CN108785673B - Sodium nitroprusside conjugated drug-loaded Prussian blue analogue nano photothermal therapeutic agent and preparation method thereof - Google Patents
Sodium nitroprusside conjugated drug-loaded Prussian blue analogue nano photothermal therapeutic agent and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a sodium nitroprusside conjugated drug-loaded Prussian blue analogue nano photothermal therapeutic agent and a preparation method thereof. Under the irradiation of near-infrared laser, the nano photothermal therapeutic agent can not only induce photothermal ablation tumor cells through excellent photothermal conversion efficiency, but also control NO release, thereby improving EPR effect and increasing the delivery in nanoparticle tumors. Meanwhile, NO can also inhibit tumor progression by inducing tumor cell apoptosis, preventing angiogenesis, reversing multidrug resistance, and the like. After carrying the chemotherapy drugs, the tumor treatment combining the dose-controllable NO release, the photothermal treatment and the chemotherapy can be realized under the irradiation of near infrared light. In addition, the sodium nitroprusside conjugated drug-loaded Prussian blue analogue nano photothermal therapeutic agent has good photothermal stability and certain photoacoustic contrast performance.
Description
Technical Field
The invention relates to the field of medical drugs, in particular to a sodium nitroprusside-conjugated drug-loaded Prussian blue analogue nano photothermal therapeutic agent and a preparation method thereof.
Background
Nitric Oxide (NO) is an important signal molecule produced endogenously by nitric oxide synthase. It plays a vital role in various biological systems such as cardiovascular, nervous, respiratory, gastrointestinal and immune systems. In recent years, the effects of NO on tumor proliferation, apoptosis and metastasis have attracted attention. Notably, the anti-tumor effect of NO strongly depends on its concentration at the target. For example, picomolar NO promotes tumor progression by stimulating tumor cell growth and enhancing angiogenesis, while micromolar NO inhibits tumor progression by inducing tumor cell apoptosis, preventing angiogenesis, reversing multidrug resistance. Therefore, strategies to precisely spatio-temporally control the release of NO in a physiological environment and to improve its bioavailability are of great importance to optimize the therapeutic effect of NO. The most common method is to photoexcite inactive precursors to release NO, and to achieve controllable dosage of NO to a specific physiological target by adjusting photoexcitation signals, and has little influence on non-target tissues. Near infrared light has a distinct advantage over ultraviolet and visible light in the light generation of NO because it has a greater depth of penetration and is relatively gentle to tissue.
Photothermal therapy is a promising tumor treatment technology recently developed. Photon energy is converted into heat energy by using a photothermal conversion material, so that the temperature of the tissue is rapidly increased to ablate tumor cells. Hyperthermia caused by photothermal therapy can be controlled to minimize damage to non-targeted tissue by locally applying minimally invasive near-infrared illumination. However, complete elimination of tumors using photothermal therapy alone is difficult due to uneven distribution of heat within the tumor tissue, which necessarily leads to tumor recurrence and metastasis. Compared with the single-use photothermal therapy, the combined chemotherapy strategy can exert obvious synergistic effect and greatly improve the treatment effect.
Prussian blue is widely known as an antidote approved by the U.S. food and drug administration for the treatment of radiation exposure, and exhibits good biocompatibility and biosafety. Recently, due to the feature that prussian blue exhibits high absorbance in the near infrared light window, it has attracted attention of many researchers as one of near infrared light-driven photothermal therapeutic agents. However, due to the heterogeneity and poor penetration of tumors, the nanoparticles accumulate less in the tumor tissue.
Sodium nitroprusside exerts its powerful vasodilating effect by the metabolic production of NO in vascular smooth muscle and is a common drug for the treatment of hypertensive emergencies and acute left heart failure. It is worth noting that sodium nitroprusside is an NO donor, and it is similar in structure to the raw material potassium ferricyanide in the mesoporous Prussian blue synthesis process. Therefore, in the synthesis process of the mesoporous Prussian blue, sodium nitroprusside is added to be embedded into a crystal structure, and the Prussian blue analogue conjugated with sodium nitroprusside is prepared.
The sodium nitroprusside-conjugated drug-loaded Prussian blue analogue nano photothermal therapeutic agent prepared by the hydrothermal synthesis method has small particle size and uniform dispersion, and can realize passive targeting through the EPR effect of a tumor part. Under the irradiation of near-infrared laser, the nano photothermal therapeutic agent can not only induce photothermal ablation tumor cells through excellent photothermal conversion efficiency, but also control NO release, thereby improving EPR effect and increasing the delivery in nanoparticle tumors. Meanwhile, NO can also inhibit tumor progression by inducing tumor cell apoptosis, preventing angiogenesis, reversing multidrug resistance, and the like. On the other hand, due to the structural difference of sodium nitroprusside and potassium ferricyanide, the lattice defect of the nanoparticle is caused, so that the drug loading rate of the nano photothermal therapeutic agent is increased. Therefore, after carrying the chemotherapeutic drug, under the irradiation of near infrared light, the combined tumor treatment of the dose-controllable NO release, the photothermal treatment and the chemotherapy is realized. However, no report is provided for the nano photothermal therapeutic agent of the drug-loaded Prussian blue analogue conjugated with sodium nitroprusside and the preparation method thereof.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a sodium nitroprusside conjugated drug-loaded Prussian blue analogue nano photothermal therapeutic agent and a preparation method thereof. The novel nano photothermal therapeutic agent has small particle size and uniform dispersion, and can realize passive targeting through the EPR effect of the tumor part. Under the irradiation of near-infrared laser, the nano photothermal therapeutic agent can not only induce photothermal ablation tumor cells through excellent photothermal conversion efficiency, but also control NO release, thereby improving EPR effect and increasing the delivery in nanoparticle tumors. Meanwhile, NO can also inhibit tumor progression by inducing tumor cell apoptosis, preventing angiogenesis, reversing multidrug resistance, and the like. On the other hand, due to the structural difference of sodium nitroprusside and potassium ferricyanide, the lattice defect of the nanoparticle is caused, so that the drug loading rate of the nano photothermal therapeutic agent is increased. Therefore, after carrying the chemotherapeutic drug, under the irradiation of near infrared light, the combined tumor treatment of the dose-controllable NO release, the photothermal treatment and the chemotherapy is realized. The advantages of the combination therapy are not only that the effect of the monotherapy is not lost, but also that the treatment effect is obviously improved, the treatment period is shortened, and the adverse side effect is reduced. In addition, the nano photothermal therapeutic agent also has good photothermal stability and certain photoacoustic contrast performance. The nano photothermal therapeutic agent of the sodium nitroprusside conjugated drug-loaded Prussian blue analogue is prepared by a hydrothermal synthesis method, the process is simple and convenient, and the adopted materials are economical and practical, have good biocompatibility and have wide application prospect.
The purpose of the invention can be realized by the following technical scheme:
step 1: weighing a proper amount of potassium ferricyanide, sodium nitroprusside and polyvinylpyrrolidone into a certain amount of hydrochloric acid solution, and stirring for a certain time under a magnetic stirrer to uniformly disperse the potassium ferricyanide, the sodium nitroprusside and the polyvinylpyrrolidone to obtain a mixed solution.
Step 2: and (3) placing the mixed solution obtained in the step (1) into a water bath kettle, and stirring and reacting for a certain hour at the temperature of 60-80 ℃.
And step 3: collecting the precipitate from the product obtained in step 2. Washing the precipitate with water and ultrasonic wave for several times to obtain sodium nitroprusside conjugated Prussian blue analogue nano-particles.
And 4, step 4: and (3) dispersing the sodium nitroprusside-conjugated Prussian blue analogue nanoparticles obtained in the step (3) in a certain amount of water, adding a certain amount of ethanol solution of a fat-soluble medicament, and stirring and reacting at room temperature for 12 hours. And volatilizing the ethanol solvent of the mixed solution obtained by the reaction on a rotary evaporator, centrifuging, collecting the precipitate, washing with water for several times, and removing the drug which is not carried, thereby obtaining the sodium nitroprusside conjugated drug-loaded prussian blue analogue nano photothermal therapeutic agent.
The invention successfully prepares the drug-loaded Prussian blue analogue nanoparticles conjugated with sodium nitroprusside by applying a hydrothermal synthesis method, the synthesis method has the advantages of low price and easy obtainment of raw materials, simple preparation process, less time consumption and easy large-scale batch production, the prepared nanoparticles have uniform particle size and good biocompatibility and biosafety, and have excellent photo-thermal conversion performance and photo-thermal stability, meanwhile, the controlled release of NO can be realized under the irradiation of near infrared light, and the photo-thermal treatment of tumors, the chemotherapy and the synergistic treatment of NO can be realized after drug loading.
Drawings
Fig. 1 is a transmission electron microscope image of sodium nitroprusside-conjugated prussian blue analogue nanoparticles in example 1 of the present invention.
Fig. 2 is a particle size distribution diagram of sodium nitroprusside-conjugated prussian blue analogue nanoparticles in example 1 of the present invention.
Fig. 3 is a fourier infrared spectrum of sodium nitroprusside-conjugated prussian blue analogue nanoparticles in example 1 of the present invention.
Fig. 4 is a temperature rise curve of 0.2mg/mL sodium nitroprusside conjugated prussian blue analogue nanoparticles in example 2 of the present invention under 808nm laser irradiation for 10 minutes at different power densities.
FIG. 5 shows the concentration at 0.8W/cm in example 3 of the present invention2And a heating curve of sodium nitroprusside conjugated Prussian blue analogue nanoparticles with different concentrations under the irradiation of laser with 808 nm.
Fig. 6 shows the release of NO from sodium nitroprusside-conjugated prussian blue analogue nanoparticles of example 4 under 808nm laser irradiation at different power densities.
Fig. 7 shows the release of NO from sodium nitroprusside-conjugated prussian blue analogue nanoparticles in example 5 of the present invention under pulsed 808nm laser irradiation.
Fig. 8 shows the cumulative drug release behavior of sodium nitroprusside conjugated drug-loaded prussian blue analogue nanoparticles in example 6 of the present invention.
Fig. 9 shows the toxicity of sodium nitroprusside-conjugated prussian blue analogue nanoparticles on 4T1 cells at different concentrations in example 7 of the present invention.
Fig. 10 shows that in example 8 of the present invention, sodium nitroprusside-conjugated prussian blue analog nanoparticles are used as a carrier to realize the synergistic tumor treatment of thermotherapy, chemotherapy and NO treatment at the cell level.
Fig. 11 shows toxicity of sodium nitroprusside-conjugated prussian blue analogue nanoparticles and sodium nitroprusside-conjugated drug-loaded prussian blue analogue nanoparticles on 4T1 cells under different laser irradiation time in example 9 of the present invention.
FIG. 12 is a tumor volume growth curve of a mouse in example 10 of the present invention.
Detailed Description
The present invention will be described in detail below with reference to the embodiments shown in the drawings, but the present invention is not limited to the embodiments.
Example 1
1. Preparation of sodium nitroprusside conjugated Prussian blue analogue nanoparticles (m-PB-NO)
60mg of potassium ferricyanide, 488.7mg of sodium nitroprusside and 3g of polyvinylpyrrolidone (PVP) were weighed into 40mL of 0.1M hydrochloric acid solution and stirred for 20 minutes to disperse them uniformly. And transferred to a water bath, and the reaction was stirred at 80 ℃ for 12 hours. And centrifuging, collecting the precipitate, and ultrasonically washing for 3 times by using water to obtain the sodium nitroprusside conjugated Prussian blue analogue nanoparticles.
2. Preparation of sodium nitroprusside conjugated drug-loaded Prussian blue analogue nanoparticles (DTX @ m-PB-NO)
Taking Docetaxel (DTX) as a model drug, dispersing 10mg of Prussian blue analogue nanoparticles conjugated with sodium nitroprusside in 10mL of water, adding 1mL of 1.5mg/mL docetaxel ethanol solution, and stirring for reaction for 12 hours. And volatilizing the ethanol solvent of the mixed solution obtained by the reaction on a rotary evaporator, centrifuging, collecting the precipitate, washing with water for several times, and removing the drug which is not carried, thereby obtaining the sodium nitroprusside conjugated drug-loaded prussian blue analogue nano photothermal therapeutic agent.
The prepared m-PB-NO is diluted by a certain multiple, and the form of the m-PB-NO is observed by a transmission electron microscope, as shown in figure 1, and the m-PB-NO is of a cuboid structure. The particle size was measured by a Malvern laser particle size analyzer, and the particle size distribution was as shown in FIG. 2, with the average particle size of m-PB-NO being 205. + -. 10.25 nm. Fourier infrared analysis verifies the successful conjugation of sodium nitroprusside, and as shown in figure 3, a cyano group at 2086cm is observed from mesoporous Prussian blue (m-PB) and m-PB-NO-1Strong stretching vibration of the parts. 1944cm observed from sodium nitroprusside and m-PB-NO-1The absorption peak of the nitroso group shows that SNP can be embedded in the m-PB framework structure to form m-PB-NO
Example 2
m-PB-NO prepared in example 1 was dispersed in water to form a 0.2mg/mL suspension, and 1mL of the suspension was taken in a quartz cuvette. The power density of the power of 0.8W/cm2、1.0W/cm2、1.5W/cm2、2.0W/cm2、2.5W/cm2Respectively irradiating with 808nm laser beams 10 minute, recording the temperature change at different time points by using a thermocouple probe thermometer as shown in FIG. 4, the temperature of the solution gradually increased with the increase of the irradiation time, and the temperature rising speed of the solution increased with the increase of the laser power when the laser power was 2.5W/cm2When the temperature of the solution was increased to 63.4 ℃, it was shown that m-PB-NO had excellent photothermal conversion efficiency.
Example 3
The m-PB-NO prepared in example 1 was dispersed in water, and 0.05mg/mL, 0.1mg/mL, 0.2mg/mL, 0.5mg/mL, 1mg/mL of m-PB-NO suspension was taken up in a quartz cuvette and water was used as a blank. The power density of the power of 0.8W/cm2The 808nm laser beams are respectively irradiated for 10 minutes, the temperature change conditions of different time points are recorded by using a thermocouple probe thermometer, as shown in figure 5, the temperature of the solution is gradually increased along with the prolonging of the irradiation time, meanwhile, the temperature rising speed of the solution is faster along with the increasing of the m-PB-NO concentration, and when the m-PB-NO concentration is 1mg/mL, the temperature of the solution is increased to 47.5 ℃, which indicates that the m-PB-NO has excellent photothermal conversion efficiency.
Example 4
The m-PB-NO prepared in example 1 was dispersed in PBS, 1mL of 1mg/mL m-PB-NO suspension was added to a quartz cuvette using a power density of 1.5W/cm2、2.0W/cm2、2.5W/cm2The 808nm laser light of (1) was irradiated for 20 minutes, and the blank was not irradiated. As shown in FIG. 6, the NO release amount of the sample measured by using the NO detection kit gradually increases with the increase of the irradiation time, and the NO release rate also increases with the increase of the laser power, and the result shows that m-PB-NO can release a certain amount of NO under the irradiation of the near-infrared laser.
Example 5
The m-PB-NO prepared in example 1 was dispersed in PBS and 1mL of a 1mg/mL suspension of m-PB-NO was added to a quartz cuvette using a power density of 2.5W/cm2808nm laser irradiation for 5 minutes, then turning off the laser for 5 minutes, then performing two laser cycles again, and measuring the amount of NO released in the sample at selected time intervals by using the NO test kit as shown in FIG. 7When the laser is turned on, the m-PB-NO quickly releases NO, and the NO release amount is hardly increased along with the turn-off of the laser, so that the result shows that the m-PB-NO can stimulate and respond to a near-infrared laser signal, and the NO can be controlled and released by adjusting the laser signal.
Example 6
Samples of DTX @ m-PB-NO prepared in example 1 and free DTX were dispersed in PBS and placed in dialysis bags, which were immersed in a PBS solution containing 0.5% (v/v) Tween 80. Shaking in a shaker at 37 ℃ with a rotation speed of 120 rpm. 2mL of the solution was removed at different time points and then the same amount of fresh PBS was added and DTX in its cumulative release was determined by high performance liquid chromatography. Test results as shown in fig. 8, the cumulative release rate of DTX suspension at 36 hours was only 50.65% due to poor water solubility of DTX, exhibiting a relatively slow release rate. In contrast, in DTX @ m-PB-NO, the cumulative release rate at 12 hours was 69.92% and at 24 hours was 81.45% due to the increased dispersibility of DTX, which exhibited a relatively fast release rate.
Example 7
The m-PB-NO prepared in example 1 was taken and prepared to a concentration of 0.0063mg/mL, 0.0125mg/mL, 0.025mg/mL, 0.05mg/mL, 0.1mg/mL, 0.2mg/mL, 0.5mg/mL in RPMI-1640 cell culture medium containing 10% fetal calf serum, and the toxicity of the different m-PB-NO carrier concentrations on 4T1 cells was evaluated by the thiazole blue (MTT) method. As shown in FIG. 9, the survival rate of 4T1 cells was as high as 90% even at a concentration of m-PB-NO as high as 0.5mg/mL, demonstrating that m-PB-NO was not toxic to cells.
Example 8
The m-PB-NO and DTX @ m-PB-NO prepared in example 1 and free DTX were taken, RPMI-1640 cell culture medium containing 10% fetal bovine serum was prepared to different concentrations containing the same amount of DTX, and the toxicity of the different treatment methods on 4T1 cells was evaluated by the thiazole blue (MTT) method. 4T1 murine mammary carcinoma cells were cultured in RPMI-1640 medium containing 10% (v/v) fetal bovine serum and 1% penicillin/streptomycin at 37 ℃ under 5% CO2Culturing under an atmosphere. Cells (5X 10 per well)3One) were seeded in 96-well culture plates and incubated for 24 hours to attach cells. Removing the culture mediumThen adding DTX, m-PB-NO and DTX @ m-PB-NO with different concentrations and the same DTX amount. After 24 hours, the power density is 1.5W/cm2The cells containing m-PB-NO and DTX m-PB-NO were irradiated with the 808nm laser for 5 minutes. After a further 24 hours of incubation, the cells were washed twice with PBS buffer, followed by addition of 10. mu. LMTT solution (5mg/mL) and 90. mu.L of fresh medium and incubated for a further 4 hours. The medium in each well was then replaced with 150 μ L of dimethyl sulfoxide (DMSO), absorbance was measured at 490nm after gentle shaking and the corresponding cell viability was calculated. As shown in fig. 10, the cell survival rate of DTX @ m-PB-NO gradually decreased with the increase of the DTX concentration, and the cell survival rate further decreased and the killing power against the cells further increased after the laser irradiation.
Example 9
The m-PB-NO and DTX @ m-PB-NO prepared in example 1 and free DTX were mixed with RPMI-1640 cell culture medium containing 10% fetal bovine serum to prepare different concentrations containing the same amount of DTX, and the toxicity of 4T1 cells was evaluated by the thiazole blue (MTT) method at different laser irradiation times. 4T1 murine mammary carcinoma cells were cultured in RPMI-1640 medium containing 10% (v/v) fetal bovine serum and 1% penicillin/streptomycin at 37 ℃ under 5% CO2Culturing under an atmosphere. Cells (5X 10 per well)3One) were seeded in 96-well culture plates and incubated for 24 hours to attach cells. The medium was removed and different concentrations of DTX, m-PB-NO and DTX @ m-PB-NO containing the same amount of DTX were added. After 24 hours, the power density is 1.5W/cm2After incubation for 24 hours, the cells were washed twice with PBS buffer, and then 10. mu.L of LMTT solution (5mg/mL) and 90. mu.L of fresh medium were added and incubated for 4 hours. The medium in each well was then replaced with 150 μ L of dimethyl sulfoxide (DMSO), absorbance was measured at 490nm after gentle shaking and the corresponding cell viability was calculated. The experimental results are shown in FIG. 11, and the cell survival rate does not change much with the increase of the laser irradiation time for the free DTX and blank groups, which indicates that the laser has NO effect on the cells of the free DTX and blank groups, while the cell survival rate is significantly reduced with the increase of the irradiation time for the m-PB-NO and DTX @ m-PB-NO groups, which is shown in the tableThe Ming m-PB-NO and the DTX @ m-PB-NO have obvious photothermal treatment effect, and can play an obvious synergistic effect after carrying DTX chemotherapeutic drugs, so that the killing rate of cells is further increased.
Example 10
4T1 tumor-bearing female BALB/c mice were randomly divided into six groups: (a) physiological saline; (b) normal saline + laser; (c) DTX; (d) DTX @ m-PB-NO; (e) m-PB-NO + laser; (f) DTX @ m-PB-NO + lasers (n ═ 5 in each group). The size of the tumor in the mouse reaches about 130mm3Thereafter, every two days, physiological saline, free DTX, m-PB-NO and DTX @ m-PB-NO were intravenously injected, respectively. 24 hours after intravenous injection, mice from groups b, e and f received 808nm laser light (1.5W/cm)-2) The irradiation was carried out for 5 minutes. Tumor volumes of mice were recorded every 2 days and calculated according to the following equation: volume is 0.5 XLXW2Where L and W are the length and width of the tumor, respectively. On day 16, mice were necropsied, tumors were collected and weighed. The experimental results are shown in fig. 12, and the tumors continued to increase daily for the group treated with saline and saline + laser. Mice treated with DTX @ m-PB-NO showed better antitumor efficacy compared to the free DTX group. This suggests that the intratumoral delivery of DTX @ m-PB-NO is increased due to the EPR effect in tumor tissues, resulting in high drug concentrations in tumor tissues, thereby exerting better antitumor effects. Under NIR irradiation, NO released from DTX m-PB-NO can reduce multidrug resistance, thereby enhancing the tumor inhibition ability of DTX. Meanwhile, the hyperthermia induced by m-PB-NO can increase the accumulation of intracellular drugs and the sensitivity of cells to the drugs. This shows that the DTX @ m-PB-NO + laser group can remarkably inhibit the growth of in vivo tumors by exerting obvious synergistic effect.
Claims (2)
1. A method for preparing a nano photothermal therapeutic agent of a drug-loaded Prussian blue analogue conjugated with sodium nitroprusside,
the method is characterized by comprising the following steps:
(1) weighing 60mg of potassium ferricyanide, 488.7mg of sodium nitroprusside and 3g of polyvinylpyrrolidone into 40mL of 0.1M hydrochloric acid solution, stirring for 20 minutes to uniformly disperse the potassium ferricyanide, transferring the potassium ferricyanide, the sodium nitroprusside and the polyvinylpyrrolidone into a water bath kettle, stirring and reacting for 12 hours at 80 ℃, centrifuging, collecting precipitate, and ultrasonically washing for 3 times by using water to obtain sodium nitroprusside conjugated Prussian blue analogue nanoparticles;
(2) dispersing 10mg sodium nitroprusside-conjugated Prussian blue analogue nanoparticles into 10mL water, adding 1mL of 1.5mg/mL docetaxel ethanol solution, stirring for reaction for 12 hours, volatilizing the ethanol solvent from the mixed solution obtained by the reaction on a rotary evaporator, centrifuging, collecting precipitate, washing with water for several times, and removing the drug which is not carried, thereby obtaining the sodium nitroprusside-conjugated drug-loaded Prussian blue analogue nano photothermal therapeutic agent.
2. A sodium nitroprusside-conjugated drug-loaded prussian blue analog photothermal therapeutic agent obtained by the method of claim 1.
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| CN111945301B (en) * | 2020-09-01 | 2021-09-21 | 潍坊医学院 | Membrane for releasing nitric oxide based on near-infrared response, preparation method and application |
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| CN114949252B (en) * | 2022-05-31 | 2023-08-29 | 华侨大学 | Intelligent acid-responsive self-assembled composite nano medicine carrying system for tumor photothermal/chemotherapy cooperative treatment and preparation method and application thereof |
| CN116421735B (en) * | 2023-06-12 | 2023-09-05 | 中南大学 | Sodium nitroprusside conjugated drug-loaded Prussian blue and preparation method and application thereof |
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