CN111939119A - Nano drug delivery system based on black phosphorus hydrogel and preparation method and application thereof - Google Patents
Nano drug delivery system based on black phosphorus hydrogel and preparation method and application thereof Download PDFInfo
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The invention provides a nano drug delivery system based on a black phosphorus hydrogel, which comprises an agarose hydrogel, and a black phosphorus nanosheet and a cell stress factor inhibitor which are loaded on the agarose hydrogel. The invention also provides a preparation method of the nano drug delivery system based on the black phosphorus hydrogel and application of the nano drug delivery system in preparation of antitumor drugs. According to the nano drug delivery system based on the black phosphorus hydrogel, the black phosphorus nanosheet absorbs NIR to generate heat energy, and the hydrogel can be subjected to reversible hydrolysis and softening at a lower temperature, so that the release of the drug to the surrounding environment is accelerated, and the nano drug delivery system based on the black phosphorus hydrogel is very beneficial to controlling the release of the drug only in a focus area; meanwhile, the released emetine can inhibit the generation of expression stress particles of some heat shock factors in cells, so that the heat resistance of the cells is reduced, and the tumor cells can be killed at a lower temperature.
Description
Technical Field
The invention relates to the technical field of medical nano materials, in particular to a nano drug delivery system based on black phosphorus hydrogel, and further relates to a preparation method of the nano drug delivery system based on the black phosphorus hydrogel and application of the nano drug delivery system based on the black phosphorus hydrogel in preparation of antitumor drugs.
Background
Photothermal therapy is a cancer therapy which has been developed in recent years with little side effect and high efficiency. It mainly uses the photothermal agent to produce local high temperature under the irradiation of near infrared laser to kill cancer cell. Because the laser with the wavelength of 808nm has less damage to tissues, and water and protein substances have weaker absorption capacity, the laser can penetrate through human tissues more deeply, so the laser with the wavelength is generally selected as a light source for treatment. The nano material has small size and large specific surface area, and can enter tumor cells through endocytosis of the cells, so the nano material has wide prospect in applying to a photo-thermal agent.
Black phosphorus is a new photo-thermal agent which is emerging in recent years, can be biodegraded and degradation products are non-toxic; meanwhile, the black phosphorus has higher extinction coefficient and photothermal conversion efficiency. Recently, a new black phosphorus hydrogel nano drug-loading system is researched and prepared, and the drug release controllability of the system is obviously improved. The hydrogel (agarose) in the system can generate phase change softening at a lower temperature, so that the medicine coated in the hydrogel can be released to kill tumor cells. In addition, increasing laser power can further promote hydrolysis and melting of the hydrogel, ultimately degrading the complex into oligomers and exiting the body through the urine after treatment is complete.
However, when applied to tumor thermotherapy, the existing photothermal preparations can induce tumor cells to generate heat stress, improve the heat resistance of the tumor cells and influence the effect of the photothermal therapy.
Disclosure of Invention
In view of the above, the invention provides a nano drug delivery system based on black phosphorus hydrogel, a preparation method of the nano drug delivery system based on black phosphorus hydrogel, and application of the nano drug delivery system based on black phosphorus hydrogel in preparation of antitumor drugs, so as to solve the defects of poor heat stress resistance, poor photo-thermal treatment effect and the like of tumor cells in the existing photo-thermal antitumor therapy.
In a first aspect, the invention provides a black phosphorus hydrogel-based nano drug delivery system, which comprises an agarose hydrogel, and black phosphorus nanosheets and a cell stress factor inhibitor loaded on the agarose hydrogel.
Preferably, the cell stress factor inhibitor is emetine. The medicine Emetine (Emetine) is an alkaloid component extracted from ipecac of Rubiaceae, and plays an important role in inhibiting expression of cell stress factors and reducing cell heat resistance.
Preferably, the size of the black phosphorus nanosheet is 50-200 nm. The black phosphorus nanosheet is small in size and large in specific surface area, has high extinction coefficient and photothermal conversion efficiency on one hand, and can enter tumor cells through endocytosis of the cells on the other hand, and finally plays a role in photothermal killing in the tumor cells.
Preferably, the mass ratio of the agarose to the black phosphorus nanosheet to the cell stress factor inhibitor in the agarose hydrogel is 5-20: 1-2: 1.
The nano drug delivery system based on the black phosphorus hydrogel comprises an agarose hydrogel, and a black phosphorus nanosheet and a cell stress factor inhibitor which are loaded on the agarose hydrogel. The black phosphorus nanosheet has good extinction coefficient and photo-thermal conversion efficiency, and can efficiently convert 808nm light into heat. The agarose hydrogel is used as a carrier of the black phosphorus nanosheet and the cell stress factor inhibitor, can load the black phosphorus nanosheet and the cell stress factor inhibitor, prevents the black phosphorus nanosheet and the cell stress factor inhibitor from being released into tissues uncontrollably, has good biocompatibility, and is finally degraded into oligomers and discharged out of a body through urine after treatment. In addition, the agarose hydrogel can generate phase change softening at a lower temperature, so that the drug coated in the agarose hydrogel can be released to kill tumor cells, and the targeted controllable drug release of the agarose hydrogel is realized by virtue of the photo-thermal conversion of the black phosphorus nanosheet, so that the targeted drug loading and treatment effects are realized. The cell stress factor inhibitor has the function of inhibiting the cell stress factor, and particularly shows the function of inhibiting the heat-resistant stress reaction of tumor cells in the process of carrying out anti-tumor treatment on the nano drug delivery system based on the black phosphorus hydrogel, so that the tumor cells are thoroughly killed. The black phosphorus nanosheet (BP) absorbs NIR to generate heat energy, and the hydrogel can be subjected to reversible hydrolysis and softening at a lower temperature, so that the release of the medicine to the surrounding environment is accelerated, and the release of the medicine only in a focus area is controlled; meanwhile, the released emetine can inhibit the generation of expression stress particles of some heat shock factors in cells, so that the heat resistance of the cells is reduced, and the tumor cells can be killed at a lower temperature. The low-temperature photothermal therapy has less stimulation to the body, greatly weakens the inflammatory reaction of the body caused by stress, and plays an important role in inhibiting the recurrence and metastasis of tumors.
In a second aspect, the present invention also provides a method for preparing a black phosphorus hydrogel-based nano drug delivery system, comprising the following steps:
preparing black phosphorus nanosheets: providing black phosphorus powder and dispersing the black phosphorus powder in isopropanol, uniformly mixing the black phosphorus powder, transferring the mixed black phosphorus powder to a water bath condition, performing probe ultrasound for 6-18 h, wherein the temperature of the water bath is 5-20 ℃, and centrifuging the mixture for 5-30 min at 5000-10000 rpm after ultrasound to obtain a black phosphorus nanosheet dispersion liquid;
preparation of agarose hydrogel: providing agarose, adding deionized water, transferring the aqueous solution to a temperature of 70-90 ℃, and uniformly mixing to prepare agarose hydrogel, wherein the concentration of the agarose in the agarose hydrogel is 8-14 mg/ml;
preparing a nano drug delivery system based on the black phosphorus hydrogel: adding the dispersion liquid of the black phosphorus nanosheets into the agarose hydrogel at 70-90 ℃, stirring and uniformly mixing, adding the cell stress factor inhibitor, and immediately cooling to room temperature to obtain the nano drug delivery system based on the black phosphorus hydrogel.
Preferably, in the step of preparing the black phosphorus nanosheet, the mass-to-volume ratio of the black phosphorus powder to the isopropanol is 1: 0.5-2 mg/ml.
Preferably, in the step of preparing the black phosphorus nanosheet, the prepared dispersion liquid of the black phosphorus nanosheet is centrifuged at 10000-15000 r/min for 2-10 min, the precipitate is collected and then dispersed into a dispersion liquid of a second black phosphorus nanosheet with the concentration of 0.5-2 mg/ml by using deionized water, and the dispersion liquid of the second black phosphorus nanosheet is used for preparing a nano drug delivery system based on the black phosphorus hydrogel.
Preferably, in the step of preparing the agarose hydrogel, providing polyethylene glycol amine, heating the polyethylene glycol amine to 70-90 ℃, transferring the polyethylene glycol amine into the agarose hydrogel, stirring and uniformly mixing to prepare a second agarose hydrogel, wherein the second agarose hydrogel is used for preparing a nano drug delivery system based on the black phosphorus hydrogel;
the volume ratio of the polyethylene glycol amine to the agarose hydrogel is 1: 1.
Preferably, in the step of preparing the nano drug delivery system based on the black phosphorus hydrogel, the cell stress factor inhibitor is emetine, and the concentration of the emetine in the nano drug delivery system based on the black phosphorus hydrogel is 100-1000 mug/ml;
wherein, the cell stress factor inhibitor is added and then immediately transferred to the condition of 2-8 ℃ to be cooled to room temperature. Emetine (Emetine) is an alkaloid component extracted from ipecac of Rubiaceae, and plays an important role in inhibiting expression of cell stress factors and reducing cell heat resistance.
According to the second aspect of the invention, the preparation method of the black phosphorus hydrogel-based nano drug delivery system can be used for preparing the high-activity black phosphorus hydrogel-based nano drug delivery system, the black phosphorus nanosheet meeting the requirement is prepared firstly, the agarose hydrogel is prepared, and finally the cell stress factor inhibitor is loaded in a molten state.
In a third aspect, the invention further provides an application of the nano drug delivery system based on the black phosphorus hydrogel in the first aspect of the invention in preparing an anti-tumor drug.
When the nano drug delivery system based on the black phosphorus hydrogel is applied to preparation of the anti-tumor drug, photo-thermal treatment of the anti-tumor drug at a tumor position can be realized, and tumor cells can be killed and killed by targeting and high-efficiency photo-thermal treatment at a low temperature. In addition, in the process of absorbing light and generating heat by the black phosphorus nanosheets, the agarose hydrogel undergoes phase change and releases cell stress factor inhibitors to inhibit the generation of expression stress particles of some heat shock factors in the tumor cells, so that the heat resistance of the cells is reduced, and the tumor cells can be killed at a lower temperature.
Advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of embodiments of the invention.
Drawings
In order to more clearly illustrate the contents of the present invention, a detailed description thereof will be given below with reference to the accompanying drawings and specific embodiments.
FIG. 1 is a graph showing the morphology of black phosphorus nanosheets in example 3 of the present invention;
FIG. 2 is the photothermal test results of a black phosphorus hydrogel based nano drug delivery system of example 3 of the present invention;
figure 3 is a cryotherapeutic test result of a black phosphorus hydrogel based nano drug delivery system of example 3 of the present invention.
Detailed Description
While the following is a description of the preferred embodiments of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
In a first aspect, the invention provides a black phosphorus hydrogel-based nano drug delivery system, which comprises an agarose hydrogel, and black phosphorus nanosheets and a cell stress factor inhibitor loaded on the agarose hydrogel.
Preferably, the cell stress factor inhibitor is emetine. The medicine Emetine (Emetine) is an alkaloid component extracted from ipecac of Rubiaceae, and plays an important role in inhibiting expression of cell stress factors and reducing cell heat resistance. In other embodiments, the inhibitor of the cellular stress factor can also be other drugs that inhibit the development of tolerance stress in tumor cells.
Preferably, the size of the black phosphorus nanosheet is 50-200 nm, and specifically can be 50nm, 100nm, 150nm and 200 nm. The black phosphorus nanosheet is small in size and large in specific surface area, has high extinction coefficient and photothermal conversion efficiency on one hand, and can enter tumor cells through endocytosis of the cells on the other hand, and finally plays a role in photothermal killing in the tumor cells.
Preferably, the mass ratio of the agarose to the black phosphorus nanosheet to the cell stress factor inhibitor in the agarose hydrogel is 5-20: 1-2: 1.
More preferably, the mass ratio of the hydrogel to the black phosphorus nanosheet to the cell stress factor inhibitor is 12:1: 1.
In a second aspect, the present invention also provides a method for preparing a black phosphorus hydrogel-based nano drug delivery system, comprising the following steps:
preparing black phosphorus nanosheets: providing black phosphorus powder and dispersing the black phosphorus powder in isopropanol, uniformly mixing the black phosphorus powder, transferring the mixed black phosphorus powder to a water bath condition, performing probe ultrasound for 6-18 h, wherein the temperature of the water bath is 5-20 ℃, and centrifuging the mixture for 5-30 min at 5000-10000 rpm after ultrasound to obtain a black phosphorus nanosheet dispersion liquid;
preparation of agarose hydrogel: providing agarose, adding deionized water, transferring the aqueous solution to a temperature of 70-90 ℃, and uniformly mixing to prepare agarose hydrogel, wherein the concentration of the agarose in the agarose hydrogel is 8-14 mg/ml;
preparing a nano drug delivery system based on the black phosphorus hydrogel: adding the dispersion liquid of the black phosphorus nanosheets into the agarose hydrogel at 70-90 ℃, stirring and uniformly mixing, adding the cell stress factor inhibitor, and immediately cooling to room temperature to obtain the nano drug delivery system based on the black phosphorus hydrogel.
Preferably, in the step of preparing the black phosphorus nanosheet, the mass-to-volume ratio of the black phosphorus powder to the isopropanol is 1: 0.5-2 mg/ml. More preferably, the mass-to-volume ratio of the black phosphorus powder to the isopropanol is 1:1 mg/ml.
Preferably, in the step of preparing the black phosphorus nanosheet, the prepared dispersion liquid of the black phosphorus nanosheet is centrifuged at 10000-15000 r/min for 2-10 min, the precipitate is collected and then dispersed into a dispersion liquid of a second black phosphorus nanosheet with the concentration of 0.5-2 mg/ml by using deionized water, and the dispersion liquid of the second black phosphorus nanosheet is used for preparing a nano drug delivery system based on the black phosphorus hydrogel.
More preferably, in the step of preparing the black phosphorus nanosheets, the prepared dispersion liquid of the black phosphorus nanosheets is centrifuged at 12000r/min for 5min, and the precipitate is collected and then dispersed into a dispersion liquid of second black phosphorus nanosheets with the concentration of 1mg/ml by using deionized water, wherein the dispersion liquid of the second black phosphorus nanosheets is used for preparing the nano drug delivery system based on the black phosphorus hydrogel.
Preferably, in the step of preparing the agarose hydrogel, providing polyethylene glycol amine, heating the polyethylene glycol amine to 70-90 ℃, transferring the polyethylene glycol amine into the agarose hydrogel, stirring and uniformly mixing to prepare a second agarose hydrogel, wherein the second agarose hydrogel is used for preparing a nano drug delivery system based on the black phosphorus hydrogel;
the volume ratio of the polyethylene glycol amine to the agarose hydrogel is 1: 1.
Preferably, in the step of preparing the nano drug delivery system based on the black phosphorus hydrogel, the cell stress factor inhibitor is emetine, and the concentration of the emetine in the nano drug delivery system based on the black phosphorus hydrogel is 100-1000 mug/ml. In specific embodiments, the concentration of ipecacine may be 100. mu.g/ml, 150. mu.g/ml, 250. mu.g/ml, 500. mu.g/ml, 700. mu.g/ml, 850. mu.g/ml, 1000. mu.g/ml.
Preferably, the cell stress factor inhibitor is added and then immediately transferred to the condition of 2-8 ℃ to be cooled to room temperature. In a specific embodiment, the mixed system is transferred to a refrigerator immediately after the addition of the inhibitor of cellular stress factor and cooled to room temperature.
In a third aspect, the invention also provides application of the nano drug delivery system based on the black phosphorus hydrogel in preparation of antitumor drugs.
The following examples are provided to describe the nano drug delivery system based on black phosphorus hydrogel and the preparation method thereof in detail.
Example 1
A preparation method of a nano drug delivery system based on black phosphorus hydrogel for tumor low-temperature thermotherapy comprises the following steps:
preparing black phosphorus nanosheets: first, 40mg of black phosphorus powder was dispersed in 40ml of isopropyl alcohol (IPA) and mixed well. Then, the mixture was placed in an ice bath and sonicated overnight using a 300W power cup probe, maintaining a low temperature environment of 5-10 ℃ during sonication, during which time the temperature was lowered using an ice pack as it increased. And centrifuging the dispersion liquid obtained after the ultrasonic treatment at 7000rpm for 20min to obtain the clear liquid on the black phosphorus nanosheet with the size of 100-200 nm.
Preparation of agarose hydrogel: weighing 15mg of agarose, preparing 1.5ml of agarose aqueous solution with the concentration of 10mg/ml by using deionized water, uniformly mixing, putting the agarose aqueous solution on a heating table, heating the agarose bath at 85 ℃, and continuously blowing by using a pipette or a rubber head dropper during the period of time to fully disperse the agarose aqueous solution to obtain the agarose aqueous solution in a molten state.
Preparing a nano drug delivery system based on the black phosphorus hydrogel: to 0.5ml of the supernatant of the black phosphorus nanoplatelets, 0.5ml of an aqueous agarose solution was added (both liquids were placed in a glycerol bath at 85 ℃ before addition, maintaining their dispersibility), placed in the glycerol bath at 85 ℃ and mixed well by a pipette. And then, adding 100-1000 mu g of ipecac base into the mixed system, putting the mixed system into a refrigerator, and quickly cooling the mixed system (about 30min) to obtain the nano drug delivery system based on the black phosphorus hydrogel.
Example 2
Preparing black phosphorus nanosheets: first, 40mg of black phosphorus powder was dispersed in 40ml of isopropyl alcohol (IPA) and mixed well. Then, the mixture was placed in an ice bath and sonicated overnight using a 300W power cup probe, maintaining a low temperature environment of 5-10 ℃ during sonication, during which time the temperature was lowered using an ice pack as it increased. And centrifuging the dispersion liquid obtained after the ultrasonic treatment at 7000rpm for 20min to obtain the clear liquid on the black phosphorus nanosheet with the size of 100-200 nm. 10ml of the supernatant (measured at 650ppm) of the BP nanosheet was removed, centrifuged at 12000r/min for 5min, the bottom precipitate was collected, and the precipitate was redispersed with deionized water to a BP solution having a concentration of 1 mg/ml.
Preparation of agarose hydrogel: weighing 15mg of agarose, preparing 1.5ml of agarose aqueous solution with the concentration of 10mg/ml by using deionized water, uniformly mixing, putting the agarose aqueous solution on a heating table, heating the agarose bath at 85 ℃, and continuously blowing by using a pipette or a rubber head dropper during the period of time to fully disperse the agarose aqueous solution to obtain the agarose aqueous solution in a molten state.
Preparing a nano drug delivery system based on the black phosphorus hydrogel: to 0.5ml of the supernatant of the black phosphorus nanoplatelets, 0.5ml of an aqueous agarose solution was added (both liquids were placed in a glycerol bath at 85 ℃ before addition, maintaining their dispersibility), placed in the glycerol bath at 85 ℃ and mixed well by a pipette. And then, adding 100-1000 mu g of ipecac base into the mixed system, putting the mixed system into a refrigerator, and quickly cooling the mixed system (about 30min) to obtain the nano drug delivery system based on the black phosphorus hydrogel.
Example 3
Preparing black phosphorus nanosheets: first, 40mg of black phosphorus powder was dispersed in 40ml of isopropyl alcohol (IPA) and mixed well. Then, the mixture was placed in an ice bath and sonicated overnight using a 300W power cup probe, maintaining a low temperature environment of 5-10 ℃ during sonication, during which time the temperature was lowered using an ice pack as it increased. And centrifuging the dispersion liquid obtained after the ultrasonic treatment at 7000rpm for 20min to obtain the clear liquid on the black phosphorus nanosheet with the size of 100-200 nm. 10ml of the supernatant (measured at 650ppm) of the BP nanosheet was removed, centrifuged at 12000r/min for 5min, the bottom precipitate was collected, and the precipitate was redispersed with deionized water to a BP solution having a concentration of 1 mg/ml. Adding polyethylene glycol amine (PEG-NH2) with the weight 10 times that of BP into the dispersed BP solution with the weight 1mg/ml, and then carrying out ultrasonic treatment in a water bath ultrasonic machine for 1min (a cup-shaped probe with the power of 300W is subjected to ultrasonic treatment overnight, the temperature is kept at 5-10 ℃ in the ultrasonic process), carrying out glycerol bath for 10s (85 ℃) to obtain the PEG modified BPNSs dispersion liquid.
Preparation of agarose hydrogel: weighing 15mg of agarose, preparing 1.5ml of agarose aqueous solution with the concentration of 10mg/ml by using deionized water, uniformly mixing, putting the agarose aqueous solution on a heating table, heating the agarose bath at 85 ℃, and continuously blowing by using a pipette or a rubber head dropper during the period of time to fully disperse the agarose aqueous solution to obtain the agarose aqueous solution in a molten state.
Preparing a nano drug delivery system based on the black phosphorus hydrogel: to 0.5ml of black phosphorus nanoplatelets supernatant (BP-PEG-NH)2) Adding 0.5ml agarose aqueous solution (before adding, the two liquids should be placed in 85 deg.C glycerol bath to keep their dispersibility), placing in 85 deg.C glycerol bath, and mixing well with pipette. And then, adding 100-1000 mu g of ipecac base into the mixed system, putting the mixed system into a refrigerator, and quickly cooling the mixed system (about 30min) to obtain the nano drug delivery system based on the black phosphorus hydrogel.
The bottom precipitate (black phosphorus nanoplate) collected in example 3 was topographically characterized, as shown in fig. 1A, as a Transmission Electron Microscope (TEM) image of the black phosphorus nanoplate. FIG. 1A shows that the BPNSs (black phosphorus nanoplates) have a lateral dimension of about 100-200 nm, and the high resolution TEM in the inset shows that the lattice of the black phosphorus nanoplates does not change significantly during exfoliation. The lattice spacings shown in the figure are 0.34nm and 0.25nm, corresponding to the (021) and (111) crystal planes, respectively. Fig. 1B is an Atomic Force Microscope (AFM) image of black phosphorus nanoplates, and fig. 1D is thickness data corresponding to fig. 1B. As shown in FIGS. 1B and 1D, the BPNSs have a size of about 100nm and a thickness of 2-4 nm, and the ultrathin thickness is favorable for the black phosphorus nanosheet to serve as a platform for loading the drug. Fig. 1C is a BPNSs raman spectrogram, and the result shows that the black phosphorus nanosheet maintains its lattice structure during the stripping process, and the high-quality black phosphorus nanosheet is prepared.
Effect embodiment:
the nano drug delivery system based on black phosphorus hydrogel prepared in example 3 was subjected to photothermal performance test and tumor cryotherapy test.
Test of photothermal Properties
We irradiated the black phosphorus hydrogel-based nano drug delivery system with a 808nm laser to determine its photothermal properties, with the laser on/off time of 10 min/10 min, temperature detected by a thermocouple thermometer, and temperature sampling interval of 2 seconds.
FIG. 2A shows 1W/cm2Under the laser power of (3), the long-time (6-cycle) photothermal effect of the BPNSs hydrogel system shows that the BPNSs has good photothermal conversion efficiency effect and good stability. Thereafter, we tested the ability of the modified system to release emetine. We prepared 0.2ml black phosphorus hydrogel based nano drug delivery system on the bottom of the quartz cuvette, and added 1.8ml deionized water on top of the drug delivery system. The power is 1W/cm2The hydrogel was irradiated downward from the top of the cuvette with an 808nm laser. Under the irradiation of laser, the temperature of the black phosphorus hydrogel system is increased, and the medicine is released into the upper layer of water. Using a UV-Vis Spectrophotometer (Cary60, Agilent), we can test free drug absorption. Considering that the absorption of the drug is roughly proportional to its concentration, we can then infer the release profile of the drug. As shown in fig. 2B, the curves correspond from bottom to top to 60 minutes of supernatant uptake with 1,2,4,6 … … 54, respectively, irradiation. The absorbance value of emetine at 280nm is increased along with the continuous extension of the irradiation time of near infrared light, which shows that the released emetine amount is increased along with the continuous extension of the irradiation time, and the medicine carrying system has good controllable release effect.
Low temperature treatment testing of tumors
As shown in FIG. 3A, the nano drug delivery system based on black phosphorus hydrogel prepared in example 3 and tumor cells were co-cultured in a 37 ℃ incubator for 24 hours, and the black phosphorus hydrogel system loaded with emetine with different concentrations had no influence on the survival of tumor cells (three human tumor cell lines of Huh7, smmc-7721 and Hela), but had strong tumor killing property after laser irradiation treatment.
To determine the role of stress particles in photothermal therapy, we used PFA to immobilize cells and achieved detection of stress particles by Immunofluorescence (IF) analysis using antibodies targeting stress particle marker protein G3BP and TIA 1. As shown in fig. 3B, in the case of laser irradiation alone or incubation with black phosphorus nanoplatelets, G3BP localized in the cytoplasm, while TIA1 localized in the nucleus and cytoplasm, indicating that SG (stress particles) was not induced. After photothermal treatment, SG was induced in the cytoplasm as shown in fig. 3b, the dotted structures marked by G3BP and TIA 1. This result indicates that photothermal treatment induces the generation of stress particles. The generation of stress particles can increase the heat resistance of cells and affect the effect of photothermal therapy. The nano drug delivery system based on the black phosphorus hydrogel prepared in example 3 can release emetine through light control, and compared with the traditional black phosphorus hydrogel photo-thermal nano agent treatment, the nano drug delivery system based on the black phosphorus hydrogel can obviously inhibit the formation of stress particles (fig. 3B), thereby reducing the tolerance of cells to heat, and killing tumor cells at a lower temperature. The medicine plays an important role in overcoming inflammatory reaction caused by overhigh temperature in the traditional photothermal treatment process, and is helpful for effectively preventing the metastasis and recurrence of cancer.
In-vivo and in-vitro experimental studies show that the ipecacuanine-loaded black phosphorus hydrogel has a good tumor killing effect. As shown in the results of fig. 3C, since BP has excellent photothermal conversion efficiency and can efficiently convert light energy into heat energy, the heat generated from the black phosphorus hydrogel can kill some tumor cells. This is shown in FIG. 3C as a change in cell morphology, rounding off and death. The experimental conditions of this example (laser power 0.925W) limited the photothermal temperature to a low level, so that only photothermal alone killed some of the cells. In the black phosphorus hydrogel-ipecacine drug-loaded system, heat generated by BP (at a lower temperature) can soften or even melt the hydrogel, so that the internal drug ipecacine is released to act on cells, the generation of stress particles of the cells is inhibited, the heat resistance of the cells is reduced, tumor cells can be killed at a lower temperature (the tumor cells are killed in a figure and are shown to be round), and the tumor killing rate is nearly 100%. After the hydrogel (Gel) and the hydrogel-coated ipecacuanine (Gel/Emetine) group are illuminated, the cell morphology is kept unchanged, and the fact that the simple hydrogel or ipecacuanine basically has no photo-thermal killing effect is proved. In the Gel/BP treatment group after the addition of black phosphorus, it was clearly found that some cells had become round and dead after the light treatment. However, due to the control of the illumination power, the photothermal effect is not sufficient to completely kill all tumor cells. After the ipecac is added on the basis, the Gel/BP/Emetine group shows nearly 100% of cancer cell killing effect under the same laser power, and proves that the existence of the ipecac can effectively inhibit the heat resistance of cancer cells and improve the effect of photothermal therapy.
FIG. 3D shows the results of in vivo tumor suppression experiments performed in mice with results similar to those of in vitro cell experiments. Mice were purchased from gempharamtech (china, nanjing). The experiment is approved by animal protection and use committee of Shenzhen university. In the experimental process, Huh7 cells were injected subcutaneously into female BALB/c nude mice to establish a tumor mouse model. Subsequently, 100 μ l of the black phosphorus hydrogel-based nano drug delivery system prepared in example 3 (both BP nanoplate and ipecacine concentrations are 500 μ g/mL, hydrogel concentration is 6mg/mL) or other control reagent was injected intratumorally into mice. Then, the power density was 0.925W cm-2808nm for 10 minutes. The temperature of the tumor was measured using a thermal imager. The body weight and tumor size of the mice were recorded every two days. Tumor volumes were normalized to their baseline size. The result shows that the black phosphorus hydrogel has a good effect of inhibiting the growth of the tumor, the tumor treatment effect is further improved after the ipecacuanine is loaded in the system, and the solid tumor in the animal body is controlled to be a small size.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A nano drug delivery system based on black phosphorus hydrogel is characterized by comprising agarose hydrogel, and black phosphorus nanosheets and cell stress factor inhibitors loaded on the agarose hydrogel.
2. The nano-delivery system based on black phosphorus hydrogel of claim 1, wherein the inhibitor of cellular stress factor is emetine.
3. The black phosphorus hydrogel-based nano drug delivery system of claim 1, wherein the black phosphorus nanoplates are 50-200 nm in size.
4. The black phosphorus hydrogel-based nano drug delivery system according to claim 1, wherein the agarose hydrogel comprises agarose, black phosphorus nanosheets and a cell stress factor inhibitor at a mass ratio of 5-20: 1-2: 1.
5. A preparation method of a nano drug delivery system based on black phosphorus hydrogel is characterized by comprising the following steps:
preparing black phosphorus nanosheets: providing black phosphorus powder and dispersing the black phosphorus powder in isopropanol, uniformly mixing the black phosphorus powder, transferring the mixed black phosphorus powder to a water bath condition, performing probe ultrasound for 6-18 h, wherein the temperature of the water bath is 5-20 ℃, and centrifuging the mixture for 5-30 min at 5000-10000 rpm after ultrasound to obtain a black phosphorus nanosheet dispersion liquid;
preparation of agarose hydrogel: providing agarose, adding deionized water, transferring the aqueous solution to a temperature of 70-90 ℃, and uniformly mixing to prepare agarose hydrogel, wherein the concentration of the agarose in the agarose hydrogel is 8-14 mg/ml;
preparing a nano drug delivery system based on the black phosphorus hydrogel: adding the dispersion liquid of the black phosphorus nanosheets into the agarose hydrogel at 70-90 ℃, stirring and uniformly mixing, adding the cell stress factor inhibitor, and immediately cooling to room temperature to obtain the nano drug delivery system based on the black phosphorus hydrogel.
6. The preparation method of the black phosphorus hydrogel-based nano drug delivery system according to claim 5, wherein in the step of preparing the black phosphorus nanosheets, the mass to volume ratio of the black phosphorus powder to the isopropanol is 1: 0.5-2 mg/ml.
7. The preparation method of the black phosphorus hydrogel-based nano drug delivery system as claimed in claim 5, wherein in the step of preparing the black phosphorus nanosheet, the prepared dispersion liquid of the black phosphorus nanosheet is centrifuged at 10000-15000 r/min for 2-10 min, and after the precipitate is collected, the precipitate is dispersed with deionized water to form a second black phosphorus nanosheet dispersion liquid with the concentration of 0.5-2 mg/ml, wherein the second black phosphorus nanosheet dispersion liquid is used for preparing the black phosphorus hydrogel-based nano drug delivery system.
8. The preparation method of the black phosphorus hydrogel-based nano drug delivery system according to claim 5, wherein in the step of preparing the agarose hydrogel, the polyethylene glycol amine is provided, the polyethylene glycol amine is heated to 70-90 ℃ and then transferred into the agarose hydrogel, and then the mixture is stirred and mixed to prepare a second agarose hydrogel, wherein the second agarose hydrogel is used for preparing the black phosphorus hydrogel-based nano drug delivery system;
the volume ratio of the polyethylene glycol amine to the agarose hydrogel is 1: 1.
9. The method for preparing the nano drug delivery system based on the black phosphorus hydrogel as claimed in claim 5, wherein in the step of preparing the nano drug delivery system based on the black phosphorus hydrogel, the cell stress factor inhibitor is ipecacine, and the concentration of the ipecacine in the nano drug delivery system based on the black phosphorus hydrogel is 100-1000 μ g/ml;
wherein, the cell stress factor inhibitor is added and then immediately transferred to the condition of 2-8 ℃ to be cooled to room temperature.
10. Use of the black phosphorus hydrogel-based nano drug delivery system according to any one of claims 1 to 4 for the preparation of an anti-tumor drug.
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