CN114767855A - Preparation method of drug-loaded photothermal photodynamic nanoparticles based on stibene - Google Patents
Preparation method of drug-loaded photothermal photodynamic nanoparticles based on stibene Download PDFInfo
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Abstract
The invention relates to the field of medicines, and discloses a preparation method of drug-loaded photothermal photodynamic nanoparticles based on stibene. The nano-particles prepared by the method have multiple functions, can realize photoacoustic imaging and photo-thermal/photodynamic/chemotherapy three-synergistic treatment, can increase the stability of nano-drugs taking stibene as a matrix, enhances the anti-tumor effect, and is expected to be practically applied to tumor treatment.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method of drug-loaded photothermal photodynamic nanoparticles based on stibene.
Background
The ultrathin two-dimensional (2D) nano material is a novel nano material. Due to the large surface volume, high drug and gene loading, high photothermal conversion efficiency and photodynamic characteristics of the 2D nano materials, the 2D nano materials have great application potential in the personalized cancer nano-medical fields of drug and gene transfer, photothermal therapy (PTT), photodynamic therapy (PDT), Magnetic Resonance Imaging (MRI), photoacoustic tomography (PAT), Computer Tomography (CT) and the like. Antimonene (AM), a novel two-dimensional material, has attracted extensive attention from researchers due to excellent physicochemical properties since first reported in 2015. Studies show that the stibene has excellent photo-thermal conversion efficiency in a near infrared region, reaches up to 45.5 percent, and has good application prospect in anti-tumor treatment.
Although the stibene nano material is a new photo-thermal therapeutic agent which appears recently, the rapid degradation of the stibene nano material in a physiological medium greatly limits the direct utilization of the stibene nano material, and the stibene nano material is rarely reported in the aspect of tumor treatment; in addition, the stibene has few surface active groups and great difficulty in chemical modification, and the product obtained by combining Van der Waals force and hydrogen bond hydrophobic interaction has poor stability.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of a drug-loaded photothermal photodynamic nanoparticle based on stibene. According to the preparation method, antimonene nanoparticles are obtained through a liquid phase mechanical stripping method and differential centrifugation, distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino is coated on the surfaces of the antimonene nanoparticles, distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino is embedded into gold nanoparticles on the surfaces of the distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino through an oxidation-reduction method, and irinotecan is loaded. The nano particles prepared by the method have multiple functions, can realize photoacoustic imaging and photo-thermal/photodynamic/chemotherapy three-synergistic treatment, can improve the stability of nano medicaments taking stibene as a matrix and enhance the anti-tumor effect, and are expected to be practically applied to tumor treatment.
The specific technical scheme of the invention is as follows: a preparation method of a drug-loaded photothermal photodynamic nanoparticle based on stibene comprises the following steps:
(1) preparing a distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino solution: dissolving distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino in water to prepare 1-2mg/mL distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino solution, and refrigerating for later use.
(2) Preparing a chloroauric acid solution: dissolving chloroauric acid in water to prepare 10-15mg/mL chloroauric acid solution, and refrigerating for later use.
(3) Preparation of irinotecan solution: dissolving irinotecan in water to prepare an irinotecan solution of 1-2mg/mL, encapsulating with tinfoil, and refrigerating for later use.
(4) Preparing an antimonene nanoparticle dispersion liquid: 2-4g of antimony powder is taken and dispersed in 40-80mL of N-methyl-2-pyrrolidone, after the container is sealed, ice-bath ultrasonic treatment is carried out by adopting an ultrasonic cell crusher, and then ice-bath ultrasonic treatment is carried out by adopting an ultrasonic cleaner; finally, carrying out ultrasonic treatment by adopting an ultrasonic cell crushing instrument; centrifuging the obtained dispersion, discarding deposited blocky antimony, centrifuging again, collecting precipitate, adding 10-15mL of water, further adding water for dilution to obtain the stibene nanoparticle dispersion with the concentration of 1-2mg/mL, and refrigerating for later use.
(5) Functional modification of stibene nanoparticles: mixing 0.5-1mL distearoylphosphatidylethanolamine-polyethylene glycol-amino solution and 100-200 μ L chloroauric acid solution, adding 0.5-1mL stibene nanoparticle dispersion, mixing, and adding NaBH4Reducing chloroauric acid into gold nano particles by using the solution; and then sequentially carrying out oscillation treatment, stirring at room temperature, ultrasonic treatment and centrifugation treatment, collecting precipitate, and adding 1-2mL of water to obtain stibene @ distearoylphosphatidylethanolamine-polyethylene glycol-amino/gold nanoparticle dispersion liquid.
(6) Irinotecan loading: and adding 1-2mL of the irinotecan solution into the stibene @ distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino/gold nanoparticle dispersion liquid, fully stirring, aging overnight, centrifuging, and collecting precipitates to obtain the drug-loaded photothermal photodynamic nanoparticles based on stibene.
Antimony is in the same family as phosphorus and has similar morphological and functional properties. The stibene has a honeycomb structure similar to that of black phosphorus, can be used for loading and conveying medicaments, has excellent photo-thermal conversion efficiency, and has environmental stability obviously better than that of the black phosphorus. In addition, the stibene nanoparticles have excellent acousto-optic performance, and show the strongest acousto-optic signal in a 2D material family, and the characteristic of the nano-particles endows the nano-particles with the acousto-optic imaging performance; and the stibene nanoparticles can be converted into Sb with specific cytotoxicity to cancer cells under the X-ray irradiation2O3 And Sb2O5,Sb2O3The strong cytotoxicity effect is exerted by inducing the excessive generation of active oxygen and the damage of mitochondria, and the characteristic endows the stibene nanoparticles with the potential in the photodynamic therapy of tumors; the spontaneous oxidation of the stibene accelerates the release of light energy, further improves the photothermal conversion by accelerating the non-radiative transition rate, and widens the absorption range of a near infrared region, so that the stibene nanoparticles have potential in photothermal treatment of tumors.
Based on the functions of the stibene, the distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino with good biocompatibility and biodegradability is introduced, the biocompatibility and the structural stability of nanoparticles of the stibene are improved in a physiological environment, irinotecan is successfully loaded on the distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino, the biological characteristics of the stibene are further optimized, and finally the obtained nano-drug has photodynamic/photothermal/chemotherapeutic three synergistic treatment effects and multimode imaging characteristics (fluorescence/photoacoustic/photothermal imaging) at the same time, so that a new direction is provided for research on the nano-drug for antitumor treatment.
According to the preparation method, antimonene nano-particles are obtained through a liquid phase mechanical stripping method and differential centrifugation, distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino is coated on the surfaces of the antimonene nano-particles, distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino is embedded into gold nano-particles through an oxidation-reduction method, and irinotecan is loaded. The nano particles prepared by the method have multiple functions, can realize photoacoustic imaging and photo-thermal/photodynamic/chemotherapy three-synergistic treatment, can improve the stability of nano medicaments taking stibene as a matrix and enhance the anti-tumor effect, and are expected to be practically applied to tumor treatment.
Preferably, in the step (4), the ice-bath ultrasonic treatment time of the ultrasonic cell crushing instrument for the first time is 8-10h, the power is 800-1200w, and the ultrasonic treatment is stopped for 1s every 2-4 s; the ice bath ultrasonic time of the ultrasonic cleaner is 2-3h, and the power is 200-400 w; the ice-bath ultrasonic time of the ultrasonic cell disruption instrument is 2-3h, and the power is 100-200 w.
The stibene nano-particles are obtained by a liquid phase mechanical stripping method and differential centrifugation. The invention adopts the three ultrasonic treatment processes with different intensities in sequence, and aims to reduce the size of the stibene nano-particles as much as possible. Meanwhile, the inventor finds that the ultrasonic intensity is high, the heat storage capacity is easy to accumulate, and the stibene is unstable and is easy to degrade. Therefore, ultrasonic treatment with high intensity and long time is firstly adopted, the intensity is gradually reduced, the time is reduced, ice bath cooling is specially adopted during the ultrasonic treatment, and the antimonene degradation can be effectively prevented.
Preferably, in the step (4), the first centrifugation rotating speed is 2000-4000rpm, and the centrifugation time is 10-15 min; the second centrifugation rotation speed is 8000-12000rpm, and the centrifugation time is 30-35 min; the centrifugation temperature does not exceed 10 ℃.
Firstly, the invention adopts the two different differential centrifugation processes, wherein the first centrifugation adopts lower rotating speed for removing the non-stripped antimonene; the second centrifugation is carried out at a higher speed in order to precipitate the antimonene completely and facilitate the separation.
Preferably, in the step (5), the oscillation treatment time is 2-4min, and the stirring time at room temperature is 2-3 h; the ultrasonic treatment time is 30-35 min; the centrifugal processing rotating speed is 10000-13000rpm, and the time of each centrifugal processing is 5-10 min. Preferably, in step (5), the NaBH is4The concentration of the solution is 0.35-0.40mg/mL, and the dosage is 0.6-1.2 mL.
Preferably, in step (6), the stirring time is 10-15h, the centrifugation speed is 10000-12000rpm, and each centrifugation time is 5-10 min.
Preferably, in the steps (1) to (4), the refrigerating temperature is 1-5 ℃.
Compared with the prior art, the invention has the following technical effects:
(1) compared with graphene nanosheets, black phosphorus and transition metal sulfide nanosheets, the antimonene nanoparticles have higher photo-thermal conversion efficiency and excellent photo-thermal performance, and have photodynamic performance due to the spontaneous oxidation of the antimonene, so that the material has a photo-thermal and photodynamic synergistic treatment effect, and the antimonene used in the invention has a photo-acoustic imaging function, has the photo-thermal and photo-acoustic imaging effects and greatly improves the accuracy of local treatment of the nano-drug.
(2) Good biocompatibility, biological safety and physiological environment stability are important indexes for inspecting the superiority of the photothermal agent. According to the invention, the stibene nano-particles are coated with distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino by utilizing electrostatic adsorption, so that the biocompatibility and the structural stability of the nano-particles are improved, and the degradation of the material in a physiological environment is slowed down, namely the stability of the material in the physiological environment is improved. Meanwhile, the gold nanoparticles and irinotecan are loaded on the surface of the material, so that the anti-tumor effect of the nano-medicament can be greatly enhanced.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
(1) Preparing a distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino solution: 20mL of distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino solution is weighed and added with 20mL of deionized water to prepare 1mg/mL distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino solution which is stored in a refrigerator at 4 ℃.
(2) Preparing a chloroauric acid solution: 20mg of chloroauric acid is weighed and dissolved in 2mL of deionized water to prepare a 10mg/mL chloroauric acid solution, and the chloroauric acid solution is placed in a refrigerator for storage at 4 ℃.
(3) Preparing an irinotecan solution: weighing 10mg of irinotecan, dissolving the irinotecan in 10mL of deionized water to prepare 1mg/mL irinotecan solution, encapsulating the solution with tinfoil, and storing the solution in a refrigerator at 4 ℃.
(4) Preparing an antimonene nanoparticle dispersion liquid: taking 2g of antimony powder to disperse in a clean beaker filled with 40ml of NMP at room temperature, sealing a preservative film, carrying out ice bath ultrasonic treatment for 8 hours by using a phi 6 ultrasonic probe under an ultrasonic cell crusher, wherein the power is 1000w, the ultrasonic treatment is stopped for 1s every 3s, stirring a dispersion liquid by using a glass rod every 30min to uniformly disperse the dispersion liquid, simultaneously observing whether ice cubes are dissolved in the ice bath, supplementing the ice cubes in time, carrying out ice bath ultrasonic treatment for 2 hours in an ultrasonic cleaner, wherein the power is 300w, and then carrying out ultrasonic treatment for 2 hours by using the ultrasonic cell crusher, wherein the power is 100 w; and finally, centrifuging: centrifuging the obtained dispersion liquid at the rotating speed of 3000rpm for 10min at the temperature of 8 ℃, discarding deposited blocky antimony, retaining supernatant, centrifuging the supernatant at the rotating speed of 8000rpm for 45min, collecting precipitate, adding 10ml of deionized water to obtain the stibene nano-particle dispersion liquid, and storing the stibene nano-particle dispersion liquid at the temperature of 4 ℃. After being diluted properly, the absorbance of the stibene nano-particle dispersion liquid under the wavelength of 808nm is measured by an ultraviolet-visible light analyzer, the concentration of antimony in the stibene nano-particle dispersion liquid prepared by the method is calculated and obtained to be 7mg/mL according to an antimony standard curve, and the stibene nano-particle dispersion liquid of 1mg/mL is obtained after being diluted by 7 times and is used for subsequent experiments.
(5) Functionalization: taking 0.5mL distearoylphosphatidylethanolamine-polyethylene glycol-amino solution and 100 mu L chloroauric acid solution, magnetically stirring uniformly, adding 1mL stibene nano-particle dispersion, mixing uniformly, adding the prepared NaBH4Reducing chloroauric acid into gold nanoparticles with 0.6mL of solution (0.38 mg/mL), oscillating for 2min with oscillator, magnetically stirring at room temperature for 2h, and ultrasonically cleaningAnd (3) ultrasonically treating the solution for 30min by using a washer, finally centrifuging the solution for 5min at the rotating speed of 10000rpm, adding 2ml of deionized water, ultrasonically dispersing the solution again according to the same centrifugation parameters, collecting the precipitate, and adding 1ml of deionized water to obtain the stibene nano-particles @ distearoylphosphatidylethanolamine-polyethylene glycol-amino/gold nano-particles dispersion solution.
(6) Irinotecan loading: and adding 1mL of irinotecan solution into the obtained nanoparticle dispersion liquid, magnetically stirring for 12h, aging overnight, centrifuging at 10000rpm for 5min, adding 2mL of deionized water, performing ultrasonic dispersion, centrifuging again according to the same centrifugation parameters, collecting precipitate, adding 1mL of deionized water, finally obtaining 1mg/mL of drug-loaded nanoparticle dispersion liquid, and refrigerating in a refrigerator at 4 ℃.
Example 2
(1) Preparing a distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino solution: 20mg of chitosan was weighed and dissolved in 10mL of acetic acid to prepare a 2mg/mL distearoylphosphatidylethanolamine-polyethylene glycol-amino solution, which was stored in a refrigerator at 4 ℃.
(2) Preparing a chloroauric acid solution: weighing 15mg of chloroauric acid, dissolving the chloroauric acid in 1mL of deionized water to prepare a 15mg/mL chloroauric acid solution, and storing the chloroauric acid solution in a refrigerator at 4 ℃.
(3) Preparing an irinotecan solution: weighing 20mg of irinotecan, dissolving the irinotecan in 10mL of deionized water to prepare a solution of irinotecan with the concentration of 2mg/mL, encapsulating the solution by tinfoil, and storing the solution in a refrigerator at 4 ℃.
(4) Preparing an antimonene nanoparticle dispersion liquid: dispersing 4g of antimony powder in a clean beaker filled with 800ml of NMP at room temperature, sealing a preservative film, carrying out ice bath ultrasonic treatment for 10 hours by using a phi 6 ultrasonic probe under an ultrasonic cell crusher, wherein the power is 1000w, the ultrasonic treatment is stopped for 1s every 3s, stirring a dispersion liquid by using a glass rod every 30min to uniformly disperse the dispersion liquid, simultaneously observing whether ice cubes are dissolved in the ice bath, supplementing the ice cubes in time, carrying out ice bath ultrasonic treatment for 3 hours in an ultrasonic cleaner, wherein the power is 300w, and then carrying out ultrasonic treatment for 3 hours by using the ultrasonic cell crusher, wherein the power is 100 w; and finally, centrifuging: centrifuging the obtained dispersion at 3000rpm for 15min at 10 ℃, discarding deposited blocky antimony, retaining supernatant, centrifuging the supernatant at 12000rpm for 30min, collecting precipitate, adding 15ml of deionized water to obtain antimonene nanoparticle dispersion, and storing at 4 ℃. After proper dilution, the absorbance of the stibene nano-particle dispersion liquid under the wavelength of 808nm is measured by an ultraviolet-visible light analyzer, the concentration of antimony in the stibene nano-particle dispersion liquid prepared by the method is 8mg/mL according to an antimony standard curve, and the stibene nano-particle dispersion liquid with the concentration of 2mg/mL is obtained after dilution by 4 times and is used for subsequent experiments.
(5) Functionalization: taking 1mL distearoylphosphatidylethanolamine-polyethylene glycol-amino solution and 200 mu L chloroauric acid solution, magnetically stirring uniformly, adding 0.5mL stibene nanoparticle dispersion liquid, mixing uniformly, and adding prepared NaBH4Reducing chloroauric acid into gold nanoparticles by using 1.2mL of solution (0.38 mg/mL), oscillating for 4min by using an oscillator, magnetically stirring for 3h at room temperature, performing ultrasonic treatment for 35min by using an ultrasonic cleaner, finally, centrifuging for 10min at the rotating speed of 13000rpm, adding 2mL of deionized water, performing ultrasonic dispersion again according to the same centrifugal parameters, collecting precipitate, and adding 1mL of deionized water to obtain the stibene nanoparticles @ distearoylphosphatidylethanolamine-polyethylene glycol-amino/gold nanoparticles dispersion solution.
(6) Irinotecan loading: and adding 2mL of irinotecan solution into the obtained nanoparticle dispersion liquid, magnetically stirring for 12h, aging overnight, centrifuging at 12000rpm for 10min, adding 2mL of deionized water, performing ultrasonic dispersion, centrifuging again according to the same centrifugation parameters, collecting precipitate, adding 2mL of deionized water, finally obtaining 1mg/mL of drug-loaded nanoparticle dispersion liquid, and refrigerating in a refrigerator at 4 ℃.
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modifications, alterations and equivalent changes made to the above embodiment according to the technical spirit of the present invention still belong to the protection scope of the technical solution of the present invention.
Claims (7)
1. A preparation method of a drug-loaded photothermal photodynamic nanoparticle based on stibene is characterized by comprising the following steps:
(1) preparing a distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino solution: dissolving distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino in water to prepare 1-2mg/mL distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino solution, and refrigerating for later use;
(2) preparing a chloroauric acid solution: dissolving chloroauric acid in water to prepare a chloroauric acid solution with the concentration of 10-15mg/mL, and refrigerating for later use;
(3) preparation of irinotecan solution: dissolving irinotecan in water to prepare 1-2mg/mL irinotecan solution, and encapsulating with tinfoil and refrigerating for later use;
(4) preparing an antimonene nanoparticle dispersion liquid: 2-4g of antimony powder is taken and dispersed in 40-80mL of N-methyl-2-pyrrolidone, after the container is sealed, ice-bath ultrasonic treatment is carried out by adopting an ultrasonic cell crusher, and then ice-bath ultrasonic treatment is carried out by adopting an ultrasonic cleaner; finally, ultrasonic treatment is carried out by adopting an ultrasonic cell crushing instrument; centrifuging the obtained dispersion liquid, discarding deposited block antimony, centrifuging again, collecting precipitate, adding 10-15mL of water, further adding water for dilution to obtain 1-2mg/mL of stibene nanoparticle dispersion liquid, and refrigerating for later use;
(5) functional modification of stibene nanoparticles: mixing 0.5-1mL distearoylphosphatidylethanolamine-polyethylene glycol-amino solution and 100-200 μ L chloroauric acid solution, adding 0.5-1mL stibene nanoparticle dispersion, mixing, and adding NaBH4Reducing chloroauric acid into gold nano particles by using the solution; then sequentially carrying out oscillation treatment, stirring at room temperature, ultrasonic treatment and centrifugation treatment, collecting precipitate, and adding 1-2mL of water to obtain stibene @ distearoylphosphatidylethanolamine-polyethylene glycol-amino/gold nanoparticle dispersion liquid;
(6) irinotecan loading: and adding 1-2mL of the irinotecan solution into the stibene @ distearoyl phosphatidyl ethanolamine-polyethylene glycol-amino/gold nanoparticle dispersion liquid, fully stirring, aging overnight, centrifuging, and collecting precipitates to obtain the drug-loaded photothermal photodynamic nanoparticles based on stibene.
2. The preparation method according to claim 1, wherein in the step (4), the first time of the ice bath ultrasonic treatment by the ultrasonic cell disruptor is performed for 8-10h at a power of 800-1200w, and the treatment is stopped for 1s every 2-4 s; the ice bath ultrasonic time of the ultrasonic cleaner is 2-3h, and the power is 200-400 w; the ice-bath ultrasonic time of the ultrasonic cell crushing instrument for the second time is 2-3h, and the power is 100-200 w.
3. The method as claimed in claim 2, wherein in the step (4), the first centrifugation speed is 2000-4000rpm, and the centrifugation time is 10-15 min; the second centrifugation rotation speed is 8000-12000rpm, and the centrifugation time is 30-35 min; the centrifugation temperature does not exceed 10 ℃.
4. The preparation method according to claim 1, wherein in the step (5), the treatment time of shaking is 2 to 4min, and the stirring time at room temperature is 2 to 3 h; the ultrasonic treatment time is 30-35 min; the centrifugal processing rotating speed is 10000-.
5. The method of claim 1, wherein in step (5), the NaBH is added to the aqueous solution of the NaBH4The concentration of the solution is 0.35-0.40mg/mL, and the dosage is 0.6-1.2 mL.
6. The method as claimed in claim 1, wherein in step (6), the stirring time is 10-15h, the centrifugation speed is 10000-12000rpm, and each centrifugation time is 5-10 min.
7. The method of claim 1, wherein the refrigerated temperature is 1-5 ℃ in steps (1) to (4).
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