CN107474845A - A kind of nanometer microvesicle mixture that biology light source is provided and preparation method thereof - Google Patents
A kind of nanometer microvesicle mixture that biology light source is provided and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of nanometer microvesicle mixture for providing biology light source, it includes：The load substrate nanometer microvesicle for carrying enzyme nanometer microvesicle and folacin receptor targeting of folacin receptor targeting, the load enzyme nanometer microvesicle is made up of the first kernel templates and the first shell, first kernel templates are the compound of CdSe/ZnS quantum dot coelenterons luciferase 8, and the first shell is folic acid cross-linked polyethylene glycol polylactic-co-glycolic acid polymer；The load substrate nanometer microvesicle is made up of the second kernel templates and second housing, and the second kernel templates are CdSe/ZnS quantum dot coelenteron luciferin complexes and/or coelenteron fluorescein, and second housing is folic acid cross-linked polyethylene glycol polylactic-co-glycolic acid polymer.Present invention also offers the preparation method of this nanometer of microvesicle mixture.Nanometer microvesicle mixture provided by the invention has Targeting delivery, delays the advantages of degraded, keeps the activity of enzyme and substrate in vivo, this nanometer of microvesicle mixture can be as the light source in optical dynamic therapy.
Description
Technical field
The present invention relates to pharmaceutical activity protective agent field and target medicine carrier synthesis field, and in particular to one kind provides life
The nanometer microvesicle mixture in object light source and preparation method thereof.
Background technology
Optical dynamic therapy (PhotodynamicTherapy, PDT) is one kind that tumour is treated after operation, chemotherapy, radiotherapy
New method.Good therapeutic effect is obtained in the superficial tissues such as cutaneum carcinoma, breast cancer tumour.At present, optical dynamic therapy mainly makes
By the use of generating laser as external light source, the sensitising agent by being injected intravenously and being distributed in tumor tissues is excited
(Photosensitizer, PS) so as to trigger photodynamic reaction (PhotodaynamicReaction, PDR) produce cell toxicant
Agent-active oxygen (ReactiveOxygenSpecies, ROS), causes tumor cell necrosis and/or apoptosis, and destroy around tumour
New vessels, and then kill tumor tissues
Because the exogenous laser penetration power used in optical dynamic therapy is weaker, deep tissue can not be acted on and trigger light
Dynamic response, therefore, optical dynamic therapy are restricted in the treatment of the deep tissues such as liver cancer.
Enzymatic in biosystem is luminous to be referred to as bioluminescence.This is one general in bacterium, algae, insect etc.
All over existing phenomenon.Bioluminescence is typically derived from enzyme (such as luciferase) catalysis substrate (such as fluorescein) and oxidation reaction occurs,
Discharge light quantum.Based on this principle, in recent years, it is deep in optical dynamic therapy liver cancer etc. that researchers have started bio-luminescence system
Research in portion's tissue, that is, by the way that enzyme-to-substrate is delivered at tumour, lighted, there is provided light source.However, enzyme or bottom
Thing is easily degraded quickly after entering in vivo, can not ensure activity.
In addition, optical dynamic therapy is also a problem urgently to be resolved hurrily in the targeting of liver cancer, because existing smooth power is controlled
The research for rarely having and being related to the deep tissues such as liver is treated, optical dynamic therapy is referred from and applies to other superficial tissues, its targeting master
It is fixed against targeting irradiation of the tumor tissues to this passive target effect of the retention effect of sensitising agent, and manipulation light source.This
The relatively low passive target of species specificity, easily causes the damage of normal structure, hinders further using for optical dynamic therapy.Cause
This, obtains a kind of material for having Targeting delivery, delaying degraded, enough light sources is provided for optical dynamic therapy, turn into light power
Treatment use is in the emphasis of the deep tissues such as liver cancer.
The content of the invention
For defect present in prior art, it is an object of the invention to provide a kind of nanometer for providing biology light source is micro-
Bubble mixt, the mixture have Targeting delivery, delay the advantages of degraded, keep the activity of enzyme and substrate in vivo, the mixing
Thing can be as the light source in optical dynamic therapy.
To achieve the above objectives, the present invention adopts the technical scheme that：A kind of nanometer microvesicle mixing that biology light source is provided
Thing, it includes：
The load enzyme nanometer microvesicle of folacin receptor targeting, the load enzyme nanometer microvesicle is by the first kernel templates and the first shell structure
Into the first kernel templates are CdSe/ZnS quantum dots-compound of coelenteron luciferase 8, and the first shell is that folic acid is crosslinked poly- second two
Alcohol polylactic-co-glycolic acid polymer；
The load substrate nanometer microvesicle of folacin receptor targeting, the load substrate nanometer microvesicle is by the second kernel templates and second housing
Form, the second kernel templates are CdSe/ZnS quantum dots-coelenteron luciferin complexes and/or coelenteron fluorescein, second housing are
Folic acid cross-linked polyethylene glycol polylactic-co-glycolic acid polymer.
Further, the CdSe/ZnS quantum dots-compound of coelenteron luciferase 8 is by CdSe/ZnS quantum dots and enteric cavity
The covalent coupling of luciferase 8 forms.
Further, it is described when second kernel templates contain CdSe/ZnS quantum dots-coelenteron luciferin complexes
CdSe/ZnS quantum dots-coelenteron luciferin complexes are formed by CdSe/ZnS quantum dots and enteric cavity fluorescein covalent coupling.
Present invention also offers a kind of preparation method of the as described above nanometer microvesicle mixture for providing biology light source, its
Including：
The step of preparing the load enzyme nanometer microvesicle；
The step of preparing the load substrate nanometer microvesicle.
Further, the preparation process of the load enzyme nanometer microvesicle is as follows：
S1：Folic acid cross-linked polyethylene glycol polylactic-co-glycolic acid polymer is prepared, and forms it into first shell；
S2：The CdSe/ZnS quantum dots-compound of coelenteron luciferase 8 is prepared, and forms it into first core
Template；
S3：First kernel templates are loaded into first shell, complete the preparation for carrying enzyme nanometer microvesicle.
Further, the first kernel templates preparation method is as follows described in S2：
1~3ml cushioning liquid is added in glutaraldehyde, and adds 8~12 μ lCdSe/ZnS quantum dots, in ar gas environment
After 1.5~2.5h of middle stirring, separating-purifying simultaneously removes glutaraldehyde；1~3mg coelenterons luciferase 8 is added, is continued in ar gas environment
After middle 9~11h of stirring reaction, separating-purifying removes coelenteron luciferase 8, obtains the CdSe/ZnS quantum dots-coelenteron fluorescence
The plain compound of enzyme 8.
Further, the preparation method that first kernel templates are loaded into first shell in S3 is as follows：
S31：First kernel templates and water are mixed to form interior aqueous phase, it is dense that interior aqueous phase is added into first shell
Spend in the dichloromethane for 0~0.050g/ml, obtain colostric fluid；
S32：First shell and water are mixed to form outer aqueous phase, are distributed to colostric fluid outside using SPG membrane emulsifiers
In aqueous phase, double emulsion is obtained；
S33：Double emulsion is transferred in magnetic stirring apparatus, stirring dichloromethane is volatilized, stir speed (S.S.) be 80~
120rpm/min, whipping temp are 30~50 DEG C, and mixing time is 8~10h；
S34：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 3~5 DEG C, 2500~3500g, is done
It is dry.
Further, the preparation process of the load substrate nanometer microvesicle is as follows：
A1：Folic acid cross-linked polyethylene glycol polylactic-co-glycolic acid polymer is prepared, and forms it into the second housing；
A2：When second kernel templates are coelenteron fluorescein, second kernel templates are loaded into outside described second
In shell, the preparation for carrying substrate nanometer microvesicle is completed；
When second kernel templates are CdSe/ZnS quantum dots-coelenteron luciferin complexes, the CdSe/ is prepared
ZnS quantum dot-coelenteron luciferin complexes, and second kernel templates are formed it into, second kernel templates are loaded into
In the second housing, the preparation for carrying substrate nanometer microvesicle is completed；
When second kernel templates are CdSe/ZnS quantum dots-coelenteron luciferin complexes and coelenteron fluorescein, system
The standby CdSe/ZnS quantum dots-coelenteron luciferin complexes, and make the CdSe/ZnS quantum dots-coelenteron luciferin complexes
Second kernel templates are formed with the coelenteron fluorescein, second kernel templates are loaded into the second housing, it is complete
Into the preparation of the load substrate nanometer microvesicle.
Further, in A2, when second kernel templates contain CdSe/ZnS quantum dots-coelenteron luciferin complexes
When, the preparation method of the CdSe/ZnS quantum dots-coelenteron luciferin complexes is as follows：
1~3ml cushioning liquid is added in glutaraldehyde, and adds 8~12 μ lCdSe/ZnS quantum dots, in ar gas environment
After 1.5~2.5h of middle stirring, separating-purifying simultaneously removes glutaraldehyde；1~3mg coelenteron fluoresceins are added, are continued in ar gas environment
After 9~11h of stirring reaction, separating-purifying removes coelenteron fluorescein, and it is compound to obtain the CdSe/ZnS quantum dots-coelenteron fluorescein
Thing.
Further, the preparation method that second kernel templates are loaded into the second housing in A2 is as follows：
A21：Second kernel templates and water are mixed to form interior aqueous phase, it is dense that interior aqueous phase is added into the second housing
Spend in the dichloromethane for 0~0.050g/ml, obtain colostric fluid；
A22：The second housing and water are mixed to form outer aqueous phase, are distributed to colostric fluid outside using SPG membrane emulsifiers
In aqueous phase, double emulsion is obtained；
A23：Double emulsion is transferred in magnetic stirring apparatus, stirring dichloromethane is volatilized, stir speed (S.S.) be 80~
120rpm/min, whipping temp are 30~50 DEG C, and mixing time is 8~10h；
A24：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 3~5 DEG C, 2500~3500g, is done
It is dry.
Compared with prior art, the advantage of the invention is that：
(1) present invention be respectively coelenteron luciferase 8 and CdSe/ZnS quantum dots-coelenteron luciferin complexes and/or
Coelenteron fluorescein has wrapped up one layer of first shell and second housing, can improve to coelenteron luciferase 8 and CdSe/ZnS amounts
The protection of sub- point-coelenteron luciferin complexes and/or coelenteron fluorescein, prevent from being degraded before the deep tissues such as liver are reached,
It ensure that bioactivity and stability.
(2) the first shell of the invention and second housing surface are modified with folic acid, can be with the folic acid of the high expression of liver cancer cells
Acceptor realizes active targeting, accurate positioning；Meanwhile first shell and second housing can play treat coelenteron luciferase 8 with
And after CdSe/ZnS quantum dots-coelenteron luciferin complexes and/or the enrichment of coelenteron fluorescein, carry out concentrating the work for exciting and discharging
With the bio-light for producing sufficient intensity is used to excite sensitising agent, and first shell and second housing are more easy to as one layer of lipid film
In penetrating tissue and cell membrane；The mixture is easily stored.
(3) the load enzyme nanometer microvesicle and carrying substrate nanometer microvesicle has envelop rate stable that prepared by the present invention, uniform particle diameter, are produced
Rate is high, and synthesis processing method is simple, no biotoxicity.
Brief description of the drawings
Fig. 1 is load enzyme nanometer microbubble structure schematic diagram provided in an embodiment of the present invention；
Fig. 2 is that the second kernel templates provided in an embodiment of the present invention are CdSe/ZnS quantum dots-coelenteron luciferin complexes
When load substrate nanometer microbubble structure schematic diagram.
Embodiment
The present invention is described in further detail below in conjunction with drawings and Examples.
Nanometer microvesicle mixture embodiment 1：
Referring to shown in Fig. 1 and Fig. 2, the present invention provides the nanometer microvesicle mixture of biology light source, and it includes：Folacin receptor target
To load enzyme nanometer microvesicle, the load enzyme nanometer microvesicle is made up of the first kernel templates and the first shell, first kernel templates
For CdSe/ZnS quantum dots-compound of coelenteron luciferase 8, first shell is folic acid cross-linked polyethylene glycol polylactic
Acetic acid polymer；The load substrate nanometer microvesicle of folacin receptor targeting, the load substrate nanometer microvesicle is by the second kernel templates and second
Shell is formed, and second kernel templates are CdSe/ZnS quantum dots-coelenteron luciferin complexes and/or coelenteron fluorescein, institute
It is folic acid cross-linked polyethylene glycol polylactic-co-glycolic acid polymer to state second housing.Wherein, the CdSe/ZnS quantum dots-coelenteron
The compound of luciferase 8 is formed by CdSe/ZnS quantum dots and the covalent coupling of coelenteron luciferase 8, the CdSe/ZnS quantum
Point-coelenteron luciferin complexes are formed by CdSe/ZnS quantum dots and enteric cavity fluorescein covalent coupling.
In the present invention, the first shell is identical with preparation method with the composition of second housing.
CdSe/ZnS quantum dots-the compound of coelenteron luciferase 8 and CdSe/ZnS quantum dots-coelenteron fluorescein
Compound preparation method is identical；Meanwhile first kernel templates are loaded into first shell to prepare the load enzyme nanometer
Microvesicle and the preparation method phase that second kernel templates loading second housing is prepared to the load substrate nanometer microvesicle
Together, difference is to use different kernel templates.
Because in the presence of without CdSe/ZnS quantum dots, coelenteron luciferase 8 is catalyzed coelenteron fluorescein and oxidation reaction occurs
What is sent is 450~480nm of wavelength or so blue wave band, and the absorbing wavelength corresponding to sensitising agent is mostly 650nm's or so
Red spectral band, therefore, it is coupled using CdSe/ZnS quantum dots with coelenteron luciferase 8 compound, CdSe/ZnS quantum dots can rise
To the effect of Wavelength-converting, 450~480nm of absorbing wavelength or so blue light and the feux rouges for being immediately converts into 650nm or so, namely
Bioluminescence resonance energy transfer effect (BioluminescenceResonanceEnergyTransfer).
Meanwhile it is compound using CdSe/ZnS quantum dots and the coupling of coelenteron fluorescein, CdSe/ZnS quantum dots can more enter one
Step plays a part of Wavelength-converting.Certainly, substrate coelenteron fluorescein can also not have to compound with CdSe/ZnS quantum point couplings.
The present invention is respectively coelenteron luciferase 8 and CdSe/ZnS quantum dots-coelenteron luciferin complexes and/or coelenteron
Fluorescein has wrapped up one layer of first shell and second housing, can improve to coelenteron luciferase 8 and CdSe/ZnS quantum dots-
The protection of coelenteron luciferin complexes and/or coelenteron fluorescein, prevent from being degraded before the deep tissues such as liver are reached, ensure that
Bioactivity and stability；Meanwhile first shell and second housing surface be modified with folic acid, can be with the high expression of liver cancer cells
Folacin receptor realizes active targeting, accurate positioning, first shell and second housing can play treat coelenteron luciferase 8 and
After CdSe/ZnS quantum dots-coelenteron luciferin complexes and/or the enrichment of coelenteron fluorescein, concentrated by ultrasound targeting blasting technique
The effect for exciting and discharging, the bio-light for producing sufficient intensity are used to excite sensitising agent, realize that drug targeting delivers；This is outside first
Shell and second housing are as one layer of lipid film, it is easier to penetrate tissue and cell membrane；The mixture is easily stored.
Preparation method embodiment 1：
The preparation method of the nanometer microvesicle mixture provided by the invention for providing biology light source, this method are preparing the load
In enzyme nanometer microvesicle and load substrate nanometer microvesicle, have envelop rate stabilization, uniform particle diameter, yield height, synthesis processing method simple
The advantages of, the mixture is easily stored, and it includes：
The step of preparing the load enzyme nanometer microvesicle；
The step of preparing the load substrate nanometer microvesicle.
Preparation method embodiment 2：
The present embodiment and the difference of preparation method embodiment 1 are, prepare in described the step of carrying enzyme nanometer microvesicle, this hair
It is bright provide it is described load enzyme nanometer microvesicle preparation process it is as follows：
S1：Folic acid cross-linked polyethylene glycol polylactic-co-glycolic acid polymer is prepared, and forms it into first shell；
S2：The CdSe/ZnS quantum dots-compound of coelenteron luciferase 8 is prepared, and forms it into first core
Template；
S3：First kernel templates are loaded into first shell, complete the preparation for carrying enzyme nanometer microvesicle.
Meanwhile present invention also offers the preparation process of the load substrate nanometer microvesicle, its preparation method and the load enzyme
Preparing for nanometer microvesicle is identical, it is only necessary to changes first kernel templates into second kernel templates, first shell
Change the second housing into, will not be described here and carry the preparation method embodiment of substrate nanometer microvesicle.
Preparation method embodiment 3：
The present embodiment and the difference of preparation method embodiment 2 are that in step sl, first shell uses molecular weight
The polylactic acid/hydroxy acetic acid (50: 50, be designated as PLGA-COOH) with carboxyl that is 25KD, surface is carrier, the poly- second two of double amino
(molecular weight 3.5KD, is designated as NH to alcohol2-PEG-NH2) it is attachment, folic acid (being designated as FA) is specific targeting ligand.Using
Five-step approach prepares PEG-PLA/glycolic acid polymer (being designated as PLGA-PEG-FA) of folate-targeted：
The first step：Synthesize PLGA-NHS：PLGA-COOH and n-hydroxysuccinimide (being designated as NHS) couple activation carboxyl.
Take 0.04MM PLGA-COOH to be dissolved in 4ml dichloromethane, take 0.4MM NHS and 0.3MM dicyclohexyl
Carbodiimide is dissolved in 2ml dichloromethane, the two mixing, is placed in shaking table and is shaken up at a slow speed overnight, add 80ml ice methanol
Shaken up with ether mixed solution (methanol and ether volume ratio be 1: 1), 4 DEG C stand overnight, and see to have a large amount of being settled out current, centrifugation
Collect precipitation, vacuum drying, you can obtain PLGA-NHS.
Second step：Synthesize the NH of mono amino protection2-PEG-NH-BOC：NH2-PEG-NH2(it is designated as with di-tert-butyl dicarbonate
BOC) react.
Take NH2-PEG-NH2It is dissolved in the sodium bicarbonate solution that pH is 7.40~7.50, final concentration of 1mg/ml；Take two
Dimethyl dicarbonate butyl ester is dissolved in 10ml dimethyl sulfoxide (DMSO)s, final concentration of 0.1mg/ml.By NH2-PEG-NH2With two dimethyl dicarbonate fourths
Ester mass ratio is 5: 1 mixing, and reaction is stirred at room temperature overnight, and upper chromatographic column 15Q is isolated and purified after di-tert-butyl dicarbonate, is obtained
NH2-PEG-NH-BOC。
3rd step：Synthesize PLGA-PEG-NH-BOC：NH2- PEG-NH-BOC and PLGA-NHS coupling reactions.
Take 0.02MM PLGA-NHS to be dissolved in 20ml dichloromethane, 0.05MM NH is added with this2-PEG-NH-
BOC and 0.4MM DIPEA, it is placed in shaking table and shakes up at a slow speed overnight, adds 80ml ice methanol and ether mixes
Close solution (methanol and ether volume ratio be 1: 1), 4 DEG C stand overnight, see have it is a large amount of being settled out current, precipitation is collected by centrifugation, very
Sky is dried, you can obtains PLGA-PEG-NH-BOC.
4th step：Synthesize PLGA-PEG-NH2：BOC in trifluoroacetic acid (being designated as TFA) displacement PLGA-PEG-NH-BOC.
Take 250mg PLGA-PEG-NH-BOC to be dissolved in 25ml100% trifluoroacetic acids, 50 times are added after being deprotected 30min
Distilled water terminating reaction, anti-phase purifying on the deprotection solution after terminating reaction, obtains PLGA-PEG-NH2Monomer；Add 5
The ice methanol and ether mixed solution (methanol and ether volume ratio be 1: 1) of times volume, 4 DEG C stand overnight, and seeing has a large amount of precipitations
During appearance, precipitation is collected by centrifugation, is dried in vacuo, you can obtain PLGA-PEG-NH2Dry powder.
5th step：PLGA-PEG-FA：PLGA-PEG-NH2It is coupled with folic acid (being designated as FA).
100ml PLGA-PEG-NH is taken respectively250ml100% dimethyl sulfoxide, final concentration 2mg/ are dissolved in folic acid
ml.The two adds 6MM dicyclohexylcarbodiimide after mixing, be placed in shaking table and shake up at a slow speed overnight, 5 times of volumes of addition
Ice methanol and ether mixed solution (methanol and ether volume ratio be 1: 1), 4 DEG C stand overnight, see have it is a large amount of be settled out it is current, from
The heart collects precipitation, vacuum drying, you can obtain PLGA-PEG-FA.
The second housing and first shell are identical material, and preparation method is the same, therefore, the second housing
Preparation method embodiment just repeats no more.
Preparation method embodiment 4：
The present embodiment and the difference of preparation method embodiment 2 are that in step s 2, first kernel templates use
CdSe/ZnS quantum dots and the covalent coupling of coelenteron luciferase 8, are prepared using Euplotes woodruffi：
1ml cushioning liquid is added in glutaraldehyde, and adds 8 μ lCdSe/ZnS quantum dots, is stirred in ar gas environment
After 2.5h, separating-purifying simultaneously removes glutaraldehyde；2mg coelenterons luciferase 8 is added, continues the stirring reaction 11h in ar gas environment
Afterwards, separating-purifying removes coelenteron luciferase 8, obtains the CdSe/ZnS quantum dots-compound of coelenteron luciferase 8, wherein,
The cushioning liquid is the borate buffer solution or citrate buffer solution that pH value is 7.4.
Preparation method embodiment 5：
The present embodiment and the difference of preparation method embodiment 2 are that in step s 2, first kernel templates use
CdSe/ZnS quantum dots and the covalent coupling of coelenteron luciferase 8, are prepared using Euplotes woodruffi：
2ml cushioning liquid is added in glutaraldehyde, and adds 10 μ lCdSe/ZnS quantum dots, is stirred in ar gas environment
After 1.5h, separating-purifying simultaneously removes glutaraldehyde；1mg coelenterons luciferase 8 is added, continues the stirring reaction 10h in ar gas environment
Afterwards, separating-purifying removes coelenteron luciferase 8, obtains the CdSe/ZnS quantum dots-compound of coelenteron luciferase 8, wherein,
The cushioning liquid is the borate buffer solution or citrate buffer solution that pH value is 7.2.
Preparation method embodiment 6：
The present embodiment and the difference of preparation method embodiment 2 are that in step s 2, first kernel templates use
CdSe/ZnS quantum dots and the covalent coupling of coelenteron luciferase 8, are prepared using Euplotes woodruffi：
3ml cushioning liquid is added in glutaraldehyde, and adds 12 μ lCdSe/ZnS quantum dots, is stirred in ar gas environment
After 2h, separating-purifying simultaneously removes glutaraldehyde；4mg coelenterons luciferase 8 is added, is continued in ar gas environment after stirring reaction 9h,
Separating-purifying removes coelenteron luciferase 8, obtains the CdSe/ZnS quantum dots-compound of coelenteron luciferase 8, wherein, institute
It is the borate buffer solution or citrate buffer solution that pH value is 7.6 to state cushioning liquid.
Because the CdSe/ZnS quantum dots-compound of coelenteron luciferase 8 and CdSe/ZnS quantum dots-coelenteron are glimmering
Light element compound preparation method is identical, therefore, need to only change the coelenteron luciferase 8 in above-mentioned preparation method embodiment 4-6 into
Coelenteron fluorescein, it is possible to the CdSe/ZnS quantum dots-coelenteron luciferin complexes are prepared, as preparation CdSe/ZnS amounts
The embodiment of the method for sub- point-coelenteron luciferin complexes, it will not be repeated here and prepare the CdSe/ZnS quantum dots-coelenteron fluorescence
The preparation method embodiment of plain compound.
Preparation method embodiment 7：
The present embodiment and the difference of preparation method embodiment 2 are, in step s3, using supersound method combination mocromembrane
Emulsifier, first kernel templates are loaded into first shell to prepare the load enzyme nanometer microvesicle.
S31：First kernel templates of above-mentioned preparation and water are mixed to form interior aqueous phase, interior aqueous phase is passed through into syringe
At the uniform velocity it is added in dichloromethane, that is, now the first shell concentration is 0g/ml dichloromethane, that is stablized is first
Emulsion；
S32：First shell of above-mentioned preparation and water are mixed to form outer aqueous phase, using SPG membrane emulsifiers by colostrum
Liquid is distributed in outer aqueous phase, obtains double emulsion；In this course, ensure that pressure is 45kPa in SPG membrane emulsifier pressure chambers,
Colostric fluid is at the uniform velocity distributed in outer aqueous phase by SPG films；
S33：When outer aqueous phase engenders milky turbidity emulsion after no longer deepening, double emulsion is transferred into magnetic force stirs
Mix in device, stirring makes dichloromethane volatilize, stir speed (S.S.) 80rpm/min, and whipping temp is 30 DEG C, mixing time 8h；
S34：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 3 DEG C, 2500g, distillation water washing is more
After secondary, vacuum freeze drying, water and dichloromethane is distilled completely, it is micro- to obtain load enzyme nanometer described in dry white powder
Bubble.
Preparation method embodiment 8：
The present embodiment and the difference of preparation method embodiment 2 are, in step s3, using supersound method combination mocromembrane
Emulsifier, first kernel templates are loaded into first shell to prepare the load enzyme nanometer microvesicle.
S31：First kernel templates of above-mentioned preparation and water are mixed to form interior aqueous phase, interior aqueous phase is passed through into syringe
At the uniform velocity it is added in the dichloromethane that the first shell concentration is 0.050g/ml, the colostric fluid stablized；
S32：First shell of above-mentioned preparation and water are mixed to form outer aqueous phase, using SPG membrane emulsifiers by colostrum
Liquid is distributed in outer aqueous phase, obtains double emulsion；In this course, ensure that pressure is 50kPa in SPG membrane emulsifier pressure chambers,
Colostric fluid is at the uniform velocity distributed in outer aqueous phase by SPG films；
S33：When outer aqueous phase engenders milky turbidity emulsion after no longer deepening, double emulsion is transferred into magnetic force stirs
Mix in device, stirring makes dichloromethane volatilize, stir speed (S.S.) 110rpm/min, and whipping temp is 40 DEG C, mixing time 10h；
S34：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 4 DEG C, 3000g, distillation water washing is more
After secondary, vacuum freeze drying, water and dichloromethane is distilled completely, it is micro- to obtain load enzyme nanometer described in dry white powder
Bubble.
Preparation method embodiment 9：
The present embodiment and the difference of preparation method embodiment 2 are, in step s3, using supersound method combination mocromembrane
Emulsifier, first kernel templates are loaded into first shell to prepare the load enzyme nanometer microvesicle.
S31：First kernel templates of above-mentioned preparation and water are mixed to form interior aqueous phase, interior aqueous phase is passed through into syringe
At the uniform velocity it is added in the dichloromethane that the first shell concentration is 0.025g/ml, the colostric fluid stablized；
S32：First shell of above-mentioned preparation and water are mixed to form outer aqueous phase, using SPG membrane emulsifiers by colostrum
Liquid is distributed in outer aqueous phase, obtains double emulsion；In this course, ensure that pressure is 55kPa in SPG membrane emulsifier pressure chambers,
Colostric fluid is at the uniform velocity distributed in outer aqueous phase by SPG films；
S33：When outer aqueous phase engenders milky turbidity emulsion after no longer deepening, double emulsion is transferred into magnetic force stirs
Mix in device, stirring makes dichloromethane volatilize, stir speed (S.S.) 100rpm/min, and whipping temp is 40 DEG C, mixing time 9h；
S34：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 4 DEG C, 3000g, distillation water washing is more
After secondary, vacuum freeze drying, water and dichloromethane is distilled completely, it is micro- to obtain load enzyme nanometer described in dry white powder
Bubble.
Preparation method embodiment 10：
The present embodiment and the difference of preparation method embodiment 2 are, in step s3, using supersound method combination mocromembrane
Emulsifier, first kernel templates are loaded into first shell to prepare the load enzyme nanometer microvesicle.
S31：First kernel templates of above-mentioned preparation and water are mixed to form interior aqueous phase, interior aqueous phase is passed through into syringe
At the uniform velocity it is added in the dichloromethane that the first shell concentration is 0.030g/ml, the colostric fluid stablized；
S32：First shell of above-mentioned preparation and water are mixed to form outer aqueous phase, using SPG membrane emulsifiers by colostrum
Liquid is distributed in outer aqueous phase, obtains double emulsion；In this course, ensure that pressure is 52kPa in SPG membrane emulsifier pressure chambers,
Colostric fluid is at the uniform velocity distributed in outer aqueous phase by SPG films；
S33：When outer aqueous phase engenders milky turbidity emulsion after no longer deepening, double emulsion is transferred into magnetic force stirs
Mix in device, stirring makes dichloromethane volatilize, stir speed (S.S.) 120rpm/min, and whipping temp is 50 DEG C, mixing time 9h；
S34：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 5 DEG C, 3000g, distillation water washing is more
After secondary, vacuum freeze drying, water and dichloromethane is distilled completely, it is micro- to obtain load enzyme nanometer described in dry white powder
Bubble.
Preparation method embodiment 11：
The present embodiment and the difference of preparation method embodiment 2 are, in step s3, using supersound method combination mocromembrane
Emulsifier, first kernel templates are loaded into first shell to prepare the load enzyme nanometer microvesicle.
S31：First kernel templates of above-mentioned preparation and water are mixed to form interior aqueous phase, interior aqueous phase is passed through into syringe
At the uniform velocity it is added in the dichloromethane that the first shell concentration is 0.025g/ml, the colostric fluid stablized；
S32：First shell of above-mentioned preparation and water are mixed to form outer aqueous phase, using SPG membrane emulsifiers by colostrum
Liquid is distributed in outer aqueous phase, obtains double emulsion；In this course, ensure that pressure is 48kPa in SPG membrane emulsifier pressure chambers,
Colostric fluid is at the uniform velocity distributed in outer aqueous phase by SPG films；
S33：When outer aqueous phase engenders milky turbidity emulsion after no longer deepening, double emulsion is transferred into magnetic force stirs
Mix in device, stirring makes dichloromethane volatilize, stir speed (S.S.) 100rpm/min, and whipping temp is 47 DEG C, mixing time 8h；
S34：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 4 DEG C, 3200g, distillation water washing is more
After secondary, vacuum freeze drying, water and dichloromethane is distilled completely, it is micro- to obtain load enzyme nanometer described in dry white powder
Bubble.
Preparation method embodiment 12：
The present embodiment and the difference of preparation method embodiment 2 are, in step s3, using supersound method combination mocromembrane
Emulsifier, first kernel templates are loaded into first shell to prepare the load enzyme nanometer microvesicle.
S31：First kernel templates of above-mentioned preparation and water are mixed to form interior aqueous phase, interior aqueous phase is passed through into syringe
At the uniform velocity it is added in the dichloromethane that the first shell concentration is 0.015g/ml, the colostric fluid stablized；
S32：First shell of above-mentioned preparation and water are mixed to form outer aqueous phase, using SPG membrane emulsifiers by colostrum
Liquid is distributed in outer aqueous phase, obtains double emulsion；In this course, ensure that pressure is 48kPa in SPG membrane emulsifier pressure chambers,
Colostric fluid is at the uniform velocity distributed in outer aqueous phase by SPG films；
S33：When outer aqueous phase engenders milky turbidity emulsion after no longer deepening, double emulsion is transferred into magnetic force stirs
Mix in device, stirring makes dichloromethane volatilize, stir speed (S.S.) 90rpm/min, and whipping temp is 38 DEG C, mixing time 8h；
S34：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 4 DEG C, 2700g, distillation water washing is more
After secondary, vacuum freeze drying, water and dichloromethane is distilled completely, it is micro- to obtain load enzyme nanometer described in dry white powder
Bubble.
Due to first kernel templates loading, first shell to be prepared to the load enzyme nanometer microvesicle and by described in
It is identical to prepare the preparation method of the load substrate nanometer microvesicle that second kernel templates are loaded into the second housing, therefore, only needs
Change the first kernel templates in above-described embodiment 7-12 into second kernel templates, first shell is changed into outside described second
Shell, it is possible to prepare and carry substrate nanometer microvesicle, as the embodiment of the method for preparing load substrate nanometer microvesicle, wherein, the second core
Heart template is CdSe/ZnS quantum dots-coelenteron luciferin complexes, or coelenteron fluorescein, or CdSe/ZnS quantum dots-coelenteron is glimmering
The mixture of light element compound and coelenteron fluorescein.It will not be repeated here and prepare the embodiment of the load substrate nanometer microvesicle.
The present invention is not limited to the above-described embodiments, for those skilled in the art, is not departing from
On the premise of the principle of the invention, some improvements and modifications can also be made, these improvements and modifications are also considered as the protection of the present invention
Within the scope of.The content not being described in detail in this specification belongs to prior art known to professional and technical personnel in the field.
Claims (10)
1. a kind of nanometer microvesicle mixture that biology light source is provided, it is characterised in that it includes：
The load enzyme nanometer microvesicle of folacin receptor targeting, the load enzyme nanometer microvesicle are made up of the first kernel templates and the first shell, the
One kernel templates are CdSe/ZnS quantum dots-compound of coelenteron luciferase 8, and the first shell is the poly- breast of folic acid cross-linked polyethylene glycol
Sour glycolic acid polymer；
The load substrate nanometer microvesicle of folacin receptor targeting, the load substrate nanometer microvesicle is by the second kernel templates and second housing structure
Into the second kernel templates are CdSe/ZnS quantum dots-coelenteron luciferin complexes and/or coelenteron fluorescein, and second housing is leaf
Sour cross-linked polyethylene glycol polylactic-co-glycolic acid polymer.
A kind of 2. nanometer microvesicle mixture that biology light source is provided as claimed in claim 1, it is characterised in that：The CdSe/
ZnS quantum dot-compound of coelenteron luciferase 8 is formed by CdSe/ZnS quantum dots and the covalent coupling of enteric cavity luciferase 8.
A kind of 3. nanometer microvesicle mixture that biology light source is provided as claimed in claim 1, it is characterised in that：When described second
When kernel templates contain CdSe/ZnS quantum dots-coelenteron luciferin complexes, the CdSe/ZnS quantum dots-coelenteron fluorescein is answered
Compound is formed by CdSe/ZnS quantum dots and enteric cavity fluorescein covalent coupling.
A kind of 4. preparation method of the nanometer microvesicle mixture as claimed in claim 1 that biology light source is provided, it is characterised in that
It includes：
The step of preparing the load enzyme nanometer microvesicle；
The step of preparing the load substrate nanometer microvesicle.
5. the preparation method of the nanometer microvesicle mixture of biology light source is provided as claimed in claim 4, it is characterised in that described
The preparation process for carrying enzyme nanometer microvesicle is as follows：
S1：Folic acid cross-linked polyethylene glycol polylactic-co-glycolic acid polymer is prepared, and forms it into first shell；
S2：The CdSe/ZnS quantum dots-compound of coelenteron luciferase 8 is prepared, and forms it into first kernel templates；
S3：First kernel templates are loaded into first shell, complete the preparation for carrying enzyme nanometer microvesicle.
6. the preparation method of the nanometer microvesicle mixture of biology light source is provided as claimed in claim 5, it is characterised in that in S2
The first kernel templates preparation method is as follows：
1~3ml cushioning liquid is added in glutaraldehyde, and adds 8~12 μ l CdSe/ZnS quantum dots, in ar gas environment
After stirring 1.5~2.5h, separating-purifying simultaneously removes glutaraldehyde；1~3mg coelenterons luciferase 8 is added, is continued in ar gas environment
After 9~11h of stirring reaction, separating-purifying removes coelenteron luciferase 8, obtains the CdSe/ZnS quantum dots-coelenteron fluorescein
The compound of enzyme 8.
7. the preparation method of the nanometer microvesicle mixture of biology light source is provided as claimed in claim 5, it is characterised in that in S3
The preparation method that first kernel templates are loaded into first shell is as follows：
S31：First kernel templates and water are mixed to form interior aqueous phase, interior aqueous phase is added into the first shell concentration is
In 0~0.050g/ml dichloromethane, colostric fluid is obtained；
S32：First shell and water are mixed to form outer aqueous phase, colostric fluid is distributed to outer aqueous phase using SPG membrane emulsifiers
In, obtain double emulsion；
S33：Double emulsion is transferred in magnetic stirring apparatus, stirring makes dichloromethane volatilize, and stir speed (S.S.) is 80~120rpm/
Min, whipping temp are 30~50 DEG C, and mixing time is 8~10h；
S34：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 3~5 DEG C, 2500~3500g, is dried.
8. the preparation method of the nanometer microvesicle mixture of biology light source is provided as claimed in claim 4, it is characterised in that described
The preparation process for carrying substrate nanometer microvesicle is as follows：
A1：Folic acid cross-linked polyethylene glycol polylactic-co-glycolic acid polymer is prepared, and forms it into the second housing；
A2：When second kernel templates are coelenteron fluorescein, second kernel templates are loaded into the second housing,
Complete the preparation of the load substrate nanometer microvesicle；
When second kernel templates are CdSe/ZnS quantum dots-coelenteron luciferin complexes, the CdSe/ZnS amounts are prepared
Sub- point-coelenteron luciferin complexes, and form it into second kernel templates, second kernel templates are loaded into described the
In two shells, the preparation for carrying substrate nanometer microvesicle is completed；
When second kernel templates are CdSe/ZnS quantum dots-coelenteron luciferin complexes and coelenteron fluorescein, institute is prepared
CdSe/ZnS quantum dots-coelenteron luciferin complexes are stated, and make the CdSe/ZnS quantum dots-coelenteron luciferin complexes and institute
State coelenteron fluorescein and form second kernel templates, second kernel templates are loaded into the second housing, complete institute
State the preparation for carrying substrate nanometer microvesicle.
9. the preparation method of the nanometer microvesicle mixture of biology light source is provided as claimed in claim 8, it is characterised in that A2
In, when second kernel templates contain CdSe/ZnS quantum dots-coelenteron luciferin complexes, the CdSe/ZnS quantum
The preparation method of point-coelenteron luciferin complexes is as follows：
1~3ml cushioning liquid is added in glutaraldehyde, and adds 8~12 μ l CdSe/ZnS quantum dots, in ar gas environment
After stirring 1.5~2.5h, separating-purifying simultaneously removes glutaraldehyde；1~3mg coelenteron fluoresceins are added, continue to stir in ar gas environment
After mixing 9~11h of reaction, separating-purifying removes coelenteron fluorescein, and it is compound to obtain the CdSe/ZnS quantum dots-coelenteron fluorescein
Thing.
10. the preparation method of the nanometer microvesicle mixture of biology light source is provided as claimed in claim 8, it is characterised in that A2
The middle preparation method by second kernel templates loading second housing is as follows：
A21：Second kernel templates and water are mixed to form interior aqueous phase, interior aqueous phase is added into the second housing concentration is
In 0~0.050g/ml dichloromethane, colostric fluid is obtained；
A22：The second housing and water are mixed to form outer aqueous phase, colostric fluid is distributed to outer aqueous phase using SPG membrane emulsifiers
In, obtain double emulsion；
A23：Double emulsion is transferred in magnetic stirring apparatus, stirring makes dichloromethane volatilize, and stir speed (S.S.) is 80~120rpm/
Min, whipping temp are 30~50 DEG C, and mixing time is 8~10h；
A24：Double emulsion is transferred in centrifuge, precipitation is collected by centrifugation under the conditions of 3~5 DEG C, 2500~3500g, is dried.
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