CN107441040A - 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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- CN107441040A CN107441040A CN201710519920.8A CN201710519920A CN107441040A CN 107441040 A CN107441040 A CN 107441040A CN 201710519920 A CN201710519920 A CN 201710519920A CN 107441040 A CN107441040 A CN 107441040A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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Abstract
The invention discloses a kind of Ciclosporin A delivery system 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, obtained by block copolymer polyethylene glycol matrix metalloproteinase substrate peptide poly-aspartate phenyl boric acid self assembly, block copolymer wraps up cyclosporin A so as to which self assembly obtains carrier micelle by mating reaction.This delivery system can act on ischemic myocardial tissue by passive target; quick release goes out cyclosporin A in the presence of matrix metalloproteinase and active oxygen; the protective effect to myocardial ischemia-reperfusion injury is played, new strategy is provided for the preventing and treating of myocardial ischemia-reperfusion injury.
Description
Technical field
The present invention relates to the high drug load nano-micelle delivery system that a kind of matrix metalloproteinase and active oxygen double-bang firecracker are answered
Composition and application scheme, this delivery system for parcel cyclosporin A polyethylene glycol-matrix metalloproteinase substrate
Peptide-poly-aspartate-phenyl boric acid micella.
Background technology
With thromboembolism treatment, PCI (percutaneous coronary intervention,
PCI), CABG (coronary artery by pass grafting, CABG) etc. is in a large amount of of clinic
Using, therewith trigger myocardial ischemia/reperfusion injury (myocardial ischemia-reperfusion injury,
MI/RI) increasingly receive significant attention.Ciclosporin A (CyclosporinA, CsA) is one of most classical mPTP inhibitor,
It can be combined with CyP-D and form compound, hinder CyP-D to be combined with ANT, opened so as to suppress mPTP, reduced caspase-3
Activity, Apoptosis is reduced, plays myocardium protecting action, and be confirmed in many animals body.But with traditional ring spore bacterium
Plain fat emulsion formulation can cause cardioprotection caused by Ischemic reperfusion to be lost.Therefore, it is necessary to study new ring spore bacterium
Plain A (CsA) preparation, ensure the performance of its effect.In addition, research shows, cyclosporin A plays MI/RI protective effects
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
A (CsA) therapeutic window is very narrow.The optimal dosage that many researchs find to play protective effect is 2.5mg/kg, 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 relevant.Moreover, cyclosporin A (CsA) also serves as immunodepressant application in itself, the distribution at other positions
Larger immunosuppressive action can be produced.Therefore, passed to play the effect of cyclosporin A (CsA) to greatest extent, it is necessary to design
Medicine system, what is targetted is delivered to ischemic myocardial cells, can be discharged in site of action, plays curative effect.
Therefore, after being occurred according to myocardial ischemia-reperfusion, cardiac muscular tissue MMP-2 rise, ROS increase the characteristics of, Wo Menshe
Nano-micelle is counted, ischemic myocardial tissue is acted on by passive target, in the presence 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 in the presence of ROS, discharges cyclosporin A (CsA), make its effect
In ischemic myocardial cells, suppress mPTP and open, so as to play the effect of MI/RI preventing and treatings.
The content of the invention
It is one it is an object of the invention to provide a kind of Ciclosporin A delivery system for treating myocardial ischemia-reperfusion injury
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,
Valid density of the cyclosporin A in ischemic myocardial cells can be improved, reduces distribution of the medicine in normal structure, for impatient ischemic again
The preventing and treating of perfusion injury provides new thinking.
The technical scheme is that：A kind of Ciclosporin A delivery system for treating myocardial ischemia-reperfusion injury, it is 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 parcel cyclosporin A obtains carrier micelle so as to self assembly；Wherein
(1) polyethylene glycol-MMP-PEP-NH2 preparation method is：
By in matrix metalloproteinase peptide substrate (MMP-PEP, sequence GPLGVRGK) dimethyl sulfoxide (DMSO) (DMSO), add
NHS (n-hydroxysuccinimide) and EDCI (1- (3- dimethylamino-propyls) -3- ethyl carbodiimides), 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 react at room temperature 24h, instead
After should terminating, add the water of 5 times of load responsive fluids, filtering, filtrate is placed in dialysis membrane and dialyse 1 day, freeze produce polyethylene glycol-
MMP-PEP-NH2。
(2) preparation method of polyethylene glycol-MMP-PEP- poly-aspartates-phenyl boric acid (PEG-MMP-PASP-PP)
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
Carry out under nitrogen protection, water caused by reaction is removed by condensing.After reaction terminates, with methanol extraction reaction product, it 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 DMF (DMF), by polyethylene glycol-MMP-PEP-
NH2It is dissolved in DMF, and is added dropwise in PSI solution with triethylamine (TEA), stirring reaction 48h is reacted at 60 DEG C, so
Added afterwards by N- (3- aminopropyls) imidazoles (API) and to aminomethyl phenyl boric acid in reaction solution, continue to react 24h；After reaction terminates,
Place reaction liquid into dialysis membrane and dialyse 3 days, it is lyophilized to produce polyethylene glycol-MMP-PEP- poly-aspartates-phenyl boric acid (PEG-
MMP-PASP-PP)。
(3) preparation method of PEG-MMP-PASP-PP polymer micelles
Weigh appropriate cyclosporin A to be dissolved in methanol, weigh appropriate PEG-MMP-PASP polymer and be dissolved in DMSO,
Both mix 4h, are then added dropwise in distilled water, after 6h is stirred at room temperature, is placed in bag filter and dialyses 2 days, collect saturating
Liquid is analysed, it is lyophilized to produce the PEG-MMP-PASP polymer micelles for carrying cyclosporin A.
The present invention constructs a kind of novel nano delivery system, and this delivery system is polymer nano micelle, micellar material
For polyethylene glycol-MMP-PEP- poly-aspartates-phenyl boric acid (PEG-MMP-PASP-PP), parcel cyclosporin A obtains carrying medicine glue
Beam.The micella can by matrix metalloproteinase and active oxygen double-bang firecracker should, deliver more medicines to ischemic myocardial cells and fast
Quick-release releases medicine.So as to play the preventive and therapeutic effect of impatient ischemical reperfusion injury.
Brief description of the drawings
Fig. 1 is to carry medicine PEG-MMP-PASP-PP polymer micelles in various concentrations H2O2CsA drug release profiles figures in solution,
Wherein n=3.
Fig. 2 is the protective effect for carrying medicine PEG-MMP-PASP-PP polymer micelles for anoxia/reoxygenation H9C2 cells.
Fig. 3 is influence of the CsA and CsA carrier micelles for H9C2 anoxia/reoxygenation mitochondrial membrane potential in anoxic.
Fig. 4 is influence of the CsA and CsA carrier micelles 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.
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 evaluation parcel CsA polymer micelle to MIRI.
2 research methods：
2.1 envelop rates and drugloading rate measure
Micella is dissolved in DMSO, destroys micellar structure, HPLC-DAD methods detection envelop rate and drugloading rate.
Drugloading rate=(medication amount wrapped up in delivery system/load medicine delivery system weight) × 100%
Envelop rate=(actual drugloading rate/dosage) × 100%
2.2 ROS response characteristics are evaluated
Weigh appropriate carrier micelle and be dissolved in different drug release media, be placed in bag filter, sample, pass through under setting time point
HPLC-DAD measure various concentrations H2O2The drug release situation of lower delivery system.
2.3 cytoprotections are evaluated
The H9C2 cells in growth period of taking the logarithm are inoculated in 96 orifice plates, and density is 1 × 104, ischemic is added after cultivating 36h
Liquid, in 95%N2, 5%CO2Under conditions of 37 DEG C 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 for being not added with ischemic liquid are set to Normal group, and 20 μ L MTT continuation is added after 4h
4h is incubated, discards nutrient solution, dissolves purple crystal again with 150 μ L DMSO, ELIASA reads OD values under 490nm, draws thin
Born of the same parents' Survival curves figure, cell survival rate is calculated by formula.
Cell survival rate (%)=(test group OD values/blank control group OD values) × 100%
Influence of 2.4 medicines to hypoxia-reoxygenation H9C2 mitochondrial membrane potential in anoxic
The H9C2 cells of growth of taking the logarithm are seeded in the Tissue Culture Plate for being loaded with slide, and ischemic liquid is added after 36h,
95%N2, 5%CO2Under conditions of 37 DEG C incubation 3h, after then taking out absorb ischemic liquid, be separately added into the nutrient solution without serum,
Cyclosporin A and carrier micelle, the cell for being not added with ischemic liquid are set to Normal group, continue after being incubated 4h, remove nutrient 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 change of mitochondrial membrane potential in anoxic.
2.5 medicines are evaluated 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) through intraperitoneal injection 3% are anaesthetized
Afterwards, dorsal position is fixed on operating table.Subcutaneous, the whole lead electrocardiogram of record standard limbs II by needle electrode insertion four limbs.
Preserved skin, routine disinfection.Row tracheotomy is hit exactly in neck, inserts tracheal tube, connection lung ventilator control ventilation, end-expiratory positive pressure
Ventilation parameters are：Tidal volume 2ml, 40-50 times/min of respiratory rate, is exhaled：Inhale than being 2:1.On the left of median sternotomy about at 0.5mm
Longitudinal incision, each layer muscle of blunt separation, 3 to 5 intercostals of exposure, after vessel forceps pinch off 4,5 ribs, placement eye speculum, which struts, to be cut
Position is opened, breaks pericardium, exposure pulsatile heart is dirty.Using left coronary artery main stem as mark, with small round needle in left auricle of heart root
Through ramus descendens anterior arteriae coronariae sinistrae myocardium about at 2mm, it is standby to wear 5-0 silk threads, is recorded just after electrocardiogram recovers normal for lower section
Normal electrocardiogram.Surface places a thin plastic tube with groove and (is easy to unclamp and ligatures at ramus descendens anterior arteriae coronariae sinistrae threading
Line), coronary artery is ligatured together with tubule, sham groups are only threaded and do not ligatured.Ligation ramus descendens anterior arteriae coronariae sinistrae makes myocardial ischemia 30min
Afterwards, ligature is unclamped, makes ischemic myocardium Reperfu- sion 2h.Continuous positive pressure ventilation to Reperfu- sion terminates, respectively record myocardial ischemia and
Electrocardiogram during Reperfu- sion.5min is through jugular vein drug administration by injection before Reperfu- sion starts.
After off-test, heart is ligatured, through carotid injection Evans Blue 2ml, after removing heart, -80 DEG C freezed
At night, TTC dyeing is carried out after section.Take pictures and measure myocardial infarct size.
3 experimental results：
3.1 envelop rates and drugloading rate
The envelop rate and drugloading rate of carrier micelle are as shown in table 1.As a result the micella delivery system tool of this patent design is prompted
There are higher drugloading rate and encapsulation efficiency.
The drugloading rate and envelop rate of the delivery system of table 1
3.2 ROS response characteristics are evaluated
The drug release profiles for observing drug-carrying polymer micelle find that the release of CsA micellas is in H2O2Concentration dependant characteristic, 2mM
H2O2Under the conditions of be incubated 2h after, about 80% packaging medicine can discharge 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.
3.3 cytoprotections are evaluated
Find that there is carrier micelle stronger cell to protect by the cytoprotection for contrasting carrier micelle and free drug
Shield acts on, and its protective effect for hypoxia-reoxygenation H9C2 cells is higher than free CsA, prompts load CsA polymer micelles to improve
External antibody Monoclonal effect.
Influence of 3.4 medicines to hypoxia-reoxygenation H9C2 mitochondrial membrane potential in anoxic
Laser co-focusing result is shown, compared with free drug, raising effect of the carrier micelle for mitochondrial membrane potential
Become apparent.Prompt this delivery system to be more delivered to CsA in ischemic myocardial cells, suppress mPTP opening, so as to
Suppress the reduction of mitochondrial membrane potential.
3.5 medicines are evaluated the preventive and therapeutic effect of myocardial ischemia-reperfusion injury
Dissociate CsA compared to same dosage, carrier micelle can significantly decrease myocardial infarction area and dangerous area.Explanation
Nano-micelle can improve distribution of the cyclosporin A in ischemic myocardial tissue and cell, so as to improve therapeutic effect.
4 conclusions：
Inside and outside test result indicates 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 necessarily
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)
- A kind of 1. 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 cyclosporin A from And self assembly obtains carrier micelle；Wherein(1) polyethylene glycol-MMP-PEP-NH2Preparation method be：Matrix metalloproteinase peptide substrate (MMP-PEP) is dissolved in dimethyl sulfoxide (DMSO) (DMSO), adds NHS (N- hydroxysuccinimidyls Acid imide) and EDCI (1- (3- dimethylamino-propyls) -3- ethyl carbodiimides), room temperature is anti-under nitrogen protection for above-mentioned reaction solution 1h is answered, is then instilled mPEG-NH2DMSO solution in, mixed liquor continue react at room temperature 24h, reaction terminate after, add 5 The water of times load responsive fluid, filtering, filtrate are placed in dialysis membrane and dialyses 1 day, freeze and produce polyethylene glycol-MMP-PEP-NH2；(2) preparation method of polyethylene glycol-MMP-PEP- poly-aspartates-phenyl boric acid (PEG-MMP-PASP-PP)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 Carried out under gas shielded, water caused by reaction is removed by condensing；After reaction terminates, 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 (PSI)；Polysuccinimide (PSI) is dissolved in DMF (DMF), by polyethylene glycol-MMP-PEP-NH2With Triethylamine (TEA) is dissolved in DMF, and is added dropwise in PSI solution, stirring reaction 48h is reacted at 60 DEG C, then by N- (3- aminopropyls) imidazoles (API) and to aminomethyl phenyl boric acid add reaction solution in, continue react 24h；After reaction terminates, it will react Liquid is placed in dialysis membrane and dialysed 3 days, lyophilized to produce polyethylene glycol-MMP-PEP- poly-aspartates-phenyl boric acid (PEG-MMP- PASP-PP)；(3) preparation method of PEG-MMP-PASP-PP polymer micelles is：Weigh appropriate cyclosporin A to be dissolved in methanol, weigh appropriate PEG-MMP-PASP-PP polymer and be dissolved in DMSO, Both mix 4h, are then added dropwise in distilled water, after 6h is stirred at room temperature, is placed in bag filter and dialyses 2 days, collect saturating Liquid is analysed, it is lyophilized to produce the PEG-MMP-PAS-PP polymer micelles for carrying cyclosporin A.
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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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| 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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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113952468A (en) * | 2021-09-26 | 2022-01-21 | 中国人民解放军空军军医大学 | Cyclosporin A nano-medicine for treating myocardial ischemia reperfusion injury |
| CN115684608A (en) * | 2022-11-03 | 2023-02-03 | 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 |
-
2017
- 2017-06-30 CN CN201710519920.8A patent/CN107441040B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| GENTARO IKEDA ETAL: "Nanoparticle-Mediated Targeting of Cyclosporine A Enhances Cardioprotection Against Ischemia-Reperfusion Injury Through Inhibition of Mitochondrial Permeability Transition Pore Opening", 《SCIENTIFIC REPORTS》 * |
| JUNJIE LI ETAL: "PEG-sheddable polyplex micelles as smart gene carriers based on MMP-cleavable peptide-linked block copolymers", 《CHEM. COMMUN》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113952468A (en) * | 2021-09-26 | 2022-01-21 | 中国人民解放军空军军医大学 | Cyclosporin A nano-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 |
| CN115684608A (en) * | 2022-11-03 | 2023-02-03 | 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 |
| 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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