CN111265544A - Nano calcium carbonate particle and preparation method and application thereof - Google Patents
Nano calcium carbonate particle and preparation method and application thereof Download PDFInfo
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- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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Abstract
The invention relates to the technical field of biology, and provides a nano calcium carbonate particle, which takes polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers and calcium carbonate as a core layer. The nano calcium carbonate particles (polylactic acid-calcium carbonate glycolate preparation) provided by the invention are composed of polylactic acid-glycolic acid, polylactic acid-glycolic acid-polyethylene glycol and calcium carbonate, have uniform particle size, are well dispersed in water, and are mainly concentrated at about 120nm in the water. Experiments show that the polylactic acid-calcium carbonate glycolate particle has good effect of enhancing tumor immunotherapy and can be used as an adjuvant for tumor immunotherapy.
Description
Technical Field
The invention relates to the field of biotechnology, in particular to a nano calcium carbonate particle and preparation and application thereof.
Background
Tumor (tumor) refers to a new organism (neograwth) formed by local tissue cell proliferation of the body under the action of various tumorigenic factors, because the new organism is mostly in the form of space-occupying block-shaped protrusion, also called neoplasms (neoplasms). According to the cellular characteristics of the new organism and the degree of harm to the organism, tumors are divided into two major categories, namely benign tumors and malignant tumors, and cancers are a general term for malignant tumors. Compared with benign tumors, malignant tumors grow rapidly, grow infiltratively, are easy to bleed, necrotize, ulcer and the like, and often metastasize at a distance, so that emaciation, weakness, anemia, inappetence, fever, serious organ function impairment and the like of a human body are caused, and finally, the patient dies. Due to aging of population and other reasons, the incidence and mortality of cancer in China are on a continuous increasing trend. The worldwide cancer report estimates that the number of cancer attacks in the middle of 2012 is 306.5 ten thousand, which accounts for about one fifth of the number of attacks in the world; the number of cancer deaths is 220.5 ten thousand, accounting for about one fourth of the cancer deaths worldwide. In the future for 20 years, the number of diseases and deaths of cancers in China will continuously rise: according to the prediction of the international cancer research institute, if no effective measures are taken, the number of cancer diseases and deaths in China will rise to 400 ten thousand and 300 ten thousand in 2020; the year 2030 will rise to 500 and 350 thousands of people.
However, the current problems still face lower response rate and limit clinical application of the treatment, and solid tumors often have a series of microenvironment characteristics different from normal tissues, such as hypoxia, microacid, high interstitial pressure, high active oxygen, immune tolerance and the like due to the reasons of rapid proliferation, metabolic pathway change, tumor vascular development malformation and the like of tumor cells, wherein the tumor microacid can not only inhibit the anti-tumor immune function of a body by reducing effector cytokines such as IFN- β and TNF- α and inducing pathways such as T lymphocyte apoptosis and the like, but also cause degradation and inactivation of antibodies, and further generate a large amount of immune therapeutic effects on immune therapies based on anti-PD-1/PD-1 and the like to develop a scientific immune therapy method for enhancing the tumor therapeutic effect.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a nano calcium carbonate particle, which has a good effect of regulating tumor microacid environment and can enhance tumor immunotherapy effect.
The invention provides a nano calcium carbonate particle, which takes polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers and calcium carbonate as a core layer.
Preferably, the particle size of the nano calcium carbonate particles is 100-120 nm.
The invention provides a preparation method of nano calcium carbonate particles, which comprises the following steps:
A) mixing polylactic acid-glycolic acid and polylactic acid-glycolic acid-polyethylene glycol in a solvent to obtain a PLGA and PLGA-PEG mixed solution;
B) mixing PLGA and PLGA-PEG mixed solution with NaHCO3Mixing the solutions, and emulsifying to obtain a first emulsion;
mixing PLGA and PLGA-PEG mixed solution with CaCl2Mixing the aqueous solutions, and emulsifying to obtain a second emulsion;
C) mixing the first emulsion and the second emulsion, and emulsifying to obtain a third emulsion;
D) dispersing the third emulsion in a polyvinyl alcohol aqueous solution, stirring and washing to obtain CaCO3@PLGA-PEG。
Preferably, the mass ratio of the PLGA to the PLGA-PEG is 1-2: 1-2; the concentration of the mixed solution of the PLGA and the PLGA-PEG is 25-35 mg/ml; the solvent is dichloromethane.
Preferably, said NaHCO3The concentration is 0.6-0.7M, and the CaCl is2The concentration of the solution is 1-1.5M.
Preferably, the PLGA and PLGA-PEG mixed solution and NaHCO3The volume ratio of the solution is 2-3: 1; the PLGA and PLGA-PEG mixed solution and CaCl2The volume ratio of the aqueous solution is 3-4: 1.
Preferably, the emulsification in the step C) is ultrasonic emulsification, and the ultrasonic power is 80-120W; the ultrasonic time is 250-350 s.
Preferably, the mass fraction of the polyvinyl alcohol aqueous solution in the step C) is 1-2%; the stirring time is 10-14 h; the washing is centrifugation for 20-30 min under the condition of 14000-15000 rpm, and washing is carried out for 2-3 times by using ultrapure water.
The invention provides application of the nano calcium carbonate particles in any one of the technical schemes or the nano calcium carbonate particles prepared by the preparation method in any one of the technical schemes in preparing an adjuvant for tumor immunotherapy.
The invention provides a tumor immunotherapy adjuvant, which comprises the nano calcium carbonate particles or the nano calcium carbonate preparation prepared by the preparation method.
Compared with the prior art, the invention provides a nano calcium carbonate particle, which takes polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers and calcium carbonate as a core layer. The nano calcium carbonate particles (polylactic acid-calcium carbonate glycolate preparation) provided by the invention are composed of polylactic acid-glycolic acid, polylactic acid-glycolic acid-polyethylene glycol and calcium carbonate, have uniform particle size, are well dispersed in water, and are mainly concentrated at about 120nm in the water. Experiments show that the polylactic acid-calcium glycolate particle has good effect of enhancing tumor immunotherapy and can be used as an adjuvant for tumor immunization therapy.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows a transmission electron micrograph of a poly (lactic-co-glycolic acid) calcium carbonate formulation of example 2;
FIG. 2 shows the particle size distribution of the poly (lactic-co-glycolic acid) calcium carbonate formulation of example 2 in water;
FIG. 3 shows the growth and survival curves of tumors from different groups of mice of example 3 after immunotherapy; the control group (saline only) and the immunotherapy group of aPD-1 are included; the polylactic acid-calcium glycolate and aPD-1 immunotherapy group were injected.
Detailed Description
The invention provides a nano calcium carbonate particle and preparation and application thereof, and a person skilled in the art can realize the nano calcium carbonate particle by properly improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The invention provides a nano calcium carbonate particle, which takes polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers and calcium carbonate as a core layer.
The nano calcium carbonate particle provided by the invention takes polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers.
The shell layer of the invention is PLGA-PLGA-PEG, wherein, the hydrophilic group of PEG is at the outermost layer, and the hydrophobic group of PLGA-PLGA is at the inner layer.
The nano calcium carbonate particle provided by the invention takes calcium carbonate as a core layer.
The particle size of the nano calcium carbonate particles is preferably 100-120 nm; more preferably 105 to 120 nm.
The invention provides a preparation method of nano calcium carbonate particles, which comprises the following steps:
A) mixing polylactic acid-glycolic acid and polylactic acid-glycolic acid-polyethylene glycol in a solvent to obtain a PLGA and PLGA-PEG mixed solution;
B) mixing PLGA and PLGA-PEG mixed solution with NaHCO3Mixing the solutions, and emulsifying to obtainA first emulsion;
mixing PLGA and PLGA-PEG mixed solution with CaCl2Mixing the aqueous solutions, and emulsifying to obtain a second emulsion;
C) mixing the first emulsion and the second emulsion, and emulsifying to obtain a third emulsion;
D) dispersing the third emulsion in a polyvinyl alcohol aqueous solution, stirring and washing to obtain CaCO3@PLGA-PEG。
The preparation method of the nano calcium carbonate particles provided by the invention comprises the steps of mixing polylactic acid-glycolic acid and polylactic acid-glycolic acid-polyethylene glycol in a solvent to obtain a PLGA and PLGA-PEG mixed solution.
The solvent is preferably dichloromethane. Namely: and (3) taking dichloromethane as a solvent to prepare a mixed solution of PLGA and PLGA-PEG.
According to the invention, the mass ratio of PLGA to PLGA-PEG is preferably 1-2: 1-2; more preferably 1: 1.
The concentration of the mixed solution of PLGA and PLGA-PEG is preferably 25-35 mg/mL; more preferably 27 to 32 mg/mL; most preferably 30 mg/mL.
In this case, the solution was an oil phase solution because methylene chloride was used as a solvent.
Then, water is used as a solvent to prepare NaHCO respectively3With CaCl2And (3) solution. NaHCO according to the invention3The concentration is preferably 0.6 to 0.7M, more preferably 0.62 to 0.68M, and most preferably 0.625M.
Mixing PLGA and PLGA-PEG mixed solution with NaHCO3Mixing the solutions, and emulsifying to obtain a first emulsion; the preferable concrete is as follows: NaHCO is added3And mixing the aqueous solution with a dichloromethane mixed solution of PLGA and PLGA-PEG, and ultrasonically emulsifying by using an ultrasonic cell disruptor to obtain a first emulsion. NaHCO 23@PLGA-PEG)。
The first emulsion is water-in-oil emulsion, namely PLGA and PLGA-PEG are out and are oil phase, NaHCO3Is an aqueous phase.
According to the invention, the PLGA and PLGA-PEG mixed solution and NaHCO3The volume ratio of the solution is preferably 3-4: 1; more preferably 3: 1.
The emulsification is preferably ultrasonic emulsification, and the ultrasonic power is preferably 80-120W; more preferably 90-110W; most preferably 100W; the ultrasonic time is preferably 250-350 s; more preferably 260 to 330 s; most preferably 280 to 310 s; particularly preferably 297 to 300 seconds.
Mixing PLGA and PLGA-PEG mixed solution with CaCl2And mixing the aqueous solutions, and emulsifying to obtain a second emulsion. The preferable concrete is as follows: adding CaCl2And mixing the aqueous solution with a dichloromethane mixed solution of PLGA and PLGA-PEG, and ultrasonically emulsifying by using an ultrasonic cell disruptor to obtain a second emulsion. CaCl2@PLGA-PEG。
According to the invention, the PLGA and PLGA-PEG mixed solution and CaCl2The volume ratio of the aqueous solution is 3-4: 1; more preferably 3: 1.
CaCl according to the invention2The concentration of the solution is preferably 1-1.5M; more preferably 1.1-1.4M; most preferably 1.25 to 1.35M.
The emulsification is preferably ultrasonic emulsification, and the ultrasonic power is preferably 80-120W; more preferably 90-110W; most preferably 100W; the ultrasonic time is preferably 250-350 s; more preferably 260 to 330 s; most preferably 280 to 310 s; particularly preferably 297 to 300 seconds.
The second emulsion is a water-in-oil emulsion, namely PLGA and PLGA-PEG, and the second emulsion is an oil phase CaCl2Is an aqueous phase.
Mixing the first emulsion and the second emulsion, and emulsifying to obtain a third emulsion;
the mixing method of the present invention is not limited, and those skilled in the art will be familiar with it. After mixing, NaHCO3And CaCl2Reaction to obtain CaCO3@ PLGA- -PEG. The calcium carbonate is obtained as an aqueous phase, an inner layer and a core layer.
The emulsification is preferably ultrasonic emulsification, and the ultrasonic power is preferably 80-120W; more preferably 90-110W; most preferably 100W; the ultrasonic time is preferably 250-350 s; more preferably 260 to 330 s; most preferably 280 to 310 s; particularly preferably 297 to 300 seconds.
Dispersing the third emulsion in the aqueous solution of polyvinyl alcohol, stirring and washingWashing to obtain CaCO3@PLGA-PEG。
Dispersing the third emulsion in a polyvinyl alcohol aqueous solution, continuously stirring to remove dichloromethane, and washing to obtain a product CaCO3@PLGA-PEG。
According to the invention, the mass fraction of the polyvinyl alcohol aqueous solution is preferably 1-2%; more preferably 1%; the stirring time is preferably 10-14 h; more preferably 11-13 h; most preferably 12 h.
The washing is preferably carried out for 20-30 min under the condition of 14000-15000 rpm, and washing is carried out for 2-3 times by using ultra-pure water; more preferably, centrifuging for 20-28 min under the condition of 14200-14800 rpm, and washing for 2-3 times by using ultrapure water; most preferably 14500-14800 rpm for 20-25 min, and washing with ultrapure water for 3 times.
The invention provides application of the nano calcium carbonate particles in any one of the technical schemes or the nano calcium carbonate particles prepared by the preparation method in any one of the technical schemes in preparing an adjuvant for tumor immunotherapy.
The invention provides a tumor immunotherapy adjuvant, which comprises the nano calcium carbonate particles or the nano calcium carbonate particles prepared by the preparation method in any one of the technical schemes.
The invention provides a nano calcium carbonate particle, which takes polylactic acid-glycolic acid (PLGA) and polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) as shell layers and calcium carbonate as a core layer. The nano calcium carbonate particles (polylactic acid-calcium carbonate particles) provided by the invention are composed of polylactic acid-glycolic acid, polylactic acid-glycolic acid-polyethylene glycol and calcium carbonate, have uniform particle size, are well dispersed in water, and are mainly concentrated at about 120nm in the water. Experiments show that the polylactic acid-calcium glycolate preparation has good effect of enhancing tumor immunotherapy and can be used as an adjuvant for tumor immunotherapy.
In order to further illustrate the present invention, the following will describe in detail a nano calcium carbonate particle, its preparation and application, and its preparation and application in combination with the examples.
Example 1 preparation of polylactic acid-calcium carbonate microparticles
Weighing PLGA and PLGA-PEG according to the mass ratio of 1:1, and dissolving in dichloromethane to prepare a 30mg/ml PLGA and PLGA-PEG mixed solution. Weighing NaHCO3With CaCl2Separately dissolved in water to prepare 0.625M NaHCO3Aqueous solution with 1.25M CaCl2An aqueous solution. NaHCO prepared3Aqueous solution with CaCl2Respectively mixing the aqueous solution with PLGA and PLGA-PEG dichloromethane mixed solution according to the volume ratio of 1:3, and ultrasonically emulsifying 297s by using an ultrasonic cell disruptor under the condition that the ultrasonic power is 100W to obtain emulsion A (NaHCO)3@ PLGA-PEG) and emulsion B (CaCl)2@ PLGA-PEG). Mixing emulsion A and emulsion B, and ultrasonic emulsifying 297s with ultrasonic cell disruptor under the condition of ultrasonic power of 100W to obtain emulsion C (CaCO)3@ PLGA- -PEG). The resulting emulsion C was dispersed in a 1% aqueous PVA solution and stirred continuously for 12h to remove methylene chloride. Centrifuging at 14800rpm for 20min, and washing with ultrapure water for three times to obtain the polylactic acid-glycolic acid nano calcium carbonate preparation.
Example 2 detection of Properties of calcium carbonate Poly (lactic acid-glycolic acid)
The polylactic acid-calcium glycolate microparticles prepared in example 1 were qualitatively detected, and subjected to transmission electron microscopy and dynamic light scattering, respectively.
The transmission electron microscope results are shown in fig. 1, and the results show that the calcium poly (lactic-co-glycolic acid) carbonate particles prepared in example 1 are monodisperse in water, which indicates that the calcium poly (lactic-co-glycolic acid) carbonate particles prepared by the present invention have uniform particle size and good dispersibility in water.
The results of dynamic light scattering measurement are shown in FIG. 2, which shows that the particle size of the poly (lactic acid-co-glycolic acid) calcium carbonate fine particles obtained in example 1 is mainly concentrated at about 120nm in water.
Example 3 immunotherapy of tumors
Mice bearing subcutaneous tumor models of colon cancer were divided into three groups, which included: first group, control group (saline only injection); second, injection aPD-1 immunotherapy group; and the third group, injection of polylactic acid-calcium glycolate and aPD-1 immunotherapy group. The growth of the tumors was measured after the corresponding treatment of the mice, and the results are shown in fig. 3. The results show that the second group showed only partial inhibition of tumor growth compared to the control group, while the third group showed effective inhibition of tumor growth. The polylactic acid-calcium glycolate preparation can realize enhanced immunotherapy on tumors.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The nanometer calcium carbonate particle features that polylactic-co-glycolic acid (PLGA) and polylactic-co-glycolic acid-polyethylene glycol (PLGA-PEG) are used as the shell layer and calcium carbonate as the core layer.
2. The nano calcium carbonate fine particles according to claim 1, wherein the nano calcium carbonate fine particles have a particle size of 100 to 120 nm.
3. A method for preparing nano calcium carbonate particles is characterized by comprising the following steps:
A) mixing polylactic acid-glycolic acid and polylactic acid-glycolic acid-polyethylene glycol in a solvent to obtain a PLGA and PLGA-PEG mixed solution;
B) mixing PLGA and PLGA-PEG mixed solution with NaHCO3Mixing the solutions, and emulsifying to obtain a first emulsion;
mixing PLGA and PLGA-PEG mixed solution with CaCl2Mixing the aqueous solutions, and emulsifying to obtain a second emulsion;
C) mixing the first emulsion and the second emulsion, and emulsifying to obtain a third emulsion;
D) dispersing the third emulsion in a polyvinyl alcohol aqueous solution, stirring and washing to obtain CaCO3@PLGA-PEG。
4. The preparation method according to claim 3, wherein the mass ratio of the polylactic acid-glycolic acid to the polylactic acid-glycolic acid-polyethylene glycol is 1-2: 1-2; the concentration of the mixed solution of the PLGA and the PLGA-PEG is 25-35 mg/ml; the solvent is dichloromethane.
5. The process of claim 3, wherein said NaHCO is used as a feed additive3The concentration is 0.6-0.7M, and the CaCl is2The concentration of the solution is 1-1.5M.
6. The method for preparing the pharmaceutical composition according to claim 3, wherein the PLGA and PLGA-PEG mixed solution is mixed with NaHCO3The volume ratio of the solution is 3-4: 1; the PLGA and PLGA-PEG mixed solution and CaCl2The volume ratio of the aqueous solution is 3-4: 1.
7. The preparation method according to claim 3, wherein the emulsification in the step C) is ultrasonic emulsification, and the ultrasonic power is 80-120W; the ultrasonic time is 250-350 s.
8. The preparation method according to claim 3, wherein the mass fraction of the polyvinyl alcohol aqueous solution in the step C) is 1-2%; the stirring time is 10-14 h; the washing is centrifugation for 20-30 min under the condition of 14000-15000 rpm, and washing is carried out for 2-3 times by using ultrapure water.
9. Use of the nano calcium carbonate particles according to any one of claims 1 to 2 or the nano calcium carbonate particles prepared by the preparation method according to any one of claims 3 to 8 in the preparation of an adjuvant for tumor immunotherapy.
10. An adjuvant for tumor immunotherapy, comprising the nano calcium carbonate fine particles according to any one of claims 1 to 2 or the nano calcium carbonate fine particles produced by the production method according to any one of claims 3 to 8.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911377716.2A CN111265544A (en) | 2019-12-27 | 2019-12-27 | Nano calcium carbonate particle and preparation method and application thereof |
| CN202010967945.6A CN111888337B (en) | 2019-12-27 | 2020-09-15 | Calcium carbonate-based composite particles, preparation and application thereof |
| CN202010967914.0A CN111888375B (en) | 2019-12-27 | 2020-09-15 | Polylactic acid-calcium carbonate glycollate particle and preparation method and application thereof |
| PCT/CN2020/121602 WO2022056984A1 (en) | 2019-12-27 | 2020-10-16 | Polylactic acid-glycolic acid calcium carbonate microparticle, preparation method therefor and use thereof |
| PCT/CN2020/121606 WO2022056986A1 (en) | 2019-12-27 | 2020-10-16 | Calcium carbonate-based compound micro particles, and preparation and application thereof |
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| CN201911377716.2A CN111265544A (en) | 2019-12-27 | 2019-12-27 | Nano calcium carbonate particle and preparation method and application thereof |
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| CN202010967914.0A Active CN111888375B (en) | 2019-12-27 | 2020-09-15 | Polylactic acid-calcium carbonate glycollate particle and preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111888337A (en) * | 2019-12-27 | 2020-11-06 | 苏州大学 | Calcium carbonate-based composite particles, preparation and application thereof |
| WO2022056984A1 (en) * | 2019-12-27 | 2022-03-24 | 苏州大学 | Polylactic acid-glycolic acid calcium carbonate microparticle, preparation method therefor and use thereof |
| WO2022056985A1 (en) * | 2019-12-27 | 2022-03-24 | 苏州大学 | Calcium carbonate poly(lactic acid-glycolic acid) composite microparticle, and preparation therefor and use thereof |
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| WO2024112867A1 (en) * | 2022-11-23 | 2024-05-30 | University Of Georgia Research Foundation, Inc. | Compositions and methods of use thereof for increasing immune responses |
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| CN102772825B (en) * | 2012-07-06 | 2014-06-11 | 华南理工大学 | Polylactic-co-glycolic acid (PLGA)/calcium carbonate compound microsphere with porous shell and preparation method for compound microsphere |
| CN104434806B (en) * | 2014-11-06 | 2017-05-03 | 中国人民解放军第四军医大学 | Lipid-mixed poly (lactic-co-glycolic acid) (PLGA) nanoparticle having high drug loading amount and active targeting effect |
| CN111265483A (en) * | 2019-12-27 | 2020-06-12 | 苏州大学 | Calcium carbonate poly (lactic acid-glycolic acid) composite particle and preparation method and application thereof |
| CN111265544A (en) * | 2019-12-27 | 2020-06-12 | 苏州大学 | Nano calcium carbonate particle and preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111888337A (en) * | 2019-12-27 | 2020-11-06 | 苏州大学 | Calcium carbonate-based composite particles, preparation and application thereof |
| CN111888337B (en) * | 2019-12-27 | 2021-07-27 | 苏州大学 | Calcium carbonate-based composite particles, preparation and application thereof |
| WO2022056986A1 (en) * | 2019-12-27 | 2022-03-24 | 苏州大学 | Calcium carbonate-based compound micro particles, and preparation and application thereof |
| WO2022056984A1 (en) * | 2019-12-27 | 2022-03-24 | 苏州大学 | Polylactic acid-glycolic acid calcium carbonate microparticle, preparation method therefor and use thereof |
| WO2022056985A1 (en) * | 2019-12-27 | 2022-03-24 | 苏州大学 | Calcium carbonate poly(lactic acid-glycolic acid) composite microparticle, and preparation therefor and use thereof |
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| Publication number | Publication date |
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| WO2022056984A1 (en) | 2022-03-24 |
| CN111888375B (en) | 2021-07-27 |
| CN111888375A (en) | 2020-11-06 |
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