CN110115769A - A kind of Brain targeting excretion body and its preparation method and application - Google Patents
A kind of Brain targeting excretion body and its preparation method and application Download PDFInfo
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- CN110115769A CN110115769A CN201910278139.5A CN201910278139A CN110115769A CN 110115769 A CN110115769 A CN 110115769A CN 201910278139 A CN201910278139 A CN 201910278139A CN 110115769 A CN110115769 A CN 110115769A
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Abstract
The invention discloses a kind of Brain targeting excretion body and its preparation method and application, preparation method is the following steps are included: (1) cultivates stem cell under low oxygen conditions, to stem cell progress targeting modification；The hypoxia condition are as follows: temperature is 30~40 DEG C, and oxygen concentration is 0.5~5%, and gas concentration lwevel is 1~10%；(2) stem cell after targeting modification is transferred to regular culture conditions to cultivate, collects stem cell and trains liquid, extracted separation from the stem cell training liquid, obtain Brain targeting excretion body.The Brain targeting excretion body of acquisition can be applied to the drug of preparation treatment cerebral arterial thrombosis.Preparation method of the invention modifies excretion body by the transformation to stem cell indirectly, improves the expression of its film surface CXCR4, to improve its brain targeting.
Description
Technical field
The present invention relates to bio-carrier targeting drug delivery technical field more particularly to a kind of Brain targeting excretion body and its preparation sides
Method and application.
Background technique
The transformation of variation and human life style recently as global environment, cardiovascular and cerebrovascular disease gradually occupy people
The first place of the class cause of death.Wherein, the annual kainogenesis cerebrovascular disease about 3,400,000 of China, mortality of cerebrovascular disease newly occur is about 160
Ten thousand, morbidity and mortality are also rising year by year.Cerebral arterial thrombosis has the spy of high incidence, high lethality rate, high disability rate
Point.The most common cerebral arterial thrombosis be due to the feeding artery of brain is narrow or occlusion, encephalic blood circulation disorder and cause
The necrosis of local brain tissue hypoxic-ischemic, it is final to generate nervous function and dyskinesia, brought to patient and its family
Huge body and mind pain and financial burden, it is serious to hinder social development.
In recent years, stem cell transplantation shows good therapeutic effect in the treatment of a variety of brain diseases.The study found that
Stem cell can move to diseased region after transplanting enters in vivo, on the one hand by itself differentiation potential in brain diseases region point
Turn to nerve cell, on the other hand also can secretory nerve trophic factors, adjust disease microenvironment, promote autologous stem cells migrate to
Injury tissue is repaired and is regenerated, and huge potential is presented in the treatment of brain diseases.But the transplantation treatment of stem cell
There is also certain risks.And a kind of important vesica that excretion body is transmitted as cell-tocell, due to its low immunogenicity,
High-biocompatibility, stable structure, safety, the advantages that easily propagating through internal barrier, it is potential become it is a kind of based on cell, have
Its advantage can have both safety and modifiable pharmaceutical carrier again.Include the albumen in its close source cell in excretion body simultaneously
The contents such as matter, lipid, gene can also generate certain therapeutic effect to disease.
The targeting of excretion body is related to its close source cell, and targeting ability is weaker.This, which will lead to, extracts difficult excretion body
Waste in use, affects the treatment.Therefore, the targeting of excretion body needs to improve.
Stem cell membrane surface has the receptor CXCR 4 of chemotactic factor (CF) SDF-1 to express.SDF-1 expressed in normal cerebral tissue compared with
It is low, but in anoxic and areas of inflammation expression up-regulation.It is able to guide stem cell migration and carries out repairing and treating to damage field, is dry thin
The important component of born of the same parents' targeting ability.
Since the membrane structure of excretion body is derived partly from cell membrane, the variation of protein receptor can also be transferred on cell membrane
On excretion body.CXCR4 by improving excretion body surface face to the modification of stem cell is expressed, to effectively improve the brain of excretion body
Targeting.
Therefore, modification excretion body makes Brain targeting bio-carrier and has to the treatment of cerebral arterial thrombosis answers well
With prospect and important scientific meaning.
Summary of the invention
The present invention provides a kind of preparation methods of Brain targeting excretion body, modify excretion indirectly by the transformation to stem cell
Body, improves the expression of its film surface CXCR4, to improve its brain targeting.
Specific technical solution is as follows:
A kind of preparation method of Brain targeting excretion body, comprising the following steps:
(1) stem cell is cultivated under low oxygen conditions, targeting modification is carried out to stem cell；
The hypoxia condition are as follows: temperature be 30~40 DEG C, oxygen concentration be 0.5~5%, gas concentration lwevel be 1~
10%；
(2) stem cell after targeting modification is transferred to regular culture conditions to cultivate, collects stem cell and train liquid, from institute
Separation is extracted in the stem cell training liquid stated, obtains Brain targeting excretion body.
The regular culture conditions are as follows: temperature is 30~40 DEG C, and oxygen concentration is 15~20%, and gas concentration lwevel is
1~10%.
After hypoxia condition culture, stem cell will not show overt toxicity, and the excretion body of stem cell and its secretion
Film surface CXCR4 expression quantity increase is the most significant, and has not significant impact to the excretion body secretion capacity of stem cell, the excretion bodily form
State is complete, is not destroyed.
And CXCR4 is the receptor of chemotactic factor (CF) SDF-1, SDF-1 expressed in normal cerebral tissue it is lower, but in anoxic and inflammation
The up-regulation of disease Zonal expression, therefore, CXCR4 are able to guide stem cell migration and carry out repairing and treating to damage field, are stem cell targets
The important component of ability.CXCR4 by improving excretion body surface face to the modification of stem cell is expressed, to effectively improve
The brain targeting of excretion body.
When hypoxemia culture, oxygen concentration is excessively high to generate apparent hypoxemia effect of stimulation, oxygen concentration mistake to stem cell
It is low to will affect cell activity.
Preferably, the hypoxia condition are as follows: temperature is 30~40 DEG C, and oxygen concentration is 0.5~2%, and carbon dioxide is dense
Degree is 3~6%.
Preferably, stem cell is subjected to 4~36h of culture under low oxygen conditions.
With the growth of hypoxemia incubation time, excretion body CXCR4 expression is gradually increased, and has afterwards for 24 hours in hypoxemia culture aobvious
Difference is write, after hypoxemia culture for 24 hours, excretion body CXCR4 is expressed significantly beyond normal culture group.
It is further preferred that stem cell to be carried out to culture 12~for 24 hours under low oxygen conditions.
Specifically, stem cell is resuspended in culture solution in step (1), cell suspension is made；The cell suspension
In, the concentration of stem cell is 104~107cell/mL。
Concentration of stem cells is excessively high to be unfavorable for cell survival, influences cell activity.Concentration is too low to be unfavorable for cell survival, and difficult
To collect enough excretion bodies.
Preferably, in the cell suspension, the concentration of stem cell is 1 × 105~5 × 105cell/mL。
The culture solution is the cell culture additive B 27 comprising 2%, 1 μ g/mL basic fibroblast growth factor
(bFGF), the DMEM/F12 culture solution of 2 μ g/mL epithelical cell growth factors (EGF).
In step (2), separation is extracted from the stem cell training liquid, obtains Brain targeting excretion body, comprising: by stem cell
It accompanies liquid to be centrifuged, takes supernatant；The supernatant is concentrated by ultrafiltration again, concentrate uses excretion body splitter column separation, obtains
Brain targeting excretion body.
The centrifugation, concentration include: to take supernatant first by stem cell training liquid by 3000g centrifugation 30min；It again will be upper
Clear liquid 10000g is centrifuged 30min, takes supernatant 100KD super filter tube with the speed centrifugal concentrating of 4000g.
The excretion body splitter is the extracellular vesica of qEV (excretion body) splitter.
The present invention also provides Brain targeting excretion body made from above-mentioned preparation method, which can be applied to make
The drug of standby treatment cerebral arterial thrombosis.
Compared with prior art, the invention has the benefit that
(1) preparation method of the invention will not show overt toxicity to stem cell, secrete energy to the excretion body of stem cell
Power has not significant impact；
(2) excretion body film surface CXCR4 expression quantity made from increases significantly, and Brain targeting ability significantly improves, and enhances outer
Body is secreted in the aggregation in cerebral arterial thrombosis necrosis brain domain；
(3) destruction to excretion body is not related to the film modified process of excretion body, excretion body film can be kept to greatest extent
Integrality protects it to have the content of therapeutic effect not to be lost；
(4) preparation method is easy to operate, convenient for control.
Detailed description of the invention
Fig. 1 is the excretion body transmission electron microscope picture of the stem cell secretion of non-hypoxemia culture；
Fig. 2 is the excretion body transmission electron microscope picture of the stem cell secretion after hypoxemia culture；
Fig. 3 is the excretion body CXCR4 expression quantity of stem cell and its secretion variation after hypoxemia culture；Wherein (a) is excretion body
(exosomes) total protein concentration changes, and (b) changes for stem cell (NSCs) total protein concentration, (c) is the total quantitative change of CXCR4 of excretion body
Change, (d) change for the CXCR4 total amount of stem cell, (e) change for the CXCR4 relative protein amounts of excretion body, is (f) stem cell
The variation of CXCR4 relative protein amounts, *, * * respectively represent P < 0.05, P < 0.01；
Fig. 4 is excretion body in MCAO rat kidney tissue situation；Wherein (a) is the outer of the stem cell secretion of non-hypoxemia culture
Body is secreted, is (b) the excretion body of the stem cell secretion after hypoxemia culture；
The effect picture that Fig. 5 treats cerebral arterial thrombosis mouse for the excretion body of stem cell and its secretion；Wherein MCAO group
Not treat after mouse MCAO modeling, NSC group is controlled for the NSCs after tail vein injection hypoxemia culture after mouse MCAO modeling
It treats；Exosomes group is treated for the excretion body of the NSCs secretion after tail vein injection hypoxemia culture after mouse MCAO modeling.
Specific embodiment
1, the extraction separation of the excretion body of stem cell secretion
Stem cell is resuspended in culture solution, cell suspension (2 × 10 is made5Cell/mL), in 37 DEG C, normal condition (oxygen
Gas concentration is 20%, gas concentration lwevel 5%) in cultivate 48h.
Culture solution includes the cell culture additive of basic culture solution DMEM/F12 (Gibco, article No. 11330032), 2%
B27 (Gibco, article No. 17504-044), 1 μ g/mL basic fibroblast growth factor (bFGF, PeproTech, article No. 450-
33-50), 2 μ g/mL epithelical cell growth factor (EGF, PeproTech, article No. 315-09-100).
It collects stem cell and trains liquid, low-speed centrifugal is centrifuged 30min by 3000g, takes supernatant；It is centrifuged again by 10000g
30min takes supernatant, discards the sediments such as cell fragment and organelle.By after centrifugation cell training liquid with 100KD super filter tube with
The speed centrifugal concentrating of 4000g.Cell training liquid after concentration passes through the extracellular vesica of qEV (excretion body) splitter, column separation
Excretion body.Separating obtained excretion body transmission electron microscope photo is extracted as shown in Figure 1, excretion body is cup-shaped of the partial size in 100nm or so
Vesica.
2, the extraction separation for the excretion body secreted after the culture of stem cell hypoxemia
Stem cell is resuspended in DMEM/F12 culture solution, cell suspension (2 × 10 is made5Cell/mL), in 37 DEG C, it is low
Oxygen condition (oxygen concentration 1%, gas concentration lwevel 5%) culture 0~for 24 hours.Cell is transferred to regular culture conditions again
In, continue to cultivate 48h.
It collects stem cell and trains liquid, low-speed centrifugal is centrifuged 30min by 3000g, takes supernatant；It is centrifuged again by 10000g
30min takes supernatant, discards the sediments such as cell fragment and organelle.By after centrifugation cell training liquid with 100KD super filter tube with
The speed centrifugal concentrating of 4000g.Cell training liquid after concentration passes through the extracellular vesica of qEV (excretion body) splitter, column separation
Excretion body.Separating obtained excretion body transmission electron microscope photo is extracted as shown in Fig. 2, excretion body is cup-shaped of the partial size in 100nm or so
Vesica.
3, the excretion body film surface CXCR4 expression quantity of stem cell and its secretion measures
(1) with SDS lysate cracking stem cell and its excretion body of secretion；
(2) using the ELISA kit of CXCR4 to the excretion body film surface CXCR4 expression quantity of stem cell and its secretion into
Row measurement；
(3) the excretion body protein total amount of stem cell and its secretion is detected with micro BCA kit, with quantitative stem cell and its
The excretion body of secretion.
As shown in (a) and (b) in Fig. 3, low-oxygen environment influences smaller, Bu Huixian to the excretion body of stem cell and its secretion
Write the excretion body secretion capacity for changing stem cell.
Such as (c) and (d) display in Fig. 3, hypoxemia processing will increase the expression of the CXCR4 in excretion body surface face.With hypoxemia
The growth of time, CXCR4 expression is gradually increased, and there were significant differences after hypoxemia culture for 24 hours.But in stem cell, CXCR4's
Expression total amount has no significant change.
Stem cell and excretion body are measured with protein content, are shown by (e) and (f) in Fig. 3, with hypoxemia incubation time
Extend, the relative expression quantity of excretion body surface face CXCR4 is gradually increased, hypoxemia culture for 24 hours when significantly beyond normal culture group, and
CXCR4 relative expression quantity on stem cell is without significant changes；Meanwhile compared to stem cell, CXCR4 is enriched in excretion body surface face.
4, zoopery
(1) foundation of arteria cerebri media embolism (MCAO) model.
The male C57BL6 mouse of 20~25g is selected to carry out the operation of MCAO model foundation.
With 1% yellow Jackets anesthetized mice.Mouse is lain on the back and is fixed on operating table, positive split shed at neck, separation
Muscle, body of gland find the arteria carotis communis of beating, separate vagus nerve, ligature proximal part after threading.Distal end beats slip-knot, top
It is clamped with hemostatic clamp.
Scissors opens an osculum between both threads, is inserted at line bolt to hemostatic clamp, and slip-knot before is fastened, and opens hemostasis
Folder, is pushed further into line bolt, and line bolt enters blood vessel fork and goes out about 8~10mm, stops when meeting obvious resistance.It sews up a wound, mouse is set
In 37 DEG C of constant-temperature warm-keepings in heating plate.Outlet bolt is pulled out after ischemic 60min, carries out Reperfu- sion.
(2) fluorescent marker is carried out to the excretion body after excretion body and hypoxemia modification, is entered respectively by tail vein injection
In MCAO Mice Body.After for 24 hours, mouse is put to death, heart, liver, spleen, brain, lung, kidney is taken out and is imaged.
(3) will be set to the 0th day on the day of modeling.Respectively at the 1st day, the 7th day by tail vein injection stem cell (NSCs, 3 ×
105) or excretion body (exosomes, 10 μ g) cell.MNss scoring is carried out to mouse respectively within 1st, 4,7,14,21,28 day.This is commented
Divide including movement, feeling, reflection and balance test, to evaluate the nervous function of mouse.
Excretion body after targeting modification increases in the aggregation of lesion location, and targeting is remarkably reinforced (such as Fig. 4 institute
Show).
As shown in figure 5, after modeling, MCAO mouse mNss is improved to 13 points or so the mNss appraisal result of mouse.It is not right
MCAO mouse is treated, and mouse mNss can continue to rise until dead.And after transplanting NSCs, mouse mNss can be gradually reduced,
Nervous function and capacity are gradually recovered, and after treatment is finished, mNss is about 6 points.
Exosomes group mouse mNss entire lowering amplitude is smaller, and performance is not so good as NSC group in recovery process, final to score
It is about 6 points, similar to NSCs group.
This result illustrates that the therapeutic substance in stem cell is transferred to cerebral arterial thrombosis disease location by excretion physical efficiency, to disease
Disease generates certain therapeutic effect.
Technical solution of the present invention and beneficial effect is described in detail in embodiment described above, it should be understood that
Above is only a specific embodiment of the present invention, it is not intended to restrict the invention, it is all to be done in spirit of the invention
Any modification, supplementary, and equivalent replacement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Brain targeting excretion body, which comprises the following steps:
(1) stem cell is cultivated under low oxygen conditions, targeting modification is carried out to stem cell；
The hypoxia condition are as follows: temperature is 30~40 DEG C, and oxygen concentration is 0.5~5%, and gas concentration lwevel is 1~10%；
(2) stem cell after targeting modification is transferred to regular culture conditions to cultivate, collects stem cell and train liquid, from described
Stem cell, which is trained, extracts separation in liquid, obtain Brain targeting excretion body.
2. the preparation method of Brain targeting excretion body according to claim 1, which is characterized in that the hypoxia condition are as follows:
Temperature is 30~40 DEG C, and oxygen concentration is 0.5~2%, and gas concentration lwevel is 3~6%.
3. the preparation method of Brain targeting excretion body according to claim 1, which is characterized in that by stem cell in hypoxia condition
Under carry out 4~36h of culture.
4. the preparation method of Brain targeting excretion body according to claim 3, which is characterized in that by stem cell in hypoxia condition
Under carry out culture 12~for 24 hours.
5. the preparation method of Brain targeting excretion body according to claim 1, which is characterized in that in step (1), by stem cell
It is resuspended in culture solution, cell suspension is made；In the cell suspension, the concentration of stem cell is 104~107cell/mL。
6. the preparation method of Brain targeting excretion body according to claim 5, which is characterized in that in the cell suspension,
The concentration of stem cell is 1 × 105~5 × 105cell/mL。
7. the preparation method of Brain targeting excretion body according to claim 5, which is characterized in that the culture solution be comprising
2% cell culture additive B 27,1 μ g/mL basic fibroblast growth factor, 2 μ g/mL epithelical cell growth factors
DMEM/F12 culture solution.
8. the preparation method of Brain targeting excretion body according to claim 1, which is characterized in that in step (2), from described
Stem cell, which is accompanied, extracts separation in liquid, obtain Brain targeting excretion body, comprising: accompany liquid to be centrifuged stem cell, take supernatant；It again will be described
Supernatant is concentrated by ultrafiltration, and concentrate uses excretion body splitter column separation, obtains Brain targeting excretion body.
9. a kind of Brain targeting excretion body, which is characterized in that be made by the preparation method described in claim 1~8.
10. a kind of Brain targeting excretion body according to claim 9 answering in the drug of preparation treatment cerebral arterial thrombosis
With.
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| CN111000868A (en) * | 2020-01-06 | 2020-04-14 | 浙江大学 | Application of hypoxia-treated stem cell exosome in preparation of drug or scaffold material for treating spinal cord injury |
| CN113337468A (en) * | 2021-05-27 | 2021-09-03 | 上海市伤骨科研究所 | Dual-functional exosome, preparation method thereof and application thereof in cerebral apoplexy repair |
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| CN116173214A (en) * | 2023-04-27 | 2023-05-30 | 暨南大学附属第一医院（广州华侨医院） | Application of exosome RNA binding protein FUS as acute ischemic stroke treatment target |
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