CN111821283A - Zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane and preparation method of zinc glutamate-coated Prussian blue nanoparticles - Google Patents

Zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane and preparation method of zinc glutamate-coated Prussian blue nanoparticles Download PDF

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CN111821283A
CN111821283A CN202010719855.5A CN202010719855A CN111821283A CN 111821283 A CN111821283 A CN 111821283A CN 202010719855 A CN202010719855 A CN 202010719855A CN 111821283 A CN111821283 A CN 111821283A
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prussian blue
lonidamine
triphenylphosphine
zinc glutamate
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CN111821283B (en
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刘源岗
王士斌
王沛
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Huaqiao University
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Abstract

The invention discloses zinc glutamate wrapped Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and a preparation method thereof, wherein the zinc glutamate wrapped Prussian blue nanoparticles comprise a Prussian blue nano core, the surface of the Prussian blue nano core is wrapped with at least one zinc glutamate layer, the surface of the zinc glutamate layer positioned on the outermost layer is provided with a loading layer loaded with the triphenylphosphine-lonidamine, and the loading layer is wrapped with a tumor cell membrane layer. The invention has the capacity of targeting tumor cells, has long circulation time in vivo, can gather in mitochondria and cause dysfunction, reduces the synthesis of ATP, down-regulates the synthesis of various heat shock proteins, causes apoptosis and effectively enhances the curative effect of low-temperature photothermal therapy of tumors.

Description

Zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane and preparation method of zinc glutamate-coated Prussian blue nanoparticles
Technical Field
The invention belongs to the technical field of drug carriers, and particularly relates to zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membranes and a preparation method thereof.
Background
Cancer, a type of malignant tumor, is a non-infectious disease with very high worldwide morbidity and mortality, and about 2 million cancer cases are newly added in 2025 years as predicted by the international cancer institute. At present, the traditional cancer treatment means still occupies the main position, such as chemotherapy, radiotherapy and operation, and the traditional cancer treatment means has the defects of high recurrence rate, strong side effect and the like. Photothermal therapy is a novel treatment means, and is a treatment mode of utilizing a photothermal conversion preparation to rapidly convert light energy into heat energy to kill tumor cells. Compared with the traditional treatment method, photothermal treatment has many advantages, but is limited by the penetration depth of laser, the deeper part of tumor tissue is heated less, and the satisfactory treatment effect is achieved by increasing the dosage of the photothermal conversion preparation and/or the laser power. However, due to non-selective heat diffusion, high temperature may cause irreversible damage to normal tissues in the vicinity of the tumor and may cause a series of side effects such as inflammation, tumor metastasis, and the like. Although the low temperature does not cause the damage of normal tissues near the tumor or other side effects, the treatment effect is poor, so that the realization of low-temperature photothermal therapy is a problem which is urgently needed to be solved in clinical transformation.
Compared with normal cells, the tumor cells over-express heat shock proteins, so that the heat sensitivity of the tumor cells is reduced, and the activity of the tumor cells at high temperature is maintained. Therefore, in order to improve the sensitivity of tumor cells to heat, photothermal therapy by combining a heat shock protein inhibitor and a photothermal conversion agent in the same nanosystem is an effective approach. The weli database (advanced materials, 2017, volume 29, page 1703588) reports that a one-dimensional nano MOF material with indocyanine green as a ligand is designed and constructed by a Liuzhuang topic group, gambogic acid is loaded to inhibit the effect of heat shock protein 90, and an excellent anti-tumor effect under low-temperature (43 ℃) photo-thermal treatment is realized. The Willi database (advanced functional materials, 2016, volume 26, page 3480-3489) reports that the peritectic subject group utilizes the up-conversion nanoparticles as a carrier, and siRNA blocks the synthesis of heat shock protein 70, thereby improving the effect of the photothermal conversion preparation on tumor cells. Although the two schemes well solve the problems of activity and expression quantity of the heat shock protein, the two schemes only can aim at one heat shock protein, and the heat shock protein has various types and can play a role in photothermal therapy to influence the photothermal therapy effect.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membranes.
The invention also aims to provide a preparation method of the zinc glutamate wrapped Prussian blue nanoparticles wrapped by the cancer cell membrane and loaded with triphenylphosphine-lonidamine.
The invention further aims to provide the application of the zinc glutamate wrapped Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine in the wrapping of the cancer cell membrane.
The technical scheme of the invention is as follows:
a zinc glutamate wrapped Prussian blue nanoparticle loaded with triphenylphosphine-lonidamine and wrapped by a cancer cell membrane comprises a Prussian blue nano core, wherein at least one zinc glutamate layer is wrapped on the surface of the Prussian blue nano core, a loading layer loaded with the triphenylphosphine-lonidamine is arranged on the surface of the outermost zinc glutamate layer, and a tumor cell membrane layer is wrapped outside the loading layer.
In a preferred embodiment of the present invention, the tumor cell membrane layer is made of extracted HepG2 cell membrane.
In a preferred embodiment of the present invention, the triphenylphosphine-lonidamine is prepared by linking triphenylphosphine and lonidamine with (2-bromomethyl) dimethylamine hydrobromide.
In a preferred embodiment of the present invention, the particle size is 100-200 nm.
Further preferably, the particle size of the prussian blue nano-core is 70-90 nm.
As shown in fig. 1, the preparation method of the zinc glutamate-coated prussian blue nanoparticle loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane comprises the following steps:
(1) preparing prussian blue nanoparticles by a hydrothermal synthesis method;
(2) the preparation method of the zinc glutamate coated Prussian blue nanoparticles comprises the following steps:
a. mixing the prussian blue nanoparticles with a polyvinylpyrrolidone aqueous solution, dropwise adding a zinc nitrate solution for reaction, centrifuging, washing with water, and dispersing;
b. dropwise adding a glutamic acid disodium solution into the material obtained in the step a for reaction, centrifugally washing, collecting precipitates, repeating the steps for 1-3 times, and centrifugally collecting to obtain zinc glutamate-coated prussian blue nanoparticles;
(3) preparing zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine: dispersing the zinc glutamate-coated Prussian blue nanoparticles obtained in the step (2) in methanol, adding a triphenylphosphine-lonidamine methanol solution, fully stirring, centrifuging, washing with water, and adding a disodium glutamate solution for reaction to obtain triphenylphosphine-lonidamine-loaded zinc glutamate-coated Prussian blue nanoparticles;
(4) preparing zinc glutamate wrapped Prussian blue nanoparticles with cancer cell membranes wrapped and loaded with triphenylphosphine-lonidamine: ultrasonically dispersing the zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine obtained in the step (3) into ultrapure water, dropwise adding the extracted tumor cell membranes in the ultrasonic process, centrifuging and collecting after 2-5min, and fully washing to obtain the zinc glutamate-coated Prussian blue nanoparticle.
In a preferred embodiment of the present invention, the step (1) is: dissolving ferric chloride hexahydrate and citric acid monohydrate in ultrapure water to prepare a ferric chloride solution; dissolving potassium ferrocyanide trihydrate and citric acid monohydrate in ultrapure water to prepare a potassium ferrocyanide solution; slowly dropwise adding a potassium ferrocyanide solution into the ferric chloride solution at 58-62 ℃ while stirring; and after the dripping is finished, continuously stirring for 0.8-1.2min at the constant temperature of 58-62 ℃, then transferring to room temperature, stirring for 4-6min, slowly pouring 120mL of acetone for inducing crystallization, and sequentially carrying out centrifugal collection, full water washing and vacuum freeze drying to obtain the Prussian blue nanoparticles.
In a preferred embodiment of the present invention, the frequency of the ultrasonic dispersion in the step (4) is 35 to 45 kHz.
The other technical scheme of the invention is as follows:
the zinc glutamate coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by the cancer cell membrane are applied to preparation of low-temperature tumor photothermal treatment medicines.
The invention adopts another technical scheme as follows:
the application of zinc glutamate coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine in the coating of cancer cell membranes in the preparation of mitochondria-targeted drugs.
The invention has the beneficial effects that:
1. the invention has the capacity of targeting tumor cells, has long circulation time in vivo, can gather in mitochondria and cause dysfunction, reduces the synthesis of ATP, down-regulates the synthesis of various heat shock proteins, causes apoptosis and effectively enhances the curative effect of low-temperature photothermal therapy of tumors.
2. The invention can prolong the circulation time in the nanoparticle through the components of the CD47 protein and the phospholipid bilayer on the cancer cell membrane, and the surface adhesion factors on the cancer cell membrane can actively target the same kind of cancer cells.
3. The invention can solve the problem of low drug effect caused by slow diffusion of lonidamine in a cell matrix, and the high potential of mitochondria can be quickly accumulated by electrostatic attraction of triphenylphosphine-lonidamine, thereby increasing the drug effect.
4. The invention has excellent photo-thermal performance, can diagnose the tumor area in a mouse body through photo-acoustic imaging, and can judge the tumor position of the nanoparticle through the photo-thermal imaging.
Drawings
FIG. 1 is a schematic diagram of the preparation principle of the present invention.
Fig. 2 is an X-ray diffraction pattern of prussian blue nanoparticles and prussian blue nanoparticles coated with zinc glutamate in example 2 of the present invention.
Fig. 3 is a transmission electron micrograph of prussian blue nanoparticles in example 2 of the present invention.
Fig. 4 is a transmission electron microscope photograph of prussian blue nanoparticles coated with zinc glutamate in embodiment 2 of the present invention.
Fig. 5 is a transmission electron microscope photograph of prussian blue nanoparticles coated with lonidamine-loaded zinc glutamate in cancer cell membrane in embodiment 4 of the present invention.
Fig. 6 is a transmission electron microscope photograph of prussian blue nanoparticles coated with zinc glutamate loaded with triphenylphosphine-lonidamine and wrapped with cancer cell membrane in embodiment 4 of the present invention.
FIG. 7 is a drug release curve diagram of zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membranes at different pH values (7.4 and 5.0) and different temperatures (42 ℃ and 37 ℃) in example 5 of the invention.
FIG. 8 is a graph showing the results of the relative survival rates of HepG2 cells in example 6 of the present invention when co-cultured with lonidamine for (a)24h and (b)48h, and with triphenylphosphine-lonidamine for (c)24h and (d)48h (10 h at 37 ℃ prior, 0, 0.5, 1, 2h at 42 ℃ prior, and 37 ℃ at the end).
Fig. 9 is a graph of the results of experiments on the uptake of zinc glutamate-coated prussian blue nanoparticles and zinc glutamate-coated prussian blue nanoparticles coated with cancer cell membranes by HepG2 cells in example 7 of the present invention.
FIG. 10 is a graph showing the results of cell viability of HepG2 cells treated under different conditions in example 8 of the present invention (808 nm laser irradiation at power density of 1.0W/cm2 for 10min at a drug concentration of 20. mu.g/mL)
FIG. 11 is a (a) Western Blot and (b) relative expression of heat shock protein 90 and heat shock protein 70 expressed by HepG2 cells after different conditions of treatment in example 9 of the present invention.
FIG. 12 is the photo-acoustic imaging images of the tumor sites of the tumor-bearing nude mice in example 10 of the present invention at 0, 4, 8, 12, 24 h.
FIG. 13 is a graph showing the change in tumor volume (a) and the change in body weight (b) of nude mice every other day for 16 days of treatment in example 11 of the present invention.
FIG. 14 is a graph comparing the mean weights of (a) tumors and (b) tumor sizes (n 5, P < 0.05, P < 0.01, P < 0.001) after 16 days of treatment in different ways according to example 12 of the present invention
Detailed Description
The technical solution of the present invention will be further illustrated and described below with reference to the accompanying drawings by means of specific embodiments.
Example 1: preparation of prussian blue nano-particle
135mg of ferric chloride hexahydrate and 2625mg of citric acid monohydrate are weighed and dissolved in 500mL of ultrapure water to prepare a ferric chloride solution; 210mg of potassium ferrocyanide trihydrate and 2625mg of citric acid monohydrate were then dissolved in 500mL of ultrapure water to prepare a solution. 60mL of ferric chloride solution was measured in a beaker, and 60mL of potassium ferrocyanide solution was slowly added dropwise with stirring in a water bath at 60 ℃. And after the dripping is finished, continuously stirring for 1min at the constant temperature of 60 ℃, then transferring to room temperature, stirring for 5min, slowly pouring 120mL of acetone for inducing crystallization, finally centrifugally collecting, washing for 3 times, and carrying out vacuum freeze drying to obtain the Prussian blue nanoparticles.
Example 2: preparation of zinc glutamate coated prussian blue nano particle
3mg of prussian blue nanoparticles of example 1 were dispersed in ultrapure water, 10mL of a polyvinylpyrrolidone solution of 0.5mg/mL was added, and the mixture was stirred for 30min and mixed thoroughly. Then 8mL of a 5mol/L zinc nitrate solution was added dropwise, and the mixture was stirred for 30min to assemble layer 1. After centrifugation, the mixture was washed with water and redispersed. 5mL of 5mol/L disodium glutamate solution is added dropwise, the mixture is stirred for 30min to assemble a layer 2, and the precipitate is collected by centrifugal water washing. And repeatedly assembling 4 layers in the way, centrifugally collecting, washing for 2 times, and carrying out vacuum freeze drying to obtain the zinc glutamate coated Prussian blue nanoparticles.
According to the X-ray diffraction patterns (fig. 2) of the products of example 1 and example 2, all diffraction peak positions correspond to the diffraction surfaces of the prussian blue nanoparticles and the prussian blue nanoparticles coated with zinc glutamate respectively, and the formation of the prussian blue nanoparticles coated with zinc glutamate is shown; the transmission electron microscope photograph (figure 3) of the prussian blue nanoparticles shows that the prussian blue nanoparticles are uniform and square; the transmission electron microscope photograph (figure 4) of the prussian blue nano-particle coated by zinc glutamate can show that the prussian blue nano-particle is of a uniform core-shell structure, the average particle size of the prussian blue nano-particle is 80nm by counting the size distribution of the particle through dynamic light scattering, and the average particle size of the prussian blue nano-particle coated by zinc glutamate is 120 nm.
Example 3: loading of drugs
Weighing 5mg of the prussian blue nanoparticle coated with zinc glutamate prepared in example 2, dispersing the prussian blue nanoparticle in methanol, adding a methanol solution of zinc nitrate to assemble a layer 5, then adding a methanol solution of 2mg of lonidamine, stirring for 2 hours, centrifuging and washing for 2 times to obtain the lonidamine-loaded prussian blue nanoparticle coated with zinc glutamate.
38.1mmol each of triphenylphosphine and 2-aminobromoethane hydrobromide were weighed into a 100mL round-bottomed flask, and 50mL of acetonitrile was added and the reaction stirred at 82 ℃ for 24 h. After the reaction is finished, drying and precipitating to obtain the product triphenylphosphine-aminoethane hydrobromide. 3mmol of lonidamine, 3mmol of 4-dimethylaminopyridine and 3mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are weighed into a round-bottomed flask, 10mL of dimethyl sulfoxide are added and stirred at room temperature in the dark for 6 h. Then 3mmol of triphenylphosphine-aminoethane hydrobromic acid are added, and the mixture is continuously stirred for 72 hours at room temperature in the dark. After the reaction is finished, extracting with dichloromethane and ultrapure water (volume ratio is 5: 1) to obtain the triphenylphosphine-lonidamine.
5mg of prussian blue nanoparticles coated with zinc glutamate prepared in example 2 were weighed and dispersed in methanol, and 2mg of the above methanol solution of triphenylphosphine-lonidamine was added, stirred for 2 hours, centrifuged, and washed with water for 2 times. And 5mL of 5mol/L disodium glutamate solution is added to assemble a layer 5 to obtain zinc glutamate wrapped Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine.
Measuring absorbance of the unloaded lonidamine and the triphenylphosphine-lonidamine in the supernatant, calculating the concentration according to a standard curve, and simultaneously calculating the drug loading rate and the encapsulation rate of the lonidamine to be 21.0 +/-2.2 percent and 51.8 +/-3.5 percent respectively, and the drug loading rate and the encapsulation rate of the triphenylphosphine-lonidamine to be 23.5 +/-2.9 percent and 59.3 +/-2.5 percent respectively.
Example 4: preparation of drug-loaded nanoparticles wrapped by cancer cell membrane
2mg of the lonidamine-loaded zinc glutamate-coated Prussian blue nanoparticles prepared in the embodiment 3 and triphenylphosphine-lonidamine-loaded zinc glutamate-coated Prussian blue nanoparticles are put in ultrapure water and are arranged in a centrifuge tube, the centrifuge tube is placed in an ultrasonic cleaning instrument to be ultrasonically dispersed at the frequency of 40kHz, 50 mu L of extracted HepG2 cell membrane is added in the ultrasonic process, and after 3min, the mixture is centrifuged and washed for 2 times to obtain the zinc glutamate-coated Prussian blue nanoparticles loaded with lonidamine and cancer cell membrane-coated zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine.
According to the transmission electron microscope photographs (fig. 5 and 6), the product prepared in this example is in a cubic structure, and it can be seen that the outer surface is wrapped by a layer of cell membrane, and the thickness is about 10 nm; the average particle diameter of the nanoparticles was 150nm as shown by the statistics of the size distribution of the particles by dynamic light scattering.
Example 5: release of drug under different conditions
2mg of triphenylphosphine-lonidamine-loaded zinc glutamate-coated prussian blue nanoparticles prepared in example 3 and 2mg of triphenylphosphine-lonidamine-loaded zinc glutamate-coated prussian blue nanoparticles prepared in example 4, which are coated with cancer cell membranes, are respectively put into a dialysis bag with the molecular weight cut-off of 3500Da, the dialysis bag is clamped and then put into a centrifuge tube, and 30mL of PBS with the pH value of 7.4 or 5.0 is added. The temperature of the shaker was set at 43 ℃ and 37 ℃ respectively for drug release. At different time points 0.5, 1, 2, 4, 6, 9, 12, 24, 36, 48.. h the absorbance was determined with 3mL of drug-released PBS and supplemented with 3mL of fresh PBS, each group in triplicate. The corresponding concentration was calculated from the standard curve and the cumulative release rate of the drug was calculated.
Fig. 7 shows a drug release curve, which shows that the cumulative release rate of triphenylphosphine-lonidamine to triphenylphosphine-lonidamine of zinc glutamate-coated prussian blue nanoparticles loaded with triphenylphosphine-lonidamine wrapped by cancer cell membranes is about 50% within 120h at the pH of 5.0 and 42 ℃; a cumulative release rate of about 40% at pH 5.0 and 37 ℃; a cumulative release rate of about 35% at pH 7.4 and 42 ℃; the cumulative release rate at pH 7.4 and 37 ℃ was about 20%, the release was slowest, and pH-and temperature-responsive drug release was exhibited.
Example 6: antitumor effect of free drug
HepG2 cells were seeded at a cell density of 8X 103 cells/well in a 96-well plate, and 100. mu.L of DMEM complete medium was added to each well, and cultured at 37 ℃ for 24 hours under 5% CO2 conditions. Then DMEM complete culture medium containing lonidamine and triphenylphosphine-lonidamine is replaced, and the drug concentration is 2, 5, 10, 20 and 50 mu g/mL respectively. The 96-well plate is firstly placed in an incubator at 37 ℃ for culturing for 10h, then transferred to an incubator at 42 ℃, cultured for 0.5h, 1h and 2h at 42 ℃ respectively, and finally transferred to the incubator at 37 ℃ for culturing. After the total culture time is 24h and 48h, the cell survival rate is measured by the CCK-8 method.
In FIG. 8, lonidamine, a drug with low antitumor effect, maintains high cell survival rate after 24h and 48h of co-culture with HepG2 even at a concentration as high as 50 μ g/mL; after incubation at 42 ℃, the cell survival rate is reduced by about 25%, which shows that the sensitivity of HepG2 cells to high temperature is obviously improved under the action of lonidamine, and the lonidamine is also proved to have the effect of overcoming the heat resistance of tumor cells. When the concentration of the triphenylphosphine-lonidamine is 20 mug/mL, the inhibition effect of the lonidamine on HepG2 cells at 50 mug/mL is higher, which shows that the triphenylphosphine-lonidamine has stronger drug effect, so that the HepG2 cells are more sensitive to high temperature; shows that the antitumor effect of the compound is enhanced after the target mitochondrion group triphenylphosphine is connected.
Example 7: cellular uptake
HepG2 cells were seeded onto a slide in a 24-well plate at a cell density of 1X 105 cells/well. After 24h, the medium was changed to a new medium containing 50. mu.g/mL of Prussian blue nanoparticles coated with the product zinc glutamate of example 2 and Prussian blue nanoparticles coated with the product zinc glutamate of example 3, which was coated with cancer cell membrane. Incubations were continued for 2h and 4h in the 37 ℃ incubator, followed by 3 washes with PBS and fixation with 0.5mL 4% paraformaldehyde per well for 15 min. EB dye is used for shading and dyeing cell nucleus for 5-10min, 10 mu L of anti-fluorescence quenching agent is dripped on the slide, and the slide is sealed after the slide is placed and observed under CLSM.
In fig. 9, HepG2 cells were incubated with zinc glutamate-coated prussian blue nanoparticles and cancer cell membrane-coated zinc glutamate-coated prussian blue nanoparticles for 2h, and the tumor cells were stained with dye EB and observed under CLSM, and the prussian blue nanoparticles were excited under 405nm laser to generate blue fluorescence. The blue fluorescence of the zinc glutamate-coated Prussian blue nanoparticle group is stronger, which indicates that more zinc glutamate-coated Prussian blue nanoparticles enter HepG2 cells, and the fact that the Prussian blue nanoparticles obtain targeting capability after being coated with HepG2 cell membranes is confirmed.
Example 8: low temperature photothermal effect on tumor cells
HepG2 cells were seeded in 96-well plates at a cell density of 8X 103 cells/well, and medium containing triphenylphosphine-lonidamine and zinc glutamate-coated Prussian blue nanoparticles, loaded with triphenylphosphine-lonidamine, coated with the cancer cell membrane of the product of example 3 were added at concentrations of 10, 20, 50, 100, 150, and 200. mu.g/mL, respectively. After 10h, the cells were irradiated with 808nm laser at 1.0W/cm2 for 10min, and then cultured at 37 ℃. The total time of the culture was 24h, and 100. mu.L of DMEM medium and 10. mu.L of CCK-8 reagent were used instead, wherein the blank was CCK-8 reagent. Continuously culturing in the incubator for 1-4h, detecting by a microplate reader at the wavelength of 450nm, and calculating the cell survival rate.
In FIG. 10, the triphenylphosphine-lonidamine equivalent concentration remained unchanged at 20. mu.g/mL under the different treatment conditions, and the effect on tumor cells was weak. Under the laser irradiation of zinc glutamate wrapped Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membranes, the survival rate of HepG2 cells is 39.7 +/-6.1%, and the effect of cell inhibition is better than that of independent treatment of triphenylphosphine-lonidamine and photo-thermal treatment. After the prussian blue nanoparticle group is wrapped by zinc glutamate wrapped by cancer cell membranes through laser irradiation, the temperature rise caused by photothermal effect is limited, so that a large amount of cell death is not caused. In the zinc glutamate-wrapped Prussian blue nanoparticle group loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membranes, the laser irradiation temperature is the same, but a large number of cells die, which shows that the triphenylphosphine-lonidamine drug enables HepG2 cells to be more sensitive to heat. The experimental results and the experimental results fully show that the prussian blue nanoparticle coated with zinc glutamate loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane can enhance the tumor photothermal treatment effect.
Example 9: ATP level detection
HepG2 cells were seeded at 1X 105 cells/well in 6-well plates and cultured for 24 h. Absorbing the culture medium, and adding a culture medium containing lonidamine, triphenylphosphine-lonidamine, and the product of example 4, wherein the cancer cell membrane wraps lonidamine-loaded zinc glutamate-wrapped Prussian blue nanoparticles, and the cancer cell membrane wraps triphenylphosphine-lonidamine-loaded zinc glutamate-wrapped Prussian blue nanoparticles, wherein the concentration of the drug is 20 mug/mL. After 12h of culture, 200. mu.L of lysate was added to each well, the lysed cells were repeatedly blown up, and then centrifuged at 12000g at 4 ℃ for 5min, and the supernatant was measured. Add 100. mu.L of ATP detection working solution to 96-well plate, add 20. mu.L of sample, mix well rapidly, and measure fluorescence signal with chemiluminescence apparatus.
In fig. 11, when the concentration of the drug is 20 μ g/mL, the ATP levels of the lonidamine group and the zinc glutamate-coated prussian blue nanoparticle group loaded with lonidamine and wrapped by the cancer cell membrane are higher, and the ATP levels of the triphenylphosphine-lonidamine group and the zinc glutamate-coated prussian blue nanoparticle group loaded with triphenylphosphine-lonidamine and wrapped by the cancer cell membrane are lower, which indicates that the drug effect of lonidamine is enhanced after the triphenylphosphine is linked to the targeting group.
Example 10: western Blot
Planting HepG2 cells in a 6-well plate, adding various groups of solutions for treatment after the cells are cultured for 12h to adhere to the wall, dividing the cells into a first group of negative control groups, and carrying out no treatment; second group, incubation at 42 ℃ for 30 min; adding zinc glutamate wrapped by cancer cell membrane to wrap Prussian blue nanoparticles, and irradiating for 10min under 808nm laser; the fourth group is added with triphenylphosphine-lonidamine with the concentration of 20 mug/mL; the fifth group corresponds to a triphenylphosphine-lonidamine concentration of 20. mu.g/mL. Incubation was continued for 24h, then the old medium was carefully discarded to avoid the cells that were not tightly detached, and DMEM medium was removed by washing 2 times with PBS. Prepared according to the ratio of 1mL lysate to 10. mu.L PMSF (100mM) and shaken well on ice. Adding lysate, fully lysing, centrifuging at 4 deg.C for 5min with high speed centrifuge, storing the supernatant as extracted HepG2 cell whole protein in-20 deg.C refrigerator, and detecting expression levels of heat shock protein 70 and heat shock protein 90 by Western blot.
In fig. 12, in the zinc glutamate-coated prussian blue nanoparticle group coated with cancer cell membrane at high temperature of 42 ℃ and laser irradiation, the expression levels of heat shock protein 70 and heat shock protein 90 increased by about 30% using GADPH as an internal standard protein, indicating that heat shock protein is synthesized in large amounts under the induction of thermal stimulation to protect cells from damage. Under the action of triphenylphosphine-lonidamine, the ATP content is reduced, which results in insufficient energy for synthesizing heat shock protein in cells, and the contents of heat shock protein 70 and heat shock protein 90 are greatly reduced to about 1/4 of a negative control group. The Western Blot experiment result corresponds to the change of mitochondrial membrane potential and ATP level content, confirms the action mechanism of triphenylphosphine-lonidamine, reduces the synthesis of heat shock protein by reducing ATP content, and achieves the purpose of improving the photothermal treatment effect.
Example 11: in vivo photoacoustic imaging
When the tumor volume grows to about 200mm3, 200 μ L of PBS, PBS suspension of example 3 product of zinc glutamate wrapped Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine, and PBS suspension of example 4 product of cancer cell membrane wrapped Prussian blue nanoparticles loaded with zinc glutamate wrapped Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine are injected into tail vein of BALB/c nude mice inoculated with HepG2 cell tumor respectively, and the concentration of the relative Prussian blue nanoparticles is 1mg/mL, and each group contains three relative to the concentration of the Prussian blue nanoparticles. Photoacoustic signals at the tumor site were detected by small animal photoacoustic imagers at different time points 0, 4, 8, 12, 24h, respectively, to observe the enrichment in tumor tissue.
FIG. 13 shows that in 12h after the Prussian blue nanoparticles are wrapped by zinc glutamate loaded with triphenylphosphine-lonidamine through tail vein injection and the Prussian blue nanoparticles are wrapped by zinc glutamate loaded with triphenylphosphine-lonidamine through cancer cell membrane, photoacoustic signals in tumor tissues are gradually increased along with blood circulation of the nanoparticles in a mouse body. The photoacoustic signal area is the largest and strongest by 12h, and the photoacoustic signal strength and area are weakened after 24 h. In addition, tumor tissues generate strong photoacoustic signals, the appearance of the tumor tissues is displayed, and therefore the tumor tissues are distinguished from normal tissues, the signal to noise ratio of the photoacoustic signals is greatly increased, and certain reference is provided for diagnosis of tumors. The photoacoustic signals in the tumor tissue are more strongly distributed after the cancer cell membrane is wrapped, and the targeting property of the cancer cell membrane is verified.
Example 12: animal level verification for enhancing photothermal treatment effect
30 BALB/c nude mice inoculated with HepG2 cell tumor were randomly divided into 6 groups of 5 mice each. When the tumor volume is about 200mm3, 200 mu L solution is injected into tail vein by different treatment modes: PBS was injected into tail vein of the first group; injecting PBS into tail vein of the second group, and irradiating 808nm laser for 5 min; the third group of Prussian blue nano-particles are wrapped by zinc glutamate wrapped by cancer cell membranes through tail vein injection; irradiating the fourth group of Prussian blue nanoparticles wrapped by zinc glutamate and wrapped by cancer cell membrane by tail vein injection for 5min with laser of 808 nm; a fifth group of tail vein injection cancer cell membranes wrap zinc glutamate wrapped Prussian blue nano-particles loaded with triphenylphosphine-lonidamine; and a sixth group of tail vein injection cancer cell membranes wrap zinc glutamate wrapped Prussian blue nano-particles loaded with triphenylphosphine-lonidamine, and then 808nm laser is irradiated for 5 min. It was treated 1 more times every other day for a total of 2 times, and the body weight and tumor volume changes of the nude mice were recorded. After 16 days of treatment, the mice were dissected to obtain tumor tissues, and the tumor inhibition rates were calculated by weighing the tumor tissues.
FIG. 14 shows that the size of the tumor volume in the first group increased from about 200mm3 to 985.5. + -. 165.5mm3 and the tumor volume in the second group increased to 964.7. + -. 119.9mm3 after 16d treatment, indicating that the growth of the tumor tissue was hardly affected by the irradiation of the near-infrared laser. The inhibition effect of triphenylphosphine-lonidamine on tumor cells is observed, the size of the tumor volume of the zinc glutamate wrapped Prussian blue nanoparticle group loaded with triphenylphosphine-lonidamine wrapped by the cancer cell membrane is 874.4 +/-189.9 mm3, and the tumor volume is slightly reduced, which shows that the inhibition effect of triphenylphosphine-lonidamine on the tumor is not large when the triphenylphosphine-lonidamine is used alone. After treatment, mice were euthanized and tumor tissue was dissected out, weighed and photographed. The mean tumor weight of the PBS control group was 1.02g, the mean tumor mass in the sixth group was 0.11g, and the tumor inhibition rate was 89.2%. The average mass of zinc glutamate wrapped Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine under the independent action of laser irradiation and cancer cell membrane wrapping is 0.58g and 0.89 g. The body weight of each group of mice does not change obviously before and after treatment, and the nano drug-loaded system has good biological safety. From the combined treatment result of tumor-bearing mice, the zinc glutamate-wrapped Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membranes have good treatment effect on the tumor-bearing mice with HepG2, which indicates that the zinc glutamate-wrapped Prussian blue nanoparticles have certain application potential in the field of biological medicine.
The above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, which is defined by the appended claims.

Claims (10)

1. A zinc glutamate wrapped Prussian blue nanoparticle loaded with triphenylphosphine-lonidamine and wrapped by a cancer cell membrane is characterized in that: the tumor cell membrane comprises a Prussian blue nano core, wherein the surface of the Prussian blue nano core is coated with at least one zinc glutamate layer, the surface of the outermost zinc glutamate layer is provided with a loading layer loaded with triphenylphosphine-lonidamine, and the loading layer is coated with a tumor cell membrane layer.
2. The method for coating zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine on cancer cell membranes according to claim 1, which is characterized in that: the tumor cell membrane layer is made of extracted HepG2 cell membrane.
3. The method for coating zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine on cancer cell membranes according to claim 1, which is characterized in that: the triphenylphosphine-lonidamine is prepared by connecting triphenylphosphine and lonidamine through (2-bromomethyl) dimethylamine hydrobromide.
4. The zinc glutamate-coated Prussian blue nanoparticle loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane according to any one of claims 1 to 3, wherein: the particle size is 100-200 nm.
5. The zinc glutamate-coated Prussian blue nanoparticle loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane according to claim 4, wherein: the particle size of the Prussian blue nano-core is 70-90 nm.
6. The preparation method of zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane according to any one of claims 1 to 5, which is characterized in that: the method comprises the following steps:
(1) preparing prussian blue nanoparticles by a hydrothermal synthesis method;
(2) the preparation method of the zinc glutamate coated Prussian blue nanoparticles comprises the following steps:
a. mixing the prussian blue nanoparticles with a polyvinylpyrrolidone aqueous solution, dropwise adding a zinc nitrate solution for reaction, centrifuging, washing with water, and dispersing;
b. dropwise adding a glutamic acid disodium solution into the material obtained in the step a for reaction, centrifugally washing, collecting precipitates, repeating the steps for 1-3 times, and centrifugally collecting to obtain zinc glutamate-coated prussian blue nanoparticles;
(3) preparing zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine: dispersing the zinc glutamate-coated Prussian blue nanoparticles obtained in the step (2) in methanol, adding a triphenylphosphine-lonidamine methanol solution, fully stirring, centrifuging, washing with water, and adding a disodium glutamate solution for reaction to obtain triphenylphosphine-lonidamine-loaded zinc glutamate-coated Prussian blue nanoparticles;
(4) preparing zinc glutamate wrapped Prussian blue nanoparticles with cancer cell membranes wrapped and loaded with triphenylphosphine-lonidamine: ultrasonically dispersing the zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine obtained in the step (3) into ultrapure water, dropwise adding the extracted tumor cell membranes in the ultrasonic process, centrifuging and collecting after 2-5min, and fully washing to obtain the zinc glutamate-coated Prussian blue nanoparticle.
7. The method of claim 6, wherein: the step (1) is as follows: dissolving ferric chloride hexahydrate and citric acid monohydrate in ultrapure water to prepare a ferric chloride solution; dissolving potassium ferrocyanide trihydrate and citric acid monohydrate in ultrapure water to prepare a potassium ferrocyanide solution; slowly dropwise adding a potassium ferrocyanide solution into the ferric chloride solution at 58-62 ℃ while stirring; and after the dripping is finished, continuously stirring for 0.8-1.2min at the constant temperature of 58-62 ℃, then transferring to room temperature, stirring for 4-6min, slowly pouring acetone for inducing crystallization, and sequentially carrying out centrifugal collection, full water washing and vacuum freeze drying to obtain the Prussian blue nanoparticles.
8. The method of claim 6, wherein: the frequency of the ultrasonic dispersion in the step (4) is 35-45 kHz.
9. The use of zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane as claimed in any one of claims 1 to 5 in the preparation of low-temperature tumor photothermal therapy medicine.
10. The use of zinc glutamate-coated Prussian blue nanoparticles loaded with triphenylphosphine-lonidamine and wrapped by cancer cell membrane as claimed in any one of claims 1-5 in the preparation of mitochondria-targeted drugs.
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