CN114522157A - Application of calcium ion chelating agent in preparation of preparation for improving phagocytic capacity of vascular endothelial cells - Google Patents
Application of calcium ion chelating agent in preparation of preparation for improving phagocytic capacity of vascular endothelial cells Download PDFInfo
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- CN114522157A CN114522157A CN202210167310.7A CN202210167310A CN114522157A CN 114522157 A CN114522157 A CN 114522157A CN 202210167310 A CN202210167310 A CN 202210167310A CN 114522157 A CN114522157 A CN 114522157A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the technical field of medicines for treating cardiovascular and cerebrovascular diseases, and particularly relates to application of a calcium ion chelating agent in preparation of a preparation for improving phagocytic capacity of vascular endothelial cells. According to the embodiment of the invention, compared with the prior art, the calcium ion chelating agent is proved to reduce the viscosity of the endothelial cell membrane and improve the fluidity of the endothelial cell membrane through the cell and animal experiment level, so that the phagocytosis of the endothelial cell membrane on the nano-medicament is promoted, and the utilization rate of the nano-medicament can be obviously improved.
Description
Technical Field
The invention belongs to the technical field of medicines for treating cardiovascular and cerebrovascular diseases, and particularly relates to application of a calcium ion chelating agent in preparation of a preparation for improving phagocytic capacity of vascular endothelial cells.
Background
Cardiovascular and cerebrovascular diseases seriously endanger human health, and Atherosclerosis (AS) is considered AS the main pathological basis of cardiovascular diseases. Numerous studies have shown that atherosclerotic lesions may well originate in certain areas of vascular blood flow disturbances, such as areas of narrowing and bending of blood vessel branches, which may form reverse flow, turbulence, etc. In the vascular lumen, endothelial cells are in direct contact with the blood stream and have the ability to sense changes in the shear stress of the blood stream. The disturbed flow region at the atherosclerotic lesion causes cell debris, nano-materials, bacteria, etc. to accumulate in the region near the inner wall of the blood vessel due to flow field changes, and the vascular endothelial cells can phagocytose these materials by phagocytosis independent of specific protein receptors. At present, the development of endothelial phagocytosis and atherosclerosis is still under investigation.
At present, no relevant literature reports substances relevant to promotion of phagocytosis of vascular endothelial cells or treatment of atherosclerosis by promotion of phagocytosis of vascular endothelial cells.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of a calcium ion chelating agent in preparation of an agent for improving phagocytic ability of vascular endothelial cells.
Further, the calcium ion chelating agent is selected from one or more of ethylene diamine tetraacetic acid and derivatives thereof, ethylene glycol bis (2-amino ethyl ether) tetraacetic acid and derivatives thereof, and 1,2 bis (2-amino phenoxy) ethane N, N, N 'N' tetraacetic acid and derivatives thereof.
Further, the calcium ion chelating agent can also play the same role in endothelial cells in other calcium environments.
The invention also aims to provide the application of the calcium ion chelating agent in preparing a preparation for treating atherosclerosis.
Further, the calcium ion chelating agent is selected from one or more of ethylene diamine tetraacetic acid and derivatives thereof, ethylene glycol bis (2-amino ethyl ether) tetraacetic acid and derivatives thereof, and 1,2 bis (2-amino phenoxy) ethane N, N, N 'N' tetraacetic acid and derivatives thereof.
In particular, when nano-drugs enter blood vessels and are administered through endothelium, endothelial cell phagocytosis is a new mechanism for promoting atherosclerosis by abnormal shear stress. Therefore, a molecular mechanism influencing the formation and development of atherosclerosis by phagocytosis of endothelial cells under the condition of low oscillation flow is deeply discussed, and a new target and a clinical strategy are provided for the effective prevention and treatment of atherosclerosis. The calcium ion chelating agent is used for partially removing or completely removing calcium around or in the endothelial cells, so that the phagocytic capacity of the endothelial cells on the nano-drugs is effectively improved.
The invention also aims to provide application of the calcium ion chelating agent in preparing a preparation for promoting vascular endothelial cells to absorb medicaments.
Further, the calcium ion chelating agent is selected from one or more of ethylene diamine tetraacetic acid and derivatives thereof, ethylene glycol bis (2-amino ethyl ether) tetraacetic acid and derivatives thereof, and 1,2 bis (2-amino phenoxy) ethane N, N, N 'N' tetraacetic acid and derivatives thereof.
Further, the medicine comprises one or more of extracellular vesicles, exosomes, artificial vesicles, organic nano-medicine particles and inorganic nano-medicine particles.
Specifically, after the calcium ion chelating agent rapidly chelates calcium ions of vascular endothelium, the phagocytosis of endothelial cells is increased rapidly by the nano-drug or the bio-vesicle drug.
In certain embodiments, the concentration of the calcium ion chelating agent is selected to be 0.5-1.5mM, preferably 1 mM. More preferably, the mass ratio of the calcium ion chelating agent to the drug is 0.5-1: 0.5-1.
In certain embodiments, the calcium chelating agent is administered to C57BL/6 mice by tail vein injection, and it was found that when the calcium chelating agent depletes the calcium ions in the endothelial cells, i.e. in a calcium-deficient environment, the phagocytosis of the endothelial cells to the RBCEVs is enhanced, and it is clear that the calcium chelating agent can increase the fluidity of the endothelial cell membranes by reducing the intracellular calcium, thereby promoting the endothelial cells to phagocytize the RBCEVs and further improving the availability of the RBCEVs to the RBCEVs.
The invention also provides a method for improving the utilization rate of an endothelial drug, which is characterized in that the endothelial drug is combined with a calcium ion chelating agent, and the endothelial drug comprises the following components: one or more of extracellular vesicles, exosomes, artificial vesicles, organic nano-drug particles or inorganic nano-drug particles.
Further, the calcium ion chelating agent is selected from one or more of ethylene diamine tetraacetic acid and derivatives thereof, ethylene glycol bis (2-aminoethylether) tetraacetic acid and derivatives thereof, and 1,2 bis (2-aminophenoxy) ethane N, N, N 'N' tetraacetic acid and derivatives thereof.
The invention has the beneficial effects that
Compared with the prior art, the embodiment of the invention proves that the calcium ion chelating agent can reduce the viscosity of the endothelial cell membrane and improve the fluidity of the endothelial cell membrane through the level of cell and animal experiments, thereby promoting the phagocytosis of the nano-drug, namely obviously improving the utilization rate of the nano-drug.
Drawings
FIG. 1 shows the effect of calcium chelators and calcium chloride, respectively, on phagocytosis of RBCEVs by endothelial cells, en face staining (scale bar 20 μm).
Fig. 2 is a statistical plot of the effect of calcium chelators and calcium chloride, respectively, on endothelial cell phagocytosis of RBCEVs (n is 5, P <0.05 or P < 0.001).
Fig. 3 shows en face staining of mice injected with calcium chloride and calcium chelator into tail vein of mice on RBCEVs phagocytosis by left carotid LCA and right carotid RCA endothelial cells (scale bar 10 μm).
Fig. 4 is a statistical plot of the effect of the injection of calcium chloride and calcium chelator into the tail vein of mice on left carotid LCA and right carotid RCA endothelial cell phagocytosis of RBCEVs, respectively (n is 5, P is 0.01 or P is 0.001).
Fig. 5 shows the different cell viscosities under calcium ion treatment ((n ═ 3,. times.p <0.05 or. times.p <0.01,. times.p < 0.001).
Figure 6 shows the different cell viscosities under treatment with calcium chelators (n 3, P <0.05 or P <0.01, P < 0.001).
Figure 7 is a graph of the effect of different concentrations of BAPTAAM on endothelial cell survival (n-3).
Detailed Description
The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Example 1 cell experiments
In the embodiment of the invention, the cell culture medium is a common culture medium, and no calcium ion or calcium ion chelating agent is additionally added.
In the embodiment of the invention, endothelial cells are inoculated in a cell pore plate, after the cells grow full, the cells are pretreated by a calcium ion chelating agent for 30 minutes, then the cells are washed by a fresh cell culture medium for at least 3 times, and when the cells are treated by BAPTA-AM, the cells are firstly dissolved in 10% DMSO and then dissolved in 90% normal saline (containing 20% SBE-beta-CD); the concentration of calcium chloride-treated cells was 10. mu.g/mL. Results as shown in fig. 1 and 2, endothelial cells were treated with calcium chloride, which inhibits endothelial cell phagocytosis of erythrocyte extracellular vesicles RBCEVs, and with a calcium ion chelator, BAPTAAM, which promotes endothelial cell phagocytosis of erythrocyte extracellular vesicles, respectively.
Example 2 animal experiments
In the present example, when injecting BAPTAAM into mice, it is dissolved in 10% DMSO and then dissolved in 90% physiological saline (containing 20% SBE beta CD).
In the embodiment of the invention, the concentration of the calcium chloride injection injected into a mouse is 10 mug/mL, the calcium chloride injection needs to be taken slowly during injection, otherwise, hypotension or arrhythmia of the mouse is easily caused.
In the embodiment of the invention, 15 male C57BL/6 mice with the weight of 15-20g and the age of 6 weeks are selected and subjected to carotid artery ligation operation to construct a mouse OSS carotid artery ligation model. The ligation is specifically performed as follows:
(1) anaesthetizing the mouse, fixing the mouse on an operating table in a supine position, cutting the skin from the position right above the trachea, and separating the muscles on the left side and the right side of the trachea respectively; first, forceps are used for peeling off muscles along the left trachea layer by layer to find a left carotid sheath, and then the forceps are used for carefully separating fascia close to the left carotid and vagus nerve to separate a left common carotid artery (LCA); dissection was continued up the common carotid artery, and the External Carotid Artery (ECA), Internal Carotid Artery (ICA), Occipital Artery (OA) and suprathyroid artery (STA) were found.
(2) Three branch vessels (ECA, ICA and OA) except STA were tied with 90-grade medical sutures and the blood flow was secured to STA.
(3) A right common carotid artery (RCA) was isolated and found 4 branch vessels, but not ligated, as a control group.
(4) The mouse was sutured layer by layer with 50 sutures, the wound was wiped with iodophor after suturing, and the mouse was placed on a 37 ℃ thermostatic board and transferred to the corresponding mouse cage after waiting for awakening.
In the embodiment of the invention, in the constructed OSS model, the blood flow of LCA is OSS, and the blood flow at RCA is NSS. From the results of the en face staining and data statistics shown in fig. 3 and 4, it can be seen that the LCA group had a clear red fluorescence signal of RBCEVs co-localized with endothelial cells, compared to the RCA group; when calcium chloride was injected intravenously through the tail of mice (LCA + Ca)2+)，LCA+Ca2+The RBCEVs red fluorescence signal of the group was significantly lower than that of the LCA group, i.e., calcium chloride inhibited endothelial cell phagocytosis of the LCA group; in contrast, when BAPTAAM was injected (LCA + BAPTAAM), the RBCEVs red fluorescence signal was significantly stronger than the LCA group. Namely, the tail vein of the mouse is injected with calcium chloride and BAPTAAM which is a calcium chelating agent respectively, and the BAPTAAM obviously promotes the phagocytosis of the vascular endothelial cells in the area of the right carotid artery ligation OSS to the erythrocyte extracellular vesicle RBCEVs.
The results are consistent with the results of the cells of example 1, BAPTAAM inhibits calcium ion concentration in blood, promotes endothelial cells to phagocytose RBCEVs, and increases the availability of RBCEVs.
EXAMPLE 3 detection of endothelial cell Membrane fluidity by DPH Probe
The method for detecting the fluidity of the endothelial cell membrane by using the DPH probe comprises the following specific steps:
(1) preparing a working solution: and (3) diluting the DPH probe by using a diluent in the kit according to an instruction, wherein the dilution range can be up to 10000 times according to the experiment requirement, and preparing the DPH dyeing working solution.
(2) Endothelial cells are inoculated to a 12-well plate, staining treatment can be carried out after the cells are overgrown under a microscope, a culture medium is sucked away by a pipette, a staining working solution is added, and the cells are incubated in a cell incubator for at least 0.5 hour.
(3) The cells were resuspended after washing 1 time with pH 7.4HBSS or 20mM HEPES or PBS.
(4) The cells were detected using a spectrophotometer with a bias light. The setting parameters are as follows: the excitation wavelength is 355nm, and the emission wavelength is 430 nm.
The fluorescence polarization degree P is calculated according to the following formula: p ═ (IVV-GIVHIHV)/(IVV + GIVH), where the correction factor G ═ IHV/IHH, where: IVV fluorescence intensity measured when the optical axes of the polarization and analyzer are vertical; IVH, measuring fluorescence intensity when optical axes of the polarization analyzer and the polarization analyzer are respectively in vertical and horizontal directions; IHV, measured fluorescence intensity when the optical axes of the polarization analyzer and the polarization analyzer are respectively in the horizontal direction and the vertical direction; IHH fluorescence intensity measured when the optical axes of the polarization and analyzer are in the same horizontal direction; p reflects the viscosity (. eta.) of the membrane lipid domain, whereas η is inversely proportional to membrane fluidity.
As shown in FIGS. 5 and 6, the DPH probe detects BAPTAAM to reduce the viscosity of endothelial cell membrane, improve the fluidity of endothelial cell membrane, and promote the phagocytosis of RBCEVs, and the opposite is true to calcium chloride.
Example 4 cytotoxicity assay
The effect of different concentrations of BAPTAAM on endothelial cell viability was studied by MTS assay, cells were tested at BAPTAAM recommended concentrations and times (1mM, 30 min) and the following experimental steps were performed:
(1) HUVEC cells were cultured to logarithmic growth phase.
(2) Taking 96-well cell culture plate, adding 0.1ml of 1 × 10-contained solution per well4～2×1041640 medium (10% calf serum) of one of the above cells.
(3) Adding 20 mu L MTS into each well, and continuing culturing for 3-4 hours for color development.
(4) The plates were shaken for 10 seconds before detection and the color was mixed. The absorbance (OD) of each well was measured at a wavelength of 570nm (or 490nm, or 570nm and 690nm) on an enzyme-linked detector. Dose-response curves were plotted with sample dilution versus OD value (OD570, OD490, or OD570/OD690), and the amount of cytokine in the sample was calculated from the standard curve.
The results are shown in figure 7, according to BAPTAAM suggested concentration and time (1mM, 30 minutes) on cell toxicity, has better safety.
Finally, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. Use of a calcium ion chelator for the preparation of a formulation for increasing phagocytic capacity of vascular endothelial cells.
2. The use according to claim 1, wherein the calcium ion chelating agent is selected from one or more of ethylenediaminetetraacetic acid and derivatives thereof, ethylene glycol bis (2-aminoethylether) tetraacetic acid and derivatives thereof, 1,2 bis (2-aminophenoxy) ethane N, N' tetraacetic acid and derivatives thereof.
3. Use of a calcium ion chelating agent in the manufacture of a formulation for the treatment of atherosclerosis.
4. The use according to claim 3, wherein the calcium ion chelating agent is selected from one or more of ethylenediaminetetraacetic acid and derivatives thereof, ethylene glycol bis (2-aminoethylether) tetraacetic acid and derivatives thereof, 1,2 bis (2-aminophenoxy) ethane N, N, N 'N' tetraacetic acid and derivatives thereof.
5. Use of a calcium ion chelating agent in the manufacture of a formulation for promoting the absorption of a drug by endothelial cells.
6. The use according to claim 5, wherein the calcium ion chelating agent is selected from one or more of ethylenediaminetetraacetic acid and derivatives thereof, ethylene glycol bis (2-aminoethylether) tetraacetic acid and derivatives thereof, 1,2 bis (2-aminophenoxy) ethane N, N, N 'N' tetraacetic acid and derivatives thereof.
7. The use of claim 5, wherein the drug comprises one or more of extracellular vesicles, exosomes, artificial vesicles, organic nano-drug particles, inorganic nano-drug particles in admixture.
8. The use of any one of claims 5-7, wherein said endothelial cells comprise vascular endothelial cells.
9. A method of increasing the availability of an endothelially administered drug wherein said endothelially administered drug is combined with a calcium ion sequestering agent and wherein said endothelially administered drug comprises: one or more of extracellular vesicles, exosomes, artificial vesicles, organic nano-drug particles or inorganic nano-drug particles.
10. The method of claim 9, wherein the calcium ion chelating agent is selected from one or more of ethylenediaminetetraacetic acid and derivatives thereof, ethylene glycol bis (2-aminoethylether) tetraacetic acid and derivatives thereof, 1,2 bis (2-aminophenoxy) ethane N, N' tetraacetic acid and derivatives thereof.
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