied to mesoporous silica particles surface as crosslinking using this characteristic
Site blocks mesopore orbit, prevents drug from revealing in advance.And cumarin is connected to by the suitable rhizome of Chinese monkshood amido bond of pH sensitivity
On block copolymer, in acid condition along rhizome of Chinese monkshood amido bond meeting spontaneous disruption, the cumarin being cross-linked to each other is detached from Jie therewith
Hole silica surface, drug are released out.And polymethylacrylic acid diformazan ammonia ethyl ester segment contains on block copolymer
There is a large amount of tertiary amino, thus have positive charge abundant, can be used to load electronegative gene.
In Fig. 1, A represents the anticancer drug of load, and B is represented mesoporous silica nano-particle (MSN), and C indicates that block is total
The poly (glycidyl methacrylate) chain section of side group modification 7- (along rhizome of Chinese monkshood amide ethyoxyl) -4- methylcoumarin, D in polymers
Indicate that polymethylacrylic acid diformazan ammonia ethyl ester segment in block copolymer, E represent the therapeutic gene combined.
As shown in Figure 1, nano material carries out illumination, block copolymer side group after loading anticancer drug, to nano material
On cumarin pyranone ring and neighbouring cumarin pyranone ring cycloaddition reaction, that is, photodimerization phenomenon, block copolymer point occurs
It is crosslinked between subchain, this crosslinked action plugs mesopore orbit, so that anticancer drug can not be let out in neutral conditions
Expose, process is as shown in route I → II.
When solution environmental is transformed into acid condition by neutrality, the acid-sensitive of cumarin and block copolymer is connected along the rhizome of Chinese monkshood
Amido bond hydrolyzes, and the cumarin of photodimerization is detached from from block copolymer, disappears, loads to the ponding of meso-hole structure
Anticancer drug be released out, process is as shown in route I → III.
In neutral conditions, uncle on polymethylacrylic acid diformazan ammonia ethyl ester segment in the block copolymer of nano-material surface
Amino protonates, becoming positively charged property of block copolymer, so as to adsorb electronegative while loading anticancer drug
Gene, process is as shown in route I → III.
Below with reference to embodiment and attached drawing, the invention will be further described.
Embodiment 1
1. the preparation of mesoporous silica nano-particle
It weighs 0.5g cetyl trimethylammonium bromide (CTAB) to be placed in 500mL flask, it is water-soluble that 240mL deionization is added
Solution, is vigorously stirred (500 revs/min), is heated to 80 DEG C.2M NaOH solution (1.75mL) is taken to be added in above-mentioned solution, stirring
30min.Then 2.5mL tetraethyl orthosilicate (TEOS) is slowly added dropwise dropwise into mixed liquor, gradually appears white opacity, 80 DEG C
Lower mechanical stirring 2h.After reaction, it is filtered while hot with sand core funnel, obtains white solid, then washed with a large amount of deionizations
White solid is washed, 50 DEG C of vacuum drying obtain the mesoporous silica nano-particle (MCM-41 (CTAB)) containing CTAB template.
The synthesis of bromo- 2- methyl-N-3 (trimethoxy silane) propionamide of 2.2-
Bibliography [Sun Y, Ding X, Zheng Z, et al.Surface initiated ATRP in the
synthesis of iron oxide/polystyrene core/shell nanoparticles[J].European
Polymer Journal, 2007,43 (3): 762-772.] preparation, specifically:
Measure 1.74mL 3- aminopropyl trimethoxysilane (APTMOS) and 2.08mL triethylamine (TEA) be dissolved in 50mL without
1.85mL 2- bromo isobutyl acylbromide (BIBB) is added dropwise toward above-mentioned solution in ice bath under nitrogen atmosphere in water methylene chloride, reaction
2h.Then solution is heated to room temperature with continuous stirring, overnight.After the reaction was completed, successively 0.01M HCl (2 × 20mL) is used
Mixture is washed with cold water (3 × 20mL), to remove by-product triethylamine hydrobromide.Organic phase anhydrous Na2SO4It is dry.Rotation
After turning evaporation of solvent, light yellow oil 2- bromine 2- methyl-N-3 [(trimethoxy silane) propyl] propionamide (Br- is obtained
APTMOS)。
3. bromo- 2- methyl-N-3 (trimethoxy silane) propionamide of mesoporous silica nano-particle surface modification 2-
200mg MCM-41 (CTAB) ultrasonic disperse is weighed in 50mL dry toluene, 50 μ L Br- are then added dropwise
APTMOS, under nitrogen protection, 90 DEG C of reflux 12h of oil bath are collected by centrifugation white solid, are sufficiently washed with dry toluene and methanol,
Then obtained solid is dispersed in the mixed solution of 3mL concentrated hydrochloric acid and 50mL methanol, is flowed back for 24 hours at 60 DEG C.It is collected by centrifugation,
And washed with methanol, it is dry under vacuum to obtain MSNs-Br.
4. mesoporous silica nano-particle surface grafting poly (glycidyl methacrylate)
100mg MSNs-Br ultrasonic disperse is weighed in the anhydrous N of 2mL, N '-dimethyl formamide, ultrasound 30min, connects altogether
Dropwise addition 0.1mL monomer methacrylic acid ethylene oxidic ester (GMA) and 10 μ L ligand pentamethyldivinyltriamine.Then pass through
Four air for vacuumizing/leading in nitrogen circulation removing reaction system, in a nitrogen atmosphere, the 3.5mg protobromide that will be purified
Copper is added in above-mentioned solution, vacuumizes/leads to anaerobic in nitrogen circulation guarantee system again by four times, react 5min at room temperature.
After open bottle stopper manually, to stop reacting.Product is placed in EDTA aqueous solution and is dialysed for 24 hours, to remove copper catalyst
And residual monomer.Then by centrifuge separation, white solid is obtained, is washed with distilled water and methanol, is dried in vacuo, obtains at 50 DEG C
To MSNs-g-PGMA.
5. mesoporous silica nano-particle surface is further grafted polymethylacrylic acid diformazan ammonia ethyl ester
100mg MSNs-g-PGMA ultrasonic disperse is weighed in 3mL methanol/water (1/1, v/v) solution, is then added
0.3mL monomer methacrylic acid diformazan ammonia ethyl ester and 16 μ L ligand pentamethyldivinyltriamine.Then vacuumized by four times/
Logical nitrogen circulation removes the air in reaction system, in a nitrogen atmosphere, the 5.3mg cuprous bromide purified is added above-mentioned molten
In liquid, anaerobic in nitrogen circulation guarantee system is vacuumized/led to again by four times, reacts 3h at room temperature.After open manually
Bottle stopper, to stop reacting.Product is placed in EDTA aqueous solution and is dialysed for 24 hours, to remove copper catalyst and residual monomer.Then
By centrifuge separation, white solid is obtained, is washed with distilled water and methanol, is dried in vacuo at 50 DEG C, obtains MSNs-g-PGMA-
b-PDMAEMA。
6. the block polymer decorated cumarin molecule in mesoporous silica nano-particle surface
100mg MSNs-g-PGMA-b-PDMAEMA ultrasonic disperse is weighed in 10mL anhydrous tetrahydro furan and is stirred, so
2mL ethylenediamine is added afterwards, flows back 24 hours for 60 DEG C in a nitrogen atmosphere, centrifuge separation is successively washed with tetrahydrofuran and methanol,
Vacuum drying obtains solid product MSN-g-PEDA-b-PDMAEMA.
Weigh 40mg 7- (along rhizome of Chinese monkshood amide ethyoxyl) -4- methylcoumarin (CA-AMC), 205mg 1- ethyl-(3- bis-
Dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 123mg N- hydroxysuccinimide be dissolved in anhydrous N, N '-dimethyl first
Carboxyl in amide, in activation 7- (along rhizome of Chinese monkshood amide ethyoxyl) -4- methylcoumarin.12h is stirred at 25 DEG C, it will be above-mentioned molten
Drop is added to the N of the MSN-g-PEDA-b-PDMAEMA containing 50mg, in N '-dimethyl formamide dispersion liquid, lower 25 DEG C of nitrogen atmosphere
It is protected from light stirring 36h, after reaction, N, N '-dimethyl formamide and methanol washing, vacuum at 50 DEG C are successively used in centrifuge separation
It is dry, obtain MSNs-g-PCAAMC-b-PDMAEMA.
7. mesoporous silica nano-particle loads 5-fluor-uracil
It weighs 15mg 5-fluor-uracil to be dissolved in 3mL distilled water, 100mg MSNs-g-PCAAMC-b-PDMAEMA is surpassed
Sound disperses in the above solution, and centrifugation obtains solid after room temperature is vigorously stirred 48h under dark condition.Then this dispersion liquid is placed
Prolonged exposure is carried out under 365nm ultraviolet lamp, is collected by centrifugation after irradiating 12h, and sufficiently washed with distilled water to remove surface
5-fluor-uracil is dried to obtain the mesoporous silica nano-particle MSNs-g-PCAAMC-b- of load 5-fluor-uracil under vacuum
PDMAEMA@5-FU。
The stimulating responsive of 8.5- fluorouracil discharges
In order to study the controlled release behavior of pharmaceutical carrier at various ph values obtained, tested as follows: by it is ultraviolet can
See spectrophotometer test dissolution medium in different time points 266nm place absorbance, according to the standard of 5-fluor-uracil work
Curve calculates 5-fluor-uracil concentration in each time point dissolution medium, and the 5-fluor-uracil release obtained under different pH value is bent
Line.Concrete operations are as follows: it weighs 1.5mg MSNs-g-PCAAMC-b-PDMAEMA@5-FU and is placed in bag filter (MWCO 3500),
Be then immersed in 10mL PBS buffer solution (pH=7.4,5.0 or 2.0) in, persistently stir at room temperature.At scheduled time point, inhale
It takes 3mLPBS buffer solution for testing, then supplements the new PBS buffer solution of equal volume.It is surveyed by ultraviolet specrophotometer
Determine absorbance of the PBS buffer solution at 266nm, its cumulative release amount is calculated according to the standard curve of 5-fluor-uracil.
9. loading the mesoporous silica nano-particle combination gene of 5-fluor-uracil
It weighs 1mg and grinds thin MSNs-g-PCAAMC-b-PDMAEMA@5-FU, be dispersed in by strong vortex effect
In the PBS buffer solution (pH=7.4) of 1mL, then draw above-mentioned dispersion liquid and the buffer solution containing 0.2 μ g pDNA with 10~
60 different quality ratio is acted on by vortex and being mixed, and the mixture (MSNs-g-PCAAMC-b-PDMAEMA@5-FU/pDNA) is made
The stationary incubation 30min at 37 DEG C obtains the drug gene carrier MSNs-g-PCAAMC-b- of response pH and ultraviolet light
PDMAEMA@5-FU/pDNA。
Embodiment 2
1. the preparation of mesoporous silica nano-particle
It weighs 0.5g cetyl trimethylammonium bromide (CTAB) to be placed in 500mL flask, it is water-soluble that 240mL deionization is added
Solution, is vigorously stirred (500 revs/min), is heated to 80 DEG C.2M NaOH solution (1.75mL) is taken to be added in above-mentioned solution, stirring
30min.Then 2.5mL tetraethyl orthosilicate (TEOS) is slowly added dropwise dropwise into mixed liquor, gradually appears white opacity, 80 DEG C
Lower mechanical stirring 2h.After reaction, it is filtered while hot with sand core funnel, obtains white solid, then washed with a large amount of deionizations
White solid is washed, 50 DEG C of vacuum drying obtain the mesoporous silica nano-particle (MCM-41 (CTAB)) containing CTAB template.
The synthesis of bromo- 2- methyl-N-3 (trimethoxy silane) propionamide of 2.2-
Bibliography [Sun Y, Ding X, Zheng Z, et al.Surface initiated ATRP in the
synthesis of iron oxide/polystyrene core/shell nanoparticles[J].European
Polymer Journal, 2007,43 (3): 762-772.] preparation, specifically:
Measure 1.74mL 3- aminopropyl trimethoxysilane (APTMOS) and 2.08mL triethylamine (TEA) be dissolved in 50mL without
1.85mL 2- bromo isobutyl acylbromide (BIBB) is added dropwise toward above-mentioned solution in ice bath under nitrogen atmosphere in water methylene chloride, reaction
2h.Then solution is heated to room temperature with continuous stirring, overnight.After the reaction was completed, successively 0.01M HCl (2 × 20mL) is used
Mixture is washed with cold water (3 × 20mL), to remove by-product triethylamine hydrobromide.Organic phase anhydrous Na2SO4It is dry.Rotation
After turning evaporation of solvent, light yellow oil 2- bromine 2- methyl-N-3 [(trimethoxy silane) propyl] propionamide (Br- is obtained
APTMOS)。
3. bromo- 2- methyl-N-3 (trimethoxy silane) propionamide of mesoporous silica nano-particle surface modification 2-
200mg MCM-41 (CTAB) ultrasonic disperse is weighed in 50mL dry toluene, 200 μ L Br- are then added dropwise
APTMOS, under nitrogen protection, 90 DEG C of oil bath reflux for 24 hours, are collected by centrifugation white solid, are sufficiently washed with dry toluene and methanol,
Then obtained solid is dispersed in the mixed solution of 3mL concentrated hydrochloric acid and 50mL methanol, is flowed back for 24 hours at 60 DEG C.It is collected by centrifugation,
And washed with methanol, it is dry under vacuum to obtain MSNs-Br.
4. mesoporous silica nano-particle surface grafting poly (glycidyl methacrylate)
100mg MSNs-Br ultrasonic disperse is weighed in the anhydrous N of 2mL, N '-dimethyl formamide, ultrasound 30min, connects altogether
Dropwise addition 0.3mL monomer methacrylic acid ethylene oxidic ester (GMA) and 30 μ L ligand pentamethyldivinyltriamine.Then pass through
Four air for vacuumizing/leading in nitrogen circulation removing reaction system, in a nitrogen atmosphere, the 10.6mg protobromide that will be purified
Copper is added in above-mentioned solution, vacuumizes/leads to anaerobic in nitrogen circulation guarantee system again by four times, react 15min at room temperature.
After open bottle stopper manually, to stop reacting.Product is placed in EDTA aqueous solution and is dialysed for 24 hours, to remove copper catalyst
And residual monomer.Then by centrifuge separation, white solid is obtained, is washed with distilled water and methanol, is dried in vacuo, obtains at 50 DEG C
To MSNs-g-PGMA.
5. mesoporous silica nano-particle surface is further grafted polymethylacrylic acid diformazan ammonia ethyl ester
100mg MSNs-g-PGMA ultrasonic disperse is weighed in 3mL methanol/water (1/1, v/v) solution, is then added
0.5mL monomer methacrylic acid diformazan ammonia ethyl ester and 26 μ L ligand pentamethyldivinyltriamine.Then vacuumized by four times/
Logical nitrogen circulation removes the air in reaction system, in a nitrogen atmosphere, the 8.9mg cuprous bromide purified is added above-mentioned molten
In liquid, anaerobic in nitrogen circulation guarantee system is vacuumized/led to again by four times, reacts 5h at room temperature.After open manually
Bottle stopper, to stop reacting.Product is placed in EDTA aqueous solution and is dialysed for 24 hours, to remove copper catalyst and residual monomer.Then
By centrifuge separation, white solid is obtained, is washed with distilled water and methanol, is dried in vacuo at 50 DEG C, obtains MSNs-g-PGMA-
b-PDMAEMA。
6. the block polymer decorated cumarin molecule in mesoporous silica nano-particle surface
100mg MSNs-g-PGMA-b-PDMAEMA ultrasonic disperse is weighed in 10mL anhydrous tetrahydro furan and is being stirred,
Then, 2mL ethylenediamine is added, flows back 36 hours for 60 DEG C in a nitrogen atmosphere, centrifuge separation is successively washed with tetrahydrofuran and methanol
It washs, vacuum drying obtains solid product MSN-g-PEDA-b-PDMAEMA.
Weigh 40mg 7- (along rhizome of Chinese monkshood amide ethyoxyl) -4- methylcoumarin (CA-AMC), 205mg 1- ethyl-(3- bis-
Dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 123mg N- hydroxysuccinimide be dissolved in anhydrous N, N '-dimethyl first
Carboxyl in amide, in activation 7- (along rhizome of Chinese monkshood amide ethyoxyl) -4- methylcoumarin.It is stirred at 25 DEG C for 24 hours, it will be above-mentioned molten
Drop is added to the N of the MSN-g-PEDA-b-PDMAEMA containing 50mg, in N '-dimethyl formamide dispersion liquid, lower 25 DEG C of nitrogen atmosphere
It is protected from light stirring 48h, after reaction, N, N '-dimethyl formamide and methanol washing, vacuum at 50 DEG C are successively used in centrifuge separation
It is dry, obtain MSNs-g-PCAAMC-b-PDMAEMA.
7. mesoporous silica nano-particle loads 5-fluor-uracil
It weighs 30mg 5-fluor-uracil to be dissolved in 3mL distilled water, 100mg MSNs-g-PCAAMC-b-PDMAEMA is surpassed
Sound disperses in the above solution, and centrifugation obtains solid after room temperature is vigorously stirred 48h under dark condition.Then this dispersion liquid is placed
Prolonged exposure is carried out under 365nm ultraviolet lamp, irradiation is collected by centrifugation afterwards for 24 hours, and is sufficiently washed with distilled water to remove surface
5-fluor-uracil is dried to obtain the mesoporous silica nano-particle MSNs-g-PCAAMC-b- of load 5-fluor-uracil under vacuum
PDMAEMA@5-FU。
The stimulating responsive of 8.5- fluorouracil discharges
In order to study the controlled release behavior of pharmaceutical carrier at various ph values obtained, tested as follows: by it is ultraviolet can
See spectrophotometer test dissolution medium in different time points 266nm place absorbance, according to the standard of 5-fluor-uracil work
Curve calculates 5-fluor-uracil concentration in each time point dissolution medium, and the 5-fluor-uracil release obtained under different pH value is bent
Line.Concrete operations are as follows: it weighs 1.5mg MSNs-g-PCAAMC-b-PDMAEMA@5-FU and is placed in bag filter (MWCO 3500),
Be then immersed in 10mL PBS buffer solution (pH=7.4,5.0 or 2.0) in, persistently stir at room temperature.At scheduled time point, inhale
It takes 3mL PBS buffer solution for testing, then supplements the new PBS buffer solution of equal volume.Pass through ultraviolet specrophotometer
Absorbance of the PBS buffer solution at 266nm is measured, its cumulative release amount is calculated according to the standard curve of 5-fluor-uracil.
As shown in Fig. 2, in acid condition nano-carrier can realizing controlled-release release 5-fluor-uracil, and in neutral conditions
Substantially it does not discharge.After for 24 hours, the 5-fluor-uracil for only having 9.5% at pH=7.4 is leaked from nano-carrier, and
5-fluor-uracil burst size can reach 41.8% under pH=5.0.When pH value is further reduced to 2.0,5-fluor-uracil burst size
It can reach maximum, be 73.0%.Under conditions of different pH, the burst size of 5-fluor-uracil is different, shows that the nano-carrier can
To realize stimulating responsive controlled release.
9. loading the mesoporous silica nano-particle combination gene of 5-fluor-uracil
It weighs 1mg and grinds thin MSNs-g-PCAAMC-b-PDMAEMA@5-FU, be dispersed in by strong vortex effect
In the PBS buffer solution (pH=7.4) of 1mL, the above-mentioned dispersion liquid of certain volume and the buffering for containing 0.2 μ g pDNA are then drawn
Solution is acted on by vortex with the different quality ratio of 10-60 and being mixed, and the mixture (MSNs-g-PCAAMC-b-PDMAEMA@5- is made
FU/pDNA) the stationary incubation 30min at 37 DEG C obtains the drug gene carrier MSNs-g-PCAAMC- of response pH and ultraviolet light
b-PDMAEMA@5-FU/pDNA。
As shown in figure 3, as the mass ratio of MSNs-g-PCAAMC-b-PDMAEMA@5-FU and pDNA increase to from 10:1
The migration of 60:1, pDNA on Ago-Gel is gradually obstructed.As MSNs-g-PCAAMC-b-PDMAEMA@5-FU and pDNA
When mass ratio increases to 30:1, pDNA is stuck in well completely, shows that nano-carrier has stronger combination energy to gene
Power.
Comparative example 1
This comparative example is substantially the same manner as Example 1, it is unique unlike monomer methacrylic acid glyceride in step 4, match
Body pentamethyldivinyltriamine and catalyst cuprous bromide dosage are respectively 0.5 μ of every milligram of mesoporous silica nano-particle
L, 0.052 μ L and 0.018mg；Monomer methacrylic acid diformazan ammonia ethyl ester in step 5, ligand pentamethyldivinyltriamine with urge
Agent cuprous bromide dosage is respectively 1 μ L, 0.052 μ L and 0.018mg of every milligram of mesoporous silica nano-particle.It obtains
The polymer molecular weight of MSNs-g-PGMA and MSNs-g-PGMA-b-PDMAEMA surface grafting is too small, can not effectively adsorb anticancer
Drug and gene.
Comparative example 2
This comparative example is substantially the same manner as Example 1, it is unique unlike monomer methacrylic acid glyceride in step 4, match
Body pentamethyldivinyltriamine and catalyst cuprous bromide dosage are respectively 5 μ L of every milligram of mesoporous silica nano-particle,
0.52 μ L and 0.18mg；Monomer methacrylic acid diformazan ammonia ethyl ester in step 5, ligand pentamethyldivinyltriamine and catalyst
Cuprous bromide dosage is respectively 10 μ L, 0.52 μ L and 0.18mg of every milligram of mesoporous silica nano-particle.Obtained MSNs-g-
The polymer molecular weight of PGMA and MSNs-g-PGMA-b-PDMAEMA surface grafting is excessive, and product is in hard block, can not
For subsequent application.
Claims (10)
1. responding the drug gene carrier of pH and ultraviolet light, which is characterized in that the carrier is using mesoporous silicon oxide as skeleton
Building, surface grafting cationic block polymer, chemical structure are as follows:
Wherein, A represents the anticancer drug of load, and B represents mesoporous silica nano-particle, and C indicates that 7- is (suitable in block copolymer
Rhizome of Chinese monkshood amide ethyoxyl) the modified poly (glycidyl methacrylate) chain section of -4- methylcoumarin, D expression block copolymer
Middle polymethylacrylic acid diformazan ammonia ethyl ester segment, E represent the therapeutic gene combined.
2. drug gene carrier according to claim 1, which is characterized in that it is phonetic that the anticancer drug is selected from 5- fluorine urea
Pyridine, adriamycin, Chlorambucil or mitoxantrone.
3. the preparation method of the drug gene carrier of response pH according to claim 1 or 2 and ultraviolet light, feature exist
In, the specific steps are as follows:
Step 1, by mesoporous silica nano-particle and bromo- 2- methyl-N-3 (trimethoxy silane) propionamide of 2- in no water beetle
It flows back in benzene, dealcoholization is carried out under nitrogen protection, obtains MSNs-Br；
Step 2, MSNs-Br is ground and be dried in vacuo, by monomer methacrylic acid glyceride, ligand pentamethyl divinyl
Triamine and catalyst cuprous bromide dosage be respectively every milligram of mesoporous silica nano-particle 1~3 μ L, 0.1~0.3 μ L and
Glyceral methacrylate, pentamethyldivinyltriamine and cuprous bromide is added in anhydrous N, N '-two in 0.035~0.106mg
It is reacted in methylformamide, the atom transition free radical polymerization reaction of first step surface initiation is carried out under oxygen free condition, through dialysing
Excessive cuprous bromide catalyst and residual monomer are removed, is dried in vacuo, obtains MSNs-g-PGMA；
Step 3, after MSNs-g-PGMA being ground, by monomer methacrylic acid diformazan ammonia ethyl ester, ligand pentamethyl divinyl three
Amine and catalyst cuprous bromide dosage be respectively every milligram of mesoporous silica nano-particle 3-5 μ L, 0.16~0.26 μ L and
0.053~0.089mg, be added dimethylaminoethyl acrylate methyl ammonia ethyl ester, pentamethyldivinyltriamine and cuprous bromide in methanol and
It is reacted in the mixed solution of water, the atom transition free radical polymerization reaction of second step surface initiation is carried out under oxygen free condition, through saturating
Analysis removes excessive cuprous bromide catalyst and residual monomer, and vacuum drying obtains MSNs-g-PGMA-b-PDMAEMA；
Step 4, ethylenediamine, nitrogen is added in anhydrous tetrahydro furan in ultrasonic disperse after MSNs-g-PGMA-b-PDMAEMA being ground
Row ring-opening reaction is flowed back under gas atmosphere, is collected by centrifugation and washed product, vacuum drying obtain MSNs-g-PEDA-b-
PDMAEMA；
Step 5, ultrasonic disperse is in anhydrous N, N '-dimethyl formamide after MSNs-g-PEDA-b-PDMAEMA being ground, and benefit
With 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and N- hydroxysuccinimide activation 7- (along rhizome of Chinese monkshood acyl
Amine ethyoxyl) carboxyl on -4- methylcoumarin, 7- (along rhizome of Chinese monkshood amide ethyoxyl) -4- methylcoumarin after activation is added
Enter into above-mentioned dispersion liquid, carry out dehydration condensation, is collected by centrifugation and washed product, vacuum drying obtain MSNs-g-
PCAAMC-b-PDMAEMA；
Step 6, ultrasonic disperse in the aqueous solution of anticancer drug, keep away by room temperature after MSNs-g-PCAAMC-b-PDMAEMA being ground
Light is stirred to being uniformly mixed, and then uses the ultraviolet light dispersion liquid of 365nm, makes the cumarin on block copolymer that light occur
After illumination, product is collected by centrifugation in dimerization reaction, and vacuum drying obtains MSNs-g-PCAAMC-b-PDMAEMA@5-FU；
Step 7, it is dispersed in PBS buffer solution after MSNs-g-PCAAMC-b-PDMAEMA@5-FU grinding by vortex, with base
It dilutes because being mixed with vortex, and with PBS buffer solution, is incubated at 37 DEG C, obtain the drug gene carrier of response pH and ultraviolet light
MSNs-g-PCAAMC-b-PDMAEMA@5-FU/pDNA。
4. preparation method according to claim 3, which is characterized in that in step 1, the bromo- 2- methyl-N-3 (three of the 2-
Methoxy silane) propionamide occurs nucleophilic substitution by 3- aminopropyl trimethoxysilane and 2- bromine isobutyl acylbromide and is made；Institute
The dosage of bromo- 2- methyl-N-3 (trimethoxy silane) propionamide of the 2- stated is that every milligram of mesoporous silica nano-particle uses
0.25~1 μ L, the reaction time be 12~for 24 hours.
5. preparation method according to claim 3, which is characterized in that in step 2, the first step atom transfer is free
Base polymerization reaction time is 5~15min.
6. preparation method according to claim 3, which is characterized in that in step 3, the second step atom transfer is free
Base polymerization reaction time is 3~5h, and the volume ratio of first alcohol and water is 1:1.
7. preparation method according to claim 3, which is characterized in that in step 4, the ring-opening reaction time be 24~
36h；In step 5, the activated carboxylic time be 12~for 24 hours, reaction carry out at room temperature；When the described dehydration condensation
Between be 36~48h.
8. preparation method according to claim 3, which is characterized in that in step 6, the anticancer drug aqueous solution it is dense
Degree is 5~10mg/mL, and the ultraviolet light time is 12-24h.
9. preparation method according to claim 3, which is characterized in that in step 7, the MSNs-g-PCAAMC-b-
The mass ratio of PDMAEMA@5-FU and gene is 10~60:1.
10. the drug gene carrier of response pH according to claim 1 or 2 and ultraviolet light is in drug and gene controlled release
Using.
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