CN105535974B - A kind of acoustic control nano particle carries jamaicin release system and its preparation method and application - Google Patents
A kind of acoustic control nano particle carries jamaicin release system and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of acoustic control nano particles to carry jamaicin release system and its preparation method and application.Acoustic control nano particle of the present invention carries jamaicin release system and carries out amido modified SiO comprising surface2Up-conversion nanoparticles, singlet oxygen sentive switch, hyaluronic acid and the jamaicin of cladding；One end of singlet oxygen sentive switch carries out amido modified SiO by amido bond coupled surfaces2The up-conversion nanoparticles of cladding, for the other end by linkage hyaluronic acid, jamaicin is contained in a manner of wrapping up or being covalently attached carries out amido modified SiO on surface2In the up-conversion nanoparticles of cladding, jamaicin discharges singlet oxygen under ultrasonication, so that the carbon-carbon double bond in singlet oxygen sentive switch is broken, releases jamaicin, can reduce aggregation of the drug in non-target tissue.The blank of sound sensitiser carrier in SDT researchs has been filled up in the proposition of acoustic control nano particle load jamaicin release system of the present invention, realizes application of the acoustic control nano particle drug-loading system in SDT.
Description
Technical field
The present invention relates to the sound sensitiser carriers in a kind of sound dynamic therapy, and in particular to a kind of acoustic control nano particle load barberry
Alkali release system and preparation method thereof, and application in the sound sensitiser for preparing sound dynamic therapy atherosclerosis and making
Application in standby pharmaceutical carrier.The invention belongs to the technical fields that sonar release drug is combined with nanosecond medical science.
Background technology
Sound dynamic therapy (Sonodynamic Therapy, SDT) is to be moved in light by Japanese scholars Umemura etc. for 1989
A kind of completely new non-invasive treatment methods being put forward for the first time on the basis of power treatment.Compared with optical dynamic therapy, in sound dynamic therapy
Attenuation coefficient is low in the tissue, penetration capacity is strong for ultrasound used, and activation is gathered in the sound sensitiser in target tissue and generates active oxygen, hair
A series of raw biologicallies, at the same it is not damaged to normal surrounding tissue.The selection of sound sensitiser is to therapeutic effect in SDT treatments
Critical impact is played, currently, previous experiments result successfully confirms that water-soluble Chinese medicine jamaicin (berberine) is tried in vitro
It can be applied to the research of SDT in testing as sound sensitiser.However, being found when carrying out animal preliminary experiment, applied in clinical small
Bark of a cork tree alkali only has oral preparation, and injection is because there are safety issues for vein direct injection, so failing in clinical success application.For solution
It is certainly injected intravenously this problem, large dosage of drug is avoided directly to enter blood as far as possible, while reducing drug and assembling in non-target tissue,
We synthesize acoustic control nanometer and carry jamaicin release system.
In the experiment of sound dynamic therapy research, is there is no at present using acoustic control nano drug-carrying and discharge system as sound sensitiser load
The research of body.The present invention is directed to fill up the blank of sound sensitiser carrier in the research of sound dynamic therapy, a kind of acoustic control nanometer is mainly provided
It carries jamaicin and discharges system, be conducive to experimental study and be pushed further into clinical application.Present invention firstly provides release acoustic control
It puts Chinese medicine sound sensitiser harmony dynamic therapy atherosclerotic plaque to combine, has filled up the blank in the domestic field.And
Synthesis acoustic control nanometer carries jamaicin release system for the first time, and the clinical application for future SDT provides material and theoretical foundation.
Invention content
The present invention has synthesized on the basis of nano particle carries barberry by the acoustic control nano particle of core of Chinese medicine sound sensitiser
Alkali discharges system, realizes application of the acoustic control nano medicament carrying system in SDT.The blank for compensating for the prior art, provides one
Kind carries medicine as the acoustic control nano particle of core using Chinese medicine sound sensitiser and discharges system.
In order to reach object above, the technical solution adopted in the present invention is：
The technical scheme is that with low toxicity and be easy to metabolism nano material combine can be by macrophage targets identification
Hyaluronic acid structure " singlet oxygen sentive switch ", load Chinese medicine sound sensitiser jamaicin formed nano-particle complex.It is compound
Jamaicin generates singlet oxygen under certain strength ultrasound in object, activates " singlet oxygen sentive switch ", compound shown in formula I
In carbon-carbon double bond fracture release jamaicin to macrophage.
A kind of acoustic control nano particle load jamaicin release system, which is characterized in that carried out comprising surface amido modified
SiO2Up-conversion nanoparticles, singlet oxygen sentive switch, hyaluronic acid and the jamaicin of cladding；The singlet oxygen sensitivity is opened
One end of pass is coupled the surface by amido bond and carries out amido modified SiO2The up-conversion nanoparticles of cladding, the other end are logical
Hyaluronic acid described in linkage is crossed, the jamaicin contains in a manner of wrapping up or be covalently attached carries out amino on the surface
The SiO of modification2In the up-conversion nanoparticles of cladding, jamaicin discharges singlet oxygen under ultrasonication, keeps singlet oxygen quick
Carbon-carbon double bond fracture in sense switch, releases jamaicin；
Wherein, the singlet oxygen sentive switch is cis- sulfanyl allyl diacid, and structural formula is shown in formula I：
In the present invention, it is preferred to, the surface carries out amido modified SiO2It is more than the up-conversion nanoparticles of cladding
Conversion nanoparticles are core, and the average grain diameter of core is 28nm, with SiO2For shell, and carry out on the surface of shell amido modified.
In the present invention, it is preferred to, up-conversion nanoparticles are yttrium fluoride natrium nano-particle.
Further, the present invention provides a kind of sides for preparing the acoustic control nano particle and carrying jamaicin release system
Method includes the following steps：
(1) solvent-thermal process up-conversion nanoparticles；
(2) ethanol solution of ethyl orthosilicate is added dropwise to the cetyl trimethylammonium bromide of upper conversion sodium nano-particle
In aqueous solution, for 24 hours, centrifugation, ethyl alcohol is washed 3 times, and SiO is obtained for reaction2The up-conversion nanoparticles of cladding；
(3) under nitrogen protection, SiO is added in 3- aminopropyl triethoxysilanes2The up-conversion nanoparticles of cladding
In toluene solution, for 24 hours, centrifugation is cleaned 3-4 times with toluene and ethyl alcohol, is dried in vacuo, is obtained amido modified silicon for 80 DEG C of reactions
Ball；
(4) compound shown in Formulas I is dissolved in DMF, with 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
With n-hydroxysuccinimide activated carboxyl 1h, reaction solution is obtained；Amido modified silicon ball is added in reaction solution, amidation is anti-
12h is answered, is centrifuged, is cleaned 3-4 times with ethyl alcohol and water, is dried in vacuo, obtains amidated silicon ball；
(5) amidated silicon ball is mixed with jamaicin in DMSO, for 24 hours, 1- ethyls-(3- diformazans are added in physical absorption
Base aminopropyl) carbodiimide hydrochloride and n-hydroxysuccinimide activated carboxyl 1h, 12h is reacted with hyaluronic acid esterification,
Centrifugation, with DMSO and ethyl alcohol clean to get.
In the present invention, it is preferred to, up-conversion nanoparticles are yttrium fluoride natrium nano-particle.
In the present invention, it is preferred to, the yttrium fluoride natrium nano-particle is prepared according to the following steps：
1. by six chloride hydrate yttriums, six hydrous ytterbium chlorides and six water erbium chlorides according to mass ratio 30~31:10~11:1
Ratio mixes, and oleic acid and octadecylene is added, and obtains mixture；
Wherein, the mass volume ratio (mg/mL) of six chloride hydrate yttriums and oleic acid is 1:30~1:40, six chloride hydrate yttriums with
The mass volume ratio (mg/mL) of octadecylene is 1:20~1:25；
2. in the case of logical argon gas, 160 DEG C of holding 30min are stirred the mixture for and be heated to, then add 18
Alkene naturally cools to 50 DEG C after keeping 160 DEG C of stirring 1h；
Wherein, it is 1 according to the mass volume ratio of six chloride hydrate yttriums and octadecylene:40~1:50 ratio is added 18
The octadecylene of 40~50mL is added in alkene, i.e. six chloride hydrate yttriums of 1mg；
3. the methanol solution and sodium hydroxide solution of ammonium fluoride is added, 50 DEG C of stirring 30min nucleation are kept, later at 70 DEG C
It is lower to boil off methanol；
Wherein, a concentration of 14~15mg/mL of the methanol solution of ammonium fluoride, the amount of substance of sodium hydroxide solution are a concentration of
2.5mol/L；
4. being heated rapidly to 300 DEG C and keeping 1h under magnetic stirring, after reaction, mixture is down to room naturally
Temperature is added ethyl alcohol and centrifuges to obtain solid, and ethyl alcohol cleans 3 times and obtains yttrium fluoride natrium nano-particle.
In the present invention, it is preferred to, the ethanol solution of the ethyl orthosilicate described in step (2) is ethyl orthosilicate and second
Alcohol is according to volume ratio 1:5 ratio is mixed to get；The cetyl trimethylammonium bromide water of the upper conversion sodium nano-particle
Solution be up-conversion nanoparticles are added in the cetyl trimethylammonium bromide aqueous solution of 25mg/mL, ultrasonic agitation and
At pH value 8-9.
In the present invention, it is preferred to, the SiO described in step (3)2The toluene solution of the up-conversion nanoparticles of cladding
A concentration of 6mg/mL, SiO2The up-conversion nanoparticles of cladding and mass volume ratio (the mg/ μ of 3- aminopropyl triethoxysilanes
L it is) 3:5.
The present invention has detected jamaicin under ultrasonication1O2Production, the results showed that various concentration jamaicin
(0.5mg/mL, 1.0mg/mL) generates a certain amount of after ultrasonication1O2, reason is provided for opening " singlet oxygen sentive switch "
By foundation, it was demonstrated that " singlet oxygen sentive switch " has feasibility.
Acoustic control nanometer load jamaicin release system jamaicin under ultrasonication that the present invention has detected synthesis is terraced with concentration
Spend release conditions, the results showed that acoustic control nanometer carries jamaicin and discharges system drug release as time increases under ultrasonication
Percentage increases, and cannot discharge barberry with the time without carrying jamaicin release system by the acoustic control nanometer of the effect of ultrasound
Alkali, as compound are stable state in the solution.
The present invention carries jamaicin release system to acoustic control nanometer and has carried out safety experiment, by tail vein respectively to difference
The mouse internal injection nano particle of dosage grouping, dosage is respectively 25mg/kg, 50mg/kg, 100mg/kg, is observed after a week,
The equal Non Apparent Abnormality such as low dosage, middle dosage, high dose, control group 4 groups of mouse growth activities, external appearance characteristics, naked eyes after dissection
It can be seen that its heart, liver, kidney Non Apparent Abnormality.Prove that the acoustic control nano particle load jamaicin release systemic drug of synthesis is safe,
It can be used for clinical research.
Therefore, further, jamaicin release system is carried the present invention also provides the acoustic control nano particle making
Application in the sound sensitiser of standby sound dynamic therapy atherosclerosis.And
The acoustic control nano particle carries application of the jamaicin release system in preparing pharmaceutical carrier.
Compared with prior art, beneficial effects of the present invention are embodied in：
Invention demonstrates a method carry jamaicin using acoustic control nanometer to discharge system as the physical and chemical experiment of sound sensitiser carrier as a result, card
Real acoustic control nanometer carries jamaicin drug delivery system composite structure rule and stablizes, and can be broken carbon carbon pair under Ultrasound-activated
Key releases jamaicin, can achieve the purpose that sonar release.Reaching control drug by ultrasound the present invention provides one kind to release
The method put, this method carry the " singlet oxygen that jamaicin discharges system by acoustic control nano particle in Ultrasound-activated target tissue
Sentive switch " makes jamaicin be discharged into target tissue, can reduce aggregation of the drug in non-target tissue.
Description of the drawings
Fig. 1 is the NaYF4 of solvent-thermal process:20Yb, 2Er transmission electron microscope picture；
Fig. 2 is NaYF4:20Yb,2Er@mSiO2Nucleocapsid transmission electron microscope picture；
Fig. 3 is NaYF4:20Yb,2Er@mSiO2Nitrogen adsorption desorption result figure；
Fig. 4 is NaYF4:20Yb,2Er@mSiO2–NH2Modify Zeta potential figure；
Fig. 5 is targeted drug delivery system through sonar release schematic diagram；Wherein A figures are " singlet oxygen sentive switch " mechanism of action
Figure, B figures are targeting acoustic control drug-loading system through sonar release figure；C figures are single duct schematic diagram；
Fig. 6 is that Berberine (jamaicin) is generated through ultrasonication1O2Figure；
Fig. 7 is that the Berberine (jamaicin) that acoustic control nano particle carries in jamaicin release system is released after ultrasonication
Put figure；Wherein, the solution colour in second test tube is faint yellow；
Fig. 8 is that detection acoustic control nanometer carries jamaicin release system complexities safety experiment result figure.
Specific implementation mode
Below by experiment and the present invention will be further described in conjunction with the embodiments, it should be understood that these embodiments
It is only used for the purpose of illustration, is never limited in protection scope of the present invention.
The explanation of abbreviation appeared in the present invention：
CTAB cetyl trimethylammonium bromides
TEOS ethyl orthosilicates
APTES 3- aminopropyl triethoxysilanes
NHS n-hydroxysuccinimides
EDC 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
DMF dimethylformamides
DMSO dimethyl sulfoxide (DMSO)s
A kind of 1 acoustic control nano particle of embodiment carries the construction method of medicine release system
(1) synthesis of up-conversion nanoparticles core (yttrium fluoride natrium nano-particle)
Six chloride hydrate yttriums (0.237mg, 0.78mmol), six hydrous ytterbium chlorides (0.0775mg, 0.2mmol), with six water
Erbium chloride (0.0077mg, 0.02mmol) is added in the three neck round bottom flask of 250mL together, then be added oleic acid (6mL) with
Octadecylene (5mL), obtains mixture；In the case of logical argon gas, 160 DEG C of holding 30min are stirred the mixture for and are heated to, with
After add 10mL octadecylenes, mixture naturally cools to 50 DEG C after keeping 160 DEG C of stirring 1h；First is added into mixture at this time
The ammonium fluoride (148.16mg, 4mmol) and sodium hydroxide (100mg, 2.5mmol) solution of alcohol (10mL) dissolving, are kept for 50 DEG C and stirred
30min nucleation is mixed, later boils off methanol at 70 DEG C；Mixture is heated rapidly to 300 DEG C and is kept under magnetic stirring
Mixture is down to room temperature, ethyl alcohol is added, product is centrifuged with centrifuge at 10000rpm, uses second by 1h naturally after reaction
Alcohol cleans solid, this process 3 times repeatedly.Finally obtained yttrium fluoride natrium nano-particle 188mg is distributed in 10mL hexamethylenes.
Fig. 1 is the transmission electron microscope picture of the upper conversion nano particle of solvent-thermal process.Synthesis can be clearly seen from Fig. 2
Upper conversion nano granular size is uniform, form rule, and diameter is average in 28nm or so.
(2)SiO2Cladding
It takes CTAB 200mg to be dissolved in 8mL water, dissolves by heating, 400 μ L of diluted yttrium fluoride natrium nano-particle are added to
CTAB solution stirs 30min, and solution is heated to 80 DEG C of removal hexamethylenes, and ultrasonic 30min is stirred until solution went clear shape,
Add 20mL water to dilute, the pH to 8-9 of solution, ultrasonic 30min is adjusted, by 250 μ L TEOS (ethyl orthosilicate, Si (OC2H5)4) molten
Solution is added dropwise in nano-particle solution with peristaltic pump and is reacted for 24 hours in 1.25mL ethyl alcohol, and 10min, ethyl alcohol are centrifuged under 10000rpm
It washes 3 times, obtains SiO2The silicon ball of cladding.
Fig. 2 is that SiO is added on the basis of upper conversion nano particle2Nucleocapsid coats (NaYF4:20Yb,2Er@mSiO2) after
Transmission electron microscope picture, can be clearly seen from Fig. 3 silica core-shell cladding upper conversion nano granular size it is uniform, diameter
Averagely in 50nm or so.
Fig. 3 is NaYF4:20Yb,2Er@mSiO2Nitrogen adsorption desorption result figure, from figure 3, it can be seen that higher-pressure region is stagnant
Ring illustrates synthetic material for mesoporous material afterwards, and BJH curves show that mesopore orbit size is 3nm or so in Fig. 3, show that material has
The characteristic of carrying medicament.
(3) amido modified
By 30mg SiO2The silicon ball of cladding is distributed in 5mL dry toluenes, ultrasonic disperse.Under nitrogen protection, by 50 μ L
APTES is added in reaction system, is heated to 80 DEG C of reactions for 24 hours, and centrifugation cleans nano-particle 3-4 times, vacuum with toluene and ethyl alcohol
Drying for 24 hours, obtains amido modified silicon ball.
Fig. 4 is NaYF4:20Yb,2Er@mSiO2–NH2Zeta potential figure is modified, figure 4, it is seen that silicon ball surface is big
It is negatively charged to measure hydroxyl, charge becomes just, illustrating that amido is modified successfully after modifying amido, in further modification with carboxyl
Can be after scission of link Linker molecules, particle surface has amido to become carboxyl, and charge becomes negative value, illustrate Linker molecular modifications at
Work(.
(4) switch modification
Cis- sulfanyl allyl diacid (shown in formula I) 71mg is dissolved with DMF, NHS 170mg and EDC 290mg are added and activate
Reaction system is added in amido modified silicon ball 140mg by carboxyl 1h, reacts 12h, and centrifugation cleans silicon ball 3-4 times with ethyl alcohol and water,
Vacuum drying for 24 hours, obtains dry silicon ball.
(5) medicine and targeting modification are carried
Dry silicon ball (15mg) is mixed with jamaicin 15mg in DMSO, for 24 hours, NHS 170mg are added in Drug absorbability
With EDC 290mg activated carboxyl 1h, hyaluronic acid is added and carries out esterification 12h, centrifugation is cleaned with DMSO, ethyl alcohol, obtains sound
It controls nano particle and carries medicine release system.
2 acoustic control nano particle of embodiment carries the vitro drug release of medicine release system
Fig. 5 is targeted drug delivery system through sonar release schematic diagram；Wherein, A figures are " singlet oxygen sentive switch " effect machine
System, singlet oxygen (1O2) aoxidize the carbon-carbon double bond of compound shown in formula I, form unstable tetrad ring, the fracture of tetrad ring, cut-out
Singlet oxygen sentive switch, to discharge drug；B figures are targeting acoustic control drug-loading system through sonar release, silica (SiO2)
Conversion nano particle in cladding, NH2Base group modification SiO2, key connects singlet oxygen sentive switch (compound shown in formula I), and physics is inhaled
Attached jamaicin, by compound shown in formula I-COOH group key connects hyaluronic acid, form targeted drug delivery system, work as low frequency ultrasound
When acting on the jamaicin in system, generate1O2, the carbon-carbon double bond (singlet oxygen sentive switch) of compound shown in formula I is disconnected
It splits, discharges jamaicin；C figures are single duct schematic diagram.
Fig. 6 is detection jamaicin under ultrasonication1O2Production, the results showed that various concentration jamaicin (0.5mg/
ML, 1.0mg/mL) generated after ultrasonication it is a certain amount of1O2, theoretical foundation is provided for opening " singlet oxygen sentive switch ",
Prove that " singlet oxygen sentive switch " has feasibility.
Fig. 7 is that the acoustic control nano particle of detection synthesis carries jamaicin release system (preparation of embodiment 1) under ultrasonication
The release figure that jamaicin changes over time, the results showed that acoustic control nano particle carry jamaicin discharge system under ultrasonication with
The increase drug release percentage of time increases, and discharges system without carrying jamaicin by the acoustic control nano particle of the effect of ultrasound
Jamaicin cannot be discharged with the time, as compound is stable state in the solution.It can also be obtained from the photo in Fig. 7
Compound after ultrasonication can be because the release of jamaicin makes solution become faint yellow (jamaicin is yellow).
3 acoustic control nano particle of embodiment carries the drug safety experiment of medicine release system
By tail vein respectively to various dose be grouped mouse internal injection nano particle, dosage be respectively 25mg/kg,
50mg/kg, 100mg/kg are observed after a week, observation indicate that：4 groups of low dosage, middle dosage, high dose, control group mouse lifes
The equal Non Apparent Abnormalities such as long activity, external appearance characteristic, its visible heart of naked eyes, liver, kidney Non Apparent Abnormality after dissection (shown in Fig. 8).It says
The acoustic control nano particle of bright synthesis carries jamaicin compound drug safety height, can be used for clinical research.
The foregoing is merely the preferred embodiment of the present invention, are merely illustrative for the purpose of the present invention, and not restrictive；
Those of ordinary skill in the art understand that can carry out many to it in the spirit and scope defined by the claims in the present invention changes
Become, modification or even equivalent change, but falls in protection scope of the present invention.
Claims (10)
1. a kind of acoustic control nano particle, which carries jamaicin, discharges system, which is characterized in that carry out amido modified SiO comprising surface2Packet
Up-conversion nanoparticles, singlet oxygen sentive switch, hyaluronic acid and the jamaicin covered；The one of the singlet oxygen sentive switch
End is coupled the surface by amido bond and carries out amido modified SiO2The up-conversion nanoparticles of cladding, the other end pass through ester bond
Be coupled the hyaluronic acid, the jamaicin contained in a manner of wrapping up or being covalently attached carried out on the surface it is amido modified
SiO2In the up-conversion nanoparticles of cladding, jamaicin discharges singlet oxygen under ultrasonication, makes singlet oxygen sentive switch
In carbon-carbon double bond fracture, release jamaicin；
Wherein, the singlet oxygen sentive switch is cis- sulfanyl allyl diacid, and structural formula is shown in formula I：
The acoustic control nano particle carries jamaicin release system and is prepared according to the following steps：
(1) solvent-thermal process up-conversion nanoparticles；
(2) ethanol solution of ethyl orthosilicate is added dropwise to the cetyl trimethylammonium bromide aqueous solution of up-conversion nanoparticles
In, for 24 hours, centrifugation, ethyl alcohol is washed 3 times, and SiO is obtained for reaction2The up-conversion nanoparticles of cladding；
(3) under nitrogen protection, SiO is added in 3- aminopropyl triethoxysilanes2The toluene of the up-conversion nanoparticles of cladding is molten
In liquid, for 24 hours, centrifugation is cleaned 3-4 times with toluene and ethyl alcohol, is dried in vacuo, is obtained amido modified silicon ball for 80 DEG C of reactions；
(4) compound shown in Formulas I is dissolved in DMF, with 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride and N-
Hydroxysuccinimide-activated carboxyl 1h, obtains reaction solution；Amido modified silicon ball is added in reaction solution, amidation process
12h, centrifugation are cleaned 3-4 times with ethyl alcohol and water, are dried in vacuo, are obtained amidated silicon ball；
(5) amidated silicon ball is mixed with jamaicin in DMSO, for 24 hours, 1- ethyls-(3- dimethylaminos are added in physical absorption
Base propyl) carbodiimide hydrochloride and n-hydroxysuccinimide activated carboxyl 1h, esterification 12h is carried out with hyaluronic acid,
Centrifugation, with DMSO and ethyl alcohol clean to get.
2. acoustic control nano particle according to claim 1, which carries jamaicin, discharges system, which is characterized in that the surface carries out
Amido modified SiO2For the up-conversion nanoparticles of cladding using up-conversion nanoparticles as core, the average grain diameter of core is 28nm.
3. acoustic control nano particle according to claim 1 or 2, which carries jamaicin, discharges system, which is characterized in that upper conversion is received
Rice corpuscles is yttrium fluoride natrium nano-particle.
4. a kind of method for preparing acoustic control nano particle described in claim 1 and carrying jamaicin release system, which is characterized in that packet
Include following steps：
(1) solvent-thermal process up-conversion nanoparticles；
(2) ethanol solution of ethyl orthosilicate is added dropwise to the cetyl trimethylammonium bromide aqueous solution of up-conversion nanoparticles
In, for 24 hours, centrifugation, ethyl alcohol is washed 3 times, and SiO is obtained for reaction2The up-conversion nanoparticles of cladding；
(3) under nitrogen protection, SiO is added in 3- aminopropyl triethoxysilanes2The toluene of the up-conversion nanoparticles of cladding is molten
In liquid, for 24 hours, centrifugation is cleaned 3-4 times with toluene and ethyl alcohol, is dried in vacuo, is obtained amido modified silicon ball for 80 DEG C of reactions；
(4) compound shown in Formulas I is dissolved in DMF, with 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride and N-
Hydroxysuccinimide-activated carboxyl 1h, obtains reaction solution；Amido modified silicon ball is added in reaction solution, amidation process
12h, centrifugation are cleaned 3-4 times with ethyl alcohol and water, are dried in vacuo, are obtained amidated silicon ball；
(5) amidated silicon ball is mixed with jamaicin in DMSO, for 24 hours, 1- ethyls-(3- dimethylaminos are added in physical absorption
Base propyl) carbodiimide hydrochloride and n-hydroxysuccinimide activated carboxyl 1h, esterification 12h is carried out with hyaluronic acid,
Centrifugation, with DMSO and ethyl alcohol clean to get.
5. according to the method described in claim 4, it is characterized in that, up-conversion nanoparticles are yttrium fluoride natrium nano-particle.
6. according to the method described in claim 5, it is characterized in that, the yttrium fluoride natrium nano-particle is made according to the following steps
It is standby to obtain：
1. by six chloride hydrate yttriums, six hydrous ytterbium chlorides and six water erbium chlorides according to mass ratio 30~31:10~11:1 ratio
Mixing, and oleic acid and octadecylene is added, obtain mixture；
Wherein, the mass volume ratio mg/mL of six chloride hydrate yttriums and oleic acid is 1:30~1:40, six chloride hydrate yttriums and octadecylene
Mass volume ratio mg/mL be 1:20~1:25；
2. in the case of logical argon gas, 160 DEG C of holding 30min are stirred the mixture for and be heated to, octadecylene is then added, protects
50 DEG C are naturally cooled to after holding 160 DEG C of stirring 1h；
Wherein, it is 1 according to the mass volume ratio of six chloride hydrate yttriums and octadecylene:40~1:Octadecylene is added in 50 ratio, i.e.,
The octadecylene of 40~50mL is added in six chloride hydrate yttriums of 1mg；
3. the methanol solution and sodium hydroxide solution of ammonium fluoride is added, 50 DEG C of stirring 30min nucleation are kept, it later will at 70 DEG C
Methanol boils off；
Wherein, a concentration of 14~15mg/mL of the methanol solution of ammonium fluoride, the amount of substance of sodium hydroxide solution are a concentration of
2.5mol/L；
4. being heated rapidly to 300 DEG C and keeping 1h under magnetic stirring, after reaction, mixture is down to room temperature naturally, is added
Enter ethyl alcohol to centrifuge to obtain solid, ethyl alcohol cleans 3 times and obtains yttrium fluoride natrium nano-particle.
7. according to the method described in claim 4, it is characterized in that, the ethanol solution of the ethyl orthosilicate described in step (2)
It is ethyl orthosilicate and ethyl alcohol according to volume ratio 1:5 ratio is mixed to get；The cetyl of the up-conversion nanoparticles
Trimethylammonium bromide aqueous solution is the cetyl trimethylammonium bromide aqueous solution that up-conversion nanoparticles are added to 25mg/mL
In, it is stirred by ultrasonic, pH value 8-9.
8. according to the method described in claim 5, it is characterized in that, SiO described in step (3)2The upper conversion nano grain of cladding
A concentration of 6mg/mL, SiO of the toluene solution of son2The matter of the up-conversion nanoparticles and 3- aminopropyl triethoxysilanes of cladding
It is 3 to measure volume mg/ μ L ratios:5.
9. acoustic control nano particle described in claim 1 carries jamaicin release system and is preparing sound dynamic therapy atherosclerosis
Sound sensitiser in application.
10. acoustic control nano particle described in claim 1 carries application of the jamaicin release system in preparing pharmaceutical carrier.
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| CN103923277A (en) * | 2014-04-28 | 2014-07-16 | 苏州大学 | Amphipathic polymer, preparation method thereof, composite nano medicine carrier and preparation method thereof |
| CN103980434A (en) * | 2014-05-19 | 2014-08-13 | 苏州大学 | Amphiphilic polymer, preparation method, composite nano drug carrier and preparation method thereof |
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| CN103980434A (en) * | 2014-05-19 | 2014-08-13 | 苏州大学 | Amphiphilic polymer, preparation method, composite nano drug carrier and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| Jessica M. Taylor et al..Synthesis and characterization of Na(Y,Gd)F4 upconversion nanoparticles and an investigation of their effects on the photophysical properties of an unsubstituted tetrathiophenoxy phthalocyanine.《J Nanopart Res》.2015,第17卷(第85期), * |
| Tianye et al..SONODYNAMIC EFFECT OF BERBERINE ON.《Heart》.2012,第98卷 * |
| Xing Zhu et al..Upconversion nanoparticle-mediated photodynamic therapy induces THP-1 macrophage apoptosis via ROS bursts and activation of the mitochondrial caspase pathway.《InternationalJournal of Nanomedicine》.2015,第10卷 * |
| 高鑫等.声动力学疗法治疗脑动脉粥样硬化机制的研究进展.《临床超声医学杂志》.2015,第17卷(第3期), * |
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