CN110448698A - A kind of medicine controlled releasing nanometer particle and preparation method thereof - Google Patents
A kind of medicine controlled releasing nanometer particle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of medicine controlled releasing nanometer particles and preparation method thereof; wherein; preparation method is the following steps are included: 3-aminopropyltriethoxysilane is added into nanometer particle in (1); using toluene as solvent; back flow reaction under nitrogen protection; ultrapure water and ethanol washing are used after reaction, and vacuum drying obtains amination nanometer particle MSN-NH2；(2) amination nanometer particle is dissolved in acetonitrile, 1- pyrene formaldehyde is added and is reacted, is centrifuged after reaction, with ultrapure water and ethanol washing, vacuum drying obtains MSN-N=CH-Py；(3) take MSN-N=CH-Py, the drug solution that being added need to load is reacted, beta-cyclodextrin is added after reaction and continues to react, is centrifuged after the reaction was completed, with ultrapure water and ethanol washing, vacuum drying to get.Medicine controlled releasing nanometer particle of the invention has good responsiveness to pH, and has good medicine delivered payload capability and medicine controlled releasing performance.
Description
Technical field
The present invention relates to medicine controlled releasing technical field, in particular to a kind of medicine controlled releasing nanometer particle and
Preparation method.
Background technique
Edaravone (ED) is a kind of effective free radical scavenger, is now clinically widely used in treatment ischemic cerebral apoplexy
In.It has been reported that in IRI (Ischemic Reperfusion Injury, the ischemia-reperfusion damage of the organs such as lung, kidney, the heart, liver
Wound) in, ED also has protective effect.ROS (reactive oxygen species, reactive oxygen species) damage can result in cell
Oedema and Apoptosis, a large number of studies show that, ED can be by removing internal ROS to reduce Apoptosis.Shimoda M etc.
It was found that Edaravone can mitigate HIRI (Ischemia-reperfusion Injury in Rat) by inhibiting Apoptosis.
Nanometer particle (MSNs) because its with large specific surface area, surface be easy to modify, biocompatibility preferably etc.
Characteristic is widely used in field of medicine release in recent years.Compared with carbon nano-particle etc., nanometer particle can be in biology
Internal natural degradation and it is non-toxic.The partial size of MSNs can be adjusted in the section 50~1000nm, have good biology
Compatibility is easy to by cellular uptake.By modifying the structure with particular organisms function on the surface thereof, can obtain specific
Cell-targeting effect.The surface of mesoporous silicon oxide has silicone hydroxyl abundant, its surface is made to be easy to modify various functional groups, In
It can be realized the functions such as target administration, cell imaging after combining with fluorescent material, polypeptide etc..MSNs after modification can be to specific
Stimulation, such as pH, enzyme etc. responded, and can contain the release of drug in target position but will not transported
Journey and normal portions response, are able to achieve good targeted therapy in this way, and reduction contains drug in the release at other positions, significant drop
The low potential side effect of drug.Therefore, MSNs has become the research hotspot of multiple subjects such as medicine, materialogy.
The Design Mechanism of pH response medicine controlled release system is based on regions such as internal different parts tissue or inflammation, tumours
PH value it is different.During HIRI, tissue ischemia anoxic, intracellular acidosis, a large amount of lactic acid of glycolysis enhancing generation,
Local microenvironment is in acidity, this good response condition become as controlled drug delivery system.Existing controlled drug delivery system is also deposited
In the problem that pH responsiveness is bad, medicine delivered payload capability and medicine controlled releasing performance are bad.
Summary of the invention
The main purpose of the present invention is to provide a kind of medicine controlled releasing nanometer particles and preparation method thereof, at least
Solve the problems, such as that controlled drug delivery system pH responsiveness in the prior art is bad, medicine controlled releasing performance is bad.
To achieve the goals above, according to an aspect of the invention, there is provided a kind of medicine controlled releasing nanometer
Grain preparation method, the preparation method the following steps are included:
(1) 3-aminopropyltriethoxysilane is added into nanometer particle, using toluene as solvent, is protected in nitrogen
Lower back flow reaction is protected, uses ultrapure water and ethanol washing after reaction, vacuum drying obtains amination nanometer particle MSN-
NH2；
(2) amination nanometer particle obtained by step (1) is dissolved in acetonitrile, 1- pyrene formaldehyde is added and is reacted, makes
Aldehyde radical in 1- pyrene formaldehyde reacts to form carbon-to-nitrogen double bond with the amino on amination nanometer particle, after reaction from
The heart, with ultrapure water and ethanol washing, vacuum drying obtains MSN-N=CH-Py；
(3) MSN-N=CH-Py obtained by step (2) is taken, the drug solution that being added need to load is reacted, after reaction
Beta-cyclodextrin is added to continue to react, is centrifuged after the reaction was completed, with ultrapure water and ethanol washing, is dried in vacuo to get loading
The medicine controlled releasing nanometer particle of drug.
The present invention for drug carrier material, utilizes 3-aminopropyltriethoxysilane with nanometer particle (MSNs)
(APTES) amino group is modified in nanometer particle surface, obtains amination nanometer particle；Recycle aldehyde radical
(pyrene formaldehyde, Py-CHO) and amino interact to form carbon-to-nitrogen double bond；It loads drug (such as Edaravone) and uses beta-cyclodextrin afterwards
It blocks, forms medicine controlled releasing nanometer particle.
The present invention uses pH response medicine slow-releasing system, in the acidic environment of tumor tissue sections, carbon-to-nitrogen double bon meeting
Fracture, exposes amino, has the effect of assistant carrier cross-film, and cyclodextrin is left away as gate group at the same time, discharges medicine
Object.The system encounters acidic environment when being in tumor microenvironment can begin to slow-released part drug, but mesoporous silicon outside cancer cell
It can actively be swallowed by cell, compared to the acidity of tumor microenvironment, the acidity of intracellular lysosome is lower, and the system may be implemented
The controlled release of more drug after into cell；And being discharged into the drug outside cancer cell can still enter in neighbouring cancer cell
Reach therapeutic effect.
Further, in step (1), the nanometer particle is prepared via a method which to obtain: by cetyl
Trimethylammonium bromide is dissolved in deionized water, and sodium hydroxide solution is added, and temperature adjustment is to 65-75 DEG C, in play after heat preservation 25-35min
Ethyl acetate is added after 1-2min in fast drop ethyl orthosilicate under strong stirring, continues to stir 1.5-2.5h, after reaction from
The heart is dried in vacuum overnight to get nanometer particle with ultrapure water and ethanol washing at 55-65 DEG C.
Further, further comprising the steps of after being dried in vacuo: to be added into the product after drying in step (1)
The concentrated hydrochloric acid that ethyl alcohol and mass fraction are 37%, 20-28h is reacted at 65-75 DEG C, is centrifuged after reaction, with ultrapure water and
Methanol washing, is dried in vacuum overnight at 55-65 DEG C, obtains amination nanometer particle.
Further, in step (1), the time of back flow reaction is 20-28h, uses ultrapure water and second after back flow reaction
Alcohol washs at least three times, and vacuum drying temperature is 65-75 DEG C.
Further, in step (1), the matter that feeds intake of nanometer particle and the 3-aminopropyltriethoxysilane
Amount volume ratio is 2:1mg/ μ L.
Further, in step (2), it is 2.5-3.5h that time for being reacted of 1- pyrene formaldehyde, which is added, after reaction from
Then the heart at least three times with ultrapure water and ethanol washing is dried in vacuo at 65-75 DEG C.
Further, in step (2), the mass ratio that feeds intake of amination nanometer particle and 1- pyrene formaldehyde is 10:1.
Further, in step (3), the reaction time that the drug solution that being added need to load is reacted is 2.5-3.5h,
Beta-cyclodextrin is added and continues the reaction time of reaction as 20-28h.
Further, in step (3), the concentration for the drug solution that need to be loaded is 1-2mg/mL, and the concentration of beta-cyclodextrin is
1.5-2.5mmol/L。
According to another aspect of the present invention, a kind of medicine controlled releasing nanometer particle is provided, the medicine controlled releasing is mesoporous
Nano silicon particles are prepared by the preparation method of above-mentioned medicine controlled releasing nanometer particle.
Further, the drug of loading is Edaravone.
Compared with prior art, the invention has the following advantages:
The present invention is using nanometer particle as drug carrier material, using 3-aminopropyltriethoxysilane mesoporous
Nano silicon particles surface modification amino group obtains amination nanometer particle, recycles aldehyde radical (pyrene formaldehyde) and amino
Interaction forms carbon-to-nitrogen double bond, which can be broken under the acidic environment of tumor tissue sections, loads drug (such as
Edaravone) it is blocked afterwards using beta-cyclodextrin, to form the medicine controlled releasing nanometer particle with pH responsiveness.Gained
Medicine controlled releasing nanometer particle has good responsiveness to pH, and release rate is extremely low in the normal tissue, but in ischemic
In the acidic micro-environments such as Reperfu- sion, tumour, since carbon-carbon double bond is broken, beta-cyclodextrin falls off from mesoporous silicon face, thus largely
Drug is released from duct.Therefore, under conditions of identical dosage, better function and effect be can achieve.The drug
Controlled release nanometer particle has good medicine delivered payload capability and medicine controlled releasing performance.
Detailed description of the invention
The accompanying drawings constituting a part of this application is used to provide further understanding of the present invention, and of the invention shows
Examples and descriptions thereof are used to explain the present invention for meaning property, does not constitute improper limitations of the present invention.In the accompanying drawings:
Fig. 1 is preparation and the release schematic diagram of medicine controlled releasing nanometer particle prepared by the embodiment of the present invention 1.
Fig. 2 is the transmission electron microscope picture of nanometer particle prepared by the embodiment of the present invention 1.
Fig. 3 is the infared spectrum of nanometer particle prepared by the embodiment of the present invention 1.
Fig. 4 is the UV absorption figure of various concentration Edaravone.
Fig. 5 is Edaravone concentration-ultraviolet absorptivity standard curve.
Fig. 6 is two-photon dyestuff In-vitro release curves under different pH value.
Specific embodiment
To facilitate the understanding of the present invention, present invention work more comprehensively, is meticulously described below in conjunction with preferred embodiment,
But the protection scope of the present invention is not limited to the following specific embodiments.
Unless otherwise defined, all technical terms used hereinafter and the normally understood meaning of those skilled in the art
It is identical.Technical term used herein is intended merely to the purpose of description specific embodiment, is not intended to the limitation present invention
Protection scope.
Unless otherwise specified, various raw material, reagent, the instrument and equipment etc. used in the present invention can pass through city
Field is commercially available or can be prepared by existing method.
Embodiment 1
A kind of preparation method of the medicine controlled releasing nanometer particle of the embodiment of the present invention, which includes following
Step:
(1) synthesis of nanometer particle
It weighs 0.50g cetyl trimethylammonium bromide (CTAB) to be dissolved in 240mL deionized water, 2.0M is added
NaOH solution 1.75mL, temperature adjustment keep the temperature fast drop 2.75mL ethyl orthosilicate with vigorous stirring after 30min to 70 DEG C
(TEOS), ethyl acetate 2.50mL is added after 1min, persistently stirs 2h, until there are white depositions, uses ultrapure water after centrifugation
With ethanol washing (three times), it is dried in vacuum overnight at 60 DEG C, obtains white solid nanometer particle；
(2) amination of nanometer particle is modified
Nanometer particle 100mg obtained is weighed, 50 μ L 3-aminopropyltriethoxysilane (APTES) are added,
In 10mL dry toluene nitrogen protection reflux for 24 hours, after being centrifuged off toluene, with ultrapure water and ethanol washing (three times), 70 DEG C
Lower vacuum drying；
(3) cetyl trimethylammonium bromide is removed
Product 1g obtained above is weighed, the concentrated hydrochloric acid that 100mL ethyl alcohol and 1mL mass fraction are 37% is added, in 70 DEG C
Reaction for 24 hours, i.e., the surfactant cetyl trimethylammonium bromide inside removal mesoporous silicon duct, after centrifugation with ultrapure water and
It after methanol acutely washs, is dried in vacuum overnight at 60 DEG C, obtains the amination nanometer particle for eliminating surfactant
(MSN-NH2)；
(4) pyrene formaldehyde reacts to form carbon-to-nitrogen double bond with amino
By 100mg MSN-NH2It is dissolved in 30mL acetonitrile, is added 10mg 1- pyrene formaldehyde (Py-CHO), be centrifuged after reacting 3h,
With ultrapure water and ethanol washing (three times), up to MSN-N=CH-Py after 70 DEG C of vacuum drying；
(5) drug Edaravone is loaded
1.5mg/mL Edaravone Injection 5mL is added in the MSN-N=CH-Py 10mg weighed, after reacting 3h, adds
Enter 2mM beta-cyclodextrin (β-CD) 1mL, reaction is centrifuged afterwards for 24 hours, and ultrapure water and ethanol washing for several times, collect cleaning solution, vacuum drying
Overnight to get the pH response medicine controlled release nanometer particle (ED@MSN) for arriving loading Edaravone.
Fig. 1 is preparation and the release schematic diagram of the medicine controlled releasing nanometer particle of the present embodiment；Fig. 2 is the present embodiment
The transmission electron microscope picture of the nanometer particle of preparation；Fig. 3 is the red of amination nanometer particle manufactured in the present embodiment
Outer map.
Measure the Edaravone amount of containing:
By ultraviolet spectroscopy, Edaravone has absorption peak at 280nm.Various concentration Edaravone solution is prepared,
Its UV absorption angle value is measured, Edaravone concentration-ultraviolet absorptivity standard curve is drawn.Measure cleaning solution UV absorption angle value
Its concentration, and then the amount of containing of available Edaravone can be calculated.Fig. 4 is the UV absorption figure of various concentration Edaravone,
Fig. 5 is Edaravone concentration-ultraviolet absorptivity standard curve.
The external release behavior of the medicine controlled releasing nanometer particle of the present embodiment is investigated:
Load aids drug -- two-photon dyestuff:
Obtained MSN-N=CH-Py 14.7mg is weighed, is dissolved in 4mL deionized water, 20 μM of two-photon dyestuffs are added
(TP) after reacting 3h, 2mM beta-cyclodextrin (β-CD) 1mL is added in 10 μ L, and reaction is centrifuged afterwards for 24 hours, ultrapure water and ethanol washing number
It is secondary, it is dried in vacuum overnight to get the responsibility mesoporous nano silicon particles of pH (TP MSN) for loading two-photon dyestuff (TP) are arrived.
The release rate of two-photon dyestuff is detected under different pH environment:
Secure ph is respectively 3,4,5,6,7,8,9 Tris-Hcl buffer.Two-photon dyestuff (TP) is released through glimmering
Photothermal spectroscopic analyzer measurement, exciting is 370 μm, there is maximum wavelength at 460nm.It prepares the TP solution of various concentration and detects its fluorescence
Value makes concentration-fluorescent value standard curve.The Tris-Hcl that above-mentioned prepared pH value is respectively 3,4,5,6,7,8,9 is delayed
Fliud flushing is as release liquid.The TP@MSN of the equivalent 1mL buffer for being dissolved in above-mentioned configuration is placed in bag filter, by bag filter
It is respectively placed in the test tube accordingly containing 4mL release liquid, is observed, interval sampling detects TP dye strength in release liquid.
Release experiment operation repetitive 3 times, calculate the release conditions of two-photon dyestuff.Fig. 6 is that two-photon dyestuff is released in vitro under different pH value
Put curve.As seen from Figure 6, when buffer is acid, the release rate of (pH 3,4,5,6) two-photon dyestuff is higher, and when buffering
The release rate of (pH 7,8,9) two-photon dyestuff is relatively low when liquid is alkalinity or is neutral.Illustrate that medicine controlled releasing of the invention is situated between
Hole nano silicon particles have good pH responsiveness and good medicine controlled releasing performance.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of medicine controlled releasing nanometer particle, which is characterized in that the preparation method includes following step
It is rapid:
(1) 3-aminopropyltriethoxysilane is added into nanometer particle, using toluene as solvent, under nitrogen protection
Back flow reaction, uses ultrapure water and ethanol washing after reaction, and vacuum drying obtains amination nanometer particle MSN-NH2；
(2) amination nanometer particle obtained by step (1) is dissolved in acetonitrile, 1- pyrene formaldehyde is added and is reacted, 1- pyrene is made
Aldehyde radical in formaldehyde reacts to form carbon-to-nitrogen double bond with the amino on amination nanometer particle, is centrifuged after reaction, uses
Ultrapure water and ethanol washing, vacuum drying, obtain MSN-N=CH-Py；
(3) MSN-N=CH-Py obtained by step (2) is taken, the drug solution that being added need to load is reacted, and is added after reaction
Beta-cyclodextrin continues to react, and is centrifuged after the reaction was completed, with ultrapure water and ethanol washing, is dried in vacuo to get medicine is loaded with
The medicine controlled releasing nanometer particle of object.
2. the preparation method of medicine controlled releasing nanometer particle according to claim 1, which is characterized in that the step
(1) in, the nanometer particle is prepared via a method which to obtain:
Cetyl trimethylammonium bromide is dissolved in deionized water, sodium hydroxide solution is added, temperature adjustment is to 65-75 DEG C, heat preservation
Fast drop ethyl orthosilicate with vigorous stirring after 25-35min is added ethyl acetate after 1-2min, continues to stir 1.5-
2.5h is centrifuged after reaction, with ultrapure water and ethanol washing, is dried in vacuum overnight at 55-65 DEG C to get nanometer
Grain.
3. the preparation method of medicine controlled releasing nanometer particle according to claim 2, which is characterized in that the step
(1) further comprising the steps of after being dried in vacuo in:
The concentrated hydrochloric acid that ethyl alcohol and mass fraction are 37% is added into the product after drying, 20-28h is reacted at 65-75 DEG C, instead
It is centrifuged after answering, is washed with ultrapure water and methanol, is dried in vacuum overnight at 55-65 DEG C, obtain amination nanometer
Grain.
4. the preparation method of medicine controlled releasing nanometer particle according to claim 1, which is characterized in that the step
(1) in, the time of the back flow reaction is 20-28h, uses ultrapure water and ethanol washing at least three times after back flow reaction, institute
Stating vacuum drying temperature is 65-75 DEG C.
5. the preparation method of medicine controlled releasing nanometer particle according to claim 1, which is characterized in that the step
(1) in, the mass volume ratio that feeds intake of the nanometer particle and the 3-aminopropyltriethoxysilane is 2:1mg/ μ
L。
6. the preparation method of medicine controlled releasing nanometer particle according to claim 1, which is characterized in that the step
(2) in, it is 2.5-3.5h that the time that 1- pyrene formaldehyde is reacted, which is added, is centrifuged after reaction, with ultrapure water and ethanol washing
At least three times, it is then dried in vacuo at 65-75 DEG C.
7. the preparation method of medicine controlled releasing nanometer particle according to claim 1, which is characterized in that the step
(2) in, the mass ratio that feeds intake of the amination nanometer particle and the 1- pyrene formaldehyde is 10:1.
8. the preparation method of medicine controlled releasing nanometer particle according to claim 1, which is characterized in that the step
(3) in, reaction time that the drug solution that the addition need to load is reacted is 2.5-3.5h, the addition beta-cyclodextrin after
The continuous reaction time reacted is 20-28h；The concentration of the drug solution that need to be loaded is 1-2mg/mL, the β-ring paste
The concentration of essence is 1.5-2.5mmol/L.
9. a kind of medicine controlled releasing nanometer particle, which is characterized in that the medicine controlled releasing nanometer particle is by right
It is required that the preparation method of medicine controlled releasing nanometer particle described in any one of 1-8 is prepared.
10. medicine controlled releasing nanometer particle according to claim 9, which is characterized in that the drug of the loading is
Edaravone.
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| CN111184869B (en) * | 2020-02-24 | 2021-05-18 | 福州大学 | Mesoporous silicon controlled release system based on dual-target driving DNA logic gate sealing |
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