CN116270533A - Application of macrophage membrane-coated PCOD 585-containing nano-particles in myocardial ischemia reperfusion injury - Google Patents
Application of macrophage membrane-coated PCOD 585-containing nano-particles in myocardial ischemia reperfusion injury Download PDFInfo
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
The invention discloses an application of macrophage membrane-coated PCOD 585-containing nano particles in myocardial ischemia reperfusion injury. The macrophage membrane-coated PCOD585 nanoparticle-containing M/PCOD@PLGA prepared by the invention can effectively target ischemic myocardium and release carbon monoxide, so that myocardial ischemia reperfusion injury can be effectively treated; experimental results show that macrophage membrane coating can remarkably increase aggregation of drugs in hearts, M/PCOD@PLGA can effectively reduce heart functions of ischemia reperfusion mice, and compared with PCOD585 and PCOD@PLGA, the macrophage membrane coating has a better effect of treating myocardial ischemia reperfusion. Therefore, the PCOD 585-containing nano particles coated by the macrophage membrane improve the capability of targeting CO to disease parts, improve the effect of treating myocardial ischemia reperfusion by CO, and have important significance for promoting the clinical application of CO.
Description
Technical Field
The invention relates to an application of a macrophage membrane-coated PCOD 585-containing nanoparticle in myocardial ischemia reperfusion injury, and belongs to the technical field of biological medicines.
Background
After acute myocardial infarction, early recovery of myocardial perfusion by thrombolysis or Percutaneous Coronary Intervention (PCI) is the most effective method for reducing myocardial infarction area and improving clinical prognosis, however, recovery of ischemic myocardial blood flow may cause myocardial reperfusion injury, which in turn reduces the efficacy of myocardial reperfusion. The mechanisms of myocardial ischemia reperfusion injury involve oxygen radical generation, calcium ion imbalance, activation of inflammatory response, apoptosis, and the like. Such damage can cause myocardial cell death and dysfunction, which can have serious consequences if not treated in time.
Although carbon monoxide (CO) has been considered as a harmful substance in the past, recent studies have shown that CO can act as a signaling molecule at low doses to activate some pathways in cells, such as cGMP and HO-1, to thereby exert effects of reducing apoptosis, inhibiting inflammatory reactions, improving mitochondrial function, and the like. And animal experiments prove that the CO donor such as CORM-3 and the like can effectively treat heart diseases such as myocardial infarction, myocarditis and the like. However, because the CO donor cannot accurately release CO at the disease site, as reported in the prior art for ONOO - The activated CO donor-PCOD 585 can controllably release CO (principle is shown in fig. 1), but there is still a problem of targeting accuracy, so clinical application of CO donor may bring about some potential side effects. Therefore, to facilitate clinical application of CO, there is a need to improve the ability of CO donors to target disease sites, enabling controlled release of CO at the disease site.
Disclosure of Invention
The purpose of the invention is that: in order to solve the technical problem that the existing CO donor can not accurately release CO at a disease part, the invention realizes the local release of carbon monoxide to the myocardial ischemia part and treats myocardial ischemia reperfusion injury by wrapping a macrophage membrane outside a nano microsphere containing carbon monoxide release particles (PCOD 585).
In order to solve the problems, the technical scheme adopted by the invention is to provide the application of the PCOD 585-containing nano particles coated by the macrophage membrane in preparing medicaments for treating myocardial ischemia reperfusion injury.
Preferably, the preparation method of the macrophage membrane-coated PCOD 585-containing nanoparticle comprises the following steps:
step 1: extracting macrophage membranes;
step 2: preparing a nanoparticle solution containing PCOD585 by taking PCOD585 and a degradable high polymer nanomaterial as raw materials;
step 3: mixing the macrophage membrane extracted in the step 1 and the PCOD 585-containing nanoparticle solution prepared in the step 2, and carrying out ultrasonic treatment, wherein the obtained mixture solution is extruded through a polycarbonate porous membrane by an extruder, so that the macrophage membrane coats the PCOD 585-containing nanoparticle, and the macrophage membrane-coated PCOD 585-containing nanoparticle is prepared.
Preferably, the extraction of step 1 is extraction of macrophage membranes from RAW264.7 cells.
Preferably, the specific preparation method of the nanoparticle solution containing PCOD585 in the step 2 comprises the following steps: respectively dissolving PCOD585 and degradable polymer nano material, sequentially mixing and ultrasonically emulsifying, adding into aqueous phase solution, ultrasonically stirring, and finally ultrafiltering and freeze-drying the obtained mixture to obtain the nano particle solution containing PCOD 585.
Preferably, the degradable polymer nano material is PLGA-PEG-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the The aqueous solution is a PVA aqueous solution (polyvinyl alcohol aqueous solution).
Preferably, the PCOD585 and the degradable polymer nano material PLGA-PEG-NH 2 The mass ratio of (3-4): 100.
preferably, the mass ratio of the macrophage membrane to the PCOD 585-containing nano-particles in the macrophage membrane-coated PCOD 585-containing nano-particles is 8-12: 1.
preferably, the method for extracting macrophage membrane in step 1 comprises: the RAW264.7 cells are resuspended in separation buffer, the precipitate is collected after centrifugation and resuspended in homogenization buffer, after sufficient grinding, the supernatant is removed by centrifugation, and the obtained precipitate is macrophage membrane.
Compared with the prior art, the invention has the beneficial effects that:
the invention prepares a macrophage membrane-coated PCOD585 nanoparticle-containing M/PCOD@PLGA by wrapping a macrophage membrane outside a nanoparticle containing carbon monoxide release particles (PCOD 585), receptors such as CCR2 and the like on the macrophage membrane can respond to chemotactic factors and recruit to inflammatory sites, and the nanoparticles coated by the macrophage membrane can be enriched in myocardial ischemia sites, so that the capability of targeting disease sites by CO donors is improved; further experimental results show that the macrophage membrane coating can remarkably increase the aggregation of the drug in the heart, the M/PCOD@PLGA can effectively reduce the heart function of an ischemia reperfusion mouse, and compared with PCOD585 and PCOD@PLGA, the macrophage membrane coating has a better effect of treating myocardial ischemia reperfusion.
Drawings
FIG. 1 is a schematic diagram of the principle of controlled CO release by PCOD 585;
FIG. 2 is a comparison of left ventricular ejection fraction between five groups; * **: p is less than 0.001;
FIG. 3 is a comparison of short axis shortening of the left chamber between five groups; * **: p is less than 0.001;
FIG. 4 is enrichment of drug at a heart site in mice; * *: p is less than 0.01.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments accompanied with figures are described in detail below.
Examples
1. Macrophage membrane-coated nanoparticles
(1) Macrophage membrane extraction: RAW264.7 cells were resuspended in 3ml separation buffer (formulation: 250mM sucrose, 20mM N-tris (hydroxymethyl) methylglycine, 1mM ethylenediamine tetraacetic acid in ddH) 2 O). After centrifugation (4 ℃,1000g,5 min), the pellet was collected and resuspended in homogenization buffer (225 mM mannose, 75mM sucrose, 0.5)% bovine serum albumin, 0.5mM EDTA,30mM tris (hydroxymethyl) methyl aminomethane, protease and phosphatase inhibitor cocktail (Thermo Scientific) TM 78440; 1:100) dissolved in ddH 2 O). After 20 to 30 times of grinding, the supernatant was removed by centrifugation (4 ℃,100000g,1 h). The obtained precipitate is macrophage membrane.
(2) Preparation of PLGA microspheres (PCOD@PLGA) containing PCOD 585: 3.6mg of PCOD585 was dissolved in 500. Mu.l of the mixed solution (200. Mu.l of dimethyl sulfoxide (DMSO) +300. Mu.l of chloroform), and 100mg of PLGA-PEG-NH was added 2 (100 mg) was dissolved in 2.2ml of chloroform. PCOD585 and PLGA-PEG-NH 2 The solution was mixed, then phacoemulsified, and added to the aqueous phase (10 ml 1% pva). The mixture was sonicated at 192w for 4 minutes with stirring (100 rpm) for 12 hours. The remaining solution was collected in a 100kD ultrafiltration tube and ultrafiltered at 4 ℃ for 15 minutes (EMD Millipore UFC 910024). We then collected and lyophilized a solution containing pcod@plga nanoparticles.
(3) Preparation of macrophage Membrane coated nanoparticles (M/PCOD@PLGA) the harvested macrophage membranes (1 mg protein) were mixed with PCOD@PLGA (100 μg). The mixture was then sonicated on ice (100 w,2 min). Subsequently, the mixture solution was extruded 10 times sequentially at 400, 200nm of polycarbonate porous film using an Avestin mini-extruder (Avestin, 610000, canada).
Wherein the principle of controlled release of CO by PCOD585 is shown in fig. 1, PCOD585 releases carbon monoxide only in the presence of peroxynitrite.
2. Animal experiment
(1) Experimental animals and animal model preparation: SPF-grade male C57BL/6 mice (purchased from Shanghai Jieshijie laboratory animal Co., ltd.) were selected, and the week-old animals were 8-10 weeks and the body weights were 20-25g. 8 week old male C57BL6/J mice were anesthetized with 2% isoflurane. After the mice were anesthetized, an oblique skin incision was made along the lower edge of the left pectoral muscle of the mice, obliquely to the left upper limb of the mice, exposing the pectoral muscle. The vessel forceps were used to poke the intercostal space from the widest point of the 3 rd intercostal space, and the perpendicular intercostal space separated the forceps tips and began to squeeze the heart. After the heart is extruded, the coronary artery is seen to run clearly, a needle is inserted from a position 1-2 mm above the bifurcation point at the tail end and 0.5-1 mm far to the left, and the needle is withdrawn from the right side of the heart, so that the bifurcation point at the tail end of the vein is approximately positioned between the needle insertion point and the needle withdrawal point, a slipknot is ligated, and a thread end with the length of 3-4 cm is reserved outside the chest cavity. Electrocardiogram shows ST elevation confirming success of coronary occlusion. The slipknot is released 45 minutes after ischemia. The SHAM group (SHAM group) passed the wire through the heart without tying knots. Then, the ischemia reperfusion mice were given corresponding interventions (control (5% DMSO+5% Tween 80+40% PEG300+50% PBS), PCOD585 (6 mg/kg), PCOD@PLGA (dose 6mg/kg PCOD 585), M/PCOD@PLGA (dose 6mg/kg PCOD 585)). Echocardiography was performed 24 hours later to assess cardiac function.
(2) Experimental grouping:
the experiments were performed in 5 groups: SHAM group; ischemia reperfusion group; ischemia reperfusion + PCOD585 intervention group; ischemia reperfusion + pcod@plga intervention group; ischemia reperfusion +M/PCOD@PLGA intervention group. Three intervention groups (PCOD 585 intervention group; PCOD@PLGA intervention group; M/PCOD@PLGA intervention group) were each given intervention immediately after releasing the slip knot (i.e. after reperfusion was started).
(3) Evaluation of mouse cardiac Functions by echocardiography
Echocardiography was detected after 24 hours with a probe frequency of 30MHz. In particular, after isoflurane-tingling animals, M-mode images were recorded while the heart rate of the mice was maintained between 450 and 550 beats/min. The method is characterized in that a long-axis section beside the sternum and a four-cavity section B-Mode image of the apex of the heart are collected. The parasternal left ventricular short axis was taken, 2D ultrasound was taken to show the left ventricular short axis section, the left ventricular motion was recorded using M-ultrasound at the papillary muscle level, and its Left Ventricular Ejection Fraction (LVEF) was mainly observed. The mice of each group were compared for heart morphology and functional changes. All measurements were averaged over 5 consecutive cardiac cycles and were made by 3 experienced technicians. The results show that: the heart function index of the mice in the ischemia reperfusion group is obviously lower than that of the mice in the SHAM group, the heart function of the mice is improved after the injection of M/PCOD@PLGA in the ischemia reperfusion group, and the LVEF of the mice in the ischemia reperfusion group after the injection of M/PCOD@PLGA is 18.42% higher than that of the mice in the control group (P < 0.001), as shown in figure 2; the LVEF of the mice injected with M/PCOD@PLGA was 10.76% (P < 0.001) higher than that of the control mice LVFS in the ischemia reperfusion group, as shown in FIG. 3.
(4) Aggregation of drug in heart was observed by in vivo imaging of small animals: the same procedure was used in the experiment to encapsulate the fluorochrome CY5.5 in microspheres and inject C57BL/6J mice for 8 weeks via the tail vein. Drug aggregation at the heart site was observed by a small animal living imaging system for 6 hours. As a result, it was found that the cell membrane coating significantly increased the aggregation of the drug at the heart site, as shown in FIG. 4.
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to be limiting in any way and in nature, and it should be noted that several modifications and additions may be made to those skilled in the art without departing from the invention, which modifications and additions are also intended to be construed as within the scope of the invention.
Claims (7)
1. An application of macrophage membrane-coated PCOD 585-containing nanoparticle in preparing medicine for treating myocardial ischemia reperfusion injury.
2. The use according to claim 1, wherein the method for preparing the macrophage membrane-coated PCOD 585-containing nanoparticle comprises the steps of:
step 1: extracting macrophage membranes;
step 2: preparing a nanoparticle solution containing PCOD585 by taking PCOD585 and a degradable high polymer nanomaterial as raw materials;
step 3: mixing the macrophage membrane extracted in the step 1 and the PCOD 585-containing nanoparticle solution prepared in the step 2, and carrying out ultrasonic treatment, wherein the obtained mixture solution is extruded through a polycarbonate porous membrane by an extruder, so that the macrophage membrane coats the PCOD 585-containing nanoparticle, and the macrophage membrane-coated PCOD 585-containing nanoparticle is prepared.
3. The use of claim 2, wherein the extraction of step 1 is extraction of macrophage membranes from RAW264.7 cells.
4. The use according to claim 2, wherein the specific preparation method of the nanoparticle solution containing PCOD585 in step 2 comprises: respectively dissolving PCOD585 and degradable polymer nano material, sequentially mixing and ultrasonically emulsifying, adding into aqueous phase solution, ultrasonically stirring, and finally ultrafiltering and freeze-drying the obtained mixture to obtain the nano particle solution containing PCOD 585.
5. The use according to claim 4, wherein the degradable polymeric nanomaterial is PLGA-PEG-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the The aqueous solution is a PVA aqueous solution (polyvinyl alcohol aqueous solution).
6. The use according to claim 5, wherein the PCOD585 and the degradable polymeric nanomaterial PLGA-PEG-NH 2 The mass ratio of (3-4): 100.
7. the use according to any one of claims 1 to 6, wherein the mass ratio of macrophage membrane to PCOD 585-containing nanoparticle in the macrophage membrane-coated PCOD 585-containing nanoparticle is from 8 to 12:1.
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