CN113244407B - Application of antioxidant and hematopoietic accelerator in preparation of medicine for treating acute radiation injury - Google Patents
Application of antioxidant and hematopoietic accelerator in preparation of medicine for treating acute radiation injury Download PDFInfo
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- CN113244407B CN113244407B CN202110593268.0A CN202110593268A CN113244407B CN 113244407 B CN113244407 B CN 113244407B CN 202110593268 A CN202110593268 A CN 202110593268A CN 113244407 B CN113244407 B CN 113244407B
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Abstract
The application discloses an application of an antioxidant and hematopoietic accelerator in preparing a medicament for treating acute radiation injury; the hematopoietic accelerator is used for promoting hematopoietic recovery and increasing neutrophil generation and reducing risk of infection after ARS in the application; the antioxidant is used for improving the hematopoietic microenvironment of HSC, and the combination of the antioxidant and the antioxidant can better accelerate the hematopoietic process of bone marrow and promote the repair of acute radiation injury.
Description
Technical Field
The application relates to the technical field of acute radiation injury medicaments, in particular to application of an antioxidant and hematopoietic accelerator combined in preparation of a medicament for treating acute radiation injury.
Background
Today nuclear technology has found widespread use. Whether the nuclear technology and the peace period are used, the rapid and efficient emergency treatment is provided for the public under the nuclear emergency, the nuclear terrorism or the nuclear war occurrence condition, and the rapid and efficient emergency treatment scheme is reserved for the radiotherapy patients and the professional radiological staff, so that the comprehensive national force is reflected.
After encountering nuclear exposure, elevated ROS levels are one of the main causes of acute radiation damage (ARS) in the body. Resveratrol (RES) is one of the representatives of strong antioxidants, and can scavenge and inhibit oxygen free radicals, but RES has the defects of poor water solubility, low in vivo bioavailability, high metabolism speed and the like, so that the clinical application of the resveratrol is limited. In addition, as hematopoietic accelerators, gold standard such as ARS treatment, human natural or recombinant granulocyte stimulating factor (G-CSF), granulocyte-macrophage stimulating factor (GM-CSF), thrombopoietin (TPO), macrophage stimulating factor (M-CSF), erythropoietin (EPO), interleukin 3 (IL-3), interleukin-12 (IL-12), stem Cell Factor (SCF), interleukin-5 (IL-5), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-11 (IL-11) and the like can stimulate proliferation and differentiation of Hematopoietic Stem Cells (HSC) which are self-preserved after radiation exposure to neutrophils, macrophages and the like, reduce the risk of infection or bleeding and the like, and have positive effects on hematopoietic and survival after radiation. These cytokines have a short in vivo half-life and require multiple injections per day or a day, resulting in poor patient compliance.
In view of this, the present application has been made.
Disclosure of Invention
The application aims to provide an application of an antioxidant combined hematopoietic accelerator in preparing a medicament for treating acute radiation injury, wherein the hematopoietic accelerator is used for promoting hematopoietic recovery and increasing neutrophil generation, reducing risk of post ARS infection, the antioxidant is used for improving hematopoietic microenvironment of HSC, and the combined administration of the antioxidant and the hematopoietic accelerator can better accelerate bone marrow hematopoietic and repair of acute radiation injury.
In order to achieve the above object of the present application, the following technical solutions are specifically adopted:
the application provides an application of an antioxidant combined with a hematopoietic accelerator in preparing a medicament for treating acute radiation injury.
Preferably, the antioxidant is selected from at least one of Resveratrol (RES), glutathione, glutamine, natural vitamin a, anthocyanin, tea polyphenols, ascorbic acid, phytic acid, tocopherol, beta-carotene, selenium, alpha-lipoic acid, genistein, bei Jiayin, 5-hydroxytryptamine, 5-methoxy tryptamine, melatonin, baicalin, quercetin, rutin, genistein, estriol, kaempferol, huperzine, epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), and epigallocatechin gallate (EGCG).
Preferably, the hematopoietic promoter is selected from at least one of human natural or recombinant granulocyte-stimulating factor (G-CSF), granulocyte-macrophage-stimulating factor (GM-CSF), thrombopoietin (TPO), macrophage-stimulating factor (M-CSF), erythropoietin (EPO), interleukin 3 (IL-3), interleukin 12 (IL-12), stem Cell Factor (SCF), interleukin 5 (IL-5), interleukin 1 (IL-1), interleukin 6 (IL-6) and interleukin 11 (IL-11).
In a second aspect, the present application provides a medicament for the treatment of acute radiation injury, the medicament comprising nanoparticles encapsulating an antioxidant and a hematopoietic promoter as described above; alternatively, nanoparticles encapsulating the antioxidant and nanoparticles encapsulating the hematopoietic accelerator may be used.
Preferably, the carrier used for entrapment is selected from at least one of PLGA, PLA, PCL, PGA, PLGA-PEG, PLA-PEG, PCL-PEG, PLGA/PLA and PLGA/PCL/PLA/PCL.
Preferably, the mass ratio of the carrier to the antioxidant to the hematopoiesis promoter is (2-80) to (0.8-1.2) to (0.5-2); preferably (2-10) to (0.8-1.2) to (0.5-2).
The third aspect of the present application provides a method for preparing the above-mentioned drug, comprising a preparation process of nanoparticles encapsulating the above-mentioned antioxidant and hematopoietic promoter, the preparation process being carried out under a light-shielding condition, specifically comprising:
(a) Dissolving a carrier and an antioxidant in a solvent to obtain a mixed solution;
(b) Under the ultrasonic condition, dropwise adding the mixed solution into PVA water solution for continuing ultrasonic treatment to obtain mixed solution;
(c) Volatilizing and removing the solvent in the mixed solution, centrifuging and collecting the precipitate, and washing with water to obtain antioxidant-loaded nanoparticles;
(d) Re-suspending the antioxidant-loaded nanoparticles with deionized water to obtain suspension;
(e) Adding hematopoietic accelerator solution into the suspension, mixing, adding dropwise into carrier dichloromethane solution under ultrasonic or high-speed stirring to obtain suspension loaded with antioxidant and hematopoietic accelerator;
(f) Under the condition of ultrasonic or high-speed stirring, dropwise adding the suspension of the antioxidant and the hematopoiesis promoter into the PVA aqueous solution for continuous treatment to obtain the nanoparticle carrying the antioxidant and the hematopoiesis promoter together.
Preferably, in the step (a), the solvent is selected from at least one of acetone, chloroform, dichloromethane and ethanol.
Preferably, in the step (b), the dropping temperature is 0-8 ℃, and the dropping mode is dropwise adding; the volume ratio of the mixed solution to the PVA water solution is 1:10-50; the concentration of PVA aqueous solution is 2.5-7.5 mg/mL.
Preferably, in the step (d), the concentration of the antioxidant-loaded nanoparticles in the suspension is 10-30 mg/mL.
Preferably, in the step (e), the volume ratio of the suspension to the hematopoiesis promoter solution is 1: (0.1-0.5); the concentration of the hematopoiesis promoter solution is 0.5-2 mg/mL; the volume ratio of the suspension added with the hematopoietic accelerator solution to the dichloromethane solution of the carrier is 1:2-6; the concentration of the carrier in the dichloromethane solution of the carrier is 20-70 mg/mL.
Preferably, in the step (f), the volume ratio of the suspension of the antioxidant and the hematopoiesis promoter to the PVA aqueous solution is 1 (15-25); the concentration of the PVA aqueous solution is 0.2 to 0.5 percent; the continuous treatment time is 2-10 min.
Preferably, the preparation method further comprises a preparation process of the nanoparticles for encapsulating the antioxidant and the nanoparticles for encapsulating the hematopoietic accelerator, wherein the preparation process is performed under a light-shielding condition and specifically comprises the following steps:
(1) Dissolving antioxidant/hematopoiesis promoter and carrier in solvent to obtain mixed solution;
(2) Under the ultrasonic condition, dropwise adding the mixed solution into PVA water solution for continuing ultrasonic treatment to obtain mixed solution;
(3) Volatilizing and removing the solvent in the mixed solution, centrifuging and collecting the precipitate, washing with water, and freeze-drying to obtain the nanometer granule loaded with antioxidant/hematopoiesis promoter.
Preferably, in the step (1), the solvent is selected from at least one of acetone, chloroform, dichloromethane and ethanol.
Preferably, in the step (2), the dropping temperature is 0-8 ℃, and the dropping mode is dropwise adding; the volume ratio of the mixed solution to the PVA water solution is 1:10-50; the concentration of PVA aqueous solution is 2.5-7.5 mg/mL.
Compared with the prior art, the application has the beneficial effects that at least:
the hematopoietic accelerator is used for promoting hematopoietic recovery and increasing neutrophil generation and reducing risk of infection after ARS in the application; the antioxidant is used for improving the hematopoietic microenvironment of HSC, and the combination of the antioxidant and the antioxidant can better accelerate the hematopoietic process of bone marrow and promote the repair of acute radiation injury.
The nano particles are prepared by entrapment of the antioxidant and/or the hematopoietic accelerator in the medicament, so that the in vivo half-life of the antioxidant and the hematopoietic accelerator can be effectively prolonged, the programmed controlled release of the antioxidant and the hematopoietic accelerator is realized, the medicament activity is increased, and the toxicity of the medicament is reduced or avoided; the medicine can better promote bone marrow hematopoiesis and quick and effective reconstruction of peripheral blood, and promote the repair of intestinal tissues; the medicine has the characteristics of good biodegradability and biocompatibility, and protection of medicine activity and medicine slow release.
The preparation method of the co-carried/single-carried nano-particles of the antioxidant and/or the hematopoietic accelerator is simple and quick; in addition, the nanoparticle prepared by the preparation method has uniform and stable particle size and is easy to store.
Drawings
In order to more clearly illustrate the embodiments of the present application 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. Like elements or portions are generally identified by like reference numerals throughout the several figures. In the drawings, elements or portions thereof are not necessarily drawn to scale.
FIG. 1 is an electron microscopic view of nanoparticles of the present application carrying antioxidants and hematopoiesis promoting agents together, prepared in example 1;
FIG. 2 is an electron microscopic view of nanoparticles of the present application carrying an antioxidant and a hematopoietic accelerator together, prepared in comparative example 1;
FIG. 3 shows cell viability of NIH3T3 after co-culture with different concentrations of PRG, PLGA, RES, human recombinant G-CSF (rhG-CSF), respectively;
FIG. 4 shows the intracellular hydrogen peroxide content of RAW246.7 cells incubated with PRG and RES at different concentrations, respectively;
FIG. 5 shows the cell proliferation rate of NFS-60 cells after co-culture with rhG-CSF or PRG;
FIG. 6 is a graph showing peripheral blood reconstitution after treatment with ARS mouse model;
FIG. 7 shows the hematopoietic reconstitution of bone marrow after treatment with ARS mouse model;
FIG. 8 shows the repair of intestinal lesions after treatment in the ARS mouse model.
Detailed Description
Embodiments of the technical scheme of the present application will be described in detail below with reference to the embodiments. The following examples are only for more clearly illustrating the technical aspects of the present application, and thus are merely examples, and are not intended to limit the scope of the present application.
It is noted that unless otherwise indicated, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this application belongs.
Example 1
1. Medicine for treating acute radiation injury
The above-mentioned drugs for treating acute radiation injury include: nanoparticles encapsulating antioxidants and hematopoiesis promoters;
the carrier used for encapsulation is PLGA; the antioxidant is resveratrol; the hematopoiesis promoter is rhG-CSF;
the mass ratio of the carrier, the antioxidant and the hematopoiesis promoter is 5:1:1.5.
2. Preparation method
The preparation method of the nanoparticle coated with the antioxidant and the hematopoiesis promoter comprises the following steps of:
(a) Dissolving a carrier and an antioxidant in an acetone solution to obtain a mixed solution, wherein the mass ratio of the carrier to the antioxidant is 4:1;
(b) Under the ultrasonic condition, dropwise adding the mixed solution into PVA water solution, and continuing ultrasonic treatment for 5min to obtain mixed solution, wherein the dropwise adding temperature is 4 ℃, and the dropwise adding mode is dropwise adding; the volume ratio of the mixed solution to the PVA water solution is 1:20; the concentration of the PVA aqueous solution is 4mg/mL;
(c) Magnetically stirring the mixed solution in a fume hood overnight, volatilizing to remove acetone in the mixed solution, centrifuging at 20000rpm for 12min, collecting precipitate, and washing with water for 3 times to obtain antioxidant-loaded nanoparticles;
(d) Re-suspending the antioxidant-loaded nanoparticles with deionized water to obtain a suspension with the concentration of 20mg/mL;
(e) Adding 1mg/mL of hematopoiesis promoter solution into the suspension according to the volume ratio of 1:0.2, uniformly mixing, and dropwise adding into dichloromethane solution of a carrier under the condition of high-speed stirring to obtain suspension loaded with an antioxidant and hematopoiesis promoter, wherein the mass ratio of the carrier to the hematopoiesis promoter to the antioxidant is 1:1.5:1; the volume ratio of the suspension added with the hematopoiesis promoter solution to the dichloromethane solution of the carrier is 1:4; the concentration of the carrier in the dichloromethane solution of the carrier is 50mg/mL;
(f) Under the condition of high-speed stirring, dropwise adding the suspension of the antioxidant and the hematopoiesis promoter into 0.5% PVA water solution according to the volume ratio of 1:20, and continuously treating for 5min to obtain the antioxidant and hematopoiesis promoter carried nanoparticle.
Example 2
1. Medicine for treating acute radiation injury
The above-mentioned drugs for treating acute radiation injury include: nanoparticles encapsulating antioxidants and hematopoiesis promoters;
the carrier used for encapsulation is PLGA; the antioxidant is resveratrol; the hematopoiesis promoter is rhG-CSF;
the mass ratio of the carrier, the antioxidant and the hematopoiesis promoter is 10:0.8:2.
2. Preparation method
The preparation method of the nanoparticle coated with the antioxidant and the hematopoiesis promoter comprises the following steps of:
(a) Dissolving a carrier and an antioxidant in an acetone solution to obtain a mixed solution, wherein the mass ratio of the carrier to the antioxidant is 5:0.8;
(b) Under the ultrasonic condition, dropwise adding the mixed solution into PVA water solution, and continuing ultrasonic treatment for 1min to obtain mixed solution, wherein the dropwise adding temperature is 2 ℃, and the dropwise adding mode is dropwise adding; the volume ratio of the mixed solution to the PVA water solution is 1:10; the concentration of PVA aqueous solution was 7.5mg/mL;
(c) Magnetically stirring the mixed solution in a fume hood overnight, volatilizing to remove acetone in the mixed solution, centrifuging at 3000rpm for 50min, collecting precipitate, and washing with water for 3 times to obtain antioxidant-loaded nanoparticles;
(d) Re-suspending the antioxidant-loaded nanoparticles with deionized water to obtain a suspension with the concentration of 30 mg/mL;
(e) Adding 2mg/mL of hematopoiesis promoter solution into the suspension according to the volume ratio of 1:0.5, uniformly mixing, dropwise adding into dichloromethane solution of a carrier under ultrasonic conditions to obtain suspension loaded with an antioxidant and hematopoiesis promoter, wherein the mass ratio of the carrier to the hematopoiesis promoter to the antioxidant is 5:2:0.8; the volume ratio of the suspension added with the hematopoiesis promoter solution to the dichloromethane solution of the carrier is 1:6; the concentration of the carrier in the dichloromethane solution of the carrier is 70mg/mL;
(f) Under the ultrasonic condition, dropwise adding the suspension of the antioxidant and the hematopoiesis promoter into 0.2% PVA water solution according to the volume ratio of 1:15, and continuously treating for 10min to obtain the antioxidant and hematopoiesis promoter carried nanoparticle.
Example 3
1. Medicine for treating acute radiation injury
The above-mentioned drugs for treating acute radiation injury include: nanoparticles encapsulating antioxidants and hematopoiesis promoters;
the carrier used for encapsulation is PLGA; the antioxidant is resveratrol; the hematopoiesis promoter is rhG-CSF;
the mass ratio of the carrier, the antioxidant and the hematopoiesis promoter is 2:1.2:0.5.
2. Preparation method
The preparation method of the nanoparticle coated with the antioxidant and the hematopoiesis promoter comprises the following steps of:
(a) Dissolving a carrier and an antioxidant in an acetone solution to obtain a mixed solution, wherein the mass ratio of the carrier to the antioxidant is 1:1.2;
(b) Under the ultrasonic condition, dropwise adding the mixed solution into PVA water solution, and continuing ultrasonic treatment for 50min to obtain mixed solution, wherein the dropwise adding temperature is 6 ℃, and the dropwise adding mode is dropwise adding; the volume ratio of the mixed solution to the PVA water solution is 1:50; the concentration of PVA aqueous solution was 2.5mg/mL;
(c) Magnetically stirring the mixed solution in a fume hood overnight, volatilizing to remove acetone in the mixed solution, centrifuging at 30000rpm for 5min, collecting precipitate, and washing with water for 3 times to obtain antioxidant-loaded nanoparticles;
(d) Re-suspending the antioxidant-loaded nanoparticles with deionized water to obtain suspension with the concentration of 10 mg/mL;
(e) Adding 0.5mg/mL hematopoiesis promoter solution into the suspension according to the volume ratio of 1:0.1, uniformly mixing, and dropwise adding into dichloromethane solution of a carrier under the condition of high-speed stirring to obtain suspension loaded with an antioxidant and hematopoiesis promoter, wherein the mass ratio of the carrier to the hematopoiesis promoter to the antioxidant is 1:0.5:1.2; the volume ratio of the suspension added with the hematopoiesis promoter solution to the dichloromethane solution of the carrier is 1:2; the concentration of the carrier in the dichloromethane solution of the carrier is 20mg/mL;
(f) Dropwise adding the suspension of the antioxidant and the hematopoiesis promoter into 0.5% PVA water solution according to the volume ratio of 1:25 under the condition of high-speed stirring, and continuously treating for 2min to obtain the nanoparticles carrying the antioxidant and the hematopoiesis promoter together.
Example 4
1. Medicine for treating acute radiation injury
The above-mentioned drugs for treating acute radiation injury include: the nanometer particles are coated with antioxidant and hematopoietic accelerator;
the carrier used for encapsulation is PLGA; the antioxidant is resveratrol; the hematopoiesis promoter is rhG-CSF;
the mass ratio of the carrier, the antioxidant and the hematopoiesis promoter is 5:1:1.5.
2. Preparation method
The preparation method of the antioxidant-entrapped nanoparticles and hematopoiesis promoter-entrapped nanoparticles comprises the following steps of:
(1) Dissolving an antioxidant/hematopoiesis promoter and a carrier in an acetone solution to obtain a mixed solution, wherein the mass ratio of the carrier to the antioxidant is 5:1; the mass ratio of the carrier to the hematopoietic accelerator is 5:1.5;
(2) Under the ultrasonic condition, dropwise adding the mixed solution into PVA water solution, and continuing ultrasonic treatment for 5min to obtain mixed solution, wherein the dropwise adding temperature is 4 ℃, and the dropwise adding mode is dropwise adding; the volume ratio of the mixed solution to the PVA water solution is 1:30; the concentration of the PVA aqueous solution is 5mg/mL;
(3) Magnetically stirring the mixed solution in a fume hood overnight, volatilizing to remove acetone in the mixed solution, centrifuging at 20000rpm for 10min, collecting precipitate, washing with water for 3 times, and freeze-drying to obtain nanometer granule loaded with antioxidant/hematopoiesis promoter.
Comparative example 1
The present comparative example is a method for preparing the above nanoparticle coated with the antioxidant and hematopoietic promoter, which is substantially the same as that of example 1 except that in step (a), the mass ratio of the carrier to the antioxidant is 1:1.
Experimental example
1. Nanoparticles carrying an antioxidant and a hematopoietic accelerator were obtained in accordance with the preparation methods in example 1 and comparative example 1;
scanning the nanoparticles prepared in the above example 1 and comparative example 1 by electron microscopy, wherein the scanning result of the nanoparticles in the example 1 is shown in fig. 1, and the scanning result of the nanoparticles in the comparative example 1 is shown in fig. 2;
as can be seen from fig. 1 and 2, the nanoparticle prepared by the embodiment of the application has uniform particle size, particle size of 150-200 nm and stable structure; however, the nanoparticles prepared in comparative example 1 were unable to form nanoparticles, which were crosslinked and unstable in structure.
2. PLGA, RES, rhG-CSF and biotoxicity study of nanoparticles (denoted PRG) prepared in example 1:
PRG, PLGA, RES, rhG-CSF was formulated as 12.5, 25, 50, 100, 200. Mu.g/ml solutions, respectively; then, respectively co-culturing NIH3T3 with the above solutions for 48h, and respectively detecting the activity of NIH3T3, wherein the detection result is shown in figure 3;
as can be seen from FIG. 3, the PRG prepared by the embodiment of the application has lower biotoxicity and can effectively reduce the biotoxicity of RES.
3. Study of in vitro antioxidant function of the RES and nanoparticles (denoted PRG) prepared in example 1:
PRG and RES are respectively prepared into 12.5, 25, 50 and 100 mug/mL solutions;
incubating RAW246.7 cells with RES or PRG and LPS (the concentration is 10 ng/mL), and detecting the content of hydrogen peroxide in the cells by taking DCFH-DA as a ROS fluorescent probe; the detection result is shown in fig. 4;
as can be seen from fig. 4, the PRG prepared in the embodiment of the present application has more excellent oxidation resistance.
4. Study of in vitro Activity of rhG-CSF and nanoparticles (denoted PRG) prepared in example 1:
PRG and rhG-CSF were formulated as solutions of 3.125, 6.25, 12.5, 25, 50, 100 μg/mL, respectively;
co-culturing NFS-60 cells with rhG-CSF or PRG for 24h; the proliferation rate of NFS-60 was examined, and the examination results are shown in FIG. 5;
as can be seen from FIG. 5, the PRG prepared by the embodiment of the application has higher activity and can obviously improve the proliferation rate of NFS-60.
5. Study of nanoparticles (denoted as PRG) prepared in example 1 on acute radiation injury model mice peripheral blood reconstruction and tissue injury repair:
(1) construction of sub-lethal dose irradiation ARS mouse model
C57BL/6 mice, once irradiated with 6Gy throughout the body, were then randomly assigned to irradiation groups (n=10); and (3) grouping design: control group (non-irradiated+normal saline), 6Gy irradiation+normal saline group, 6Gy irradiation+res group, 6Gy irradiation+rhg-CSF group, 6Gy irradiation+plga nanoparticle group, 6Gy irradiation+prg nanoparticle group. After the irradiation of the group, the PRG was administered subcutaneously in an amount of 100. Mu.L/dose, containing 15mg of PRG. RES and rhG-CSF were administered daily at 100 μl/dose containing 15mg of RES or rhG-CSF, the remaining groups were administered 1 dose every three days, and body weights were recorded every two days;
(2) peripheral blood cell detection
Treatment with post-irradiation dosing was stopped at 14d, 100 μl of blood was collected from the orbital venous plexus, and the peripheral blood cell change was detected, and the detection results are shown in fig. 6;
as can be seen from figure 6 of the drawings,
the PRG prepared by the embodiment of the application can obviously promote the recovery of RBC, WBC and PLT in peripheral blood.
(3) Tissue HE staining
At 14d, the mice were sacrificed by cervical removal and the tibia of the mice was placed in a petri dish containing 10mL PBS in a sterile environment; the small intestine of the mice was then fixed in 4% formaldehyde solution.
HE staining experiments were performed on the tibial and small intestine tissues fixed in step 3.3.3. The method comprises the following specific steps:
1. dehydrating: the fixed tissues are cleaned and sequentially immersed in five alcohols of 70%, 75%, 80%, 90%, 95% and 100% for gradient dehydration.
2. And (3) transparency: the tissue was placed in xylene for transparency.
3. Wax dipping and embedding: placing the tissue subjected to the transparent treatment into liquid after paraffin melting, placing the liquid into a paraffin melting box for heat preservation, and embedding the tissue by an embedding machine after the paraffin liquid is immersed into the tissue.
4. Slicing: the embedded wax block was fixed on a microtome and cut into fixed sheets with a thickness of about 5 μm.
5. Baking slices: the sections were placed on glass slides and placed in a drying oven for baking treatment at 60 ℃.
6. Dewaxing and hydration: the slices were immersed once in the following solutions, in order of 5min for xylene (I), 5min for xylene (II), 5min for xylene (III), 2min for 100% ethanol, 1min for 95% ethanol, 1min for 80% ethanol, and 1min for 75% ethanol.
7. Flushing: the slices were rinsed in distilled water for 2min.
8. Hematoxylin staining: the sections are placed in hematoxylin for dyeing treatment for 5min, then washed by running water for 3-5s, and then subjected to color separation treatment by 1% hydrochloric acid alcohol for 3-5s.
10. The slices are rinsed in distilled water for 5-10min.
11. Eosin staining: the sections were placed in eosin solution and stained for 2min.
12. The slices were placed in distilled water and rinsed rapidly for 3-5s.
13. Dehydrating, transparentizing and sealing: the slices are sequentially put into 95% ethanol for 1min, 100% ethanol (I) for 1min, 100% ethanol (II) for 1min, xylene (I) for 1min, xylene (II) for 1min and xylene (III) for 1min.
14. The sections were sealed with neutral resin and microscopic photographed to assess the tissue structure status.
Note that: bone marrow was decalcified in PBS before dehydration, gently shaken with 10% EDTA at room temperature for 72h, and the rest of the procedure was identical to that of the other tissues.
The results of the bone marrow hematopoietic reconstitution of the ARS model mice are shown in fig. 7, and the results of the intestinal injury repair are shown in fig. 8;
from fig. 7 and 8, it can be seen that the PRG prepared by the embodiment of the present application not only can significantly promote hematopoietic reconstruction of bone marrow, but also can promote recovery of intestinal mucosa.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present application, and not for limiting the same; although the application has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the application, and are intended to be included within the scope of the appended claims and description.
Claims (3)
1. The application of an antioxidant combined with a hematopoiesis promoter in preparing a medicament for treating acute radiation injury, wherein the antioxidant is resveratrol; the hematopoietic promoter is a human natural or recombinant granulocyte stimulating factor;
the medicament comprises nanoparticles encapsulating the antioxidant and hematopoietic promoter;
the carrier used for entrapment is at least one selected from PLGA, PLA, PCL, PGA, PLGA-PEG, PLA-PEG, PCL-PEG, PLGA/PLA and PLGA/PCL/PLA/PCL;
the mass ratio of the carrier to the antioxidant to the hematopoietic accelerator is (2-80) to (0.8-1.2) to (0.5-2);
the preparation method of the medicine comprises a preparation process of nanoparticles which encapsulate the antioxidant and the hematopoiesis promoter, wherein the preparation process of the nanoparticles is carried out under a light-shielding condition, and specifically comprises the following steps:
(a) Dissolving a carrier and an antioxidant in a solvent to obtain a mixed solution;
(b) Under the ultrasonic condition, dropwise adding the mixed solution into PVA water solution for continuing ultrasonic treatment to obtain mixed solution;
(c) Volatilizing and removing the solvent in the mixed solution, centrifuging and collecting the precipitate, and washing with water to obtain antioxidant-loaded nanoparticles;
(d) Re-suspending the antioxidant-loaded nanoparticles with deionized water to obtain suspension;
(e) Adding hematopoietic accelerator solution into the suspension, mixing, adding dropwise into carrier dichloromethane solution under ultrasonic or high-speed stirring to obtain suspension loaded with antioxidant and hematopoietic accelerator;
(f) Under the condition of ultrasonic or high-speed stirring, dropwise adding the suspension of the antioxidant and the hematopoiesis promoter into the PVA aqueous solution for continuous treatment to obtain the nanoparticle carrying the antioxidant and the hematopoiesis promoter together.
2. A medicament for treating acute radiation injury comprising nanoparticles encapsulating the antioxidant and hematopoietic promoter of claim 1; the carrier used for entrapment is at least one selected from PLGA, PLA, PCL, PGA, PLGA-PEG, PLA-PEG, PCL-PEG, PLGA/PLA and PLGA/PCL/PLA/PCL;
the mass ratio of the carrier to the antioxidant to the hematopoietic accelerator is (2-80) to (0.8-1.2) to (0.5-2);
the preparation method of the medicine for treating acute radiation injury comprises a preparation process of nanoparticles which encapsulate the antioxidant and the hematopoiesis promoter, wherein the preparation process is carried out under a light-shielding condition and specifically comprises the following steps:
(a) Dissolving a carrier and an antioxidant in a solvent to obtain a mixed solution;
(b) Under the ultrasonic condition, dropwise adding the mixed solution into PVA water solution for continuing ultrasonic treatment to obtain mixed solution;
(c) Volatilizing and removing the solvent in the mixed solution, centrifuging and collecting the precipitate, and washing with water to obtain antioxidant-loaded nanoparticles;
(d) Re-suspending the antioxidant-loaded nanoparticles with deionized water to obtain suspension;
(e) Adding hematopoietic accelerator solution into the suspension, mixing, adding dropwise into carrier dichloromethane solution under ultrasonic or high-speed stirring to obtain suspension loaded with antioxidant and hematopoietic accelerator;
(f) Under the condition of ultrasonic or high-speed stirring, dropwise adding the suspension of the antioxidant and the hematopoiesis promoter into the PVA aqueous solution for continuous treatment to obtain the nanoparticle carrying the antioxidant and the hematopoiesis promoter together.
3. The medicament for treating acute radiation injury according to claim 2, wherein in step (a), the solvent is selected from at least one of acetone, chloroform, dichloromethane and ethanol;
in the step (b), the dripping temperature is 0-8 ℃, and the dripping mode is dropwise dripping; the volume ratio of the mixed solution to the PVA water solution is 1:10-50; the concentration of PVA aqueous solution is 2.5-7.5 mg/mL.
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