CN113730600A - Palladium-gold alloy diagnosis and treatment integrated nano composite system, preparation method and application thereof - Google Patents
Palladium-gold alloy diagnosis and treatment integrated nano composite system, preparation method and application thereof Download PDFInfo
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- CN113730600A CN113730600A CN202110971564.XA CN202110971564A CN113730600A CN 113730600 A CN113730600 A CN 113730600A CN 202110971564 A CN202110971564 A CN 202110971564A CN 113730600 A CN113730600 A CN 113730600A
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Abstract
The invention discloses a palladium-gold alloy diagnosis and treatment integrated nano composite system, a preparation method and application thereof, wherein the system takes palladium-gold alloy nano particles as an inner core, a dopamine monomer which generates polymerization reaction forms a polydopamine shell layer coated on the outer surface of the palladium-gold alloy nano particles, the polydopamine layer is used for loading a drug 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride, and the core-shell structure material loaded with the drug is integrally coated by Gd-protein complex to form an organic/inorganic hybrid nano biomaterial. The nano composite system provided by the invention has the advantages of high thermal stability, good biocompatibility and the like, has the functions of thermodynamic therapy and photothermal therapy, and can be applied to the field of the multi-mode imaging guided cancer thermodynamic therapy and photothermal therapy cooperative therapy such as magnetic resonance imaging, photoacoustic imaging and CT imaging. The preparation method has the characteristics of mild and simple synthesis conditions, high repeatability and the like.
Description
Technical Field
The invention relates to the technical field of nano biomaterials, in particular to a gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system, a preparation method and application thereof.
Background
According to the latest data research released by the international agency for research on cancer (IARC), about 1930 ten thousand new cancer cases and about 1000 ten thousand deaths are shown worldwide in 2020; according to statistics, the morbidity and mortality of cancer cases in China show a trend of rising year by year. At present, most of clinically diagnosed cancer patients belong to middle and late stages, the optimal period of treatment is missed, and doctors mostly adopt a single surgical treatment mode to excise tumors, so that the risk is high, and the success rate is low. Therefore, if accurate diagnosis can be made at an early stage of cancer and a highly effective treatment means is used, it is of great promoting significance to the progress in the field of cancer treatment.
However, the current imaging modes for clinically determining cancer all have certain technical defects, different imaging technical principles are different, and the reaction information is emphasized and has respective advantages and disadvantages. For example, in CT imaging, due to the strong penetration of X-rays, the effect of imaging soft tissues is not obvious, so that there is no strong judgment for some soft tissue lesions; PET has high sensitivity, is favorable for analyzing the distribution condition of a medicine or a probe in a living body, but has lower spatial resolution; MRI is sensitive, but its spatial resolution is not high, and it is not effective in imaging some early stage diseases, such as tumor margins and normal tissues, which cannot be distinguished well in early stage diagnosis of tumors. Therefore, researchers hope to integrate the advantages of different imaging modes and improve the early diagnosis rate of cancer by developing a contrast medium integrating a tumor multi-modal imaging technology.
Chinese invention patent application no: CN201210309662.8 discloses preparation and application of a lung cancer tumor marker immunosensor constructed by a gold-palladium core-shell material, and the immunosensor utilizes Au @ Pd core-shell nano-materials, has the characteristics of large specific surface area, good biocompatibility, high catalytic efficiency and the like, and obviously improves the sensitivity of the immunosensor. The lung cancer tumor marker immunosensor constructed by the gold-palladium core-shell material has the advantages of high sensitivity, good specificity and easiness in operation, can realize the sensitive, rapid and accurate detection of various lung cancer tumor markers in a serum sample, has important significance for early diagnosis of lung cancer, but has no treatment function.
Hypoxic microenvironment is one of the typical characteristics of solid tumors, and is an imbalance between high oxygen consumption due to rapid proliferation of tumor cells and insufficient oxygen supply due to malformation of tumor vasculature. Previous reports have demonstrated that cancer cells are extremely resistant to chemotherapy and oxygen-dependent photodynamic therapy of hypoxic regions of tumors. Therefore, the development of effective strategies to overcome tumor hypoxia microenvironment and increase the accumulation of biocompatible nanomaterials on tumor parts has important significance for obtaining good synergistic anticancer therapeutic effect.
Chemotherapy and radiotherapy are two major means for clinically treating cancer at present, but both of them often fail to completely ablate the tumor. Chemotherapy generally injects a large amount of free drugs into a patient, but the free drugs have no specificity to tumors, so that only a small amount of drugs can reach a tumor focus area of the patient through blood circulation, most of the drugs are phagocytized by normal organs such as liver, spleen and the like, and systemic toxic and side effects exist. Radiotherapy, which is a medical technology with a hundred-year development history, can efficiently inhibit local growth of malignant tumors; unfortunately, because hypoxic cells which are not sensitive to X-rays exist in tumors, a small amount of hypoxic cells left after the action of the X-rays can cause local recurrence of the tumors, and meanwhile, the high-dose X-rays are used for repeated irradiation for many times, so that surrounding normal tissues are inevitably damaged, and finally the radiotherapy fails. In addition to the treatment means of chemotherapy and radiotherapy, which are commonly used in clinical practice, photothermal therapy, photodynamic therapy and thermodynamic therapy are representative of one of the emerging tumor treatment technologies, but the photothermal therapy alone is limited by the limited penetration depth of light, while the photodynamic therapy is limited by tumor hypoxia to produce sufficient active oxygen and thus does not achieve an effective killing effect.
Disclosure of Invention
The invention aims to provide a gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano complex system material, aiming at the defects that the single imaging mode or treatment means in the prior art has limitations and cannot achieve the most effective tumor killing effect, and the multifunctional tumor diagnosis and treatment integrated nano material which combines a plurality of tumor treatment modes by taking multi-mode imaging as guidance is constructed through unique component and microstructure design, so that the material simultaneously has the characteristics of magnetic resonance imaging, CT imaging and photoacoustic imaging and multi-mode treatment, namely thermodynamic treatment and photothermal treatment of cancer, and provides a new strategy for the field of clinical multi-mode diagnosis and multi-mode treatment integration.
The invention also aims to provide a preparation method of the material, optimize the preparation process, and have the characteristics of simple and mild synthesis conditions and high repeatability;
the invention also provides the application of the material in the integration of multi-mode imaging diagnosis and dual-mode treatment.
In order to achieve the purpose, the invention adopts the technical scheme that:
a palladium-gold alloy diagnosis and treatment integrated nano composite material is characterized in that palladium-gold alloy nanoparticles are used as an inner core, a dopamine monomer undergoing a polymerization reaction forms a polydopamine shell layer coated on the outer surface of the palladium-gold alloy nanoparticles, the polydopamine layer is used for loading a drug 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride, and then Gd-protein complexes are used for integrally coating the core-shell structure material loaded with the drug to form an organic/inorganic hybrid nano biomaterial, namely a gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system.
The poly dopamine layer coated on the surface of the palladium-gold alloy nano particle utilizes pi-pi interaction to load a drug 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride.
The Gd-protein complex is: gd-bovine serum albumin complex (Gd-BSA), Gd-human serum albumin complex (Gd-HSA).
The preparation method of the palladium-gold alloy diagnosis and treatment integrated nano composite system is characterized by comprising the following steps of:
(1) preparing a first dispersion: respectively preparing sodium citrate, a chloropalladic acid aqueous solution and a chloroauric acid aqueous solution, as well as surfactants Cetyl Trimethyl Ammonium Bromide (CTAB) and Cetyl Trimethyl Ammonium Chloride (CTAC), reducing the chloropalladic acid aqueous solution and the chloroauric acid aqueous solution by using the sodium citrate to synthesize palladium-gold alloy nanoparticles, and dispersing the palladium-gold alloy nanoparticles in deionized water; then, under an alkaline condition, adding a dopamine monomer, polymerizing the dopamine monomer to form a polydopamine layer to coat on the surface of the palladium-gold alloy nano particle, centrifuging after ultrasonic dispersion, and dispersing a solid in deionized water to form a first dispersion liquid;
(2) preparing a second dispersion: preparing 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride, and dissolving the 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in a set amount of deionized water to obtain an aqueous solution of 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride; mixing the 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride aqueous solution with the first dispersion liquid, stirring in the dark at room temperature for a set time, performing ultrasonic dispersion, centrifuging, and dispersing solids in deionized water to form a second dispersion liquid;
(3) preparing a third dispersion: separately preparing protein powder and gadolinium chloride (GdCl)3) Aqueous solution,An aqueous sodium hydroxide solution; dissolving protein powder in deionized water under constant temperature, adding GdCl3Adding sodium hydroxide aqueous solution into the aqueous solution, continuously keeping constant temperature and rapidly stirring, and dialyzing by using a dialysis bag and deionized water to obtain Gd-protein complex to form third dispersion liquid;
(4) integral coating: and mixing the second dispersion liquid and the third dispersion liquid according to a set proportion, stirring in a dark place at 15-25 ℃, performing ultrasonic dispersion after reaching a set time, centrifuging, dispersing a solid in deionized water, and integrally coating the core-shell structure material with the Gd-protein complex to form an organic/inorganic hybrid nano biomaterial so as to obtain the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite material.
The step (1) of preparing the first dispersion liquid comprises the following specific steps:
(1-1) respectively preparing a chloropalladate aqueous solution and a chloroauric acid aqueous solution;
(1-2) uniformly mixing 44 ml of cetyltrimethylammonium bromide (CTAB) and 5 ml of a surfactant of cetyltrimethylammonium chloride (CTAC), adding 1.2 ml of a mixed solution of 10mmol/L of chloropalladate aqueous solution and 10mmol/L of chloroauric acid aqueous solution (the molar ratio of the chloropalladate to the chloroauric acid is 1: 1-1: 2), adding 200-250 mu L of sodium citrate with the concentration of 100mmol/L after 20 minutes, and preserving heat at a constant temperature of 80-100 ℃ for 16-20 hours under a sealed condition to synthesize palladium-gold alloy nanoparticles;
(1-3) dispersing the palladium-gold alloy nanoparticles in 20 ml of deionized water, then adding 5 mg of dopamine monomer salt, polymerizing and coating dopamine monomer on the surfaces of the palladium-gold alloy nanoparticles to form a polydopamine layer under an alkaline condition with the pH value of 9-12, centrifuging at 13000-15000 r/min after ultrasonic dispersion, and dispersing the obtained solid in 20 ml of deionized water to form a first dispersion liquid.
The step (2) for preparing the second dispersion liquid comprises the following specific steps:
(2-1) dissolving 0.1-0.2 g of 2,2 '-azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in 5 ml of deionized water to obtain an aqueous solution of 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride;
(2-2) uniformly mixing the 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride water solution with the first dispersion solution, stirring for 10-15 hours at room temperature in a dark place, performing ultrasonic dispersion, centrifuging at a speed of 11000-13000 revolutions per minute, taking the solid, and dispersing in 20 ml of deionized water to form a second dispersion solution.
The step (3) of preparing the third dispersion liquid comprises the following specific steps:
(3-1) 0.25 g of protein powder and 1mL of 50mmol/L gadolinium chloride (GdCl) were prepared3) 1mL of sodium hydroxide aqueous solution with the concentration of 2 mol/L;
(3-2) dissolving the protein powder in 9 ml of deionized water at the physiological temperature of 37 ℃, and adding GdCl3Adding a sodium hydroxide aqueous solution after 5 minutes, continuously keeping constant temperature, stirring at the speed of 700-800 revolutions per minute, and dialyzing by adopting a dialysis bag with molecular weight cutoff of 3500 and deionized water for 24 hours to obtain a Gd-protein complex to form a third dispersion liquid;
the step (4) of integral coating comprises the following steps:
and adding 2.5 ml of the third dispersion liquid into 20 ml of the second dispersion liquid, uniformly mixing, stirring for 6-12 hours in the dark at 15-25 ℃, performing ultrasonic dispersion, centrifuging at 9000-11000 r/min, taking the solid, dispersing in deionized water, and integrally coating the core-shell structure material with the Gd-protein complex to form an organic/inorganic hybrid nano biomaterial, thus obtaining the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system.
The application of the palladium-gold alloy diagnosis and treatment integrated nano composite system is used as a material for preparing a contrast agent for magnetic resonance imaging, CT imaging and photoacoustic imaging.
The application of the palladium-gold alloy diagnosis and treatment integrated nano composite system is used for preparing materials of a photothermal reagent and a thermodynamic treatment reagent for near infrared light excited photothermal treatment.
The invention has the beneficial effects that:
(1) the invention overcomes the defects that the single diagnosis mode or treatment means in the prior art has limitations and cannot achieve the most effective tumor killing effect, the provided gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano complex material takes multi-modal imaging as guidance through unique component and microstructure design, is a multifunctional tumor diagnosis and treatment integrated nano material which can combine a plurality of tumor treatment modes, has the characteristics of magnetic resonance imaging, CT imaging and photoacoustic imaging as well as multi-modal treatment, namely thermodynamic treatment and photothermal treatment of cancer, and provides a new strategy for the field of clinical multi-modal diagnosis and multi-modal treatment integration.
(2) According to the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system and the preparation method thereof, the obtained nano composite system has the advantages of high thermal stability, good biocompatibility and the like, the photothermal conversion efficiency is high, the effects of thermodynamic treatment and photothermal treatment are realized, and the diagnosis and treatment integration is realized in the cancers guided by multimode imaging such as magnetic resonance imaging, photoacoustic imaging, CT imaging and the like.
(3) The preparation method of the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system has the characteristics of mild and simple synthesis conditions, high repeatability and easiness in industrialization; the advantage of high repeatability of the nano composite system preparation is realized by utilizing the mild and simple preparation conditions.
(4) The application of the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system provided by the invention has the functions of multi-mode imaging such as magnetic resonance imaging, CT imaging, photoacoustic imaging and the like, near infrared photothermal therapy and thermodynamic therapy, realizes diagnosis and treatment integration, can realize accurate and accurate diagnosis in early cancer stage and is assisted with efficient therapy means, has potential biomedical application prospect, and has great promotion significance for the progress of the field of cancer therapy.
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
Drawings
FIG. 1 is a Transmission Electron Microscope (TEM) photograph of a gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano-composite system according to example 1 of the present invention;
FIG. 2 is a Fourier infrared spectrum of AIPH-PAPG, PdAu @ PDA, AIPH and Gd-HSA in the preparation process of the palladium-gold alloy diagnosis and treatment integrated nano-composite system modified by gadolinium complexes in example 2 of the present invention;
fig. 3 is an in vitro thermal imaging photograph of the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano-composite system under the excitation of 808nm laser in example 6 of the present invention.
Detailed Description
The technical solution of the present invention will be clearly and completely described with reference to the accompanying drawings 1-3 and the embodiments.
Example 1
The palladium-gold alloy diagnosis and treatment integrated nano composite material provided by the embodiment of the invention takes palladium-gold alloy nano particles as an inner core, a dopamine monomer which is subjected to polymerization reaction forms a polydopamine shell layer coated on the outer surface of the palladium-gold alloy nano particles, then a drug 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride is loaded on the polydopamine layer, and then the core-shell structure material which is loaded with the drug is integrally coated by a Gd-protein complex to form an organic/inorganic hybrid nano biomaterial, namely a gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system. Wherein the poly dopamine layer coated on the surface of the palladium-gold alloy nano particle utilizes pi-pi interaction to load 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride serving as a drug; the Gd-protein complex is: gd-bovine serum albumin complex (Gd-BSA).
A preparation method of the palladium-gold alloy diagnosis and treatment integrated nano composite system comprises the following steps:
(1) preparing a first dispersion: respectively preparing sodium citrate, a chloropalladic acid aqueous solution and a chloroauric acid aqueous solution, as well as surfactants Cetyl Trimethyl Ammonium Bromide (CTAB) and Cetyl Trimethyl Ammonium Chloride (CTAC), reducing the chloropalladic acid aqueous solution and the chloroauric acid aqueous solution by using the sodium citrate to synthesize palladium-gold alloy nanoparticles, and dispersing the palladium-gold alloy nanoparticles in deionized water; then, under an alkaline condition, adding a dopamine monomer, polymerizing the dopamine monomer to form a polydopamine layer to coat on the surface of the palladium-gold alloy nano particle, centrifuging after ultrasonic dispersion, and dispersing a solid in deionized water to form a first dispersion liquid; the method comprises the following specific steps:
(1-1) respectively preparing a chloropalladate aqueous solution and a chloroauric acid aqueous solution;
(1-2) mixing 44 ml of cetyltrimethylammonium bromide (CTAB) and 5 ml of a surfactant of cetyltrimethylammonium chloride (CTAC) uniformly, adding 1.2 ml of a mixed solution of 10mmol/L of chloropalladate aqueous solution and 10mmol/L of chloroauric acid aqueous solution (the molar ratio of chloropalladic acid to chloroauric acid is 1:1), adding 240 mu L of sodium citrate with the concentration of 100mmol/L after 20 minutes, and carrying out heat preservation at a constant temperature of 90 ℃ for 16 hours under a sealed condition to synthesize palladium-gold alloy nanoparticles;
(1-3) dispersing the palladium-gold alloy nanoparticles in 20 ml of deionized water, then adding 5 mg of dopamine monomer salt, polymerizing and coating dopamine monomer on the surfaces of the palladium-gold alloy nanoparticles to form a poly-dopamine layer under an alkaline condition of pH 9, centrifuging at 14000 revolutions per minute after ultrasonic dispersion, and dispersing the obtained solid in 20 ml of deionized water to form a first dispersion liquid.
(2) Preparing a second dispersion: preparing 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride, and dissolving the 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in a set amount of deionized water to obtain an aqueous solution of 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride; mixing the 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride aqueous solution with the first dispersion liquid, stirring in the dark at room temperature for a set time, performing ultrasonic dispersion, centrifuging, and dispersing solids in deionized water to form a second dispersion liquid; the method comprises the following specific steps:
(2-1) dissolving 0.2 g of 2,2 '-azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in 5 ml of deionized water to obtain an aqueous solution of 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride;
(2-2) the aqueous 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride solution was mixed with the first dispersion uniformly, stirred at room temperature in the dark for 12 hours, ultrasonically dispersed, centrifuged at 12000 rpm, and the solid was dispersed in 20 ml of deionized water to form a second dispersion.
(3) Preparing a third dispersion: separately preparing protein powder and gadolinium chloride (GdCl)3) Aqueous solution, sodium hydroxide aqueous solution; dissolving protein powder in deionized water under constant temperature, adding GdCl3Adding sodium hydroxide aqueous solution into the aqueous solution, continuously keeping constant temperature and rapidly stirring, and dialyzing by using a dialysis bag and deionized water to obtain Gd-protein complex to form third dispersion liquid; the method comprises the following specific steps:
(3-1) 0.25 g of bovine serum albumin and 1mL of gadolinium chloride (GdCl) with a concentration of 50mmol/L were prepared3) 1mL of sodium hydroxide aqueous solution with the concentration of 2 mol/L;
(3-2) bovine serum albumin was dissolved in 9 ml of deionized water at physiological temperature of 37 ℃ and GdCl was added3Adding sodium hydroxide aqueous solution after 5 minutes, continuously keeping constant temperature and stirring at the speed of 700 revolutions per minute, and dialyzing by using a dialysis bag with molecular weight cutoff of 3500 and deionized water for 24 hours to obtain Gd-bovine serum albumin complex (Gd-BSA) to form a third dispersion liquid;
(4) integral coating: and mixing the second dispersion liquid and the third dispersion liquid according to a set proportion, stirring in a dark place at 15-25 ℃, performing ultrasonic dispersion after reaching a set time, centrifuging, dispersing a solid in deionized water, and integrally coating the core-shell structure material with the Gd-protein complex to form an organic/inorganic hybrid nano biomaterial so as to obtain the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite material. The method comprises the following specific steps:
and adding 2.5 ml of the third dispersion liquid into 20 ml of the second dispersion liquid, uniformly mixing, stirring in the dark at 25 ℃ for 6 hours, performing ultrasonic dispersion, centrifuging at a speed of 10000 revolutions per minute, taking the solid, dispersing in deionized water, and integrally coating the core-shell structure material with Gd-bovine serum albumin (Gd-BSA) to form an organic/inorganic hybrid nano biomaterial, thus obtaining the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system.
FIG. 1 is a TEM photograph of a palladium-gold alloy diagnosis and treatment integrated nano-composite system modified by gadolinium complexes prepared in example 1 of the present invention, from which it can be observed that a poly-dopamine layer, a drug-loaded 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride and a shell layer finally coated by Gd-bovine serum albumin complexes (Gd-BSA) are coated outside the palladium-gold alloy nanoparticles, which indicates that the preparation method can obtain a diagnosis and treatment integrated nano-composite system with good morphology, uniform growth and high experimental repeatability, the average diameter of the nano-materials is about 90-100 nm, because the small-size nano material is easier to be endocytosed by cells, the nano material is beneficial to circulation in organisms, and has important significance for the application of the nano material in biological imaging and treatment.
Example 2
The pd-au alloy diagnosis and treatment integrated nanocomposite material provided in this example is substantially the same as that in example 1, except that the pd-au alloy nanoparticles are used as an inner core, a dopamine monomer undergoing a polymerization reaction forms a polydopamine shell layer covering the outer surface of the pd-au alloy nanoparticles, the polydopamine layer is used to support a drug 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride, and the Gd-protein complex is used to integrally coat the core-shell structure material after drug loading, thereby forming an organic/inorganic hybrid nanomaterial, namely, a Gd complex modified pd-au alloy diagnosis and treatment integrated nanocomposite system. Wherein the poly dopamine layer coated on the surface of the palladium-gold alloy nano particle utilizes pi-pi interaction to load 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride serving as a drug; the Gd-protein complex is: gd-human serum protein complex (Gd-HSA).
A preparation method of the palladium-gold alloy diagnosis and treatment integrated nano composite system comprises the following steps:
(1) preparing a first dispersion: respectively preparing sodium citrate, a chloropalladic acid aqueous solution and a chloroauric acid aqueous solution, as well as surfactants Cetyl Trimethyl Ammonium Bromide (CTAB) and Cetyl Trimethyl Ammonium Chloride (CTAC), reducing the chloropalladic acid aqueous solution and the chloroauric acid aqueous solution by using the sodium citrate to synthesize palladium-gold alloy nanoparticles, and dispersing the palladium-gold alloy nanoparticles in deionized water; then, under an alkaline condition, adding a dopamine monomer, polymerizing the dopamine monomer to form a polydopamine layer to coat on the surface of the palladium-gold alloy nano particle, centrifuging after ultrasonic dispersion, and dispersing a solid in deionized water to form a first dispersion liquid; the method comprises the following specific steps:
(1-1) respectively preparing a chloropalladate aqueous solution and a chloroauric acid aqueous solution;
(1-2) mixing 44 ml of cetyltrimethylammonium bromide (CTAB) and 5 ml of a surfactant of cetyltrimethylammonium chloride (CTAC) uniformly, adding 1.2 ml of a mixed solution of 10mmol/L of chloropalladate aqueous solution and 10mmol/L of chloroauric acid aqueous solution (the molar ratio of chloropalladic acid to chloroauric acid is 1:1), adding 240 mu L of sodium citrate with the concentration of 100mmol/L after 20 minutes, and carrying out heat preservation at a constant temperature of 90 ℃ for 16 hours under a sealed condition to synthesize palladium-gold alloy nanoparticles;
(1-3) dispersing the palladium-gold alloy nanoparticles in 20 ml of deionized water, adding 5 mg of dopamine monomer salt, polymerizing and coating dopamine monomer on the surfaces of the palladium-gold alloy nanoparticles under an alkaline condition with the pH value of 9 to form a poly-dopamine layer, performing ultrasonic dispersion, centrifuging at 14000 revolutions per minute, and dispersing the obtained solid in 20 ml of deionized water to form a first dispersion liquid, namely PdAu @ PDA.
(2) Preparing a second dispersion: preparing 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride, and dissolving the 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in a set amount of deionized water to obtain an aqueous solution of 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride; mixing the 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride aqueous solution with the first dispersion liquid, stirring in the dark at room temperature for a set time, performing ultrasonic dispersion, centrifuging, and dispersing solids in deionized water to form a second dispersion liquid; the method comprises the following specific steps:
(2-1) taking 0.2 g of 2,2 ' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride (AIPH), and dissolving the 2,2 ' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride (AIPH) in 5 ml of deionized water to obtain an aqueous solution of 2,2 ' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride;
(2-2) the aqueous 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride solution was mixed with the first dispersion uniformly, stirred at room temperature in the dark for 12 hours, ultrasonically dispersed, centrifuged at 12000 rpm, and the solid was dispersed in 20 ml of deionized water to form a second dispersion.
(3) Preparing a third dispersion: separately preparing protein powder and gadolinium chloride (GdCl)3) Aqueous solution, sodium hydroxide aqueous solution; dissolving protein powder in deionized water under constant temperature, adding GdCl3Adding sodium hydroxide aqueous solution into the aqueous solution, continuously keeping constant temperature and rapidly stirring, and dialyzing by using a dialysis bag and deionized water to obtain Gd-protein complex to form third dispersion liquid; the method comprises the following specific steps:
(3-1) 0.25 g of human serum albumin and 1mL of gadolinium chloride (GdCl) with a concentration of 50mmol/L were prepared3) 1mL of sodium hydroxide aqueous solution with the concentration of 2 mol/L;
(3-2) dissolving the human serum albumin in 9 ml of deionized water at the physiological temperature of 37 ℃, and adding GdCl3Adding sodium hydroxide aqueous solution after 5 minutes, continuously keeping constant temperature and stirring at the speed of 700 revolutions per minute, and dialyzing by using a dialysis bag with molecular weight cutoff of 3500 and deionized water for 24 hours to obtain Gd-human serum albumin complex (Gd-HSA) to form third dispersion liquid;
(4) integral coating: and mixing the second dispersion liquid and the third dispersion liquid according to a set proportion, stirring in a dark place at 15-25 ℃, performing ultrasonic dispersion after reaching a set time, centrifuging, dispersing a solid in deionized water, and integrally coating the core-shell structure material with the Gd-protein complex to form an organic/inorganic hybrid nano biomaterial so as to obtain the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite material. The method comprises the following specific steps:
adding 2.5 ml of the third dispersion liquid into 20 ml of the second dispersion liquid, uniformly mixing, stirring in the dark at 25 ℃ for 6 hours, performing ultrasonic dispersion, centrifuging at 10000 r/min, dispersing the solid in deionized water, and integrally coating a core-shell structure material with a Gd-human serum albumin complex (Gd-HSA) to form an organic/inorganic hybrid nano-biomaterial to obtain a gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano-composite system, namely AIPH-PAPG.
FIG. 2 is a Fourier infrared spectrum of AIPH-PAPG, PdAu @ PDA, AIPH and Gd-HSA in the preparation process of gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system provided in example 2 of the present invention, and the spectrum shows that the wave number is 1350cm-1The absorption peak of (A) can be assigned to 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ]]-CH of dihydrochloride (AIPH)3Bending vibration with wave number of 1596cm-1The absorption peak of (A) is ascribed to 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ]]N-H flexural vibration of dihydrochloride (AIPH) and Gd-human serum albumin complex (Gd-HSA) at a wave number of 1395cm-1The absorption peak belongs to-OH bending vibration of Gd-human serum albumin complex (Gd-HSA), and accurate attribution of the peak positions can show the successful preparation of the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system.
Example 3
The pd-au alloy integrated nanocomposite material for diagnosis and treatment provided in this example is substantially the same as examples 1 and 2, except that the pd-au alloy nanoparticles are used as an inner core, a dopamine monomer undergoing a polymerization reaction forms a polydopamine shell layer covering the outer surface of the pd-au alloy nanoparticles, the polydopamine layer is used to carry 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride, and the Gd-protein complex is used to integrally coat the core-shell structure material carrying the drug, so as to form an organic/inorganic hybrid nano biomaterial, namely, a Gd complex modified pd-au alloy integrated nanocomposite system for diagnosis and treatment. Wherein the poly dopamine layer coated on the surface of the palladium-gold alloy nano particle utilizes pi-pi interaction to load 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride serving as a drug; the Gd-protein complex is: gd-bovine serum albumin complex (Gd-BSA).
A preparation method of the palladium-gold alloy diagnosis and treatment integrated nano composite system comprises the following steps:
(1) preparing a first dispersion: respectively preparing sodium citrate, a chloropalladic acid aqueous solution and a chloroauric acid aqueous solution, as well as surfactants Cetyl Trimethyl Ammonium Bromide (CTAB) and Cetyl Trimethyl Ammonium Chloride (CTAC), reducing the chloropalladic acid aqueous solution and the chloroauric acid aqueous solution by using the sodium citrate to synthesize palladium-gold alloy nanoparticles, and dispersing the palladium-gold alloy nanoparticles in deionized water; then, under an alkaline condition, adding a dopamine monomer, polymerizing the dopamine monomer to form a polydopamine layer to coat on the surface of the palladium-gold alloy nano particle, centrifuging after ultrasonic dispersion, and dispersing a solid in deionized water to form a first dispersion liquid; the method comprises the following specific steps:
(1-1) respectively preparing a chloropalladate aqueous solution and a chloroauric acid aqueous solution;
(1-2) mixing 44 ml of cetyltrimethylammonium bromide (CTAB) and 5 ml of a surfactant of cetyltrimethylammonium chloride (CTAC) uniformly, adding 1.2 ml of a mixed solution of 10mmol/L of chloropalladate aqueous solution and 10mmol/L of chloroauric acid aqueous solution (the molar ratio of chloropalladic acid to chloroauric acid is 1:2), adding 240 mu L of sodium citrate with the concentration of 100mmol/L after 20 minutes, and carrying out heat preservation at a constant temperature of 90 ℃ for 20 hours under a sealed condition to synthesize palladium-gold alloy nanoparticles;
(1-3) dispersing the palladium-gold alloy nanoparticles in 20 ml of deionized water, then adding 5 mg of dopamine monomer salt, polymerizing and coating dopamine monomer on the surfaces of the palladium-gold alloy nanoparticles to form a poly-dopamine layer under the alkaline condition of pH 12, centrifuging at 14000 revolutions per minute after ultrasonic dispersion, and dispersing the obtained solid in 20 ml of deionized water to form a first dispersion liquid.
(2) Preparing a second dispersion: preparing 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride, and dissolving the 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in a set amount of deionized water to obtain an aqueous solution of 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride; mixing the 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride aqueous solution with the first dispersion liquid, stirring in the dark at room temperature for a set time, performing ultrasonic dispersion, centrifuging, and dispersing solids in deionized water to form a second dispersion liquid; the method comprises the following specific steps:
(2-1) dissolving 0.2 g of 2,2 '-azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in 5 ml of deionized water to obtain an aqueous solution of 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride;
(2-2) the aqueous 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride solution was mixed with the first dispersion uniformly, stirred at room temperature in the dark for 15 hours, ultrasonically dispersed, centrifuged at 12000 rpm, and the solid was dispersed in 20 ml of deionized water to form a second dispersion.
(3) Preparing a third dispersion: separately preparing protein powder and gadolinium chloride (GdCl)3) Aqueous solution, sodium hydroxide aqueous solution; dissolving protein powder in deionized water under constant temperature, adding GdCl3Adding sodium hydroxide aqueous solution into the aqueous solution, continuously keeping constant temperature and rapidly stirring, and dialyzing by using a dialysis bag and deionized water to obtain Gd-protein complex to form third dispersion liquid; the method comprises the following specific steps:
(3-1) 0.25 g of bovine serum albumin and 1mL of gadolinium chloride (GdCl) with a concentration of 50mmol/L were prepared3) 1mL of sodium hydroxide aqueous solution with the concentration of 2 mol/L;
(3-2) bovine serum albumin was dissolved in 9 ml of deionized water at physiological temperature of 37 ℃ and GdCl was added3Adding a sodium hydroxide aqueous solution after 5 minutes into the aqueous solution, continuously keeping the constant temperature, stirring at the speed of 800 revolutions per minute, and dialyzing for 24 hours by adopting a dialysis bag with the molecular weight cutoff of 3500 and deionized water to obtain Gd-bovine serum albumin complex (Gd-BSA) to form a third dispersion liquid;
(4) integral coating: and mixing the second dispersion liquid and the third dispersion liquid according to a set proportion, stirring in a dark place at 15-25 ℃, performing ultrasonic dispersion after reaching a set time, centrifuging, dispersing a solid in deionized water, and integrally coating the core-shell structure material with the Gd-protein complex to form an organic/inorganic hybrid nano biomaterial so as to obtain the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite material. The method comprises the following specific steps:
and adding 2.5 ml of the third dispersion liquid into 20 ml of the second dispersion liquid, uniformly mixing, stirring in the dark at 25 ℃ for 10 hours, performing ultrasonic dispersion, centrifuging at a speed of 10000 revolutions per minute, taking the solid, dispersing in deionized water, and integrally coating the core-shell structure material with Gd-bovine serum albumin (Gd-BSA) to form an organic/inorganic hybrid nano biomaterial, thus obtaining the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system.
Example 4
The pd-au alloy integrated nanocomposite material for diagnosis and treatment provided in this example is substantially the same as examples 1 to 3, except that pd-au alloy nanoparticles are used as an inner core, a dopamine monomer undergoing a polymerization reaction forms a polydopamine shell layer covering the outer surface of the pd-au alloy nanoparticles, the polydopamine layer is used to support 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride, and the Gd-protein complex is used to integrally coat the core-shell structure material loaded with drugs, so as to form an organic/inorganic hybrid nano biomaterial, namely, a Gd complex modified pd-au alloy integrated nanocomposite system for diagnosis and treatment. Wherein the poly dopamine layer coated on the surface of the palladium-gold alloy nano particle utilizes pi-pi interaction to load 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride serving as a drug; the Gd-protein complex is: gd-human serum protein complex (Gd-HSA).
A preparation method of the palladium-gold alloy diagnosis and treatment integrated nano composite system comprises the following steps:
(1) preparing a first dispersion: respectively preparing sodium citrate, a chloropalladic acid aqueous solution and a chloroauric acid aqueous solution, as well as surfactants Cetyl Trimethyl Ammonium Bromide (CTAB) and Cetyl Trimethyl Ammonium Chloride (CTAC), reducing the chloropalladic acid aqueous solution and the chloroauric acid aqueous solution by using the sodium citrate to synthesize palladium-gold alloy nanoparticles, and dispersing the palladium-gold alloy nanoparticles in deionized water; then, under an alkaline condition, adding a dopamine monomer, polymerizing the dopamine monomer to form a polydopamine layer to coat on the surface of the palladium-gold alloy nano particle, centrifuging after ultrasonic dispersion, and dispersing a solid in deionized water to form a first dispersion liquid; the method comprises the following specific steps:
(1-1) respectively preparing a chloropalladate aqueous solution and a chloroauric acid aqueous solution;
(1-2) mixing 44 ml of cetyltrimethylammonium bromide (CTAB) and 5 ml of a surfactant of cetyltrimethylammonium chloride (CTAC) uniformly, adding 1.2 ml of a mixed solution of 10mmol/L of chloropalladate aqueous solution and 10mmol/L of chloroauric acid aqueous solution (the molar ratio of chloropalladic acid to chloroauric acid is 1:2), adding 240 mu L of sodium citrate with the concentration of 100mmol/L after 20 minutes, and carrying out heat preservation at a constant temperature of 90 ℃ for 20 hours under a sealed condition to synthesize palladium-gold alloy nanoparticles;
(1-3) dispersing the palladium-gold alloy nanoparticles in 20 ml of deionized water, adding 5 mg of dopamine monomer salt, polymerizing and coating dopamine monomer on the surfaces of the palladium-gold alloy nanoparticles to form a poly-dopamine layer under the alkaline condition of pH 12, centrifuging at 14000 revolutions per minute after ultrasonic dispersion, and dispersing the obtained solid in 20 ml of deionized water to form a first dispersion liquid.
(2) Preparing a second dispersion: preparing 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride, and dissolving the 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in a set amount of deionized water to obtain an aqueous solution of 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride; mixing the 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride aqueous solution with the first dispersion liquid, stirring in the dark at room temperature for a set time, performing ultrasonic dispersion, centrifuging, and dispersing solids in deionized water to form a second dispersion liquid; the method comprises the following specific steps:
(2-1) dissolving 0.2 g of 2,2 '-azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in 5 ml of deionized water to obtain an aqueous solution of 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride;
(2-2) the aqueous 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride solution was mixed with the first dispersion uniformly, stirred at room temperature in the dark for 15 hours, ultrasonically dispersed, centrifuged at 12000 rpm, and the solid was dispersed in 20 ml of deionized water to form a second dispersion.
(3) Preparing a third dispersion: separately preparing protein powder and gadolinium chloride (GdCl)3) Aqueous solution, sodium hydroxide aqueous solution; dissolving protein powder in deionized water under constant temperature, adding GdCl3Adding sodium hydroxide aqueous solution into the aqueous solution, continuously keeping constant temperature and rapidly stirring, and dialyzing by using a dialysis bag and deionized water to obtain Gd-protein complex to form third dispersion liquid; the method comprises the following specific steps:
(3-1) 0.25 g of human serum albumin and 1mL of gadolinium chloride (GdCl) with a concentration of 50mmol/L were prepared3) 1mL of sodium hydroxide aqueous solution with the concentration of 2 mol/L;
(3-2) dissolving the human serum albumin in 9 ml of deionized water at the physiological temperature of 37 ℃, and adding GdCl3Adding sodium hydroxide aqueous solution after 5 minutes, continuously keeping constant temperature and stirring at the speed of 800 revolutions per minute, and dialyzing by using a dialysis bag with molecular weight cutoff of 3500 and deionized water for 24 hours to obtain Gd-human serum albumin complex (Gd-HSA) to form third dispersion liquid;
(4) integral coating: and mixing the second dispersion liquid and the third dispersion liquid according to a set proportion, stirring in a dark place at 15-25 ℃, performing ultrasonic dispersion after reaching a set time, centrifuging, dispersing a solid in deionized water, and integrally coating the core-shell structure material with the Gd-protein complex to form an organic/inorganic hybrid nano biomaterial so as to obtain the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite material. The method comprises the following specific steps:
and adding 2.5 ml of the third dispersion liquid into 20 ml of the second dispersion liquid, uniformly mixing, stirring in the dark at 25 ℃ for 10 hours, performing ultrasonic dispersion, centrifuging at a speed of 10000 r/min, dispersing the solid in deionized water, and integrally coating the core-shell structure material with a Gd-human serum albumin complex (Gd-HSA) to form an organic/inorganic hybrid nano biomaterial, thus obtaining the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system.
Example 5
The application of the palladium-gold alloy diagnosis and treatment integrated nano composite system provided by the embodiment is to use the palladium-gold alloy diagnosis and treatment integrated nano composite system as a material for preparing a contrast agent for magnetic resonance imaging, CT imaging and photoacoustic imaging, is used for a diagnosis and treatment integrated new material integrating multimodal imaging and bimodal treatment, and provides a new strategy for the field of clinical multimodal diagnosis and multimodal treatment integration.
Example 6
The application of the integrated palladium-gold alloy diagnosis and treatment nanocomposite system provided in this embodiment is to use the diagnosis and treatment nanocomposite system material prepared in embodiment 1 as a material for preparing a near-infrared light-excited photothermal therapy photothermal reagent and a thermal dynamic therapy reagent, and the material integrates multimodal imaging and bimodal therapy, and can be widely applied to in vitro photothermal imaging.
The method for using the palladium-gold alloy diagnosis and treatment integrated nano complex material modified by the gadolinium complex in the embodiment in-vitro photothermal imaging under the excitation of 808nm laser comprises the following steps:
(1) preparing a gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system, a quartz cuvette, a continuous excitation 808nm laser and a thermal imaging camera in example 1;
(2) preparing the nano composite system in the embodiment 1 into solutions of 0 mug/mL, 50 mug/mL, 100 mug/mL, 200 mug/mL and 400 mug/mL by using deionized water, and performing ultrasonic dispersion uniformly to form a fourth dispersion liquid;
(3) adding 2mL of the fourth dispersion solution with different concentrations into a quartz cuvette, fixing the cuvette on an iron support, and measuring with 1.5W/cm2While the 808nm laser continuously irradiates the fourth dispersion, real-time temperature and thermographic photographs of the fourth dispersion were recorded at different times with a thermographic camera.
FIG. 3 is a photograph of a gadolinium complex modified Pd-Au alloy diagnosis and treatment integrated nanocomposite material obtained in example 1 of the present invention used for in vitro photothermal imaging, wherein it can be seen that under the excitation of laser light of 808nm, the temperature gradually increases with the increase of the concentration of the fourth dispersion; at the same time the temperature of the dispersion also increased with the irradiation time delay, after 8 minutes the temperature of the solution had already stabilized up to 60 ℃. The related literature reports that excellent photothermal treatment and cancer cell killing effects can be achieved after the nano complex system is cultured with tumor cells for 1 hour at 42 ℃, and the characterization shows that the nano complex system provided by the invention has great application prospects in photothermal treatment of tumor cells.
According to the preparation method of the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system, firstly, under the condition that a surfactant exists, sodium citrate is used for reducing chloropalladic acid and chloroauric acid to obtain palladium-gold alloy nanoparticles; then, polymerizing a dopamine monomer under an alkaline condition to coat a polydopamine layer on the surface of the palladium-gold alloy nanoparticle, wherein the drug 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride generates pi-pi interaction with rich pi electron cloud of the polydopamine layer structure to be loaded on the surface of the palladium-gold alloy nanoparticle; and finally, coating the material with a prepared Gd-protein complex to obtain a gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way. Those skilled in the art can make many possible variations or modifications to the disclosed solution, using the methods and techniques disclosed above, to equivalents thereof without departing from the scope of the invention. Therefore, all equivalent modifications made according to the structure, structure and principle of the present invention should be covered within the protection scope of the present invention without departing from the contents of the technical scheme of the present invention.
Claims (10)
1. A palladium-gold alloy diagnosis and treatment integrated nano composite system is characterized in that palladium-gold alloy nanoparticles are used as an inner core, a dopamine monomer undergoing a polymerization reaction forms a polydopamine shell layer coated on the outer surface of the palladium-gold alloy nanoparticles, the polydopamine layer is used for loading a drug 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride, and then Gd-protein complexes are used for integrally coating a core-shell structure material loaded with the drug to form an organic/inorganic hybrid nano biomaterial, namely a gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system.
2. The palladium-gold alloy integrated nanocomposite system for diagnosis and treatment according to claim 1, wherein the poly dopamine layer coated on the surface of the palladium-gold alloy nanoparticles is loaded with 2, 2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride using pi-pi interaction.
3. The palladium-gold alloy theranostic nanocomposite system according to claim 1, wherein the Gd-protein complex is: gd-bovine serum albumin complex (Gd-BSA), Gd-human serum albumin complex (Gd-HSA).
4. A method for preparing a palladium-gold alloy diagnostically integrated nanocomposite system according to one of claims 1 to 3, comprising the following steps:
(1) preparing a first dispersion: respectively preparing sodium citrate, a chloropalladic acid aqueous solution and a chloroauric acid aqueous solution, as well as surfactants Cetyl Trimethyl Ammonium Bromide (CTAB) and Cetyl Trimethyl Ammonium Chloride (CTAC), reducing the chloropalladic acid aqueous solution and the chloroauric acid aqueous solution by using the sodium citrate to synthesize palladium-gold alloy nanoparticles, and dispersing the palladium-gold alloy nanoparticles in deionized water; then, under an alkaline condition, adding a dopamine monomer, polymerizing the dopamine monomer to form a polydopamine layer to coat on the surface of the palladium-gold alloy nano particle, centrifuging after ultrasonic dispersion, and dispersing a solid in deionized water to form a first dispersion liquid;
(2) preparing a second dispersion: preparing 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride, and dissolving the 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in a set amount of deionized water to obtain an aqueous solution of 2,2 ' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride; mixing the 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride aqueous solution with the first dispersion liquid, stirring in the dark at room temperature for a set time, performing ultrasonic dispersion, centrifuging, and dispersing solids in deionized water to form a second dispersion liquid;
(3) preparing a third dispersion: separately preparing protein powder and gadolinium chloride (GdCl)3) Aqueous solution, sodium hydroxide aqueous solution; dissolving protein powder in deionized water under constant temperature, adding GdCl3Adding sodium hydroxide aqueous solution into the aqueous solution, continuously keeping constant temperature and rapidly stirring, and dialyzing by using a dialysis bag and deionized water to obtain Gd-protein complex to form third dispersion liquid;
(4) integral coating: and mixing the second dispersion liquid and the third dispersion liquid according to a set proportion, stirring in a dark place at 15-25 ℃, performing ultrasonic dispersion after reaching a set time, centrifuging, dispersing a solid in deionized water, and integrally coating the core-shell structure material with the Gd-protein complex to form an organic/inorganic hybrid nano biomaterial so as to obtain the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite material.
5. The preparation method of the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system as set forth in claim 4, wherein the step (1) of preparing the first dispersion comprises the following specific steps:
(1) respectively preparing a chloropalladate aqueous solution and a chloroauric acid aqueous solution;
(2) uniformly mixing 44 ml of cetyltrimethyl ammonium bromide (CTAB) and 5 ml of surfactant of cetyltrimethyl ammonium chloride (CTAC), and adding 1.2 ml of mixed solution of 10mmol/L of chloropalladate aqueous solution and 10mmol/L of chloroauric acid aqueous solution, wherein the molar ratio of the chloropalladate to the chloroauric acid is 1: 1-1: 2; adding 200-250 mu L of sodium citrate with the concentration of 100mmol/L after 20 minutes, and keeping the temperature at the constant temperature of 80-100 ℃ for 16-20 hours under a closed condition to synthesize palladium-gold alloy nanoparticles;
(3) dispersing palladium-gold alloy nanoparticles into 20 ml of deionized water, then adding 5 mg of dopamine monomer salt, polymerizing and coating dopamine monomer on the surfaces of the palladium-gold alloy nanoparticles to form a polydopamine layer under an alkaline condition with the pH value of 9-12, centrifuging at a speed of 13000-15000 r/min after ultrasonic dispersion, and dispersing the obtained solid into 20 ml of deionized water to form a first dispersion liquid.
6. The preparation method of the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system as set forth in claim 4, wherein the step (2) of preparing the second dispersion comprises the following specific steps:
(1) dissolving 0.1-0.2 g of 2,2 '-azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride in 5 ml of deionized water to obtain 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride aqueous solution;
(2) uniformly mixing the 2, 2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride water solution with the first dispersion liquid, stirring for 10-15 hours at room temperature in a dark place, centrifuging at the speed of 11000-13000 revolutions per minute after ultrasonic dispersion, taking the solid, and dispersing in 20 ml of deionized water to form a second dispersion liquid.
7. The preparation method of the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system as set forth in claim 4, wherein the step (3) of preparing the third dispersion comprises the following specific steps:
(1) 0.25 g of protein powder and 1mL of 50mmol/L gadolinium chloride (GdCl) were prepared3) 1mL of sodium hydroxide aqueous solution with the concentration of 2 mol/L;
(2) dissolving protein powder in 9 ml deionized water at physiological temperature of 37 ℃, adding GdCl3And adding a sodium hydroxide aqueous solution after 5 minutes, continuously keeping the constant temperature, stirring at the speed of 700-800 revolutions per minute, and dialyzing for 24 hours by adopting a dialysis bag with the molecular weight cutoff of 3500 and deionized water to obtain the Gd-protein complex to form a third dispersion liquid.
8. The preparation method of the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system according to claim 4, wherein the step (4) of integrally coating specifically comprises the following steps:
and adding 2.5 ml of the third dispersion liquid into 20 ml of the second dispersion liquid, uniformly mixing, stirring for 6-12 hours in the dark at 15-25 ℃, performing ultrasonic dispersion, centrifuging at 9000-11000 r/min, taking the solid, dispersing in deionized water, and integrally coating the core-shell structure material with the Gd-protein complex to form an organic/inorganic hybrid nano biomaterial, thus obtaining the gadolinium complex modified palladium-gold alloy diagnosis and treatment integrated nano composite system.
9. Use of a palladium-gold alloy theranostic nanocomposite system according to one of claims 1 to 3 as a material for the preparation of contrast agents for magnetic resonance imaging, CT imaging and photoacoustic imaging.
10. Use of a palladium-gold alloy theranostic nanocomposite system according to one of claims 1 to 3 for the preparation of materials for photothermal and thermokinetic therapeutic agents for near infrared light excited photothermal therapy.
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