CN105943520B - A kind of biological responding targeting double medicament controlled-release carrier material and preparation method thereof - Google Patents
A kind of biological responding targeting double medicament controlled-release carrier material and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5115—Inorganic compounds
Abstract
The invention belongs to target medicament slow release carrier material fields, and in particular to a kind of biological responding targeting double medicament controlled-release carrier material and preparation method thereof.The biological responding targeting double medicament controlled-release carrier material is a kind of bivalve layer biological responding composite nano-microsphere, and hypostracum is nanosphere made of being reunited as amphiphilic macromolecular, and outer shell is mesoporous silicon oxide.The diameter of the hypostracum is 160nm~800nm, and the mesoporous pore size of outer shell mesoporous silicon oxide is 2~4nm.Hypostracum amphiphilic macromolecular nanosphere of the present invention can provide load site for hydrophobic drug, outer shell mesoporous silicon oxide can provide load site for hydrophilic medicament, therefore, the biological responding targeting double medicament controlled-release carrier material can load two different drugs, the sustained release of double drugs is realized, to achieve the purpose that double drug synergistic treatments.
Description
Technical field
The invention belongs to target medicament slow release carrier material fields, and in particular to a kind of double drugs of biological responding targeting are slow
Release carrier material and preparation method thereof.
Background technique
As social industrialization degree increases, environmental pollution is increasingly severe, and the cancer rate of the mankind rises year by year.It is same with this
When, with the progress of social civilization, people increasingly pay attention to focusing on the quality of life and health of itself.So treating cancer
Since 20th century, scientist and physician are urgently solved the problems, such as.The drug for the treatment of cancer is mainly contained by some at present
It is made of the hydrophobicity organic molecule of a large amount of phenyl ring classes or pyridines group.And blood of human body is hydrophilic environments, drug is very
It is insoluble in blood, this proposes a significant challenge to the transport and absorption of hydrophobic drug.Simultaneously drug reach lesion it
Before, most of drug has just discharged in advance, and the dose for actually reaching lesion is seldom, this seriously reduces utilizing for drug and imitates
Rate.In addition, Chemotherapeutic Drugs On Normal cell has toxic side effect, the drug discharged before reaching lesion has normal cell
Very big damage.In order to solve these problems, targeted drug delivery systme, especially biological responding targeted drug delivery systme
Become the emphasis for research.Under the premise of not changing drug molecular structure, hydrophobicity is embedded using the macromolecule of functionalization
The method of drug not only solves the water-soluble problem of drug molecule, moreover it is possible to realize response release (such as pH sound of drug molecule
Answer, photoresponse, enzyme response, amino acid response etc.), it avoids drug and is discharged in advance before reaching lesion, improving drug utilization
While rate, injury of the drug to normal cell is also reduced.
In addition, proposing the double drug release bodies of biological responding on the basis of biological responding targeted drug delivery systme
System, the system have unique advantage in terms of solving the synergistic effect of toxic side effect and double drugs of drug.Use biofacies
Mesoporous material (the SiO of capacitive2) functionalized macromolecular for having embedded hydrophobic drug is embedded again, the system is in addition to reality
Except the response release of existing drug molecule, additionally it is possible to load two kinds of drugs of different nature, one of drug can kill disease
Attenuate born of the same parents, and another drug can repair impaired body, plays the work that can be killed sick cell and protect normal cell
With.Or the two different chemotherapeutics of load, both drugs can act synergistically, synergistic effect is far longer than wherein one
The effect of cancer cell is killed caused by kind drug.Because the double drug delivery systems of biological responding have above-mentioned advantage, close several
Nian Lai, the double drug delivery systems of biological responding receive the favor of scientist.
Summary of the invention
The present invention is in view of the deficiencies of the prior art, and it is an object of the present invention to provide a kind of biological responding targets double medicament controlled-release carrier
Material and preparation method thereof.
For achieving the above object, the technical solution adopted by the present invention are as follows:
A kind of biological responding targeting double medicament controlled-release carrier material, which is characterized in that the biological responding targeting is double
Slow releasing carrier of medication material is a kind of bivalve layer biological responding composite nano-microsphere, and hypostracum is by amphiphilic macromolecular group
Nanosphere made of poly-, outer shell is mesoporous silicon oxide.
In above scheme, the diameter of the hypostracum is 160nm~800nm.
In above scheme, the amphiphilic macromolecular exists in the form of nanometre glue (Nano-gel), and structural formula is
In above scheme, the molecular weight of the amphiphilic macromolecular is 6000Da~24000Da, and water-wet side ratio is
30wt%~70wt%.
In above scheme, the outer shell is mesoporous silicon oxide made of being hydrolyzed as silicon source, and the mesoporous aperture is 2
~4nm.
The preparation method of above-mentioned biological responding targeting double medicament controlled-release carrier material, includes the following steps:
(1) the single-stranded preparation of amphiphilic macromolecular: by RAFT reagent, PDSEMA (pyridyldithiol methacrylic acid second
Ester), polyethylene glycol methacrylate and AIBN (azodiisobutyronitrile) be dissolved in DMF (dimethylformamide), with freezing
The purification of defrosting pump circulation method degassing 3 times or more；Then reaction mixture is sealed, is put into oil bath pan and reacts；Reaction gained mixing
Object is dissolved in methylene chloride, is then fallen in n-hexane；Sediment is dissolved in methylene chloride again, is then fallen to again
In ether, it is single-stranded to obtain unreduced amphiphilic macromolecular；
(2) preparation of amphiphilic macromolecular nanosphere: acetone is dissolved in by amphiphilic macromolecular is single-stranded obtained by step (1)
In, dithiothreitol (DTT) (DTT) is slowly added dropwise thereto；Stirring 10 minutes is added deionized water, then is stirred at room temperature overnight,
After allowing organic matter sufficiently to volatilize, amphiphilic macromolecular nanosphere is obtained；
(3) it the synthesis of the biological responding composite nano-microsphere of bivalve layer: disperses amphiphilic macromolecular nanosphere in
In water, triethanolamine and surfactant is added；2h is stirred at 80 DEG C, tetraethyl orthosilicate is added, continues to stir at 80 DEG C
Mix 8h；Resulting product be filtered, washed, dry after to get to bivalve layer biological responding composite nano-microsphere.
In above scheme, the RAFT reagent is 1- dodecyl -2- (2,2- isobutyric acid)-trithiocarbonate, structure
Formula is
In above scheme, step (1) the RAFT reagent, PDSEMA, polyethylene glycol methacrylate and AIBN ratio
Example is 90mg:5g:4g:10mg；The oil bath temperature of the reaction is 70 DEG C~80 DEG C, and the reaction time is 12h~14h.
In above scheme, the single-stranded ratio with dithiothreitol (DTT) of step (2) described amphiphilic macromolecular is 10mg:2mg.
In above scheme, step (3) the amphiphilic macromolecular nanosphere, triethanolamine, surfactant and positive silicon
The ratio of sour tetra-ethyl ester is 80uL~100uL:0.21g:0.22g:1.22mL.
In above scheme, step (3) surfactant is cetyl trimethylammonium bromide, cetyl chloride ammonium
One of with cetyl ammonium bromide.
In above scheme, the RAFT reagent is made by the steps to obtain: (1) by lauryl mercaptan and tetrabutyl phosphonium bromide
Ammonium is dissolved in acetone, then it is mixed with KOH solution；(2) carbon disulfide is slowly added into mixed solution obtained by step (1) dropwise
In, it stirs 30 minutes, chloroform is added thereto, is stirred for 10min；Then under the conditions of mixed solution being placed in 0 DEG C, while stirring
It mixes side and KOH solution is added dropwise, after being added dropwise to complete, be placed in and be stirred overnight at room temperature；(3) into step (2) acquired solution be added go from
Then concentrated hydrochloric acid acidification is added in sub- water；Products therefrom is dried in vacuo to obtain solid product；With recrystallisation from isopropanol, then vacuum
Dry removal isopropanol；It is recrystallized again with n-hexane, then vacuum drying removal n-hexane, obtains RAFT reagent.
In above scheme, step (1) lauryl mercaptan, tetrabutylammonium bromide, the ratio of carbon disulfide and chloroform
For 9.5~10.1g:0.64g~0.68g:2.6mL~3.0mL:5mL, the concentration of step (1) described KOH solution is 0.9g/mL
~1.0g/mL, the concentration of step (2) described KOH solution are 1.2g/mL~1.3g/mL.
In above scheme, the PDSEMA is made by the steps to obtain: (1) by 2,2 '-two sulphur, two pyridinium dissolution in
Glacial acetic acid is added under stirring condition in methanol thereto；(2) mercaptoethanol is dissolved in methanol, under the conditions of being stirred at room temperature by
Drop is added slowly in step (1) acquired solution, after being added dropwise completely, continues to stir 3h~4h；Then rotary evaporation of solvent obtains
To crude product；(3) crude product is purified by column chromatography for separation, obtains two sulphur ethyl alcohol (PDSE) of pyridine；Two sulphur ethyl alcohol of pyridine is added
Enter into methylene chloride, add triethylamine, cooling is stirred in ice bath；(4) methacrylic chloride is dissolved in methylene chloride,
Then it is slowly added under agitation in step (3) acquired solution, then continues to stir 6h~7h under room temperature, obtain
PDSEMA crude product, purifies finally by column chromatography for separation, obtains PDSEMA；
In above scheme, described 2, the ratio of 2 '-two sulphur, two pyridine, glacial acetic acid and mercaptoethanol is 15g:1mL:2.65g；
The ratio of the two sulphur ethyl alcohol of pyridine, triethylamine and methacrylic chloride is 4.60g~4.70g:3g:2.58g.
Beneficial effects of the present invention:
(1) biological responding targeting double medicament controlled-release carrier material of the present invention has good biological responding, energy
Enough Targeting delivery is realized using biological response.
(2) hypostracum amphiphilic macromolecular nanosphere of the present invention can provide load site for hydrophobic drug,
Outer shell mesoporous silicon oxide can provide load site for hydrophilic medicament, and therefore, the biological responding targets double drugs
Slow releasing carrier material can load two different drugs, realize the sustained release of double drugs, to reach the mesh of double drug synergistic treatments
's.
(3) hypostracum amphiphilic macromolecular nanosphere of the present invention and outer shell mesoporous silicon oxide all have biology
Compatibility, and be easy to be degraded in human body, toxic side effect will not be generated to human body.
Detailed description of the invention
Fig. 1 is the small angle XRD diagram that the embodiment of the present invention 1 prepares that gained biological responding targets double medicament controlled-release carrier material
Spectrum.
Fig. 2 is the dynamic light scattering grain size distribution of hypostracum amphiphilic macromolecular nanosphere in the embodiment of the present invention 1
Spectrum.
Fig. 3 is hypostracum amphiphilic macromolecular nanosphere in the embodiment of the present invention 1 before being embedded by mesoporous silicon oxide
(a) and embedding after (b) SEM picture.
Fig. 4 is the infared spectrum that the embodiment of the present invention 1 prepares that gained biological responding targets double medicament controlled-release carrier material.
Fig. 5 is hypostracum amphiphilic macromolecular nanosphere in the embodiment of the present invention 2 before being embedded by mesoporous silicon oxide
(a) and embedding after (b) SEM picture.
Hypostracum amphiphilic macromolecular nanosphere by mesoporous silicon oxide before being embedded (a) in Fig. 6 embodiment of the present invention 3
The SEM picture of (b) after embedding.
Specific embodiment
For a better understanding of the present invention, below with reference to the embodiment content that the present invention is furture elucidated, but it is of the invention
Content is not limited solely to the following examples.
In following embodiment, the single-stranded molecular weight of the amphiphilic macromolecular is 6000Da~24000Da, water-wet side ratio
For 30wt%~70wt%.
Embodiment 1
A kind of preparation method of biological responding targeting double medicament controlled-release carrier material, includes the following steps:
(1) synthesis of RAFT reagent:
A. 2.5g KOH is dissolved in 2.5mL H2KOH solution is obtained in O；By 10.1g lauryl mercaptan and 0.64g tetrabutyl bromine
Change ammonium and be dissolved in 25mL acetone, then it is mixed with KOH solution；
B. 2.6mL carbon disulfide is slowly added into dropwise in mixed solution obtained by step (a), is stirred 30 minutes, Xiang Qi
Middle addition 5mL chloroform, is stirred for 10min；Under the conditions of solution is placed in 0 DEG C, KOH solution (12.0g is added dropwise while stirring
KOH is dissolved in 10mL H2It is prepared in O), after being added dropwise to complete, it is placed in and is stirred overnight at room temperature；
C. 60mL deionized water is added into step (b) acquired solution, the acidification of 10mL concentrated hydrochloric acid is then added；Products therefrom
Vacuum drying obtains solid product；With recrystallisation from isopropanol, then vacuum drying removes isopropanol；It is recrystallized again with n-hexane,
Then vacuum drying removal n-hexane, obtains RAFT reagent；
(2) synthesis of PDSEMA:
A. 1mL ice vinegar is added in 2,2 '-two sulphur of 15g, two pyridinium dissolution thereto in 75mL methanol, under stirring condition
Acid；
B. 2.65g mercaptoethanol is dissolved in 15mL methanol, is added slowly to walk dropwise under the conditions of being stirred at room temperature
Suddenly in (a) acquired solution, after being added dropwise completely, continue to stir 3h；Then rotary evaporation of solvent obtains crude product；
C. above-mentioned crude product is purified by column chromatography, wherein use silica gel as static phase, ethyl acetate/just oneself
Alkane mixed liquor is as eluant, eluent；It is extra by 15Vt% (volume ratio) ethyl acetate/n-hexane mixed liquor elutes first
Two sulphur, two pyridine；Colorless oil as product, i.e. two sulphur ethyl alcohol of pyridine are eluted using 40Vt% ethyl acetate/n-hexane mixed liquor again
(PDSE)；
D. two sulphur ethyl alcohol of step (c) products therefrom pyridine is added in 20mL methylene chloride, adds 3g triethylamine, so
Stir cooling in ice bath again afterwards；
E. 2.58g methacrylic chloride is dissolved in 10mL methylene chloride, it is then under agitation that the solution is slow
It is added in step (d) acquired solution, then continues to stir 6h under room temperature, obtain crude product；Wash with distilled water three times, then
It is cleaned with strong brine, retains organic layer, then dry moisture with anhydrous sodium sulfate, then filter, collect crude yellow oil, lead to
Column chromatography for separation purification is crossed, wherein using silica gel as static phase, 25Vt% ethyl acetate/n-hexane mixed liquor is as elution
Agent, purification obtain PDSEMA；
(3) the single-stranded preparation of amphiphilic macromolecular: by 90mg RAFT reagent, 5g PDSEMA, 4g polyethylene glycol methyl-prop
Olefin(e) acid rouge (Mw 500) and 10mg AIBN are dissolved in 10mL DMF, with the purification of freeze-thaw pump circulation method degassing 3 times or more；
Then reaction mixture is sealed, is put into 70 DEG C of preheated oil bath pans and reacts 12h；Reaction gained mixture is dissolved in 5mL dichloro
In methane, then fall in 20mL n-hexane；Sediment is dissolved in 5mL methylene chloride again, is then fallen to again
In 20mL ether, it is single-stranded to obtain unreduced amphiphilic macromolecular；
(4) preparation of amphiphilic macromolecular nanosphere: being dissolved in 10mg amphiphilic macromolecular is single-stranded in 200 μ L acetone,
DTT is slowly added dropwise thereto；Stirring 10 minutes is added 1mL deionized water, then is stirred at room temperature overnight, and contacts, allows with air
After organic matter sufficiently volatilizees, amphiphilic macromolecular nanosphere (NG) is obtained；
(5) synthesis of the biological responding composite nano-microsphere of bivalve layer: by amphiphilic macromolecular nanometer obtained by step (4)
Microballoon is scattered in 120mL water, and 0.21g triethanolamine and 0.22g cetyl trimethylammonium bromide is added；It is stirred at 80 DEG C
2h adds the tetraethyl orthosilicate of 1.22ml, stirs 8h at 80 DEG C；Resulting product be filtered, washed, dry after to get
To the biological responding composite nano-microsphere of bivalve layer.
Product obtained by the present embodiment (the biological responding composite nano-microsphere of bivalve layer) is by small angle X-ray diffraction point
Analysis (map of X-ray diffraction is shown in Fig. 1) determines that outer layer silica is mesoporous silicon oxide, and mesoporous diameter is 2nm~4nm.
Dynamic light scattering particle size instrument analyzes result (see Fig. 2) display, amphiphilic macromolecular nanosphere before mesoporous silicon oxide embeds
(NG) diameter is 160nm or so.Fig. 3 is seen with the SEM picture after embedding before amphiphilic macromolecular nanosphere (NG) embedding,
Because under the effect of Electronic Speculum high pressure, amphiphilic macromolecular nanosphere reunites and forms larger-size ball, double after embedding before embedding
About 1 μm of diameter or so of the biological responding composite nano-microsphere of shell.Infrared spectrum analysis shows (see Fig. 4), biological response
Property targeting double medicament controlled-release carrier material be provided simultaneously with amphiphilic macromolecular and SiO2Absorption peak.
Embodiment 2
A kind of preparation method of biological responding targeting double medicament controlled-release carrier material, includes the following steps:
(1) synthesis of RAFT reagent: with embodiment 1；
(2) synthesis of PDSEMA:
(3) the single-stranded preparation of amphiphilic macromolecular: by 90mg RAFT reagent, 7g PDSEMA, 4g polyethylene glycol methyl-prop
Olefin(e) acid rouge (Mw 500) and 10mg AIBN are dissolved in 10mL DMF, with the purification of freeze-thaw pump circulation method degassing 3 times or more；
Then reaction mixture is sealed, is put into 70 DEG C of preheated oil bath pans and reacts 12h；Reaction gained mixture is dissolved in 5mL dichloro
In methane, then fall in 20mL n-hexane；Sediment is dissolved in 5mL methylene chloride again, is then fallen to again
In 20mL ether, it is single-stranded to obtain unreduced amphiphilic macromolecular；
(4) preparation of amphiphilic macromolecular nanosphere: being dissolved in 10mg amphiphilic macromolecular is single-stranded in 200 μ L acetone,
DTT is slowly added dropwise thereto；Stirring 10 minutes is added 1mL deionized water, then is stirred at room temperature overnight, and contacts, allows with air
After organic matter sufficiently volatilizees, amphiphilic macromolecular nanosphere (NG) is obtained；
(5) synthesis of the biological responding composite nano-microsphere of bivalve layer: by amphiphilic macromolecular nanometer obtained by step (4)
Microballoon is scattered in 120mL water, and 0.21g triethanolamine and 0.22g cetyl trimethylammonium bromide is added；It is stirred at 80 DEG C
2h adds the tetraethyl orthosilicate of 1.22ml, stirs 8h at 80 DEG C；Resulting product be filtered, washed, dry after to get
To the biological responding composite nano-microsphere of bivalve layer.
This implementation preparation gained biological responding composite nano-microsphere SEM scanning electron microscope analysis (see Fig. 5) the results show that
The diameter of amphiphilic macromolecular nanosphere is 800nm or so before mesoporous silicon oxide embeds, and is slightly increased compared to embodiment 1,
It is smooth regular spherical shape after embedding, about 1 μm of diameter or so of the biological responding composite nano-microsphere of bivalve layer, with implementation
Example 1 is suitable.
Embodiment 3
A kind of preparation method of biological responding targeting double medicament controlled-release carrier material, includes the following steps:
(1) synthesis of RAFT reagent: with embodiment 1；
(2) synthesis of PDSEMA:
(3) the single-stranded preparation of amphiphilic macromolecular: by 90mg RAFT reagent, 5g PDSEMA, 4g polyethylene glycol methyl-prop
Olefin(e) acid rouge (Mw 500) and 10mg AIBN are dissolved in 10mL DMF, with the purification of freeze-thaw pump circulation method degassing 3 times or more；
Then reaction mixture is sealed, is put into 70 DEG C of preheated oil bath pans and reacts 12h；Reaction gained mixture is dissolved in 5mL dichloro
In methane, then fall in 20mL n-hexane；Sediment is dissolved in 5mL methylene chloride again, is then fallen to again
In 20mL ether, it is single-stranded to obtain unreduced amphiphilic macromolecular；
(4) preparation of amphiphilic macromolecular nanosphere: being dissolved in 10mg amphiphilic macromolecular is single-stranded in 200 μ L acetone,
DTT is slowly added dropwise thereto；Stirring 10 minutes is added 1mL deionized water, then is stirred at room temperature overnight, and contacts, allows with air
After organic matter sufficiently volatilizees, amphiphilic macromolecular nanosphere (NG) is obtained；
(5) synthesis of the biological responding composite nano-microsphere of bivalve layer: by amphiphilic macromolecular nanometer obtained by step (4)
Microballoon is scattered in 120mL water, and 0.21g triethanolamine and 0.22g cetyl trimethylammonium bromide is added；It is stirred at 80 DEG C
2h adds the tetraethyl orthosilicate of 1.22ml, stirs 8h at 80 DEG C；Resulting product be filtered, washed, dry after to get
To the biological responding composite nano-microsphere of bivalve layer.
This implementation preparation gained biological responding composite nano-microsphere SEM scanning electron microscope analysis (see Fig. 6) the results show that
The diameter of amphiphilic macromolecular nanosphere is 600nm or so before mesoporous silicon oxide embeds, and is slightly increased compared to embodiment 1,
It is smooth regular spherical shape after embedding, about 1 μm of diameter or so of the biological responding composite nano-microsphere of bivalve layer, with implementation
Example 1 is suitable.
Obviously, above-described embodiment is only intended to clearly illustrate made example, and is not the limitation to embodiment.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or
It changes.There is no necessity and possibility to exhaust all the enbodiments.And the obvious variation or change therefore amplified
It moves within still in the protection scope of the invention.
Claims (8)
1. a kind of biological responding targets double medicament controlled-release carrier material, which is characterized in that the biological responding target
It is a kind of bivalve layer biological responding composite nano-microsphere to double medicament controlled-release carrier material, hypostracum is by amphiphilic
Nanosphere made of high molecular polymer is reunited, outer shell is mesoporous silicon oxide；The amphiphilic macromolecular polymer with
The form of nanometre glue exists, and structural formula is as follows, and the molecular weight of the amphiphilic macromolecular is 6000Da ~ 24000Da, parent
Water end (W.E.) ratio is 30wt% ~ 70wt%；
。
2. biological responding according to claim 1 targets double medicament controlled-release carrier material, which is characterized in that
The diameter of the hypostracum is 160nm ~ 800nm.
3. biological responding according to claim 1 targets double medicament controlled-release carrier material, which is characterized in that
The outer shell is mesoporous silicon oxide made of being hydrolyzed as silicon source, and the mesoporous aperture is 2 ~ 4nm.
4. the preparation method of any biological responding targeting double medicament controlled-release carrier material of claim 1 ~ 3,
It is characterized in that, includes the following steps:
(1) the single-stranded preparation of amphiphilic macromolecular: by RAFT reagent, pyridyldithiol ethyl methacrylate, polyethylene glycol first
Base acrylate and azodiisobutyronitrile are dissolved in dimethylformamide, with freeze-thaw pump circulation method purification degassing 3 times with
On；Then reaction mixture is sealed, is put into oil bath pan and reacts；Reaction gained mixture is dissolved in methylene chloride, is then settled
In n-hexane；Sediment is dissolved in methylene chloride again, is then fallen in ether again, is obtained unreduced amphiphilic
Macromolecular single-chain；
(2) preparation of amphiphilic macromolecular nanosphere: being dissolved in amphiphilic macromolecular is single-stranded obtained by step (1) in acetone, to
Dithiothreitol (DTT) is wherein slowly added dropwise；Stirring 10 minutes is added deionized water, then is stirred at room temperature overnight, and organic matter is allowed to fill
After dividing volatilization, amphiphilic macromolecular nanosphere is obtained；
(3) synthesis of the biological responding composite nano-microsphere of bivalve layer: amphiphilic macromolecular nanosphere is dispersed in water,
Triethanolamine and surfactant is added；2h is stirred at 80 DEG C, adds tetraethyl orthosilicate, continues to stir 8h at 80 DEG C；
Resulting product be filtered, washed, dry after to get to bivalve layer biological responding composite nano-microsphere.
5. the preparation method according to claim 4, which is characterized in that in step (1), the RAFT
Reagent is 1-dodecyl-2-(2,2- isobutyric acid)-trithiocarbonate；The RAFT reagent, pyridyldithiol first
The ratio of base ethyl acrylate, polyethylene glycol methacrylate-styrene polymer and azodiisobutyronitrile is 90mg:5g:4g:10mg；It is described anti-
The oil bath temperature answered is 70 DEG C ~ 80 DEG C, and the reaction time is 12h ~ 14h.
6. the preparation method according to claim 4, which is characterized in that step (2) described amphiphilic macromolecular
Single-stranded and dithiothreitol (DTT) ratio is 10mg:2mg.
7. the preparation method according to claim 4, which is characterized in that step (3) described amphiphilic macromolecular
Nanosphere, triethanolamine, surfactant and tetraethyl orthosilicate ratio be 80 μ of μ L ~ 100 L:0.21g:0.22g:
1.22mL。
8. the preparation method according to claim 4, which is characterized in that step (3) described surfactant is
One of cetyl trimethylammonium bromide, cetyl chloride ammonium and cetyl ammonium bromide.
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| CN111960423A (en) * | 2020-08-28 | 2020-11-20 | 广东工业大学 | Nano hollow porous silicon material and preparation method and application thereof |
| CN112279984B (en) * | 2020-10-30 | 2023-05-09 | 浙江理工大学 | Method for preparing catalytic nano microsphere by polymerization-induced self-assembly |
| CN113105614A (en) * | 2021-04-08 | 2021-07-13 | 湘潭大学 | Easily degradable responsive core-crosslinkable amphiphilic block polymer, preparation method thereof and application of polymer as drug carrier |
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