Preparation method and application of ultra-small nano-high entropy alloy for energy CT imaging

Abstract

This invention, applicable to the field of medical contrast agents, provides a method for preparing and applying ultrasmall nano-high-entropy alloys for high-energy computed tomography (CT) imaging. Using a low-temperature oil-phase strategy, the method successfully synthesizes uniformly sized, approximately 5 nm, ultrasmall nano-high-entropy alloys (HEAs) from a mixture of cetyltrimethylammonium chloride and oleylamine, with the addition of a metal source and molybdenum hexacarbonyl, at ambient pressure and temperatures not exceeding 250°C. These ultrasmall nano-HEAs can be used in high-energy CT imaging, exhibiting excellent contrast-enhanced imaging capabilities and maintaining strong X-ray attenuation across a wide range of photon energies, particularly at high photon energies. Not only does their attenuation strength surpass that of the commercial contrast agent iohexol, but they also offer a wider energy range of application, making them valuable for the noninvasive and precise detection and diagnosis of lesions.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical contrast agents, and in particular relates to a preparation method and application of an ultra-small nano high-entropy alloy for energy CT imaging. Background Art

[0002] Computed tomography (CT) is a commonly used diagnostic technique. With its high spatial resolution and rapid image acquisition speed, it effectively provides information on the anatomical structure and density of lesions, playing a vital role in clinical diagnosis. Conventional CT imaging, without contrast agents, suffers from low soft tissue resolution, making it difficult to accurately distinguish lesions from normal tissue based solely on density differences. This poses significant challenges in the diagnosis of tumors and vascular diseases. Emerging energy-enhanced CT utilizes datasets of varying X-ray photon energies to differentiate tissues based on their attenuation characteristics. This technology can generate single-energy images, material decomposition images, effective atomic number maps, and energy spectrum curves, enabling multi-dimensional, multi-angle, and multi-parameter imaging diagnostic analysis. To enhance soft tissue contrast, iodine-based small molecule contrast agents are commonly used clinically. However, the energy produced by X-ray sources near the iodine K absorption edge (33 keV) is low, resulting in a relatively weak attenuation intensity when energy-enhanced CT uses the characteristic attenuation changes of iodine at this edge for identification and quantification. This makes it difficult to visualize fine anatomical details of lesions using iodine-enhanced energy-enhanced CT. In recent years, with the advancement of technology, many new contrast agents have been introduced, which have achieved certain improvements in CT imaging contrast and biocompatibility. However, with the increase in clinical demand, the performance requirements for contrast agents are also constantly increasing, especially in terms of reducing the risk of allergic reactions and kidney damage. Therefore, considering the advantages and disadvantages of current CT contrast agents, the development of a new energy CT contrast agent that is cost-effective, has higher biosafety, and has lower side effects has become a focus of future research. At the same time, it is necessary to explore how to improve the effectiveness of existing contrast agents in clinical applications to meet the growing demand for medical imaging.

[0003] Against this backdrop, high-entropy alloys (HEAs), emerging materials, exhibit exceptional physicochemical properties, such as excellent X-ray attenuation, high strength, good corrosion resistance, and outstanding thermal stability. These properties hold great promise for HEAs' application in medical imaging, particularly as contrast agents for high-energy computed tomography (CT). For example, HEAs can achieve enhanced X-ray attenuation by optimizing the ratio of elements with high atomic numbers and high K absorption edges, thereby producing clearer contrast at varying X-ray photon energies in CT imaging. This is crucial for the early detection of tumors, emboli, and other abnormal tissues. Furthermore, their ultrasmall nanoscale size allows HEAs to evade capture by the reticuloendothelial system and be rapidly cleared by the kidneys, preventing their long-term retention and accumulation in the body and mitigating potential toxic side effects. HEAs can also achieve multiple functionalities, such as targeted drug release and thermal therapy, through the manipulation of alloy composition, offering new avenues for integrating medical imaging and therapy.

[0004] Therefore, developing high-entropy alloys as energy CT contrast agents not only addresses the challenges currently faced by contrast agents but also provides new insights and directions for the future innovation of medical imaging. Further exploration of this research area will help advance biomedical imaging technology and improve the quality of patient diagnosis and treatment. To this end, this paper proposes a method for preparing and applying ultrasmall nano-high-entropy alloys for energy CT imaging. Summary of the Invention

[0005] The purpose of the present invention is to provide a preparation method and application of ultra-small nano high entropy alloys for energy CT imaging, aiming to solve the problems raised in the above background technology.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] A method for preparing ultra-small nano-high entropy alloy for energy CT imaging, comprising the following steps:

[0008] Step 1: Add hexadecyltrimethylammonium chloride to oleylamine, place in a bottle, and sonicate for 15 minutes. Then, add chloroplatinic acid, palladium acetylacetonate, iron acetylacetonate, chloroauric acid, copper acetylacetonate, glucose, and molybdenum hexacarbonyl, and continue sonicating for 1 hour. Transfer the mixed solution to a round-bottom flask and heat to 220°C under magnetic stirring for 2 hours. After the reaction is complete, cool to room temperature, collect the black colloidal product by centrifugation, and wash it three times with an ethanol / cyclohexane mixture. Finally, disperse the black colloidal product in cyclohexane and store for later use.

[0009] Step 2: The black colloidal product dispersed in cyclohexane was diluted with ethanol and sonicated for 2 hours; the nanoparticles were separated by centrifugation, the supernatant was discarded, and the ethanol washing was repeated three times; deionized water and polyvinyl pyrrolidone were added to the washed nanoparticles, and sonicated for 3 hours to modify the surface of the nanoparticles with polyvinyl pyrrolidone and stably dispersed in water.

[0010] Furthermore, in step 1, the magnetic stirring speed is 400 rpm.

[0011] Furthermore, in step 1, the heating rate is 5 °C / min.

[0012] Furthermore, in the ethanol / cyclohexane mixture of step 1, the volume ratio of ethanol to cyclohexane is 1:1, and the mass fractions of ethanol and cyclohexane are 96-99% and 99.7%, respectively.

[0013] Furthermore, in step 2, the volume ratio of cyclohexane to ethanol is 1:10.

[0014] Furthermore, the particle size of the ultra-small nano high entropy alloy imaged by the energy CT is 5 nm.

[0015] An ultra-small nano high-entropy alloy for energy CT imaging prepared according to the above-mentioned preparation method.

[0016] An application of the above-mentioned ultra-small nano high entropy alloy for energy CT imaging in the preparation of an energy CT imaging contrast agent.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] This study employs a low-temperature oil-phase strategy, using a mixture of cetyltrimethylammonium chloride and oleylamine as a base, with the addition of a metal source and molybdenum hexacarbonyl. Ultrasmall HEAs (HEAs) with uniform size of approximately 5 nm were successfully synthesized at ambient pressure and temperatures not exceeding 250°C. These ultrasmall nano-HEAs can be used in high-energy CT imaging, exhibiting excellent contrast-enhanced imaging capabilities and maintaining strong X-ray attenuation across a wide range of photon energies, particularly at high photon energies. Not only does their attenuation strength surpass that of the commercial contrast agent iohexol, but they also offer a wider energy range of application, making them valuable for the noninvasive and precise detection and diagnosis of lesions. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 These are digital photos of the ultrasmall nano-HEAs prepared in Example 1 on the first day of synthesis and after being placed for seven days.

[0020] Figure 2 This is a transmission electron microscope image of the ultrasmall nano-HEAs prepared in Example 1.

[0021] Figure 3 This is the particle size distribution diagram of the ultrasmall nano HEAs prepared in Example 1.

[0022] Figure 4 This is the X-ray diffraction pattern of the ultrasmall nano-HEAs prepared in Example 1.

[0023] Figure 5 This is the X-ray photoelectron spectroscopy (XPS) graph of the ultrasmall nano-HEAs prepared in Example 1.

[0024] Figure 6 These are traditional CT images of different concentrations of calcium chloride, iohexol, and the ultrasmall nano-HEAs prepared in Example 1.

[0025] Figure 7 Pseudo-color images of the effective atomic numbers of different concentrations of calcium chloride, iohexol, and the ultrasmall nano-HEAs prepared in Example 1.

[0026] Figure 8 Pseudo-color images of iodine concentrations of different concentrations of calcium chloride, iohexol, and ultrasmall nano-HEAs prepared in Example 1.

[0027] Figure 9 These are single-energy CT images of calcium chloride at a concentration of 20 mg / mL, iohexol, and the ultrasmall nano-HEAs prepared in Example 1.

[0028] Figure 10 Energy spectrum curves of calcium chloride at a concentration of 20 mg / mL, iohexol, and the ultrasmall nano-HEAs prepared in Example 1. DETAILED DESCRIPTION

[0029] In order to have a clearer understanding of the technical features, objectives and beneficial effects of the present invention, the technical solution of the present invention is now described in detail below, but it should not be understood as limiting the scope of implementation of the present invention.

[0030] The specific implementation of the present invention is described in detail below with reference to specific embodiments. The reagents and instruments used in the embodiments can all be purchased through normal commercial channels.

[0031] Example 1: Preparation and characterization of ultra-small nano-HEAs for energy CT imaging;

[0032] 1. Preparation method;

[0033] Step 1: CTAC (cetyltrimethylammonium chloride, 50 mg, 96% purity) was added to 10 mL of oleylamine (70% purity) in a 50 mL vial. After sonication for 15 minutes, HPtCl (chloroplatinic acid, 1 μmol, 37.5% based on Pt), Pd(acac) (palladium acetylacetonate, 1 μmol, 97% purity), Fe(acac) (ferric acetylacetonate, 3 μmol, 97% purity), HAuCl (chloroauric acid, 1 μmol, 47.8% based on Au), Cu(acac) (copper acetylacetonate, 1 μmol, 97% purity), glucose (60 mg), and Mo(CO) (molybdenum hexacarbonyl, 33 mg, 97% purity) were added, and sonication was continued for 1 hour. The mixed solution was transferred to a round-bottom flask and heated to 220°C at a rate of 5°C / min under magnetic stirring (400 rpm) for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and the black colloidal product was collected by centrifugation (12,000 rpm for 20 minutes). The product was washed three times with an ethanol / cyclohexane mixture (V:V = 1:1, with the mass fractions of ethanol and cyclohexane being 99% and 99.7%, respectively). Finally, the black colloidal product was dispersed in cyclohexane and stored for later use.

[0034] Step 2: The black colloid dispersed in cyclohexane was diluted with ethanol at a cyclohexane / ethanol ratio of 1:10 (V:V) and sonicated for 2 hours. The nanoparticles were separated by centrifugation (12,000 rpm, 20 minutes), the supernatant discarded, and the mixture was washed three times with 99% ethanol. 10 mL of deionized water and 30 mg of polyvinyl pyrrolidone (PVP) were added to the washed nanoparticles, and sonicated for 3 hours to modify the nanoparticle surface with PVP and stably disperse them in water, ultimately yielding ultrasmall nano-HEAs.

[0035] 2. Representation;

[0036] like Figure 1 As shown, comparing the samples on the first day and the seventh day, the black colloidal product in the bottle on the first day is dispersed in cyclohexane, and the solution system has a uniform appearance; after seven days, the solution still remains uniform, without obvious stratification, precipitation and other adverse phenomena, indicating that the ultrasmall nano-HEAs have good dispersion stability in cyclohexane within seven days.

[0037] Through transmission electron microscopy ( Figure 2 ) observation, it can be seen that ultra-small nano-HEAs exist in the form of ultra-small particles. Although there is slight agglomeration locally, the overall size is ultra-small. The particle size distribution histogram ( Figure 3) shows that the particle size distribution is concentrated at approximately 5 nm, with a significant peak. Overall, the ultrasmall nano-HEAs prepared in this example possess the morphological characteristics of ultrasmall nanomaterials and can be used as a potential material for applications such as energy CT imaging.

[0038] The crystal phase of the ultra-small nano HEAs prepared in this embodiment was characterized, and the results are as follows: Figure 4 As shown in the figure, the characteristic diffraction peaks correspond to the typical peak positions of the face-centered cubic (FCC) structure, indicating that the ultra-small nano-HEAs have a face-centered cubic crystal structure. At the same time, no characteristic peaks of other impurity phases appear in the spectrum, indicating that the product is of high purity and no impurity phases are generated.

[0039] The ultra-small nano HEAs prepared in this embodiment were analyzed by X-ray photoelectron energy (XPS). The results are as follows: Figure 5 As shown in the figure, each metal element exhibits a distinct peak at its characteristic binding energy position in its alloy state, while no characteristic peaks corresponding to metal oxides are detected. This indicates that the prepared ultrasmall nano-HEAs are composed of multiple metal elements, and the metals exist in an alloy state without significant oxidation, successfully synthesizing high-purity multi-element alloy nanomaterials.

[0040] The ultra-small nano-HEAs prepared in this example were prepared into dispersions of different concentrations (5, 10, 15, 20 mg / mL) and subjected to energy CT scanning with the same concentrations of calcium chloride (simulating calcium-rich tissue) and iohexol. The results are as follows: Figure 6 As shown in the figure, as the concentration increases, the X-ray attenuation intensity of iohexol and ultra-small nano HEAs gradually increases, which shows that ultra-small nano HEAs have good CT contrast enhancement function. The effective atomic number pseudo color image ( Figure 7 ) and iodine concentration pseudo-color image ( Figure 8 ) reconstruction. As can be seen from the figure, within the concentration range of 5–20 mg / mL, the pseudo-color of calcium chloride is relatively stable, while the pseudo-color of iohexol and ultrasmall nano-HEAs exhibits regular changes with increasing concentration, with significant color differences between the three. This indicates that ultrasmall nano-HEAs differ significantly from calcium chloride and iohexol in their effective atomic number distribution and iodine concentration correlation. These pseudo-color images can be used to accurately distinguish them, providing strong support for their use as contrast agents in high-energy CT imaging.

[0041] Single energy (40, 60, 80, 100, 120, 140, 160, 180 keV) CT image reconstruction was performed on calcium chloride, iohexol, and ultrasmall nano-HEAs at a concentration of 20 mg / mL. The results are shown in Figure 2. Figure 9As shown in the figure, there are significant differences in the images of the three at a specific single energy, and the X-ray attenuation intensity of the three gradually decreases with the increase of energy level. In the lower energy level single energy images, iohexol and ultra-small nano HEAs are clearly different from calcium chloride. In the higher energy level single energy images, the X-ray attenuation intensity of calcium chloride and iohexol is low and roughly similar, making it difficult to distinguish, while the X-ray attenuation intensity of ultra-small nano HEAs remains at a high level, which can be effectively distinguished from calcium chloride and iohexol. This shows that ultra-small nano HEAs have unique contrast enhancement advantages in CT imaging with a wide energy range, especially in high energy level scenarios.

[0042] The energy spectrum curves of calcium chloride, iohexol and ultra-small nano-HEAs at a concentration of 20 mg / mL were drawn, and the results were as follows: Figure 10 As shown in the figure, as the single energy level gradually increases (40-190 keV), the CT value (attenuation intensity) of iohexol decreases rapidly, the attenuation intensity of ultrasmall nano-HEAs decreases slowly, and the attenuation intensity of calcium chloride decreases slightly. Across the entire energy range, the attenuation intensity of iohexol and ultrasmall nano-HEAs is consistently higher than that of calcium chloride. In particular, in the energy range of 80-190 keV, ultrasmall nano-HEAs exhibit significantly higher attenuation intensity than both calcium chloride and iohexol. This demonstrates that ultrasmall nano-HEAs exhibit outstanding attenuation characteristics and excellent contrast enhancement capabilities in the high-energy range, making them suitable for high-energy CT imaging scenarios.

[0043] In summary, the ultrasmall nano HEAs particles prepared in the present invention have stable and efficient energy CT contrast-enhanced imaging capabilities, especially excellent performance in effective atomic number pseudo-color images, iodine concentration pseudo-color images and high-energy level single energy images, and are a very promising energy CT contrast agent.

[0044] The above are only preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, several variations and improvements can be made without departing from the concept of the present invention. These should also be regarded as the scope of protection of the present invention. These will not affect the effect of the implementation of the present invention and the practicality of the patent.

Claims

1. A method for preparing ultra-small nano-high entropy alloy for energy CT imaging, characterized in that: The following steps are involved: Step 1: Add hexadecyltrimethylammonium chloride to oleylamine, place in a bottle, and sonicate for 15 minutes. Then, add chloroplatinic acid, palladium acetylacetonate, iron acetylacetonate, chloroauric acid, copper acetylacetonate, glucose, and molybdenum hexacarbonyl, and continue sonicating for 1 hour. Transfer the mixed solution to a round-bottom flask and heat to 220°C under magnetic stirring for 2 hours. After the reaction is complete, cool to room temperature, collect the black colloidal product by centrifugation, and wash it three times with an ethanol / cyclohexane mixture. Finally, disperse the black colloidal product in cyclohexane and store for later use. Step 2: The black colloidal product dispersed in cyclohexane was diluted with ethanol and sonicated for 2 hours; the nanoparticles were separated by centrifugation, the supernatant was discarded, and the ethanol washing was repeated three times; deionized water and polyvinyl pyrrolidone were added to the washed nanoparticles, and sonicated for 3 hours to modify the surface of the nanoparticles with polyvinyl pyrrolidone and stably dispersed in water.

2. The preparation method according to claim 1, characterized in that In step 1, the magnetic stirring speed is 400 rpm.

3. The preparation method according to claim 1, characterized in that In step 1, the heating rate is 5 ° C / min.

4. The preparation method according to claim 1, characterized in that In the ethanol / cyclohexane mixed solution of step 1, the volume ratio of ethanol to cyclohexane is 1:1, and the mass fractions of ethanol and cyclohexane are 96-99% and 99.7%, respectively.

5. The preparation method according to claim 1, characterized in that In the step 2, the volume ratio of cyclohexane to ethanol is 1:

10.

6. The preparation method according to claim 1, characterized in that The particle size of the ultra-small nano high entropy alloy imaged by the energy CT is 5 nm.

7. An ultra-small nano-high entropy alloy for energy CT imaging prepared according to the preparation method according to any one of claims 1 to 6.

8. Use of the ultra-small nano high entropy alloy for energy CT imaging according to claim 7 in the preparation of an energy CT imaging contrast agent.

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