CN110354280A - A kind of nano-gene carrier and preparation method thereof that can be anticoagulant - Google Patents
A kind of nano-gene carrier and preparation method thereof that can be anticoagulant Download PDFInfo
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
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Abstract
The present invention provides a kind of nano-gene carrier and preparation method thereof that can be anticoagulant, and nano-gene carrier includes the low molecular weight heparin of genophore and modification on the genophore surface.Nano-gene carrier of the invention and preparation method thereof, anticoagulant and genetic safety is effectively delivered and is integrated, to obtain anticoagulant and gene therapy double effects, embolism and the high blood coagulation position penetrated in Coronary microcirculation is improved, delivery system is allowed to go deep into infarcted myocardium.
Description
Technical field
The present invention relates to a kind of nano-gene carriers that can be anticoagulant, and the invention further relates to a kind of nano gene loads that can be anticoagulant
The preparation method of body, belongs to field of biotechnology.
Background technique
Myocardial infarction (myocardial infarction, MI) is the highest cardiovascular disease of the global death rate, and long-term
The death rate is high, and miRNA is that MI clinical treatment brings new opportunity.Face well although miRNA has in the treatment of MI
Bed application prospect, but lack safe and efficient delivery system and constrain its clinical application, nano-gene carrier is expected to solve this
Obstacle.The stability of miRNA, slow release, transfection efficiency, targeting can be improved in the introducing of nano-carrier, and carries compared to virus
Body has good biological safety.
Nano-carrier leads to the phenomenon that targeting inefficiency in the presence of the bottleneck for being difficult to break through when mediating myocardial infarction is treated
It is very universal.Construction analysis is carried out to heart infarction targeted delivery process, delivery process can be divided into local lesion's infiltration, whole body body
Recycle two broad aspects: 1. heart infarction lesion is extremely special, is related to the factors such as high blood coagulation state, lateral thrombus, nanometer is caused to deliver
System is difficult to go deep into infarcted myocardium；2. long circulating is the basis of targeting, but nano particle agglutination can be such that it is quickly known by body circulation
It does not remove.
Since coronary artery endothelial cell damage, capilary primary thrombus are formed after myocardial infarction, coagulation factor in blood
It is easily activated and hypercoagulative state is presented, inflammatory cascade activation is with Leukostasis, if will lead to without early stage anticoagulant pre- preventing thrombosis progress
The thrombus of these Coronary microcirculations perfusion is retarded by silt or embolism, so that the blood fortune at ischemic myocardium position is reduced or interrupted.And it loads
The nano particle of miRNA reaches ischemic myocardium part from systemic blood circulation, and Coronary microcirculation is its only way which must be passed, but tradition
Nano-carrier be difficult to these embolisms passed through in Coronary microcirculation, lesion can not be goed deep into so as to cause it.
Summary of the invention
The purpose of the present invention is to provide a kind of nano-gene carriers and preparation method thereof that can be anticoagulant, are provided simultaneously with anticoagulant
Delivery system is allowed to go deep into improve embolism and the high blood coagulation position penetrated in Coronary microcirculation with the effect of gene therapy
Infarcted myocardium.
Present invention employs following technical solutions:
The present invention provides a kind of nano-gene carrier that can be anticoagulant characterized by comprising
Low molecular weight heparin of the genophore with modification on the genophore surface.
Further nano-gene carrier that can be anticoagulant of the invention, it is characterised in that:
Wherein, the genophore is G3 dendroid polylysine.
Further, nano-gene carrier that can be anticoagulant of the invention, it is characterised in that:
Wherein, the mass ratio of the G3 dendroid polylysine and the low molecular weight heparin are as follows: 1.5:a, wherein 0.1≤a
≦0.5。
The present invention also provides a kind of preparation methods of nano-gene carrier that can be anticoagulant, comprising:
Step 1: nucleic acid fragment to be loaded and G3 dendroid polylysine are incubated for 30min with the ratio of 1:b altogether, obtain
To reagent A；
Step 2: low molecular weight heparin and reagent A are incubated for altogether, and part positive charge is neutralized, nucleic acid fragment to be loaded,
DGL and low molecular weight heparin are with the ratio synthesis particle of 1:b:a, wherein 1≤b≤3,0.1≤a≤0.5.
Further, the preparation method of nano-gene carrier that can be anticoagulant of the invention, it is characterised in that:
In step 3, nucleic acid fragment to be loaded, DGL and low molecular weight heparin are with the ratio of 1:1.5:0.5
Further, the preparation method of nano-gene carrier that can be anticoagulant of the invention, it is characterised in that: in step 2, incubate
Condition is educated for incubation at room temperature 10 minutes.
Advantageous effect of the invention
Anticoagulant and genetic safety is effectively delivered and is combined by nano-gene carrier and preparation method thereof that can be anticoagulant of the invention
One improves embolism and the high blood coagulation portion penetrated in Coronary microcirculation to obtain anticoagulant and gene therapy double effects
Position, allows delivery system to go deep into infarcted myocardium.Nano-gene carrier that can be anticoagulant of the invention is especially suitable for myocardial ischemia and the heart
The gene delivery of flesh infarct.
Detailed description of the invention
Fig. 1 is the proportioning test result that AMO-1 is loaded completely by DGL.
Fig. 2 is low molecular sodium heparin and matching for DGL to compare the experiment that particle loads AMO-1 ability completely.
Fig. 3 is to be detected after nano-gene carrier that can be anticoagulant of the invention loads AMO-1 with Malvern particle instrument
As a result.
Fig. 4 is the experimental result of the transfection efficiency after nano-gene carrier load AMO-1 that can be anticoagulant of the invention.
Fig. 5 is the result of APTT measurement.
Fig. 6 is the result of PT measurement.
Fig. 7 is the experimental result of thrombosis situation after intravenous injection.
Fig. 8 A be by building can anticoagulant nano-gene carrier be injected into M type ultrasound figure in heart infarction animal body after 3 weeks.
Fig. 8 B be by building can anticoagulant nano-gene carrier be injected into Ejection in heart infarction animal body after 3 weeks
Figure.
Fig. 8 C by building can anticoagulant nano-gene carrier be injected into the left-ventricular short-axis in heart infarction animal body after 3 weeks contracting
The figure of short index FS.
Specific embodiment
Illustrate a specific embodiment of the invention below in conjunction with attached drawing.
The antisense sequences AMO-1 of miRNA-1 and DGL are incubated for 30min by embodiment 1. altogether in varing proportions, find AMO-1
The appropriate proportioning loaded completely by DGL.
MiRNA-1: a kind of anti-apoptotic genes expression, sequence 5'-UGGAAUGUAAAGAAGUGUGUAU-3'
The antisense sequences of AMO-1:miRNA-1 can be the inhibitor of miRNA-1, sequence 5'- with its specific binding
AUACACACUUCUUUACAUUCCA-3' is synthesized by Shanghai JiMa pharmacy Technology Co., Ltd, and with every pipe 0.5OD packing
DGL:G3 dendroid polylysine, is purchased from colcom company, MW:20000
(1) AMO-1 of a pipe 0.5OD is dissolved with 100ulDEPC water, and measures mrna concentration with nanodrop2000:
300ng/ul, 4 DEG C keep in it is spare
(2) 10mgDGL powder is weighed, and is revolved with the 10mlDEPC eddies of water and dissolves spare (1mg/ml)
(3) with 50ngAMO-1 for 1, it is 0,0.5,1,2,4,6,8,10 according to DGL:AMO-1 mass ratio, DGL solution is delayed
Slowly it is added dropwise in AMO-1, and becomes dropwise addition side and rock, be incubated at room temperature 30 minutes.
(4) the 1.5% sugar agar gel of red containing gel is prepared, respectively by above-mentioned each 10ul and loading of 8 samples
Loading after buffer is mixed
(5) stop after running 10min with the voltage of 100V, and shot with gel imaging system, as a result as shown in Figure 1.
When DGL and AMO-1 ratio is greater than 1, RNA band is just wholly constrained in well, it was demonstrated that when DGL/AMO-1 is big
When 1, AMO-1 can be loaded completely, and the ratio of 1:1.5 is selected in present embodiment.
Low molecular weight heparin is incubated for by embodiment 2. altogether in different proportions with the DGL for having loaded AMO-1, is carried out on its surface
Modification, and part positive charge is neutralized, while guaranteeing the still valid load of AMO-1.
Low molecular sodium heparin: Dalian U.S. logical sequence Technology Co., Ltd., Enoxaparin, MW:4500 are purchased from
(1) after selecting the DGL of the AMO-1 and 150ng of 100ng to be incubated for 30min, by low molecular weight heparin and DGL according to 0,
0.5,1,2,4,6 mass ratio is slowly added to low molecular weight heparin (Hep) dropwise, slowly mixes when being added dropwise, and is incubated at room temperature 10 points
Clock, 4 DEG C keep in it is spare
(2) the 1.5% sugar agar gel of red containing gel is prepared, respectively by naked AMO-1 and above-mentioned preparation each sample 10ul
Loading after being mixed with loading buffer
(3) stop after running 10min with the voltage of 100V, and shot with gel imaging system, as a result as shown in Figure 2.
When low molecular sodium heparin and DGL mass ratio are greater than 0.5, which just cannot load AMO-1 completely, therefore final
AMO-1, DGL, and low molecular weight heparin is selected to synthesize nano particle with the ratio of 1:1.5:0.5.
Embodiment 3. detects nano particle obtained in embodiment 2 with Malvern particle instrument, as shown in figure 3, knot
Fruit uniform particle sizes, average grain diameter about 180nm.Step provided by specification of the detecting step of Malvern particle instrument according to instrument
Progress.
4. transfection efficiency of embodiment
(1) the AMO-1 synthesis particle for taking fluorescence FAM to mark
(2) by AMO-1, DGL@AMO-1 and heparin modified DGL@AMO-1 respectively with the original extracted with SD rat suckling mouse
6h is incubated for for cardiac muscle cell
(3) this several groups of cells are fixed with formaldehyde respectively and flow cytometer detects
As a result as shown in Figure 4.The DGL@AMO-1 modified through low molecular weight heparin is transfected into primary cardiomyocytes quantity and does not repair
Decorations are suitable, hence it is evident that are higher than naked AMO-1 and blank control group.Illustrate to modify and does not influence transfection efficiency.
Embodiment 5.APTT, PT measurement
(1) PBS, DGL@AMO-1, the DGL@AMO-1 and low molecular weight heparin of low molecular weight heparin modification are injected into 30g respectively
In the ICR hero caudal vein of left and right, every group 6
(2) blood is taken by plucking eyeball, every mouse blood and sodium citrate is mixed according to 9:1
(3) 3000rpm under the anticoagulation room temperature after mixing is centrifuged 20 minutes
(4) upper plasma is taken to manage to 1.5mlep, 4 DEG C temporary stand-by
(5) when 200ul blood plasma being carried out upper machine testing activated partial thromboplastin with the full-automatic blood biochemistry analyzer of thunder Du
Between APTT and prothrombin time PT.
As a result as shown in Figure 5 and Figure 6 respectively:
After the particle is by intravenous injection, the DGL AMO-1 modified through low molecular weight heparin can make the plasma A PTT time bright
It is aobvious to extend, it was demonstrated that the particle has definite anticoagulation.
6. thrombosis size of embodiment
(1) PBS, DGL@AMO-1, the DGL@AMO-1 and low molecular weight heparin of low molecular weight heparin modification are injected into 30g respectively
In the ICR hero caudal vein of left and right, every group 4
(2) blood 1ml is taken by plucking eyeball, slightly mixed
(3) whole blood is stood 30 minutes
(4) 2ml physiological saline fading background color is added
(5) thrombosis size is observed
As a result as shown in fig. 7, N.S/DGL/HD/Hsp respectively corresponds PBS, DGL@AMO-1, low molecular weight heparin modification in figure
DGL@AMO-1 and low molecular weight heparin.It can be seen that the DGL@AMO-1 modified through low molecular weight heparin can from the size of thrombosis
With antithrombus formation to a certain extent.DGL@AMO-1 indicates to have loaded the DGL of AMO-1.
DGL has the advantage of high load rate, but because a large amount of positive charges in its surface will lead to reunion: with elecrtonegativity substance phase
Mutually absorption agglutination causes partial size to break through nano-scale, easily combines with blood formed element after entering body circulation by vein, into
And it is identified by RES rapidly and removes and can not play a role.
And the invention heparin is formed in conjunction with DGL can be anticoagulant nano-gene carrier, since heparin band is negative
Electricity, can neutralize the positive electricity of a part of dendritic DGL institute band, so that the reunion of DGL is avoided to a certain extent, so that
It is not easy to be identified and removed by immune system after intravenous injection.Therefore it while avoiding DGL and easily reuniting, yet forms
It is capable of the genophore of antithrombotic.
Embodiment 7
By constructed in above embodiment can anticoagulant nano-gene carrier be injected into heart infarction animal body.With AMO-1
Subject to, every 200g rat 200ug AMO-1, that is, 600ugLMWH-DGL-AMO-1,500ugDGL-AMO-1.Fig. 8 A is
By constructed in above embodiment can anticoagulant nano-gene carrier be injected into M type ultrasound figure in heart infarction animal body after 3 weeks.
Histogram in Fig. 8 B and Fig. 8 C is the figure for reflecting heart function, is that Ejection and left-ventricular short-axis shorten respectively
Index FS.Wherein MI represents the rat for only having done heart infarction art, and HD is heparin and DGL complex is free of AMO-1, and HDA is containing AMO-1
Heparin and DGL complex.The complex has protective effect to the heart function of heart infarction rat as seen from the figure.
Sequence table
<110>Xinhua Hospital Attached to Medical School, Shanghai Jiaotong Univ.
<120>a kind of nano-gene carrier and preparation method thereof that can be anticoagulant
<130> JSP11904175
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 22
<212> RNA
<213> artificial
<400> 1
uggaauguaa agaagugugu au 22
<210> 2
<211> 22
<212> RNA
<213> artificial
<400> 2
auacacacuu cuuuacauuc ca 22
Claims (6)
1. the nano-gene carrier that one kind can be anticoagulant characterized by comprising
Low molecular weight heparin of the genophore with modification on the genophore surface.
2. nano-gene carrier that as described in claim 1 can be anticoagulant, it is characterised in that:
Wherein, the genophore is G3 dendroid polylysine.
3. nano-gene carrier that as claimed in claim 2 can be anticoagulant, it is characterised in that:
Wherein, the mass ratio of the G3 dendroid polylysine and the low molecular weight heparin are as follows: 1.5:a, wherein 0.1≤a≤
0.5。
4. the preparation method for the nano-gene carrier that one kind can be anticoagulant, comprising:
Step 1: nucleic acid fragment to be loaded and G3 dendroid polylysine are incubated for 30min with 1:1.5 ratio altogether, tried
Agent A；
Step 2: low molecular weight heparin and reagent A are incubated for altogether, and part positive charge is neutralized, nucleic acid fragment to be loaded, DGL, and
Low molecular weight heparin is with the ratio synthesis particle of 1:b:a, wherein 1≤b≤3,0.1≤a≤0.5.
5. the preparation method of nano-gene carrier that as claimed in claim 4 can be anticoagulant, it is characterised in that:
In step 3, nucleic acid fragment to be loaded, DGL and low molecular weight heparin are with the ratio of 1:1.5:0.5.
6. the preparation method of nano-gene carrier that as claimed in claim 4 can be anticoagulant, it is characterised in that:
In step 2, incubation conditions are incubation at room temperature 10 minutes.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103656623A (en) * | 2013-12-06 | 2014-03-26 | 南通大学 | Nanoparticles loaded with neurotrophic factors, and preparation and applications thereof |
| CN103705465A (en) * | 2012-10-09 | 2014-04-09 | 复旦大学 | Slightly acidic environment targeted polypeptide modified tumor targeted nano drug delivery system, and preparation method thereof |
| US20190091163A1 (en) * | 2016-04-26 | 2019-03-28 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Nano-sized drug delivery structure |
| CN109529129A (en) * | 2018-12-28 | 2019-03-29 | 西南交通大学 | Nano particle, preparation method and the application of inside package zinc ion |
-
2019
- 2019-07-22 CN CN201910662494.2A patent/CN110354280B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103705465A (en) * | 2012-10-09 | 2014-04-09 | 复旦大学 | Slightly acidic environment targeted polypeptide modified tumor targeted nano drug delivery system, and preparation method thereof |
| CN103656623A (en) * | 2013-12-06 | 2014-03-26 | 南通大学 | Nanoparticles loaded with neurotrophic factors, and preparation and applications thereof |
| US20190091163A1 (en) * | 2016-04-26 | 2019-03-28 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Nano-sized drug delivery structure |
| CN109529129A (en) * | 2018-12-28 | 2019-03-29 | 西南交通大学 | Nano particle, preparation method and the application of inside package zinc ion |
Non-Patent Citations (1)
| Title |
|---|
| XIAOMEI XUE等: "Delivery of microRNA-1 inhibitor by dendrimer-based nanovector: An early targeting therapy for myocardial infarction in mice", 《NANOMEDICINE: NANOTECHNOLOGY, BIOLOGY, AND MEDICINE》 * |
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