CN111202719A - Active natural product nano drug delivery system and preparation method and application thereof - Google Patents
Active natural product nano drug delivery system and preparation method and application thereof Download PDFInfo
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- 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
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention discloses an active natural product nano drug delivery system and a preparation method and application thereof, wherein the nano drug delivery system takes active natural product ursolic acid or oleanolic acid as a drug carrier, the mass ratio of the drug carrier to a hydrophobic drug is 1-20: 1, and the hydrophobic drug is one of paclitaxel and taxane drugs thereof, curcumin and camptothecin. The nano drug-carrying system directly uses natural active small molecular ursolic acid or oleanolic acid to prepare a nano carrier without any modification for the first time, and successfully loads hydrophobic drugs to form nano drug-carrying particles; the carrier and the anti-cancer drug can block cells in different cell cycles or block the cell cycles in the same cell cycle through different mechanisms, so that the synergistic anti-tumor effect is achieved, and the tumor inhibition rate is improved; the carrier can effectively reduce tissue damage caused by chemotherapeutic drugs through an antioxidant way; and the nano drug-carrying system has good biocompatibility and system safety.
Description
Technical Field
The invention belongs to the technical field of nano-medicines, relates to a nano-medicine carrying system and a preparation method and application thereof, and particularly relates to a nano-medicine carrying system based on ursolic acid and oleanolic acid as nano-medicine carriers, a preparation method thereof and application thereof in cancer treatment.
Background
Cancer is a major public health problem worldwide, and traditional chemotherapy is still an indispensable treatment method for most cancer patients, but cannot distinguish diseased cells from normal cells, so that the cancer patients are inevitably suffered from damage to normal tissues and organs at the same time, which causes more additional pain to the patients and severely limits the clinical application of chemotherapy drugs.
The use of Drug delivery systems has attracted considerable attention in the field of nanomedics (J Drug Target 2016,24(3), 179-191). Nano-drug carriers are promising drug carriers, and the design and synthesis of highly efficient drug delivery systems are crucial for cancer therapy (chem. rev.2015,115(16), 8564-.
Various nano-drug carriers such as carbon nanotubes (int.j.pharm.2015,479(2), 357-.
However, most drug carriers have many limitations, including low drug loading, fast drug leakage in vivo, high blood clearance rate, and especially drug-loaded nanoparticles in clinical application may cause problems of poor biocompatibility, poor biodegradability and the like (JControl Release 2012,160(2), 117-. In particular, almost all drug carriers are currently only excipients for drug delivery, and the use of large amounts of carriers often leads to additional toxic effects due to poor metabolism and blood clearance (bioconjugate Chem 2016,27(4), 855-.
The natural product is the main source of medicine and health care products, and has good biological activity, biocompatibility and biological safety. Therefore, the inherent biological safety and biocompatibility of the active natural product are utilized to develop a drug carrier material with biological activity, so that the nano carrier also has a certain anti-tumor effect or health care effect, toxic and side effects caused by the intake of a large amount of nano carriers are not worried about, the purposes of cooperatively resisting tumors by the carrier and the drug and relieving the toxic and side effects caused by chemotherapeutic drugs are expected to be realized, and the safe and efficient treatment is realized in the method for treating the tumors by using the chemotherapy.
Disclosure of Invention
The invention aims to provide an active natural product nano drug-loaded system and a preparation method and application thereof, the nano drug-loaded system directly uses natural active small molecular ursolic acid or oleanolic acid to prepare a nano carrier without any modification for the first time, and successfully loads hydrophobic drugs to form nano drug-loaded particles; the carrier and the anti-cancer drug can block cells in different cell cycles or block the cell cycles in the same cell cycle through different mechanisms, so that the synergistic anti-tumor effect is achieved, and the tumor inhibition rate is improved; the carrier can effectively reduce tissue damage caused by chemotherapeutic drugs through an antioxidant way; and the nano drug-carrying system has good biocompatibility and system safety.
The purpose of the invention is realized by the following technical scheme:
an active natural product nano drug delivery system takes active natural product ursolic acid or oleanolic acid as a drug carrier, and the mass ratio of the drug carrier to a hydrophobic drug is 1-20: 1, wherein: the hydrophobic drug is one of paclitaxel and taxane drugs thereof, curcumin, camptothecin and the like, and the nano drug delivery system can be used for treating cancers (especially, breast cancer and liver cancer but not limited).
A preparation method of an active natural product nano drug delivery system comprises the following steps:
dissolving a drug carrier ursolic acid or oleanolic acid and a hydrophobic drug in a benign organic solvent to obtain a mixed solution with the concentration of 1-5 mg/mL, wherein: the benign organic solvent mainly comprises one or more of methanol, ethanol, acetone, petroleum ether, ethyl acetate, dichloromethane, trichloromethane, tetrachloromethane, n-hexane and solvents between the methanol, the ethanol, the acetone, the petroleum ether, the ethyl acetate, the dichloromethane, the trichloromethane, the tetrachloromethane and the n-hexane;
step two, adding the mixed solution obtained in the step one into a surfactant solution with the mass concentration of 1-5%, and performing vortex oscillation for 0.5-3 minutes, wherein: the volume ratio of the mixture to the surfactant solution is 1: 1-6, and the surfactant comprises one of an acidic surfactant, an alkaline surfactant and a neutral surfactant, especially polyvinyl alcohol;
step three, emulsifying the suspension obtained in the step two, particularly carrying out ultrasonic emulsification for 1-5 minutes;
step four, dropwise adding the emulsion formed in the step three into a surfactant aqueous solution with the mass concentration of 0.1-0.8%, and stirring to volatilize the organic solvent, wherein: the process is carried out in an environment of not higher than 25 ℃, the volume ratio of the emulsion to the surfactant aqueous solution is 1: 5-30, and the surfactant comprises one of an acid surfactant, an alkaline surfactant and a neutral surfactant, especially polyvinyl alcohol;
step five, carrying out high-speed centrifugal treatment (the revolution is not lower than 5000 turns) and double-distilled water washing on the solution obtained in the step four, removing residual surfactant, and harvesting drug-loaded nanoparticles;
step six, adding water, physiological saline or PBS into the drug-loaded nano-particles obtained in the step five to prepare a suspension for later use, and storing the suspension at 4 ℃; or drying or freeze-drying the drug-loaded nanoparticles obtained in the fifth step, and storing for a long time under the condition of room-temperature refrigeration or freezing.
The invention has the following advantages:
1. the invention selects active natural product ursolic acid or oleanolic acid as a drug carrier, and the carrier is composed of ursolic acid or oleanolic acid only and forms nano microspheres.
2. The ursolic acid and the oleanolic acid are not subjected to any chemical modification and structural modification, and the nano carrier system retains the complete biological activity of the ursolic acid and the oleanolic acid.
3. The nano carrier can interact with hydrophobic drugs weakly to form nano drug-loaded particles.
4. The particle size of the nano drug-loaded particles is 100-300 nm, the average particle size is about 150-190 nm, no drug delivery embolism is formed, and the nano drug-loaded particles can be used for intravenous drug delivery or abdominal drug delivery of patients.
5. The highest drug loading capacity and the optimal encapsulation rate of the ursolic acid nano drug-loaded system are as follows: 23.12% ± 1.07% and 94.41 ± 4.28%; the maximum drug loading rate and the optimal encapsulation rate of the oleanolic acid nano drug delivery system are 12.95 +/-0.51 percent and 58.76 +/-2.54 percent.
6. The hydrophilicity of the nano drug-loaded particles is obviously improved, and the half-life period of blood is prolonged by 3-6 times compared with that of chemical drugs.
7. The nano drug-loaded particles have good biological safety and no or extremely low cytotoxicity to normal cells.
8. The nanometer medicine carrying particle has synergistic antitumor effect and synergistic index less than 0.9.
9. The nano drug-loaded particles have high tumor targeting property and can effectively enrich at tumor parts.
10. 4T1 tumor-bearing mouse model, the tumor inhibition rate is higher than 70%.
11. The nanometer medicine carrying granule can effectively reduce toxic and side effects of organism, wherein the hematology index (white blood cell number, lymphocyte number, and neutrophilic granulocyte number) is remarkably improved by P <0.01 compared with paclitaxel injection.
12. The nanometer medicine carrying granule can improve oxidation resistance of human body, and has SOD (superoxide dismutase) and GSH (reduced glutathione) content in liver tissue higher than that in paclitaxel injection, with P less than 0.05.
Drawings
FIG. 1 is a scanning electron microscope image of ursolic acid nanoparticles (UA NPs) and ursolic acid loaded paclitaxel (UA-PTX NPs) with a scale of 1 micron;
FIG. 2 is a scanning electron microscope image of oleanolic acid nanoparticles (OA NPs) and oleanolic acid-loaded paclitaxel (OA-PTX NPs) with 1 micron scale;
FIG. 3 is a transmission electron microscope image of ursolic acid nanoparticles (UA NPs) and ursolic acid loaded paclitaxel (UA-PTX NPs);
FIG. 4 is a transmission electron microscope image of oleanolic acid nanoparticles (OA NPs) and oleanolic acid-loaded paclitaxel (OA-PTX NPs);
FIG. 5 is the contact angle of ursolic acid and oleanolic acid solid powder and nanoparticles;
FIG. 6 shows the drug-loading encapsulation efficiency of ursolic acid drug-loaded nanoparticles;
fig. 7 shows the drug-loading encapsulation efficiency of oleanolic acid drug-loaded nanoparticles;
FIG. 8 is a graph of in vitro release of drug-loaded nanoparticles in release media of different pH;
fig. 9 shows the in vitro cytotoxicity and cell cycle of ursolic acid nano drug-loaded particles, a, the MCF-7 cell growth inhibition effect of ursolic acid solid powder and ursolic acid nano particles 48h, the MCF-7 cell growth inhibition effect of ursolic acid nano particles 48h, the binding index (CI) of the nano particles on MCF-7 and 4T1 cells d, the retardation effect of different nano preparations on the MCF-7 cell cycle;
fig. 10 is in vitro cytotoxicity and cell cycle of oleanolic acid drug-loaded nanoparticles, a, oleanolic acid solid powder and oleanolic acid nanoparticles inhibiting MCF-7 cell growth 48h, nanoparticles binding index (CI) on MCF-7 and 4T1 cells, d, blocking effect of different nanopreparations on MCF-7 cell cycle;
FIG. 11 is a graph of tumor volume changes in tumor-bearing mice after treatment with ursolic acid drug-loaded particles (UA-PTX NPs);
FIG. 12 is a graph of tumor volume inhibition in tumor-bearing mice following oleanolic acid drug-loaded particles (OA-PTX NPs) treatment;
FIG. 13 is the biochemical index and antioxidant index evaluation of the protective effect of oleanolic acid nanoparticles on mouse liver tissue damage and H & E staining images of liver tissue sections.
Detailed Description
The technical solution of the present invention is further described below with reference to the accompanying drawings, but not limited thereto, and any modification or equivalent replacement of the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention shall be covered by the protection scope of the present invention.
The invention provides natural micromolecule nano drug-loaded particles (NPs), wherein carrier materials of the NPs mainly comprise two micromolecule active natural products: ursolic Acid (UA), Oleanolic Acid (OA), structural formula as follows:
the invention adopts an emulsion solvent volatilization method to prepare nano particles, and the method comprises the following specific steps:
(1) carrier nanoparticles: 5.0mg of carrier (ursolic acid and oleanolic acid) is dissolved in 1.0mL of dichloromethane (a small amount of methanol can be added as a cosolvent if the carrier can not be completely dissolved), then the carrier is added into 3.0mL of 2.5% polyvinyl alcohol (PVA) aqueous solution (w/v) under the condition of vortex oscillation, the mixture is subjected to vortex oscillation for 60s, and the vortex liquid is immediately transferred to a probe type ultrasonic instrument to perform ultrasonic treatment for 60 s. Then, the resulting emulsion was added dropwise to 30mL of a 0.3% aqueous PVA solution (w/v) at a magnetic stirring speed of 400 rpm. The solution is stirred at room temperature for 6-8 hours to remove the organic solvent. The nanoparticles were then centrifuged at 12,000rpm for 40 minutes at 4 ℃, collected, washed twice with double distilled water (to remove excess PVA and free drug), and lyophilized for use.
(2) The preparation method of the drug-loaded nano-particles comprises the following steps: 5.0mg of ursolic acid and 1.25mg of paclitaxel are dissolved in 1.0mL of dichloromethane (if the solvents can not be completely dissolved, a small amount of methanol can be added as a cosolvent), or 5.0mg of oleanolic acid and 1.0mg of paclitaxel are dissolved in 1.0mL of dichloromethane, and the subsequent steps are strictly carried out according to the same operation of the preparation method of the carrier nanoparticles, so as to obtain the drug-loaded nanoparticles.
Fig. 1-4 are SEM and TEM pictures of nanoparticles and drug-loaded nanoparticles prepared from two carriers, the nanoparticles composed of the two carriers are all of a nano-spherical structure with uniform morphology, and the average particle size is less than 200nm, which has excellent dispersibility; after the paclitaxel is loaded to form the drug-loaded nanoparticles, the morphology of the drug-loaded nanoparticles is not changed, which indicates that the drug-loaded nanoparticles do not bring significant changes to the carrier assembly structure. TEM image shows that the carrier nano particle formed by UA is solid sphere, the carrier nano particle formed by OA is hollow sphere, and the carrier nano particle and OA are both solid sphere structures after being loaded with drugs.
Nanoparticle characterization:
(1) three-phase contact angle measurements were performed at room temperature and the lyophilized powders were all mounted uniformly on a glass slide (average 13 mm diameter and average thickness 2 mm). 5 mu L of liquid drop deionized water is dripped on the surface of the sample, after balancing for 10 seconds, the liquid drop is shot by using a high-speed camera, the outline of the imaged liquid drop is simulated, the three-phase contact angle is obtained, and the measurement is carried out at least three times.
Fig. 5 shows the contact angle experiment result, the hydrophilicity of the product is obviously improved, and the long circulation of the nano particles in blood can be realized.
(2) And (3) measuring the drug loading rate and the encapsulation rate of the nanoparticles:
the concentration of the drug in the nanoparticle formulation was determined using a high performance liquid chromatography system. Dissolving the drug-loaded nano particle freeze-dried powder in dimethyl sulfoxide to destroy nano particles and release loaded drugs. The PTX content was analyzed by filtration through a 0.22 μm syringe filter with acetonitrile/water (65/35, v/v) as mobile phase and with a detector wavelength of 227 nm.
Fig. 6 and 7 show the drug loading and encapsulation efficiency of the natural product with small molecule activity, wherein the maximum drug loading and encapsulation efficiency of the paclitaxel loaded by ursolic acid are 23.12% ± 1.07% and 94.41 ± 4.28%, respectively; the maximum loading and encapsulation efficiency of oleanolic acid loaded paclitaxel were 12.95% + -0.51% and 58.76 + -2.54%, respectively.
(3) In vitro release experiments, in vitro release curves of the drug-loaded nanoparticles were determined at 37 ℃, pH 7.3 and 5.5, respectively.
FIG. 8 is a graph showing the release curves, at pH 7.3 and 5.5, the cumulative PTX release of UA-PTX NPs was about 40% and 30%, respectively; the cumulative PTX release of OA-PTX NPs was about 18% and 10% at pH 7.3 and 5.5, respectively. The nano drug-loaded particles show excellent stability and are expected to prevent the premature leakage of the drug in vivo.
In vitro cell experiments:
fig. 9 and fig. 10 are in vitro cell experiment results of ursolic acid drug-loaded nanoparticles and oleanolic acid drug-loaded nanoparticles, respectively, and the results show that the drug-loaded nanoparticles enhance the inhibition rate of MCF-7 cells under the same paclitaxel equivalent, and the combination index calculation shows that the combination indexes under IC50 are both less than 1.0, which indicates that the carrier and the drug have a synergistic anti-tumor effect and can effectively improve the anti-tumor effect. The cell cycle shows that ursolic acid and paclitaxel realize synergistic effect by blocking MCF-7 cells in different mitosis cycles.
In vivo antitumor effect:
FIGS. 11 and 12 show the change of tumor volume of 4T1 tumor-bearing mice treated with different drugs. The results show that the single carrier nanoparticles have different degrees of inhibition effects on tumors, and the tumor inhibition rate of the ursolic acid drug-loaded group is as high as 90 percent and is obviously higher than that of the single drug group and the single carrier group; specifically, the tumor inhibition rate of the OA-PTX NPs treatment group is 10% higher than that of the non-biological active carrier PLGA-PTX group. This result also confirms that the bioactive natural product loaded with anticancer drugs can achieve synergistic effect.
Evaluation of side effects:
fig. 13 respectively measures biochemical indexes of typical liver tissue damage and anti-oxidation indexes of liver tissues in serum, and results show that all indexes of an active natural product drug-carrying group body are slowed down to a certain extent compared with free drug groups and inactive carrier groups, which indicates that a carrier plays a positive role in a delivery system, pathological analysis is performed after H & E staining is performed on liver tissue slices of each group, and results show that liver tissue damage of the active natural product drug-carrying group is effectively repaired, and that the carrier can slow down side effects caused by chemotherapeutic drugs to a certain extent.
Claims (10)
1. The active natural product nano drug delivery system is characterized in that the nano drug delivery system takes active natural product ursolic acid or oleanolic acid as a drug carrier, the mass ratio of the drug carrier to a hydrophobic drug is 1-20: 1, and the hydrophobic drug is one of paclitaxel and taxane drugs thereof, curcumin and camptothecin.
2. A method for preparing the active natural product nano drug delivery system of claim 1, which is characterized by comprising the following steps:
dissolving a drug carrier ursolic acid or oleanolic acid and a hydrophobic drug in a benign organic solvent to obtain a mixed solution with the concentration of 1-5 mg/mL;
step two, adding the mixed solution obtained in the step one into a surfactant solution with the mass concentration of 1-5%, and performing vortex emulsification for 0.5-3 minutes;
step three, performing ultrasonic emulsification treatment on the suspension obtained in the step two;
step four, dropwise adding the emulsion formed in the step three into a surfactant aqueous solution with the mass concentration of 0.1-0.8%, and stirring to volatilize the organic solvent;
fifthly, carrying out high-speed centrifugal treatment and double-distilled water washing on the solution obtained in the fourth step, removing residual surfactant, and harvesting drug-loaded nanoparticles;
and step six, adding water, physiological saline or PBS into the drug-loaded nano-particles obtained in the step five to prepare a suspension for later use, and storing at 4 ℃.
3. The method for preparing the active natural product nano drug delivery system according to claim 2, wherein in the first step, the benign organic solvent is one or more of methanol, ethanol, acetone, petroleum ether, ethyl acetate, dichloromethane, trichloromethane, tetrachloromethane and n-hexane.
4. The preparation method of the active natural product nano drug delivery system according to claim 2, wherein in the second step, the volume ratio of the mixture to the surfactant solution is 1: 1-6, and the surfactant is one of an acidic surfactant, a basic surfactant and a neutral surfactant.
5. The method for preparing the active natural product nano drug delivery system according to claim 2, wherein in the third step, the ultrasonic emulsification time is 1-5 minutes.
6. The preparation method of the active natural product nano drug delivery system according to claim 2, wherein the step four is performed at an environment of not higher than 25 ℃, the volume ratio of the emulsion to the surfactant aqueous solution is 1: 5-30, and the surfactant comprises one of an acidic surfactant, a basic surfactant and a neutral surfactant.
7. The method for preparing the active natural product nano drug delivery system according to claim 4 or 6, characterized in that the surfactant is polyvinyl alcohol.
8. The method for preparing active natural product nano drug delivery system according to claim 2, wherein in the step five, the centrifugal rotation number is not less than 5000 turns.
9. The method for preparing the active natural product nano drug delivery system according to claim 2, wherein the step six is replaced by: and (5) drying or freeze-drying the drug-loaded nanoparticles obtained in the fifth step, and storing for a long time under the condition of room-temperature refrigeration or freezing.
10. The active natural product nano drug-carrying system of claim 1 is used for treating cancer.
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