CN115400211B - Black phosphorus nanoparticle tablet and preparation method and application thereof - Google Patents
Black phosphorus nanoparticle tablet and preparation method and application thereof Download PDFInfo
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- CN115400211B CN115400211B CN202110892079.3A CN202110892079A CN115400211B CN 115400211 B CN115400211 B CN 115400211B CN 202110892079 A CN202110892079 A CN 202110892079A CN 115400211 B CN115400211 B CN 115400211B
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title claims abstract description 70
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- FCBUKWWQSZQDDI-UHFFFAOYSA-N rhamnolipid Chemical compound CCCCCCCC(CC(O)=O)OC(=O)CC(CCCCCCC)OC1OC(C)C(O)C(O)C1OC1C(O)C(O)C(O)C(C)O1 FCBUKWWQSZQDDI-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000002135 nanosheet Substances 0.000 claims abstract description 32
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- 238000000034 method Methods 0.000 claims abstract description 23
- 239000000203 mixture Substances 0.000 claims abstract description 17
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- 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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The preparation method and application of the black phosphorus nano particle tablet comprise the steps of immersing Black Phosphorus (BP) in N, N' -Dimethylformamide (DMF) solution, and centrifuging after ultrasonic treatment to prepare the black phosphorus nano tablet; mixing the mother solution of the isowu-bane (ISL) with black phosphorus nanosheets, dissolving by ultrasonic, adding Rhamnolipid (RHL) into the mixture, fully and uniformly mixing by ultrasonic, and dripping phosphate buffer with pH of 7.4 by adopting a nano precipitation method for assembly; dialyzing in phosphate buffer solution by using a dialysis bag after the assembly is finished until the phosphate buffer solution is clear and transparent; and finally, drying the obtained sample by using a vacuum freeze dryer to obtain the black phosphorus nanoparticle sheet. The invention successfully prepares the black phosphorus nano-sheet for resisting helicobacter pylori by using ISL, and the nano-composite has the advantages of simple preparation, good particle dispersibility, high stability and better effects of resisting helicobacter pylori and acid response.
Description
Technical Field
The invention belongs to the technical field of helicobacter pylori treatment, and particularly relates to a black phosphorus nanoparticle tablet, and a preparation method and application thereof.
Background
Helicobacter pylori (Helicobacter Pylori, h.pyrri) is a highly prevalent gram-negative bacterium that infects the gastric mucosa of about 50% of the population worldwide. Studies have shown that anti-h.pyri drugs do not readily reach this site due to h.pyri colonization deep in the gastric mucosa, and on the other hand the residence time of the drug in the stomach is too short due to the emptying effect of the stomach itself. Moreover, with the use of various antibiotics, the problem of resistance to H.pyri makes treatment according to standard protocols more difficult. For example, standard first-line triple therapies, including proton pump inhibitors and two antibiotics, typically clarithromycin and amoxicillin or metronidazole, have reduced efficacy to nearly 70% below the original 80% target. Combining the above factors, how to overcome the problem of drug resistance and allow the drug to stay in the stomach for a long time to reach an effective therapeutic concentration, thereby increasing the probability of entering deep into the gastric mucosa, is now the direction of research on treatment of h. Thus, the properties of nanomedicines, due to their high drug loading, biocompatibility, and responsive release, have made them a prime in the treatment of h.pyri infections.
Oral administration remains the primary means of treating h.pyri infection, but the mucosal barrier and the large amount of mucus at the gastric mucosal surface, while protecting the exposed epithelial surface by removal of pathogens and foreign particles, also constitutes a major obstacle in the process of nano-drug absorption; on the other hand, the acidic environment of mucus formation also severely affects the performance of oral antibacterial agents. Thus, oral drugs do not achieve the desired effect due to their poor ability to penetrate the mucosa and cross the epithelial absorption barrier, as well as intolerance to the acid environment. The project is to design a novel nano-composite with excellent mucus penetrating ability, cell membrane penetrating ability and acid response function so as to promote the absorption of oral medicines and enhance the resistance to H.pyri infection.
Disclosure of Invention
The technical problems to be solved are as follows: aiming at the technical problems, the invention provides a black phosphorus nanoparticle tablet, and a preparation method and application thereof. The preparation of the Black Phosphorus (BP) nanoparticle tablet self-assembled by the Isowustite (ISL) and the Rhamnolipid (RHL) is a brand-new preparation process, and has the advantages of simple flow, simple operation and higher yield; the nanoparticle sheet prepared by the process has specific inhibition effect on H.pyri, excellent mucus and cell membrane penetrating capacity, acid response and photo-thermal conversion capacity.
The technical scheme is as follows: the preparation method of the black phosphorus nano particle sheet comprises the steps of immersing Black Phosphorus (BP) in N, N' -Dimethylformamide (DMF) solution, and centrifuging after ultrasonic treatment to prepare the black phosphorus nano sheet; mixing the mother liquor of the isowu-bane (ISL) with black phosphorus nano-sheets, ultrasonically dissolving, adding Rhamnolipid (RHL) into the mixture, fully and uniformly mixing by ultrasonic, and dripping pH 7.4 by adopting a nano-precipitation method for assembly; dialyzing in phosphate buffer solution by using a dialysis bag after the assembly is finished until the phosphate buffer solution is clear and transparent; and finally, drying the obtained sample by using a vacuum freeze dryer to obtain the black phosphorus nanoparticle sheet.
The specific preparation steps of the black phosphorus nano-sheet are as follows: taking 500mg of blocky BP, immersing the blocky BP in DMF (N, N' -dimethylformamide), carrying out ultrasonic treatment for 2 hours by a 300w ice bath probe, centrifuging at 6000rpm for 4 minutes, taking supernatant, centrifuging at 12000rpm for 4 minutes, taking precipitate, and re-suspending the supernatant in DMF to prepare 1mg/mL BP nano-sheet heavy suspension for later use.
The specific method for assembling comprises the following steps: a1 mg/mL stock solution of ISL in DMF was prepared, 100. Mu.g of BP nanoplatelets were mixed with 50. Mu.g of ISL and dissolved in 100. Mu.L of DMF, after 5min of sonication of the mixture solution, 1mg of RHL was dissolved in the above mixture, after 5min of sonication, 900. Mu.L of pH 7.4 solution was added dropwise to the mixture, after assembly, followed by dialysis in pH 7.4 phosphate buffer for 4h to remove organic solvent and unencapsulated ISL.
The black phosphorus nanoparticle tablet prepared by the method.
The application of the black phosphorus nanoparticle tablet in preparing medicines for treating helicobacter pylori.
The active ingredients of the medicine for treating helicobacter pylori are the black phosphorus nano-particle tablet.
The beneficial effects are that: the invention successfully prepares the black phosphorus nano-sheet containing the isowustide and the rhamnose for resisting H.pyrori, and the nano-composite has the advantages of simple preparation, good particle dispersibility, high stability and better effects of resisting helicobacter pylori and acid response.
Drawings
FIG. 1 is a schematic representation of synthesis and characterization of RHL@BP/ISL nanoplatelets, wherein BP@ISL (A), RHL (B) and RHL@BP/ISL (C) hydrodynamic particle size distribution and transmission electron microscopy images; zeta potential (D) of BP@ISL, RHL and RHL@BP/ISL nanocomposites;
FIG. 2 is a graph showing the photo-thermal conversion capability of RHL@BP/ISL nanosheets and release rates of ISL drugs under different acidic conditions, wherein (A) the RHL@BP/ISL nanosheets are subjected to infrared thermal imaging under 808nm near infrared laser irradiation for 10 min; (B) ISL in vitro release study: cumulative release profile for Rhl@BP/ISL nanoplatelets at different pH (pH 7.4 and pH 3.0) under 808nm laser irradiation. Data are expressed as mean ± standard deviation (n=3);
FIG. 3 is an in vitro antimicrobial capability of Rhl@BP/ISL nanoplatelets;
FIG. 4 is a schematic representation of the distribution and metabolism of the nanocomposite in vivo;
FIG. 5 is a schematic diagram of an in vivo photothermal conversion experiment of the nanocomposite, wherein an infrared thermal image (A), a BP@ISL photothermal curve (B) and an RHL@BP/ISL photothermal curve (C) of the RHL@BP/ISL nanocomposite in an animal model body are irradiated by 808nm laser for 10 min;
FIG. 6 is a schematic illustration of the in vivo antibacterial effect of Rhl@BP/ISL nanoplatelets;
FIG. 7 Rhl@BP/ISL nanoplatelets for in vivo antibacterial effect;
FIG. 8H & E and TUNEL staining to detect the repair of Rhl@BP/ISL nanoplatelets to gastric mucosa in vivo;
FIG. 9 immunofluorescence staining to detect recovery of inflammatory factors in vivo by Rhl@BP/ISL nanoplatelets;
FIG. 10 Rhl@BP/ISL nanoplatelet cytotoxicity assay.
Detailed Description
Example 1
Materials and methods
1. The Black Phosphorus (BP) nanosheet treatment method comprises the following steps: taking 500mg of blocky BP, immersing the blocky BP in DMF (N, N' -dimethylformamide), carrying out ultrasonic treatment for 2 hours by a 300w ice bath probe, centrifuging at 6000rpm for 4 minutes, taking supernatant, centrifuging at 12000rpm for 4 minutes, taking precipitate, and re-suspending the supernatant in DMF to prepare 1mg/mL BP nano-sheet heavy suspension for later use.
An assembly method of Rhl@BP/ISL comprises the following steps: the nano precipitation method is adopted, specifically, a DMF mother solution of ISL of 1mg/mL is prepared, 100 mug BP nano-sheet is mixed with 50 mug ISL and dissolved by 100 mug DMF, after the mixture solution is fully mixed by ultrasonic for 5min, 1mg RHL is dissolved in the mixture, after ultrasonic for 5min, 900 mug of pH 7.4 phosphate buffer solution is slowly dripped into the mixture, after assembly is completed, the particle size and the potential are measured, then dialysis is carried out for 4h in pH 7.4 phosphate buffer solution to remove organic solvent and unencapsulated ISL, and then the particle size and the potential are measured.
3. The drug loading testing method comprises the following steps: taking 100 mu L of the assembled RHL@BP/ISL mixed solution after dialysis, adding 100 mu L of chromatographic acetonitrile, performing ultrasonic treatment for 10min to enable the nano mixture to be fully dissolved to release ISL in a hydrophobic core, and detecting the ISL content by HPLC (high performance liquid chromatography) loading, wherein the HPLC method comprises the following steps: mobile phase: methanol: acetonitrile: water = 30:30:40, isocratic elution, column temperature: 40 ℃, flow rate: 1mL/min, detection wavelength: 235nm, elution time: 15min.
4. Particle size and Zeta potential: the BP nanosheet resuspension, RHL and RHL@BP/ISL nanocomposite are respectively added into a sample cell, placed into a Zetasizer Nano ZS laser particle sizer, the particle size is measured by using a Dynamic Light Scattering (DLS) method, and the zeta potential is measured by using an Electrophoretic Light Scattering (ELS) method.
5. Transmission electron microscopy examination: dispersing a proper amount of BP, RHL and RHL@BP/ISL nano-composite in deionized water, sucking 10 mu L of sample solution, dripping the sample solution on a carbon-coated copper wire mesh, and baking the sample solution under an infrared lamp. The sample is observed under a transmission electron microscope, and the accelerating voltage is 80kV.
Investigation of the photo-thermal conversion Capacity of Rhl@BP/ISL nanocomposite: to examine the photo-thermal conversion ability of the black phosphorus nanocomposite, 0.5mL of RHL@BP/ISL solution was prepared by using PBS as a control group and placed in an EP tube, and the EP tube was irradiated with 808nm near infrared laser emitter (1.0W/cm) 2 Irradiation for 10 minutes), the light source was set at the same distance from the EP tube and the light spot was set to cover the entire area of the dispersion liquid when each sample was irradiated. The temperature change of the dispersion during irradiation was recorded with a digital multimeter and the probe was placed in the center of the dispersion and not in contact with the EP tube. During irradiation, EP tube thermal radiation images were recorded with a thermal imager.
Investigation of release efficiency of ISL from Rhl@BP/ISL nanocomposite: to better simulate the actual environment of ISL release from Rhl@BP/ISL nanocomposite, experiments examined conditions of pH 7.4 (physiological environment), pH3.0 (gastric acidic environment)Release efficiency of ISL from rhl@bp/ISL nanocomposite after 808nm laser irradiation. Precisely weighing RHL@BP/ISL nano-composite, dispersing in 10mL deionized water with different pH values, and slowly shaking in a water bath at 37 ℃. Samples were prepared in multiple portions at 0, 2, 4, 6, 8, 10 and 12 hours, respectively, and removed from the water bath, centrifuged at 12000, g for 30 minutes, and the supernatant analyzed for ISL release by HPLC. For the illumination group, 808nm laser (1.0W/cm 2 Irradiated for 10 minutes) or 650nm laser (0.5W/cm 2 Irradiation for 10 minutes) was performed once at 0 hour.
Liquid chromatography conditions:
chromatographic column: c18, 4.6X105 mm,3.5 μm.
Mobile phase: a is deionized water to which 0.01% phosphoric acid was added, and B is acetonitrile to which 0.01% phosphoric acid was added. The mobile phase was gradually changed from 5% content B to 95% content B with a gradient time of 1.3 minutes.
Flow rate: 1.8mL/min
Column temperature: 45 DEG C
After detection, LY release was calculated from the standard curve and plotted against time to give an integrated release profile of ISL release from RHL@BP/ISL nanocomposite.
8. Strains: standard strains 26695, G27, bi Hongkai laboratory donation from university of south Beijing medical science, HYQ002 and HYQ003 (metronidazole, clarithromycin, levofloxacin resistance) were isolated from the clinic at the center of research for the control of drug-resistant microbial infections at the national medical college of dextrorotation.
9. Culture medium and main reagents: columbia medium, brain heart infusion medium, selective antibiotics (vancomycin, polymyxin B, trimethoprim), serum, omeprazole, amoxicillin, clarithromycin, gram stain, bacterial genomic DNA extraction kit, helicobacter pylori 16S rRNA specific primer.
10. Detection of inhibitory concentration of drug against H.pyri (100. Mu.L System) in different pH conditions
(1) Preparation of the medicine: RHL@BP/ISL, RHL@BP, RHL@ISL, RHL, ISL 0.1mg/mL are provided.
(2) MIC plate preparation: 90. Mu.L of medium having pH3.0, pH4.5, pH6.0 and pH7.0 was added to the 96-well plate.
(3) Preparing bacterial liquid: h.pyri (HYQ 002, 26695, G27, HYQ 003) grown in logarithmic phase on solid plates was prepared as a bacterial suspension in BHI medium to adjust the OD600 to 0.3 (1X 10) 8 CFU/mL), 10-fold dilution, 1X 10 7 CFU/mL, ready for use.
(4) Inoculating bacterial liquid: mu.L of the culture medium was added to a 96-well plate (to give a final concentration of 1X 10 6 CFU/mL)。
(5) Adding the medicine: the pre-formulated drug was added to give a final drug concentration of 0.125 μg/mL, PBS was used as a negative control. The 96-well plates were placed in a three-air shake incubator.
(6) Taking a fungus coated plate: after the medicine is acted for a certain time (such as 1h, 2h and 4 h), 100 mu L of cultured bacterial liquid is taken from the hole to dilute (10, 100 times and the like), the bacterial liquid is coated on a Columbia agar plate without an antibacterial compound, and the bacterial liquid is placed in a three-gas incubator to be cultured for 3 to 4 days.
(7) And (3) judging results: the number of bacteria grown on the agar plates was counted and each drug was repeated 3 times.
11. In vivo detection of inhibitory effect of RHL@BP/ISL nanocomposite on H.pyrori by constructing animal model
The RHI@BP/ISL nano-composite, ISL traditional Chinese medicine monomer, omeprazole, amoxicillin and clarithromycin are all dissolved and diluted to 10mg/mL. Experimental animals: c57BL/6.
Grouping animals: the experimental group equally divides the infection group (HYQ 003) with successful molding into 5 groups, namely an omeprazole+amoxicillin+clarithromycin group, an omeprazole+RHL@BP/ISL nanocomposite group (28 mg/kg), an omeprazole+RHL@BP/ISL nanocomposite group (7 mg/kg), an RHL@BP/ISL nanocomposite group (28 mg/kg), an RHL@BP/ISL nanocomposite group (7 mg/kg), an RIL@BP/ISL nanocomposite (7 mg/kg) +NIR 10min group and a PBS group, wherein 10 omeprazole+RHI@BP/ISL nanocomposite group; 10 mice not infected with H.pyri were negative controls.
(2) Animal administration: the experimental group is administrated by stomach infusion, the group with omeprazole is administrated with omeprazole firstly, then other medicines are administrated after 30min, and after the medicines are administrated, the groups are fasted and water is forbidden for 4 hours; the weight of the mice is calculated according to the average 20 g/mouse, and the dosage is 138.2mg/kg of omeprazole, 28.5mg/kg of amoxicillin, 14.3mg/kg of clarithromycin and 7mg/kg of RHI@BP/ISL nanocomposite are administered for 1 time per day for 3 times continuously; the negative control group is given PBS solution, and the capacity and the times are the same as those of the PBS solution; rhl@BP/ISL nanocomposite (7 mg/kg) +NIR 10min group mice were irradiated with infrared light for 10min. The administration was carried out 1 time per day for 3 days.
(3) And (3) drug effect detection: mice from the infected group on day 2 after withdrawal were weighed and mean body weight calculated, blood was collected from the eyeballs, sacrificed with a broken neck, gastric tissue was removed, crushed, isolated culture and identification of h.pyri, and the amount of colonization was calculated. Part of stomach tissue was sectioned in paraffin and examined by H & E staining and Tunel staining, and inflammatory factors were examined by immunofluorescence.
12. Drug cytotoxicity detection
The RHL@BP/ISL nano-composite is subjected to preliminary safety evaluation, and the cytotoxicity of the compound is detected by using a CCK-8 method, wherein the method comprises the following steps of:
(1) Preparation of Ges-1 and BGC823 cell suspensions at 1×10 5 。
(2) Inoculated into 96-well plates: 100 μl per well, the same sample was replicated 3 times.
(3) Culturing in an incubator at 37 ℃ for 24 hours.
(4) Adding Rhl@BP/ISL nanocomposite to ensure that the working concentrations are respectively as follows: 20. Mu.g/mL, 15. Mu.g/mL, 10. Mu.g/mL, 5. Mu.g/mL, 0. Mu.g/mL, no-drug-added cell line.
(5) Culturing in an incubator at 37 ℃ for 24 hours.
(6) Add 10. Mu.L CCK8, tap mix and incubate for 4 hours.
(7) Absorbance was measured at 450nm and survival was calculated according to the following formula:
cell viability = [ (As-Ab) ]/[ (Ac-Ab) ] ×100%
Wherein As is drug, CCK-8, cell culture medium pore, ac is drug-free, CCK-8 and cell culture medium pore only, ab is drug-free, cell-free, CCK-8 and cell culture medium pore only. And establishing a survival curve according to the calculated survival rate.
Results
Synthesis and characterization of Rhl@BP/ISL nanoplatelets
The Rhl@BP+ISL nanosheets are prepared by a nano precipitation method. After ultrasonic mixing, dissolving RHL in the mixed solution in a ratio of 1:4, and slowly dropwise adding a phosphate buffer solution with pH of 7.4 into the mixed solution under an ultrasonic condition to obtain RHL@BP+ISL nanosheets. After the preparation was completed, the free ISL was removed by dialysis. Hydrodynamic particle sizes of the prepared BP@ISL, RHL and RHL@BP/ISL nanosheets were determined by a dynamic light scattering method (DLS). The results are shown in FIG. 1: as shown in A-C, BP@ISL particle size was 83.9nm and polydispersity was 0.135. The RHL particle size was 132.1nm, the polydispersity was 0.216, the RHL@BP+ISL particle size was 120.4, similar to RHL, and the polydispersity was 0.152. The results of Transmission Electron Microscopy (TEM) are consistent with the particle size obtained for DLS (FIG. 1-D). Zeta potential results showed that the BP potential was-19.97.+ -. 3.19mV, the BP@ISL potential was-10.23.+ -. 1.46mV, and the Rhl@ BP+ISL potential was-2.63.+ -. 0.86mV. In the preparation process, the oxidation of the BP nano-sheet is enhanced, and the surface negative charge is increased. The RHL coating can reduce the negative surface charge of the BP nanoplatelets.
2. Evaluation of the photothermal conversion ability of RHL@BP/ISL nanosheets and release Rate of ISL drug under different acidic conditions
Under the irradiation of 808nm laser near infrared, light energy is converted into heat energy, and the ambient temperature is increased, which is the basic requirement of BP nanosheet photo-thermal treatment. To study the effect of the photo-thermal conversion capability of the BP nanoplatelets and the functionalization on the photo-thermal conversion capability of the BP nanoplatelets, rhl@BP/ISL nanocomposite was dispersed in deionized water at 806 nm,1.0W/cm 2 The temperature change of the nanocomposite was detected under near infrared light irradiation for 10min. As can be seen from fig. 2-a, the temperature of the nanocomposite increased by 20 ℃ within 10min, which demonstrates the photothermal conversion capability of BP, effectively increasing the ambient temperature without significant temperature differences between samples, indicating that functionalization did not affect the photothermal capability of BP. The release condition of the ISL in the RHL@BP/ISL nano complex under different acidic conditions is studied through in vitro release experiments. At pH3.0, the cumulative release rate of ISL after 10min of near infrared irradiation for 12h was 87.40% + -0.09, which is significantly higher than that of other groups (P<0.001 (fig. 2-B). These results indicate that the near infrared photothermal effect is evidentWhile promoting release of ISL, encapsulation of RHL renders the nanocomposite acid-responsive.
In vitro antibacterial function of Rhl@BP+ISL nanosheets
This study examined inhibition of the sensitive strain 26695, G27 and resistant strain HYQ002, HYQ003 of H.pyri at different pH (3.0, 4.5, 6.0, 7.0) by Rhl@BP/ISL nanoplatelets and components thereof. The results are shown in FIG. 3. Under the condition of pH3.0, after 2 hours of administration, the RHI@BP/ISL nanosheets (0.125 mg/mL) have a bacteriostasis rate of 99.999%, and after 10 minutes of NIR, the bacteriostasis effect is better, and the bacteriostasis effect is obviously better than that of pH4.5, 6.0 and 7.0 (P < 0.001). This result demonstrates that encapsulation of RHL on BP nanoparticles can provide an acid response effect for the drug, and that the photothermal conversion capability of BP can significantly improve the bacteriostatic effect of the drug.
In vivo metabolism condition of Rhl@BP+ISL nanosheets
Cy 5-labeled nanomedicine treats animals by gavage: the distribution and metabolic time of the nanocomposite in vivo was observed using in vivo imaging techniques. As shown in fig. 4, we detected that the nanocomposite was stronger in gastric fluorescence levels at 4 hours post-dose, and weaker elsewhere. The in vivo photo-thermal conversion experiment result shows that RHL@BP+ISL nano-sheets have obvious photo-thermal conversion capability after being orally taken for 4 hours, but the photo-thermal conversion capability of nano-sheet groups without RHL and ISL groups is greatly reduced (figure 5).
In vivo antibacterial effect of Rhl@BP+ISL nanosheets
See the antibacterial schematic diagram (figure 6) for details.
The in vivo treatment effect is that the inhibition effect of the RHL@BP+ISL+NIR group on H.pyrori, the repair effect on gastric mucosa inflammatory tissues and the recovery of inflammatory factors are obviously superior to those of triple treatment groups (omeprazole+amoxicillin+metronidazole) (P < 0.001), and the RHL@BP+ISL+ISL NIR effect is most obvious (P < 0.05) in RHL@BP+ISL+NIR (omeprazole) (figure 7) and the drug resistance of H.pyrori to metronidazole and clarithromycin is overcome, so that the drug can be used as a first-line drug for treating the acute or chronic gastritis caused by H.pyrori infection, as shown in figures 7-9.
Rhl@BP/ISL nanosheet cytotoxicity detection
The RHI@BP/ISL nano-sheet has no obvious cytotoxicity to GES-1 (A) and BGC823 (B) at 20 mug/mL, the survival rate is above 90%, and the RHI@BP/ISL nano-sheet can be used as a first-line drug for treating H.pyri, as shown in figure 10.
The above description is only a preferred embodiment of the present invention, and the scope of the present invention is not limited to the above examples, but all the solutions falling under the concept of the present invention fall within the scope of the present invention. It should be noted that modifications and adaptations to those skilled in the art without departing from the principles of the present invention are intended to be comprehended within the scope of the present invention.
Claims (6)
1. The preparation method of the black phosphorus nano particle sheet is characterized in that firstly, black phosphorus is immersed in N, N' -dimethylformamide DMF solution, and the black phosphorus nano sheet is prepared by centrifugation after ultrasonic treatment; mixing the mother liquor of the isowu-bane with black phosphorus nano-sheets, dissolving the mixture by ultrasonic, adding rhamnolipid into the mixture, fully and uniformly mixing the mixture by ultrasonic, and dripping phosphate buffer with pH of 7.4 by adopting a nano precipitation method for assembly; dialyzing in phosphate buffer solution by using a dialysis bag after the assembly is finished until the phosphate buffer solution is clear and transparent; and finally, drying the obtained sample by using a vacuum freeze dryer to obtain the black phosphorus nanoparticle sheet.
2. The method for preparing the black phosphorus nano-particle sheet according to claim 1, wherein the specific preparation steps of the black phosphorus nano-particle sheet are as follows: taking block black phosphorus 500 and mg, immersing the block black phosphorus 500 and mg in N, N '-dimethylformamide, carrying out ultrasonic treatment on the block black phosphorus by a 300w ice bath probe for 2h, centrifuging the block black phosphorus by 6000rpm for 4min, taking supernatant, centrifuging the supernatant by 12000rpm for 4min, taking precipitate, and re-suspending the precipitate in the N, N' -dimethylformamide to prepare black phosphorus nanosheet heavy suspension of 1mg/mL for later use.
3. The method for preparing the black phosphorus nanoparticle sheet according to claim 1, wherein the specific method for assembling is as follows: 1mg/mL of N, N '-dimethylformamide mother liquor of the isowurtzite is prepared, 100 mug of black phosphorus nano-sheets are mixed with 50 mug of the isowurtzite and dissolved by 100 mug of N, N' -dimethylformamide, after the mixture solution is subjected to ultrasonic treatment for 5min, 1mg rhamnolipid is dissolved in the mixture, after ultrasonic treatment for 5min, 900 mug of pH 7.4 phosphate buffer solution is dropwise added into the mixture, after assembly is completed, 4h of the mixture is dialyzed in pH 7.4 phosphate buffer solution to remove organic solvent and unencapsulated isowurtzite.
4. A black phosphorus nanoparticle sheet made by the method of any one of claims 1-3.
5. The use of the black phosphorus nanoparticle tablet of claim 4 in the preparation of a medicament for treating helicobacter pylori.
6. A medicament for treating helicobacter pylori, which is characterized in that the active ingredient is the black phosphorus nano-particle tablet of claim 4.
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