CN107441040B - A kind of Ciclosporin A delivery system for treating myocardial ischemia-reperfusion injury - Google Patents
A kind of Ciclosporin A delivery system for treating myocardial ischemia-reperfusion injury Download PDFInfo
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- CN107441040B CN107441040B CN201710519920.8A CN201710519920A CN107441040B CN 107441040 B CN107441040 B CN 107441040B CN 201710519920 A CN201710519920 A CN 201710519920A CN 107441040 B CN107441040 B CN 107441040B
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- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The invention discloses a kind of Ciclosporin A delivery systems for treating myocardial ischemia-reperfusion injury, it is characterized in that the delivery system is the high drug load polymer micelle that matrix metalloproteinase and active oxygen double-bang firecracker are answered, it is obtained by block copolymer polyethylene glycol-matrix metalloproteinase peptide substrate-poly-aspartate-phenyl boric acid self assembly, block copolymer wraps up cyclosporin A by mating reaction to which self assembly obtains carrier micelle.This delivery system can act on ischemic myocardial tissue by passive target; quick release goes out cyclosporin A under the action of matrix metalloproteinase and active oxygen; the protective effect to myocardial ischemia-reperfusion injury is played, provides new strategy for the prevention and treatment of myocardial ischemia-reperfusion injury.
Description
Technical field
The present invention relates to the high drug load nano-micelle delivery systems that a kind of matrix metalloproteinase and active oxygen double-bang firecracker are answered
Composition and application scheme, this delivery system be wrap up cyclosporin A polyethylene glycol-matrix metalloproteinase substrate
Peptide-poly-aspartate-phenyl boric acid micella.
Background technique
With thromboembolism treatment, percutaneous coronary intervention (percutaneous coronary intervention,
PCI), Coronary Artery Bypass Grafting (coronary artery by pass grafting, CABG) etc. is in a large amount of of clinic
Using, therewith cause myocardial ischemia/reperfusion injury (myocardial ischemia-reperfusion injury,
MI/RI it) increasingly receives significant attention.Ciclosporin A (CyclosporinA, CsA) is one of most classic mPTP inhibitor,
It in conjunction with CyP-D and can form compound, hinder CyP-D with ANT ining conjunction with, thus inhibit mPTP opening, reduction caspase-3
Activity reduces Apoptosis, plays myocardium protecting action, and be confirmed in many animals body.But with traditional ring spore bacterium
The cardioprotection that plain fat emulsion formulation will lead to Ischemic reperfusion generation is lost.Therefore, it is necessary to study novel ring spore bacterium
Plain A (CsA) preparation guarantees the performance of its effect.In addition to this, studies have shown that cyclosporin A plays MI/RI protective effect
Blood concentration should be in 0.4-2 μm of ol/L, and when blood concentration is higher than 5 μm of ol/L, protective effect just disappears, and illustrates cyclosporin
The therapeutic window of A (CsA) is very narrow.It is 2.5mg/kg that many research discoveries, which play the optimal dosage of protective effect, in contrast, very
More evidences show that cyclosporin A plays protective effect and dose dependent is presented again.This may be with cyclosporin A in different groups body
Interior Difference of Metabolism is related.Moreover, cyclosporin A (CsA) itself is also used as immunosuppressor application, the distribution at other positions
Biggish immunosuppressive action can be generated.Therefore, it in order to play the effect of cyclosporin A (CsA) to greatest extent, needs to design and pass
Medicine system, what is targeted is delivered to ischemic myocardial cells, can discharge in site of action, plays curative effect.
Therefore, the characteristics of after being occurred according to myocardial ischemia-reperfusion, cardiac muscular tissue MMP-2 is increased, ROS increase, Wo Menshe
Nano-micelle is counted, ischemic myocardial tissue is acted on by passive target, under the action of MMP-2, peptide bond fracture, PEG loses, glue
Positive charge is presented in beam surface, is added to born of the same parents' efficiency, then under the action of ROS, releases cyclosporin A (CsA), make its effect
In ischemic myocardial cells, it is open to inhibit mPTP, to play the effect of MI/RI prevention and treatment.
Summary of the invention
The object of the present invention is to provide a kind of Ciclosporin A delivery systems for treating myocardial ischemia-reperfusion injury, are one
The high drug load nano-micelle delivery system that kind matrix metalloproteinase and active oxygen double-bang firecracker are answered.By the design of delivery system,
Cyclosporin A can be improved in the effective concentration of ischemic myocardial cells, reduce drug in the distribution of normal tissue, again for impatient ischemic
The prevention and treatment of perfusion injury provides new thinking.
The technical scheme is that a kind of Ciclosporin A delivery system for treating myocardial ischemia-reperfusion injury, special
Sign is that the delivery system is the high drug load polymer micelle that matrix metalloproteinase and active oxygen double-bang firecracker are answered, by block copolymer
Polyethylene glycol-matrix metalloproteinase peptide substrate-poly-aspartate-phenyl boric acid self assembly obtains, and block copolymer passes through cooperation
Effect package cyclosporin A obtains carrier micelle to self assembly；Wherein
(1) preparation method of polyethylene glycol-MMP-PEP-NH2 is:
By in matrix metalloproteinase peptide substrate (MMP-PEP, sequence GPLGVRGK) dimethyl sulfoxide (DMSO), it is added
NHS (n-hydroxysuccinimide) and EDCI (1- (3- dimethylamino-propyl) -3- ethyl carbodiimide), above-mentioned reaction solution is in nitrogen
1h is reacted at room temperature under gas shielded, is then instilled mPEG-NH2DMSO solution in, mixed liquor continue room temperature reaction for 24 hours, instead
After answering, the water of 5 times of load responsive fluids is added, filters, filtrate is placed in dialysis membrane and dialyses 1 day, is lyophilized up to polyethylene glycol-
MMP-PEP-NH2。
(2) polyethylene glycol-MMP-PEP- poly-aspartate-phenyl boric acid (PEG-MMP-PASP-PP) preparation method
L-Aspartic acid is dissolved in the sulfolane containing a certain amount of phosphoric acid, 10h, above-mentioned reaction solution are stirred at 170 DEG C
It carries out under nitrogen protection, the water for reacting generation is removed by condensation.After reaction, it with methanol extraction reaction product, is used in combination
Reaction solution pH is washed till neutrality by water.80 DEG C are drying to obtain polysuccinimide (PSI).
Polysuccinimide (PSI) is dissolved in n,N-Dimethylformamide (DMF), by polyethylene glycol-MMP-PEP-
NH2It is dissolved in DMF, and is added dropwise in the solution of PSI with triethylamine (TEA), reaction is stirred to react 48h at 60 DEG C, so
It is added in reaction solution by N- (3- aminopropyl) imidazoles (API) and to aminomethyl phenyl boric acid afterwards, the reaction was continued for 24 hours；After reaction,
It places reaction liquid into dialysis membrane and dialyses 3 days, be lyophilized up to polyethylene glycol-MMP-PEP- poly-aspartate-phenyl boric acid (PEG-
MMP-PASP-PP)。
(3) preparation method of PEG-MMP-PASP-PP polymer micelle
It weighs suitable cyclosporin A to be dissolved in methanol, weighs suitable PEG-MMP-PASP polymer and be dissolved in DMSO,
4h is mixed in the two, is then added dropwise in distilled water, after 6h is stirred at room temperature, is placed in bag filter and dialyses 2 days, collects saturating
Liquid is analysed, is lyophilized up to the PEG-MMP-PASP polymer micelle of cyclosporin A is carried.
The present invention constructs a kind of novel nano delivery system, this delivery system is polymer nano micelle, micellar material
For polyethylene glycol-MMP-PEP- poly-aspartate-phenyl boric acid (PEG-MMP-PASP-PP), wraps up cyclosporin A and obtain carrying medicine glue
Beam.The micella can be answered by matrix metalloproteinase and active oxygen double-bang firecracker, deliver more drugs to ischemic myocardial cells and fast
Quick-release releases drug.To play the preventive and therapeutic effect of impatient ischemical reperfusion injury.
Detailed description of the invention
Fig. 1 is to carry medicine PEG-MMP-PASP-PP polymer micelle in various concentration H2O2CsA drug release profiles figure in solution,
Wherein n=3.
Fig. 2 is the protective effect for carrying medicine PEG-MMP-PASP-PP polymer micelle for anoxia/reoxygenation H9C2 cell.
Fig. 3 is influence of the CsA and CsA carrier micelle for H9C2 anoxia/reoxygenation mitochondrial membrane potential in anoxic.
Fig. 4 is influence of the CsA and CsA carrier micelle for Infarct area after myocardial ischemia-reperfusion injury.
Influence of Fig. 5 CsA and the CsA carrier micelle for dangerous area after myocardial ischemia-reperfusion injury.
Specific embodiment
Cyclosporin A double-bang firecracker answers the preparation of nano-micelle and its preventive and therapeutic effect to myocardial ischemia-reperfusion injury
1 purpose: preventive and therapeutic effect of the polymer micelle of evaluation package CsA to MIRI.
2 research methods:
2.1 encapsulation rates and drugloading rate measurement
Micella is dissolved in DMSO, micellar structure is destroyed, HPLC-DAD method detects encapsulation rate and drugloading rate.
Drugloading rate=(medication amount wrapped up in delivery system/load medicine delivery system weight) × 100%
Encapsulation rate=(practical drugloading rate/dosage) × 100%
The evaluation of 2.2 ROS response characteristics
It weighs appropriate carrier micelle and is dissolved in different drug release media, be placed in bag filter, sample, pass through under setting time point
HPLC-DAD measures various concentration H2O2The drug release situation of lower delivery system.
The evaluation of 2.3 cytoprotections
For the H9C2 cell inoculation of logarithmic growth phase in 96 orifice plates, density is 1 × 104, ischemic is added after cultivating 36h
Liquid, in 95%N2, 5%CO2Under conditions of 37 DEG C of incubation 3h, after then taking out absorb ischemic liquid, be separately added into the training without serum
Nutrient solution, cyclosporin A and carrier micelle, the cell that ischemic liquid is not added are set as Normal group, and 20 μ L MTT continuation is added after 4h
It is incubated for 4h, discards culture solution, re-dissolves purple crystal with 150 μ L DMSO, microplate reader reads OD value under 490nm, draws thin
Born of the same parents' Survival curves figure, is calculated by formula cell survival rate.
Cell survival rate (%)=(test group OD value/blank control group OD value) × 100%
Influence of 2.4 drugs to hypoxia-reoxygenation H9C2 mitochondrial membrane potential in anoxic
It takes the H9C2 cell inoculation of logarithmic growth into the tissue culture plate for being loaded with glass slide, ischemic liquid, In is added after 36h
95%N2, 5%CO2Under conditions of 37 DEG C of incubation 3h, ischemic liquid is absorbed after then taking out, be separately added into culture solution without serum,
Cyclosporin A and carrier micelle, the cell that ischemic liquid is not added are set as Normal group, continue after being incubated for 4h, remove culture solution, add
Enter JC-1 dyeing 30min, remove dyestuff, PBS is rinsed 3 times, and paraformaldehyde is fixed, and confocal laser scanning microscope is red green glimmering
Light, the ratio by calculating red green fluorescence reflect the variation of mitochondrial membrane potential in anoxic.
2.5 drugs evaluate the preventive and therapeutic effect of myocardial ischemia-reperfusion injury
24 SD rats are randomly divided into 4 groups, every group 6.Yellow Jackets (60mg/kg) anesthesia through intraperitoneal injection 3%
Afterwards, dorsal position is fixed on operating table.Subcutaneous, whole II lead electrocardiogram of record standard limbs by needle electrode insertion four limbs.
Preserved skin, routine disinfection.Row tracheotomy is hit exactly in neck, is inserted into tracheal tube, connection ventilator control ventilation, end-expiratory positive pressure
Ventilation parameters are as follows: tidal volume 2ml, 40-50 times/min of respiratory rate are exhaled: it inhales than being 2:1.On the left of the median sternotomy at about 0.5mm
Longitudinal incision, each layer muscle of blunt separation, 3 to 5 intercostals of exposure, after vessel forceps pinch off 4,5 rib cages, placement eye speculum, which struts, to be cut
Position is opened, pericardium, exposure beating heart are broken.It is mark with left coronary artery main stem, with small round needle in left auricle of heart root
Across ramus descendens anterior arteriae coronariae sinistrae myocardium at the about 2mm of lower section, it is spare to wear 5-0 silk thread, records just after electrocardiogram restores normal
Normal electrocardiogram.A thin plastic tube with groove is placed (convenient for unclamping ligation in surface at ramus descendens anterior arteriae coronariae sinistrae threading
Line), coronary artery is ligatured together with tubule, sham group is only threaded and do not ligatured.Ligation ramus descendens anterior arteriae coronariae sinistrae makes myocardial ischemia 30min
Afterwards, ligature is unclamped, ischemic myocardium Reperfu- sion 2h is made.Continuous positive pressure ventilation to Reperfu- sion terminates, respectively record myocardial ischemia and
Electrocardiogram when Reperfu- sion.5min is through jugular vein drug administration by injection before Reperfu- sion starts.
After the test, heart is ligatured, through carotid injection Evans Blue 2ml, after removing heart, -80 DEG C were freezed
Night carries out TTC dyeing after slice.It takes pictures and measures myocardial infarct size.
3 experimental results:
3.1 encapsulation rates and drugloading rate
The encapsulation rate and drugloading rate of carrier micelle are as shown in table 1.As a result the micella delivery system tool of prompt this patent design
There are higher drugloading rate and encapsulation efficiency.
The drugloading rate and encapsulation rate of 1 delivery system of table
The evaluation of 3.2 ROS response characteristics
The drug release profiles discovery of drug-carrying polymer micelle is observed, the release of CsA micella is in H2O2Concentration dependant characteristic, 2mM
H2O2Under the conditions of be incubated for 2h after, about 80% packaging medicine can be released from micella, prompt drug-carrying polymer micelle enter lack
After blood cardiac muscle cell, can quick release CsA, for treatment myocardial ischemia-reperfusion injury possibility is provided.
The evaluation of 3.3 cytoprotections
By the discovery of the cytoprotection of comparison carrier micelle and free drug, carrier micelle is protected with stronger cell
Shield effect is higher than free CsA for the protective effect of hypoxia-reoxygenation H9C2 cell, load CsA polymer micelle is prompted to can be improved
External antibody Monoclonal effect.
Influence of 3.4 drugs to hypoxia-reoxygenation H9C2 mitochondrial membrane potential in anoxic
For laser co-focusing the results show that compared with free drug, carrier micelle acts on the raising of mitochondrial membrane potential
It becomes apparent.It prompts this delivery system that can more be delivered to CsA in ischemic myocardial cells, inhibits the opening of mPTP, thus
Inhibit the reduction of mitochondrial membrane potential.
3.5 drugs evaluate the preventive and therapeutic effect of myocardial ischemia-reperfusion injury
Dissociate CsA compared to same dosage, carrier micelle can reduce myocardial infarction area and dangerous area significantly.Explanation
Nano-micelle can be improved cyclosporin A in the distribution of ischemic myocardial tissue and cell, to improve therapeutic effect.
4 conclusions:
Inside and outside the experimental results showed that, compared with free cyclosporin A, load the polymer micelle of cyclosporin A
PEG-MMP-PASP-PP is remarkably improved protective effect of the cyclosporin A for myocardial ischemia-reperfusion injury, has centainly
Development prospect.
Sequence table
<110>the Fourth Military Medical University of P.L.A
<120>a kind of Ciclosporin A delivery system for treating myocardial ischemia-reperfusion injury
<160>1
<210>1
<211>8 (length)
<212>DAN (type)
<213>artificial sequence (source)
<400>1
Gly-Pro-Leu-Gly-Val-Arg-Gly-Lys
Sequence table
<110>the Fourth Military Medical University of P.L.A
<120>a kind of Ciclosporin A delivery system for treating myocardial ischemia-reperfusion injury
<160> 1
<210> 1
<211>8(length)
<212>DAN(type)
<213>artificial sequence (source)
<400> 1
Gly-Pro-Leu-Gly-Val-Arg-Gly-Lys
Claims (1)
1. a kind of Ciclosporin A delivery system for treating myocardial ischemia-reperfusion injury, it is characterized in that the delivery system is matrix
The high drug load polymer micelle that metalloproteinases and active oxygen double-bang firecracker are answered, by block copolymer polyethylene glycol-matrix metal egg
White zymolyte peptide-poly-aspartate-phenyl boric acid self assembly obtains, block copolymer by mating reaction wrap up Ciclosporin A from
And self assembly obtains carrier micelle；Wherein
(1) polyethylene glycol-MMP-PEP-NH2Preparation method be:
The matrix metalloproteinase peptide substrate MMP-PEP that sequence is GPLGVRGK is dissolved in dimethyl sulfoxide, N- hydroxyl is added
Succinimide and 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide, above-mentioned reaction solution react at room temperature under nitrogen protection
1h；Then instilled mPEG-NH2Dimethyl sulphoxide solution in, mixed liquor continue room temperature reaction for 24 hours, after reaction, add
Enter the water of 5 times of load responsive fluids, filter, filtrate is placed in dialysis membrane and dialyses 1 day, is lyophilized up to polyethylene glycol-MMP-PEP-NH2；
(2) polyethylene glycol-MMP-PEP- poly-aspartate-phenyl boric acid preparation method
L-Aspartic acid is dissolved in the sulfolane containing a certain amount of phosphoric acid, 10h is stirred at 170 DEG C, above-mentioned reaction solution is in nitrogen
It is carried out under gas shielded, the water for reacting generation is removed by condensation；After reaction, with methanol extraction reaction product, and will with water
Reaction solution pH is washed till neutrality, and 80 DEG C are drying to obtain polysuccinimide；
Polysuccinimide is dissolved in n,N-Dimethylformamide, by polyethylene glycol-MMP-PEP-NH2It is molten with triethylamine
Solution is added dropwise in the solution of polysuccinimide in n,N-Dimethylformamide, and reaction is stirred to react 48h at 60 DEG C,
Then it is added in reaction solution by N- (3- aminopropyl) imidazoles and to aminomethyl phenyl boric acid, the reaction was continued for 24 hours；After reaction, will
Reaction solution is placed in dialysis membrane and dialyses 3 days, is lyophilized up to polyethylene glycol-MMP-PEP- poly-aspartate-phenyl boric acid；
(3) polyethylene glycol-MMP-PEP- poly-aspartate-phenyl boric acid polymer micelle preparation method is:
It weighs suitable Ciclosporin A to be dissolved in methanol, weighs suitable polyethylene glycol-MMP-PEP- poly-aspartate-benzene boron
Acid polymer is dissolved in dimethyl sulfoxide, and 4h is mixed in the two, is then added dropwise in distilled water, after 6h is stirred at room temperature,
It is placed in bag filter and dialyses 2 days, collect dialyzate, be lyophilized up to the poly- asparagus fern ammonia of polyethylene glycol-MMP-PEP- of Ciclosporin A is carried
Acid-phenyl boric acid polymer micelle.
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| CN201710519920.8A CN107441040B (en) | 2017-06-30 | 2017-06-30 | A kind of Ciclosporin A delivery system for treating myocardial ischemia-reperfusion injury |
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| CN112168952A (en) * | 2020-10-27 | 2021-01-05 | 成都市妇女儿童中心医院 | Application of hydrogel-carried cyclosporin A in preparation of medicine for treating myocardial ischemia-reperfusion injury |
| CN113952468B (en) * | 2021-09-26 | 2023-07-07 | 中国人民解放军空军军医大学 | Cyclosporin A nano-drug for treating myocardial ischemia reperfusion injury |
| CN115684608B (en) * | 2022-11-03 | 2024-01-09 | 大连珍奥药业股份有限公司 | Metabolic marker for treating myocardial ischemia reperfusion injury by targeting myocardial peptide and application thereof |
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Non-Patent Citations (2)
| Title |
|---|
| Nanoparticle-Mediated Targeting of Cyclosporine A Enhances Cardioprotection Against Ischemia-Reperfusion Injury Through Inhibition of Mitochondrial Permeability Transition Pore Opening;Gentaro Ikeda etal;《Scientific Reports》;20160210;第6卷;第1-13页 * |
| PEG-sheddable polyplex micelles as smart gene carriers based on MMP-cleavable peptide-linked block copolymers;Junjie Li etal;《Chem. Commun》;20131231;第49卷;第6974-6976页 * |
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