A plasma-enhanced photothermal therapy microsphere for embolism and its preparation method

Abstract

This invention proposes a plasma-enhanced photothermal therapy embolization microsphere and its preparation method. The preparation method includes: preparing a gelatin solution and a modifying solution; adding the modifying solution to the gelatin solution to obtain an aqueous prepolymer; adding a nucleophilic reagent to the aqueous prepolymer and obtaining a first modified aqueous prepolymer under ultraviolet irradiation; sequentially adding a photosensitizer and a drug to the first modified aqueous prepolymer to obtain a third modified aqueous prepolymer; preparing a dispersion; gradually adding the dispersion to the third modified aqueous prepolymer under ice bath conditions and a first ultrasonic power, ultrasonically emulsifying, then adding a crosslinking agent, and performing ultrasonic crosslinking under ice bath conditions and a second ultrasonic power to obtain an intermediate product; post-processing the intermediate product to obtain a first microsphere; forming an adhesion layer on the first microsphere, reducing the adhesion layer, and forming nano-metal particles on the surface of the microsphere. Through this invention, the embolization microsphere has plasma-enhanced imaging function and can perform photothermal therapy in conjunction with drug release to eliminate tumors.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a plasma-enhanced photothermal therapy embolism microsphere and its preparation method. Background Technology

[0002] Cancer poses a significant threat to human health and life. Currently, the main clinical treatments include surgery, chemotherapy, and radiotherapy. However, these methods often have limited effectiveness and serious side effects. Furthermore, with the development of drug resistance in tumors, resistant tumor cells utilize internal mechanisms to expel drugs that have entered the cell, rendering the drugs ineffective. Therefore, how to precisely deliver drugs to key lesion areas to achieve effective cancer treatment is a pressing problem that needs to be solved.

[0003] As interventional therapy becomes increasingly sophisticated, particle or microsphere embolization agents are commonly used in clinical practice to block the blood supply to tumor tissues. However, traditional embolization agents cannot directly kill tumor cells, thus greatly limiting their effectiveness. While embolization therapy can be achieved by using microspheres to carry chemotherapy drugs, the treatment efficacy still needs improvement due to factors such as uneven microsphere size, tumor drug resistance, and the inability of the particles themselves to be precisely delivered to the target area. Summary of the Invention

[0004] This invention proposes a plasma-enhanced photothermal therapy embolization microsphere and its preparation method. The microsphere is prepared by ultrasonic homogenization emulsification and photoinitiation grafting process. It has plasma-enhanced imaging function and can be used for photothermal therapy in conjunction with drug release to eliminate tumors.

[0005] To address the aforementioned technical problems, this invention provides a method for preparing photothermal therapy embolism microspheres with enhanced plasma imaging, comprising at least the following steps: Dissolve gelatin in water to obtain a gelatin solution; An ester modifier is dissolved in water, and acid, initiator, and additives are added under ice bath conditions to obtain a modified solution. The modified liquid is added to the gelatin solution and stirred to obtain an aqueous prepolymer solution; A nucleophilic reagent was added to the aqueous prepolymer solution, and then subjected to ultraviolet irradiation to obtain a first modified aqueous prepolymer solution. A photosensitizer is added to the first modified aqueous prepolymer solution to carry out a grafting reaction, thereby obtaining a second modified aqueous prepolymer solution. The drug is added to the second modified aqueous prepolymer solution and stirred to obtain the third modified aqueous prepolymer solution. The emulsifier is dissolved in the oil phase liquid and heated to a first preset temperature, and stirred to obtain a dispersion. The third modified aqueous prepolymer was placed in an ultrasonic disruptor, and the dispersion was gradually added dropwise under ice bath conditions and first ultrasonic power. Ultrasonic emulsification was carried out for a first preset time to obtain an ultrasonic emulsion. A crosslinking agent is added dropwise to the ultrasonic emulsion, and an ultrasonic crosslinking reaction is carried out under a second ultrasonic power for a second preset time in an ice bath to obtain an intermediate product. The intermediate product is post-processed to obtain the first microspheres; The first microspheres were dispersed in a buffer solution, an adhesive was added and the mixture was stirred for a third preset time. After centrifugation, the second microspheres with an adhesive layer were obtained. The second microsphere is placed in a metal-modified liquid, which undergoes a reduction reaction with the adhesion layer. After centrifugation, embolic microspheres with nano-metal particles attached to the adhesion layer are obtained.

[0006] In one embodiment of the present invention, the ester modifier includes at least one of 2-hydroxypropyl acrylate, acrylate, or polyurethane; and / or

[0007] The acid solution is selected, for example, at least one of hydrochloric acid or nitric acid, and the mass fraction of the acid solution is 10% to 20%; and / or

[0008] The initiator includes, for example, one or more combinations of cerium ammonium nitrate, ammonium persulfate, or potassium persulfate; and / or

[0009] The additives include one or a combination of sodium bisulfite, sodium carbonate, or sodium bicarbonate.

[0010] In one embodiment of the present invention, the mass ratio of the gelatin to the ester modifier is 1:(1~2); and / or

[0011] The mass ratio of the ester modifier, the acid, the initiator, and the auxiliary agent is (10~15):(5~10):(0.1~2):(0.5~2).

[0012] In one embodiment of the present invention, the reaction temperature of the gelatin solution and the modified liquid is less than 40°C.

[0013] In one embodiment of the present invention, the nucleophile includes at least one of ethane-1,2-diamine, ethylenediamine, N-ethylethylenediamine, dimethylethylenediamine, butane-1,4-diamine, or pentane-1,5-diamine, and the mass ratio of the nucleophile to the ester modifier is (1~2):1.

[0014] In one embodiment of the present invention, the ultraviolet irradiation conditions include: the wavelength of the ultraviolet light is 200nm~300nm, the reaction temperature is 45℃~50℃, and the reaction time is 12h~24h.

[0015] In one embodiment of the present invention, the photosensitizer includes indocyanine green, and the mass ratio of the gelatin to the photosensitizer is (10~15):1; and / or

[0016] The reaction conditions for the photosensitizer and the first modified aqueous prepolymer include: a reaction temperature of 30℃~35℃, and a stirring rate of 100r / min~150r / min for 2h~4h.

[0017] In one embodiment of the present invention, the drug includes at least one of doxorubicin, epirubicin, irinotecan, or cisplatin-based drugs, and the mass ratio of the gelatin to the drug is (150~250):1.

[0018] In one embodiment of the present invention, the emulsifier includes one or more combinations of Span 20, Span 80, Tween 20, Tween 80, PEG-40, or PEG-20, and the oil phase liquid includes low-boiling-point petroleum ether; and / or

[0019] The first preset temperature is 25℃~35℃.

[0020] In one embodiment of the present invention, the first ultrasonic power is 30W~500W, and the first preset time is 15min~30min; and / or

[0021] The second ultrasonic power is 20W~200W, and the second preset time is 10min~20min; and / or

[0022] The crosslinking agent includes at least one of glutaraldehyde, formaldehyde, or n-butyraldehyde; and / or

[0023] The mass ratio of the crosslinking agent to the gelatin is 1:(5~10).

[0024] In one embodiment of the present invention, the post-processing includes drying and impurity removal. The drying is performed under vacuum at 35°C to 40°C, and the impurity removal is performed by washing with water for injection followed by vacuum drying at 35°C to 40°C.

[0025] In one embodiment of the present invention, the buffer solution comprises tris(hydroxymethyl)aminomethane hydrochloride, and the concentration of the buffer solution is 0.1 mol / L to 0.15 mol / L; the adhesive comprises at least one of polydopamine, sodium citrate, ethylenediaminetetraacetic acid, or polyvinylpyrrolidone, and the concentration of the buffer solution is 0.5 g / L to 5 g / L, and the volume ratio of the first microsphere to the buffer solution is 1:5 to 20.

[0026] In one embodiment of the present invention, the metal modification solution includes at least one of silver nitrate solution, chloroauric acid solution or copper sulfate solution, and the concentration of the metal modification solution is 200 μg / ml to 300 μg / ml.

[0027] This invention also provides a plasma-enhanced photothermal therapy embolization microsphere, obtained by the preparation method described above. The embolization microsphere is a microsphere polymerized from gelatin and a crosslinking agent. The embolization microsphere encapsulates a therapeutic drug, and a nucleophilic reagent-modified ester copolymer is grafted onto the surface of the embolization microsphere. A photosensitizer is grafted onto the nucleophilic reagent group. An adhesion layer is formed on the embolization microsphere, and nano-metal particles are uniformly distributed on the adhesion layer.

[0028] In one embodiment of the present invention, the nano-metal particles include at least one of nano-silver particles, nano-gold particles, or nano-copper particles, and the loading of the nano-metal particles is 50wt%~60wt%.

[0029] In summary, this invention proposes a plasma-enhanced photothermal embolization microsphere and its preparation method. The resulting embolization microspheres have a high surface loading of nano-metal particles, which allows for stronger X-ray signal absorption by the detector. After conversion by an analog-to-digital converter, clearer CT images are formed, resulting in clearer imaging capabilities and precise delivery of the embolization microspheres to the lesion site. Furthermore, the embolization microspheres obtained by this invention have uniform size and high plasma shell density, thus possessing higher tissue resolution and contrast, as well as lower noise levels and no artifacts. Existing technologies typically graft iodine ions onto the surface of the microspheres. The iodine ions absorb X-rays to produce an imaging effect without affecting drug release, enabling the microspheres to achieve photothermal therapy, which has promising medical applications. Photothermal therapy can be achieved by remotely exciting a light source and using a photosensitizer to generate rapid local heating. Combined with drug therapy, targeted drug delivery can be achieved, significantly inhibiting tumor growth and preventing tumor regeneration. This treatment method can be controlled in both time and space and does not harm normal tissues. Meanwhile, the heat energy generated by photothermal therapy in this invention responds to the thermosensitive properties of gelatin, thereby altering the hydrogen bonding between gelatin molecules, enhancing its solubility, and achieving thermosensitive targeted drug release without causing serious postoperative sequelae. Furthermore, the preparation method of this invention features mild reaction conditions, high controllability, and a relatively fast reaction rate, demonstrating promising prospects for industrial application. Attached Figure Description

[0030] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0031] Figure 1This is a schematic diagram illustrating the process of obtaining a first microsphere-a second microsphere-embolized microsphere-drug-released microsphere in one embodiment of the present invention.

[0032] Figure 2 This is a scanning electron microscope image of the embolic microspheres obtained in Example 1.

[0033] Figure 3 The image shows a scanning electron microscope-X-ray energy dispersive spectroscopy (SEM) image of the embolized microspheres obtained in Example 1.

[0034] Figure 4 The image shows the energy spectrum of the embolization microspheres obtained in Example 1.

[0035] Figure 5 The temperature-time curves are for the embolization microspheres of Examples 1, 4-5 and Comparative Examples 3-4. Detailed Implementation

[0036] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0037] It should be understood that the invention can be embodied in various forms and should not be construed as being limited to the embodiments set forth herein. Rather, providing these embodiments will make the disclosure thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0038] The technical solution of the present invention will be further described in detail below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0039] This invention provides a method for preparing photothermal therapeutic embolism microspheres with plasma-enhanced imaging. The preparation method includes at least the following steps: dissolving gelatin in water to obtain a gelatin solution; dissolving an ester modifier in water and adding acid, an initiator, and an auxiliary agent under ice bath conditions to obtain a modified solution; adding the modified solution to the gelatin solution and stirring to obtain an aqueous prepolymer solution; adding a nucleophilic reagent to the aqueous prepolymer solution and subjecting it to ultraviolet irradiation to obtain a first modified aqueous prepolymer solution; adding a photosensitizer to the first modified aqueous prepolymer solution and performing a grafting reaction to obtain a second modified aqueous prepolymer solution; adding a drug to the second modified aqueous prepolymer solution and stirring to obtain a third modified aqueous prepolymer solution; and dissolving an emulsifier in an oil phase liquid and heating it to a first preset temperature. The mixture is stirred to obtain a dispersion; the third modified aqueous prepolymer is placed in an ultrasonic disruptor, and the dispersion is gradually added dropwise under ice bath conditions and a first ultrasonic power, and ultrasonic emulsification is performed for a first preset time to obtain an ultrasonic emulsion; a crosslinking agent is added dropwise to the ultrasonic emulsion, and ultrasonic crosslinking reaction is performed under ice bath conditions and a second ultrasonic power for a second preset time to obtain an intermediate product; the intermediate product is post-treated to obtain a first microsphere; the first microsphere is dispersed in a buffer solution, an adhesive is added, and the mixture is stirred and reacted for a third preset time, and centrifuged to obtain a second microsphere with an adhesive layer; the second microsphere is placed in a metal-modified solution, where the metal-modified solution undergoes a reduction reaction with the adhesive layer, and after centrifugation, embolic microspheres with nano-metal particles attached to the adhesive layer are obtained.

[0040] In one embodiment of the present invention, the solvent water in the gelatin solution is, for example, water for injection, and the mass ratio of gelatin to water is, for example, 1:(9~15). Specifically, at 40°C, gelatin is added to water for injection and stirred at a speed of 50 r / min to 60 r / min for 0.5 h to 1.5 h to dissolve it, and then the solution is prepared by allowing it to stand to remove air bubbles.

[0041] In one embodiment of the present invention, the ester modifier includes, for example, at least one selected from 2-hydroxypropyl acrylate (HPA), acrylate (ACR), or polyurethane (PU), and 2-hydroxypropyl acrylate is selected as an example. The acid solution is selected from, for example, at least one selected from hydrochloric acid or nitric acid, and the mass fraction of the acid solution is, for example, 10% to 20%. The initiator includes, for example, one or a combination of several selected from cerium ammonium nitrate, ammonium persulfate, or potassium persulfate, and cerium ammonium nitrate is selected as an example. The auxiliary agent includes, for example, one or a combination of several selected from sodium bisulfite, sodium carbonate, or sodium bicarbonate. The mass ratio of the ester modifier to water is, for example, (10 to 15): 20. In one embodiment of the present invention, for example, 10g to 15g of 2-hydroxypropyl acrylate is dissolved in 20ml of purified water, 5g to 10g of 15% hydrochloric acid is added, followed by 0.1g to 2g of cerium ammonium nitrate and 0.5g to 2g of sodium bisulfite, and the mixture is stirred until the powder is completely dissolved. An ice bath is used to release the heat generated by the neutralization reaction, controlling the temperature of the obtained modified solution to ensure the temperature during subsequent reactions with the gelatin solution, preventing excessively high reaction temperatures from affecting the reaction. An acid solution is used to control the pH of the modified solution to be less than 7, providing an initiation environment where the initiator can activate the free radical activity of gelatin in subsequent reactions. The additives can regulate the polymerization process of the ester modifier, which, after self-polymerization to form a copolymer, is used for direct grafting of gelatin.

[0042] In one embodiment of the present invention, after obtaining the modified liquid, it is added to a gelatin solution and stirred to obtain an aqueous prepolymer. The gelatin molecules are charged under initiator and acidic conditions. Then, the ester modifier, under the action of an auxiliary agent, self-polymerizes to form a copolymer and is directly grafted onto the gelatin molecules. After the modified liquid is added to the gelatin solution, the mixture is stirred at 100-150 rpm for 40-60 minutes. The mass ratio of gelatin to ester modifier is, for example, 1:(1-2). In this invention, the initiator can lower the activation energy of the reaction between the ester modifier and gelatin, stimulating free radical polymerization between them. This lowers the polymerization temperature, for example, allowing the reaction to occur below 40°C. This enables the copolymer of the ester modifier to be directly grafted onto the gelatin molecules at low temperatures, eliminating the need for a non-degradable intermediate carrier. By controlling the reaction temperature, the problem of poor stability of gelatin at high temperatures and its tendency to form gels at low temperatures is solved, thus achieving gelatin modification. This invention enables the direct grafting of ester modifiers onto gelatin molecules to form copolymers through self-polymerization, facilitating the subsequent grafting of photosensitizers.

[0043] In one embodiment of the present invention, after obtaining the aqueous prepolymer, a nucleophilic reagent is added to the aqueous prepolymer and subjected to ultraviolet irradiation to obtain a first modified aqueous prepolymer. The nucleophilic reagent includes, for example, amines such as ethane-1,2-diamine, ethylenediamine or N-ethylethylenediamine, dimethylethylenediamine, butane-1,4-diamine, and pentane-1,5-diamine, and for example, ethane-1,2-diamine. The reaction process is as follows: Figure 3 As shown in the figure. The mass ratio of the nucleophile to the ester modifier is, for example, (1~2):1. The wavelength of the ultraviolet light used is, for example, 200nm~300nm. Under ultraviolet irradiation, the reaction is carried out at 45℃~50℃ for 12h~24h. Under ultraviolet irradiation, the ester groups in the ester modifier copolymer grafted onto the gelatin molecules break down, while the amino groups in the grafted nucleophile provide positively charged amino groups, thus forming active functional groups to facilitate the grafting of photosensitizers in subsequent processes. This invention uses ultraviolet light to initiate graft polymerization, with mild reaction conditions, causing the original groups to break down while avoiding the introduction of other chemical reagents that could damage the physicochemical properties of the drug. This improves the grafting effect of the nucleophile and enhances the chemical binding ability of the formed embolic microspheres. Furthermore, ultraviolet light graft polymerization has a fast reaction rate and efficient grafting process, showing good prospects for industrial application.

[0044] In one embodiment of the present invention, the photosensitizer includes, for example, photosensitizing agents such as indocyanine green, and the photosensitizer contains negatively charged groups. The mass ratio of gelatin to photosensitizer is, for example, (10~15):1. The photosensitizer is added to a first modified aqueous prepolymer solution according to the mass ratio, and the reaction is carried out at 30℃~35℃ and 100r / min~150r / min for 2h~4h with stirring to graft the nucleophilic reagent groups onto the photosensitizer, thereby obtaining a second modified aqueous prepolymer solution. In the first modified solution, active groups are generated due to changes caused by ultraviolet irradiation, thereby grafting nucleophilic reagents, thus chemically grafting the photosensitizer onto the nucleophilic reagent.

[0045] In one embodiment of the present invention, the drug includes, for example, doxorubicin, epirubicin, irinotecan, or cisplatin-based drugs, which can be selected according to the applicable symptoms of the microspheres. In this embodiment, the mass ratio of gelatin to drug is, for example, (150~250):1. The drug is added to the second modified aqueous prepolymer solution according to the mass ratio, completely dissolved at 30℃~35℃, and stirred at 100r / min~150r / min for 1h~3h to obtain the third modified aqueous prepolymer solution. By grafting the photosensitizer first and then adding the drug, the competition between the drug and the photosensitizer for grafting sites can be prevented, thus avoiding affecting the photosensitizer grafting rate. In the third modified aqueous prepolymer solution, the drug is dissolved in the gelatin solution and, through physical mixing, is located between the gelatin molecules.

[0046] In one embodiment of the present invention, the emulsifier is, for example, one or a combination of several selected from Span 20, Span 80, Tween 20, Tween 80, PEG-40, or PEG-20, and the oil phase liquid includes, for example, one of low-boiling-point petroleum ether, and for example, a petroleum ether with a boiling point of 40°C to 50°C, to facilitate the removal of the oil phase liquid in subsequent processes and reduce cleaning steps. In one embodiment of the present invention, for example, 0.5g to 2g of emulsifier is dispersed in 200g of oil phase liquid, and the first preset temperature is, for example, 25°C to 35°C, and the mixture is stirred evenly at, for example, 200r / min to 250r / min to obtain a dispersion.

[0047] In one embodiment of the present invention, the third modified aqueous prepolymer is placed in an ultrasonic disruptor, and the ultrasonic probe is immersed at 3 / 4 of the solution interface of the third modified aqueous prepolymer. Under ice bath conditions and a first ultrasonic power, the dispersion is gradually added dropwise for ultrasonic emulsification for a first preset time to obtain an ultrasonic emulsion. The first ultrasonic power is, for example, 30W~500W, and the first preset time is, for example, 15min~30min, to improve the uniformity of the obtained dispersion. Ultrasonic homogenization emulsification can generate very fine droplets, enabling the efficient preparation of uniform and fine microspheres in a short time. Precise control of droplet size achieves controllable size, greatly improving production efficiency. Furthermore, the cavitation effect of ultrasound can generate high pressure at the water-oil interface, promoting the adsorption and spreading of the emulsifier at the interface and enhancing the interfacial stability of the emulsion.

[0048] Please see Figure 1As shown, in one embodiment of the present invention, the crosslinking agent includes, for example, aldehyde crosslinking agents such as glutaraldehyde, formaldehyde, or n-butyraldehyde, and the mass ratio of the crosslinking agent to gelatin is, for example, 1:(5~10). Specifically, the ultrasonic power of the ultrasonic disruptor is changed to a second ultrasonic power, for example, 20W~200W. Under ice bath conditions, the crosslinking agent is added, and the ultrasonic crosslinking reaction is carried out for a second preset time, for example, 10min~20min, to obtain an intermediate product. The intermediate product is post-processed to obtain the first microspheres 10, wherein the post-processing includes drying and impurity removal. Drying is, for example, vacuum drying at 35℃~40℃ for 4h~6h, and impurity removal is, for example, washing with water for injection followed by vacuum drying at 35℃~40℃. The first microsphere 10 is obtained by crosslinking gelatin molecules and a crosslinking agent. A nucleophilic reagent-modified ester copolymer is grafted onto the surface of the microsphere, and a photosensitizer is grafted onto the nucleophilic reagent group, enabling photothermal therapy. Simultaneously, during the crosslinking process, the drug between gelatin molecules is encapsulated within the first microsphere 10, achieving drug therapy and improving therapeutic efficacy. Ultrasonic homogenization crosslinking is used to form the microspheres. The appropriate temperature and pressure generated during ultrasonic homogenization crosslinking intensifies the movement of molecular chain segments, rapidly evaporating the oil phase solvent, increasing the degree of crosslinking, and promoting the crosslinking reaction for rapid crosslinking. This prevents spherical destruction and prevents drug leakage in subsequent processes, ultimately producing the first microsphere 10 with high encapsulation efficiency and uniform size. Furthermore, ice-bath ultrasonic homogenization emulsification and ice-bath ultrasonic homogenization crosslinking prevent the gelatin structure from being damaged by excessively high temperatures during ultrasonication, which could affect subsequent photothermal therapy.

[0049] Please see Figure 1 As shown, in one embodiment of the present invention, the buffer solution is, for example, Tris(Hydroxymethyl)amminomethane hydrochloride (Tris-HCl), and the concentration of the buffer solution is, for example, 0.1 mol / L to 0.15 mol / L. The adhesive is, for example, at least one of polydopamine (PDA), sodium citrate, ethylenediaminetetraacetic acid, or polyvinylpyrrolidone. Specifically, an adhesive solution of 0.5 g / L to 5 g / L is prepared using a 0.1 mol / L to 0.15 mol / L buffer solution. 1 ml of the first microsphere is dispersed in 5 ml to 20 ml of the adhesive solution and stirred for a third preset time, for example, continuously stirred at 100 r / min to 200 r / min for 3 h to 5 h. After centrifugation, a second microsphere with an adhesive layer 11 is obtained, the adhesive layer 11 comprising the adhesive.

[0050] Please see Figure 1As shown, in one embodiment of the present invention, the second microspheres are placed in a metal-modifying liquid, which includes at least one of silver nitrate solution, chloroauric acid solution, or copper sulfate solution, and the concentration of the metal-modifying liquid is 200 μg / ml to 300 μg / ml. For example, 1 ml of the second microspheres is placed in 5 ml to 500 ml of the metal-modifying liquid. The mixture is placed in a shaker and reacted for 10 h to 15 h, wherein the temperature of the shaker is, for example, 25°C to 35°C, and the rotation speed is, for example, 25 r / min to 35 r / min. The metal-modifying liquid undergoes a reduction reaction with the adhesion layer 11, reducing the metal-modifying liquid to nano-metal particles 12. The nano-metal particles 12 adhere to the adhesion layer 11, and by centrifugation, embolic microspheres 20 with attached nano-metal particles are obtained. Based on the surface plasmon resonance phenomenon of nano-metal particles 12, when the metal surface is irradiated by X-rays, the plasma on the metal surface is excited to a high energy level, coupling with the electric field of the light wave and generating resonance, thus enhancing the electric field on the metal substrate surface and thereby enhancing the optical signal. Compared with the weak absorption of X-ray signals by iodine-containing contrast agents grafted onto the surface groups of traditional embolized microspheres, the plasma resonance embolized microspheres provided by this invention can obtain a stronger X-ray signal for the detector to absorb, and after conversion by an analog-to-digital converter, form a clearer CT image, thus possessing a clearer imaging function. At the same time, the embolized microspheres obtained by this invention have uniform size and high plasma shell density, thus possessing higher tissue resolution and contrast, as well as lower noise levels and no artifact phenomena. Existing technologies usually graft iodine ions onto the surface of the sphere, and the imaging effect is produced by the absorption of X-rays by iodine ions. This invention generates at least one of the following on the surface of the sphere by reducing and generating nano-silver particles, nano-gold particles, or nano-copper particles, so that the nano-metal particles are uniformly distributed on the surface of the sphere, and the imaging signal is enhanced by the high specific surface area of ​​the nanomaterials and the plasma enhancement effect of the metal. Meanwhile, compared to microspheres encased in a dense metal shell, the gaps between the nano-metal particles of this invention allow for drug release, enabling the microspheres to produce a photothermal therapeutic effect, which has promising medical applications.

[0051] Please see Figure 1As shown, this invention also proposes a plasma-enhanced photothermal therapy embolization microsphere. The embolization microsphere 20 is obtained by the above method and is a microsphere formed by polymerization of gelatin and a crosslinking agent. The therapeutic drug is encapsulated within the embolization microsphere 20. A nucleophilic reagent-modified ester-modified copolymer is grafted onto the surface of the embolization microsphere 20, and a photosensitizer is grafted onto the nucleophilic reagent group. An adhesion layer 11 is formed on the embolization microsphere, and nano-metal particles 12 are uniformly distributed on the adhesion layer 11. The nano-metal particles 12 include at least one of nano-silver particles, nano-gold particles, or nano-copper particles, and the loading of the nano-metal particles 12 is, for example, 50wt%~60wt%. When using the embolization microsphere 20 for treatment, the embolization microsphere is delivered to the target location via a catheter using X-ray imaging and near-infrared light of 780nm~820nm at a frequency of 1W / cm². 3 The high-power irradiation causes the microspheres to heat up and release heat, simultaneously dissolving the gelatin and releasing drugs in a synergistic photothermal therapy. This means that photothermal therapy using a photosensitizer, combined with drug therapy, achieves targeted drug delivery, significantly inhibiting tumor growth and preventing tumor regeneration. Furthermore, the photothermal therapy in this invention utilizes remotely excited light sources and photosensitizers to generate rapid local heating, efficiently converting light energy into heat energy. This disrupts the mitochondrial function of cancer cells, inhibits the production of adenosine triphosphate (ATP), reduces drug efflux, and thus promotes the release of chemotherapy drugs and tumor cell uptake. This treatment method can be regulated in both time and space and does not harm normal tissues. Simultaneously, the heat generated by photothermal therapy in this invention responds to the thermosensitive properties of gelatin, thereby altering the hydrogen bonding between gelatin molecules, enhancing its solubility, and achieving thermosensitive targeted drug release. This invention uses grafted adsorption of photosensitizers uniformly loaded onto the surface of the embolized microspheres. Compared to the exothermic method of mixing the photosensitizer into the main material, this method results in more uniform heating of the embolized microspheres, avoiding localized excessively high or low temperatures. Meanwhile, grafting photosensitizers onto microspheres can prevent uncontrollable migration to other parts of the body during use, thus avoiding serious postoperative sequelae. Furthermore, during the delivery of embolized microspheres, the nano-metal particles on the surface of the embolized microspheres can be accurately delivered to the target location via plasma-enhanced imaging.

[0052] The present invention will be explained in more detail below by referring to embodiments, which should not be construed as limiting. Appropriate modifications can be made within the scope of the present invention, and all such modifications fall within the technical scope of the present invention.

[0053] Example 1

[0054] 10g of gelatin was added to 95g of water for injection and stirred at 50 rpm for 1 hour at 40℃ to dissolve. The solution was then allowed to stand to remove air bubbles, thus preparing a gelatin solution. 14g of 2-hydroxypropyl acrylate was dissolved in 20g of purified water. 9g of a 15% hydrochloric acid solution was added under ice-water bath conditions. Then, 0.5g of cerium ammonium nitrate and 1g of sodium bisulfite were added and stirred until dissolved, yielding the first modified solution. The first modified solution was added to the gelatin solution and stirred at 120 rpm for 1 hour to obtain an aqueous prepolymer solution.

[0055] 20 g of ethane-1,2-diamine was added to the aqueous prepolymer solution, and the mixture was irradiated with ultraviolet light and reacted at 50 °C for 24 h to obtain the first modified aqueous prepolymer solution. 0.75 g of indocyanine green was added to the first modified aqueous prepolymer solution, and the mixture was stirred at 100 r / min at 35 °C for 3 h to obtain the second modified aqueous prepolymer solution. 50 mg of doxorubicin was added to the second modified aqueous prepolymer solution, and the mixture was completely dissolved at 35 °C and stirred at 100 r / min for 1 h to obtain the third modified aqueous prepolymer solution.

[0056] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the third modified aqueous prepolymer was placed in an ice bath. The ultrasonic probe was immersed at 3 / 4 of the solution interface of the third modified aqueous prepolymer. The power of the device was adjusted to 350W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 100W, and 2g of glutaraldehyde was added to the ultrasonic emulsion in the ice bath. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. After ultrasonication, the ultrasonic probe was turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, yielding the first microspheres.

[0057] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0058] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0059] Example 2

[0060] 10g of gelatin was added to 95g of water for injection and stirred at 50 rpm for 1 hour at 40℃ to dissolve. The solution was then allowed to stand to remove air bubbles, thus preparing a gelatin solution. 14g of 2-hydroxypropyl acrylate was dissolved in 20g of purified water. 9g of a 15% hydrochloric acid solution was added under ice-water bath conditions. Then, 0.5g of cerium ammonium nitrate and 1g of sodium bisulfite were added and stirred until dissolved, yielding the first modified solution. The first modified solution was added to the gelatin solution and stirred at 120 rpm for 1 hour to obtain an aqueous prepolymer solution.

[0061] 20 g of ethane-1,2-diamine was added to the aqueous prepolymer solution, and the mixture was irradiated with ultraviolet light and reacted at 50 °C for 24 h to obtain the first modified aqueous prepolymer solution. 0.75 g of indocyanine green was added to the first modified aqueous prepolymer solution, and the mixture was stirred at 100 r / min at 35 °C for 3 h to obtain the second modified aqueous prepolymer solution. 50 mg of doxorubicin was added to the second modified aqueous prepolymer solution, and the mixture was completely dissolved at 35 °C and stirred at 100 r / min for 1 h to obtain the third modified aqueous prepolymer solution.

[0062] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the third modified aqueous prepolymer was placed in an ice bath. The ultrasonic probe was immersed at 3 / 4 of the solution interface of the third modified aqueous prepolymer. The power of the device was adjusted to 30W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 20W, and 2g of glutaraldehyde was added to the ultrasonic emulsion in the ice bath. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. After ultrasonication, the probe was turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, yielding the first microspheres.

[0063] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0064] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0065] Example 3

[0066] 10g of gelatin was added to 95g of water for injection and stirred at 50 rpm for 1 hour at 40℃ to dissolve. The solution was then allowed to stand to remove air bubbles, thus preparing a gelatin solution. 14g of 2-hydroxypropyl acrylate was dissolved in 20g of purified water. 9g of a 15% hydrochloric acid solution was added under ice-water bath conditions. Then, 0.5g of cerium ammonium nitrate and 1g of sodium bisulfite were added and stirred until dissolved, yielding the first modified solution. The first modified solution was added to the gelatin solution and stirred at 120 rpm for 1 hour to obtain an aqueous prepolymer solution.

[0067] 20 g of ethane-1,2-diamine was added to the aqueous prepolymer solution, and the mixture was irradiated with ultraviolet light and reacted at 50 °C for 24 h to obtain the first modified aqueous prepolymer solution. 0.75 g of indocyanine green was added to the first modified aqueous prepolymer solution, and the mixture was stirred at 100 r / min at 35 °C for 3 h to obtain the second modified aqueous prepolymer solution. 50 mg of doxorubicin was added to the second modified aqueous prepolymer solution, and the mixture was completely dissolved at 35 °C and stirred at 100 r / min for 1 h to obtain the third modified aqueous prepolymer solution.

[0068] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the third modified aqueous prepolymer was placed in an ice bath. The ultrasonic probe was immersed at 3 / 4 of the solution interface of the third modified aqueous prepolymer. The power of the device was adjusted to 500W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 200W, and 2g of glutaraldehyde was added to the ultrasonic emulsion in the ice bath. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. After ultrasonication, the probe was turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, yielding the first microspheres.

[0069] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0070] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0071] Example 4

[0072] 10g of gelatin was added to 95g of water for injection and stirred at 50 rpm for 1 hour at 40℃ to dissolve. The solution was then allowed to stand to remove air bubbles, thus preparing a gelatin solution. 10g of 2-hydroxypropyl acrylate was dissolved in 20g of purified water. 9g of a 15% hydrochloric acid solution was added under ice-water bath conditions. Then, 0.5g of ammonium persulfate and 1g of sodium bisulfite were added and stirred until dissolved, yielding the first modified solution. The first modified solution was added to the gelatin solution and stirred at 120 rpm for 1 hour to obtain an aqueous prepolymer solution.

[0073] 20g of ethylenediamine was added to the aqueous prepolymer solution, and the mixture was irradiated with ultraviolet light and reacted at 50℃ for 24h to obtain the first modified aqueous prepolymer solution. 0.75g of indocyanine green was added to the first modified aqueous prepolymer solution, and the mixture was stirred at 100r / min at 35℃ for 3h to obtain the second modified aqueous prepolymer solution. 50mg of doxorubicin was added to the second modified aqueous prepolymer solution, and the mixture was completely dissolved at 35℃ and stirred at 100r / min for 1h to obtain the third modified aqueous prepolymer solution.

[0074] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the third modified aqueous prepolymer was placed in an ice bath. The ultrasonic probe was immersed at 3 / 4 of the solution interface of the third modified aqueous prepolymer. The power of the device was adjusted to 350W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 100W, and 2g of glutaraldehyde was added to the ultrasonic emulsion in the ice bath. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. After ultrasonication, the ultrasonic probe was turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, yielding the first microspheres.

[0075] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0076] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0077] Example 5

[0078] 10g of gelatin was added to 95g of water for injection and stirred at 50 rpm for 1 hour at 40℃ to dissolve. The solution was then allowed to stand to remove air bubbles, thus preparing a gelatin solution. 14g of 2-hydroxypropyl acrylate was dissolved in 20g of purified water. 9g of a 15% hydrochloric acid solution was added under ice-water bath conditions. Then, 0.5g of cerium ammonium nitrate and 1g of sodium bisulfite were added and stirred until dissolved, yielding the first modified solution. The first modified solution was added to the gelatin solution and stirred at 120 rpm for 1 hour to obtain an aqueous prepolymer solution.

[0079] 20 g of ethane-1,2-diamine was added to the aqueous prepolymer solution, and the mixture was irradiated with ultraviolet light and reacted at 50 °C for 24 h to obtain the first modified aqueous prepolymer solution. 1 g of indocyanine green was added to the first modified aqueous prepolymer solution, and the mixture was stirred at 100 r / min at 35 °C for 3 h to obtain the second modified aqueous prepolymer solution. 50 mg of epirubicin was added to the second modified aqueous prepolymer solution, and the mixture was completely dissolved at 35 °C and stirred at 100 r / min for 1 h to obtain the third modified aqueous prepolymer solution.

[0080] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the third modified aqueous prepolymer was placed in an ice bath. The ultrasonic probe was immersed at 3 / 4 of the solution interface of the third modified aqueous prepolymer. The power of the device was adjusted to 350W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 100W, and 2g of glutaraldehyde was added to the ultrasonic emulsion in the ice bath. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. After ultrasonication, the ultrasonic probe was turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, yielding the first microspheres.

[0081] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0082] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0083] Comparative Example 1

[0084] 10g of gelatin was added to 95g of water for injection and stirred at 50 rpm for 1 hour at 40℃ to dissolve. The solution was then allowed to stand to remove air bubbles, thus preparing a gelatin solution. 14g of 2-hydroxypropyl acrylate was dissolved in 20g of purified water. 9g of a 15% hydrochloric acid solution was added under ice-water bath conditions. Then, 0.5g of cerium ammonium nitrate and 1g of sodium bisulfite were added and stirred until dissolved, yielding the first modified solution. The first modified solution was added to the gelatin solution and stirred at 120 rpm for 1 hour to obtain an aqueous prepolymer solution.

[0085] 20 g of ethane-1,2-diamine was added to the aqueous prepolymer solution, and the mixture was irradiated with ultraviolet light and reacted at 50 °C for 24 h to obtain the first modified aqueous prepolymer solution. 0.75 g of indocyanine green was added to the first modified aqueous prepolymer solution, and the mixture was stirred at 100 r / min at 35 °C for 3 h to obtain the second modified aqueous prepolymer solution.

[0086] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the second modified aqueous prepolymer was placed in an ice bath. The ultrasonic probe was immersed at 3 / 4 of the solution interface of the second modified aqueous prepolymer. The power of the device was adjusted to 350W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 100W, and 2g of glutaraldehyde was added to the ultrasonic emulsion in the ice bath. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. The ultrasonic probe was then turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, yielding the first microspheres.

[0087] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0088] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0089] Comparative Example 2

[0090] 10g of gelatin was added to 95g of water for injection and stirred at 50 rpm for 1 hour at 40℃ to dissolve. The solution was then allowed to stand to remove air bubbles, thus preparing a gelatin solution. 14g of 2-hydroxypropyl acrylate was dissolved in 20g of purified water. 9g of a 15% hydrochloric acid solution was added under ice-water bath conditions. Then, 0.5g of cerium ammonium nitrate and 1g of sodium bisulfite were added and stirred until dissolved, yielding the first modified solution. The first modified solution was added to the gelatin solution and stirred at 120 rpm for 1 hour to obtain an aqueous prepolymer solution.

[0091] 20 g of ethane-1,2-diamine was added to the aqueous prepolymer solution, and the mixture was irradiated with ultraviolet light and reacted at 50 °C for 24 h to obtain the first modified aqueous prepolymer solution. 0.75 g of indocyanine green was added to the first modified aqueous prepolymer solution, and the mixture was stirred at 100 r / min at 35 °C for 3 h to obtain the second modified aqueous prepolymer solution. 50 mg of doxorubicin was added to the second modified aqueous prepolymer solution, and the mixture was completely dissolved at 35 °C and stirred at 100 r / min for 1 h to obtain the third modified aqueous prepolymer solution.

[0092] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the ultrasonic probe was immersed at 3 / 4 of the solution interface of the third modified aqueous prepolymer. The power of the device was adjusted to 350W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 100W, and 2g of glutaraldehyde was added to the ultrasonic emulsion. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. After ultrasonication, the probe was turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, yielding the first microspheres.

[0093] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0094] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0095] Comparative Example 3

[0096] 10g of gelatin was added to 95g of water for injection and stirred at 50r / min at 40℃ for 1h to dissolve. After standing to remove air bubbles, a gelatin solution was prepared. 0.75g of indocyanine green and 50mg of doxorubicin were added to the gelatin solution and completely dissolved at 35℃. The solution was stirred at 100r / min for 1h to obtain a modified aqueous prepolymer.

[0097] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the modified aqueous prepolymer was placed in an ice bath. The ultrasonic probe was immersed at 3 / 4 of the solution interface of the modified aqueous prepolymer. The power of the device was adjusted to 350W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 100W, and 2g of glutaraldehyde was added to the ultrasonic emulsion in the ice bath. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. The ultrasonic probe was then turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, yielding the first microspheres.

[0098] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0099] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0100] Comparative Example 4

[0101] 10g of gelatin was added to 95g of water for injection and stirred at 50r / min at 40℃ for 1h to dissolve. After standing to remove air bubbles, a gelatin solution was prepared. 50mg of doxorubicin was added to the gelatin solution and dissolved completely at 35℃. The solution was stirred at 100r / min for 1h to obtain a modified aqueous prepolymer.

[0102] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the modified aqueous prepolymer was placed in an ice bath. The ultrasonic probe was immersed at 3 / 4 of the solution interface of the modified aqueous prepolymer. The power of the device was adjusted to 350W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 100W, and 2g of glutaraldehyde was added to the ultrasonic emulsion in the ice bath. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. The ultrasonic probe was then turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, yielding the first microspheres.

[0103] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0104] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0105] Comparative Example 5

[0106] 10g of gelatin was added to 95g of water for injection and stirred at 50 rpm for 1 hour at 40℃ to dissolve. The solution was then allowed to stand to remove air bubbles, thus preparing a gelatin solution. 14g of 2-hydroxypropyl acrylate was dissolved in 20g of purified water. 9g of a 15% hydrochloric acid solution was added under ice-water bath conditions. Then, 0.5g of cerium ammonium nitrate and 1g of sodium bisulfite were added and stirred until dissolved, yielding the first modified solution. The first modified solution was added to the gelatin solution and stirred at 120 rpm for 1 hour to obtain an aqueous prepolymer solution.

[0107] 20 g of ethane-1,2-diamine was added to the aqueous prepolymer solution, and the mixture was irradiated with ultraviolet light and reacted at 50 °C for 24 h to obtain the first modified aqueous prepolymer solution. 0.75 g of indocyanine green was added to the first modified aqueous prepolymer solution, and the mixture was stirred at 100 r / min at 35 °C for 3 h to obtain the second modified aqueous prepolymer solution. 50 mg of doxorubicin was added to the second modified aqueous prepolymer solution, and the mixture was completely dissolved at 35 °C and stirred at 100 r / min for 1 h to obtain the third modified aqueous prepolymer solution.

[0108] Dissolve 1g of Span 80 in 200g of petroleum ether with a boiling point of 45℃, preheat at 30℃ and stir at 200r / min to obtain a dispersion; add the third modified aqueous prepolymer to the above dispersion using a peristaltic pump, shear at 300r / min for 50min, add 2g of glutaraldehyde, and continue the reaction for 300min to obtain the first microspheres in reverse suspension.

[0109] Polydopamine was added to 0.1 mol / L Tris-HCl buffer to prepare an adhesive solution of 3 g / L. 1 ml of the first microsphere was dispersed in 15 ml of the adhesive solution. The mixture was stirred continuously at 150 rpm for 4 h at room temperature. The reaction mixture was then centrifuged to obtain the second microsphere with an adhesive layer.

[0110] 1 ml of the second microsphere was added to 100 ml of silver nitrate solution with a concentration of 300 μg / ml, and the mixture was reacted in a shaker at a temperature of 30 °C and a rotation speed of 30 r / min for 12 h. The embolization microspheres were obtained by centrifugation.

[0111] Comparative Example 6

[0112] 10g of gelatin was added to 95g of water for injection and stirred at 50 rpm for 1 hour at 40℃ to dissolve. The solution was then allowed to stand to remove air bubbles, thus preparing a gelatin solution. 14g of 2-hydroxypropyl acrylate was dissolved in 20g of purified water. 9g of a 15% hydrochloric acid solution was added under ice-water bath conditions. Then, 0.5g of cerium ammonium nitrate and 1g of sodium bisulfite were added and stirred until dissolved, yielding the first modified solution. The first modified solution was added to the gelatin solution and stirred at 120 rpm for 1 hour to obtain an aqueous prepolymer solution.

[0113] 20 g of ethane-1,2-diamine was added to the aqueous prepolymer solution, and the mixture was irradiated with ultraviolet light and reacted at 50 °C for 24 h to obtain the first modified aqueous prepolymer solution. 0.75 g of indocyanine green was added to the first modified aqueous prepolymer solution, and the mixture was stirred at 100 r / min at 35 °C for 3 h to obtain the second modified aqueous prepolymer solution. 50 mg of doxorubicin was added to the second modified aqueous prepolymer solution, and the mixture was completely dissolved at 35 °C and stirred at 100 r / min for 1 h to obtain the third modified aqueous prepolymer solution.

[0114] 1g of Span 80 was dissolved in 200g of petroleum ether with a boiling point of 45℃. The solution was preheated to 30℃ and stirred at 200r / min to obtain a dispersion. An ultrasonic homogenizer was turned on, and the third modified aqueous prepolymer was placed in an ice bath. The ultrasonic probe was immersed at 3 / 4 of the solution interface of the third modified aqueous prepolymer. The power of the device was adjusted to 350W. During ultrasonic homogenization, the dispersion was slowly added to the aqueous polymer solution. After ultrasonication for 20min, the ultrasonic probe was turned off to obtain an ultrasonic emulsion. The ultrasonic power was adjusted to 100W, and 2g of glutaraldehyde was added to the ultrasonic emulsion in the ice bath. The chamber was closed, and ultrasonic homogenization and crosslinking were performed for 15min. After ultrasonication, the ultrasonic probe was turned off to obtain an intermediate product. The intermediate product was dried to remove impurities, resulting in embolic microspheres.

[0115] Please see Figures 2 to 3 As shown, the embolic microspheres obtained in the examples were tested under a scanning electron microscope (SEM). In Example 1, the embolic microspheres obtained had good morphology and uniform size distribution. This demonstrates that the preparation method of the present invention can obtain embolic microspheres with uniform and fine particle size, and the size of the embolic microspheres can be controlled by precisely controlling the droplet size. Furthermore, the elements in the embolic microspheres are uniformly distributed, and the photosensitizer and metal nanoparticles grafted onto the embolic microspheres are also uniformly distributed.

[0116] In one embodiment of the present invention, the loading of metal nanoparticles on the embolization microspheres is obtained, for example, by energy dispersive spectroscopy.

[0117] Table 1. Elemental test results of the embolization microspheres in Example 1

[0118] Please see Figure 4 As shown in Table 1, where, Figure 4 In the diagram, the horizontal axis represents the X-ray energy during the test, measured in keV, reflecting the characteristic X-ray energy of different elements. The vertical axis represents the relative intensity of each element tested, which is positively correlated with the element content. In Example 1, the loading of silver nanoparticles in the embolization microspheres reached 59.14%, resulting in plasma resonance embolization microspheres. This allows for stronger X-ray signals to be obtained during use, which are absorbed by the detector and converted by an analog-to-digital converter to form clearer CT images, thus providing clearer imaging capabilities. Furthermore, the plasma microspheres in this invention have uniform size and high plasma shell density, resulting in higher tissue resolution and contrast, lower noise levels, and no artifacts. Compared to microspheres encased in a dense metal shell, the gaps between the silver nanoparticles in this invention allow for drug release, enabling the microspheres to produce a photothermal therapeutic effect, demonstrating promising medical applications.

[0119] In one embodiment of the present invention, to evaluate the photothermal effect of the embolic microspheres, the embolic microspheres of Examples 1, 4-5, and Comparative Examples 3-4 were placed in centrifuge tubes and dispersed with water for injection to obtain test solutions of the same concentration. Near-infrared light (808 nm, 1.2 W / cm²) was used. 2 Irradiation was performed, and the temperature-time change curve of each test liquid was recorded using an infrared thermal imager to evaluate the photothermal effect. Please refer to [link to relevant documentation]. Figure 5 As shown, the horizontal axis represents the infrared irradiation time in seconds (s), and the vertical axis represents the temperature change of the embolized microspheres in degrees Celsius (°C). Curve 110 represents the temperature-time change curve of the embolized microspheres in Example 5, curve 120 represents the temperature-time change curve of the embolized microspheres in Example 1, curve 130 represents the temperature-time change curve of the embolized microspheres in Example 4, curve 140 represents the temperature-time change curve of the embolized microspheres in Comparative Example 3, and curve 150 represents the temperature-time change curve of the embolized microspheres in Comparative Example 4. The embolized microsphere solution of Example 1, under infrared irradiation, can gradually increase in temperature over time, eventually reaching the expected temperature for tumor inactivation. In Example 4, with the reduction of ester modifier, the indocyanine green grafting rate decreased, and the photothermal performance deteriorated. In Example 5, with the increase of indocyanine green content, the photothermal temperature of the solution increased significantly. In Comparative Example 3, indocyanine green dissolved directly in water because it was not grafted. Over time, the indocyanine green failed to concentrate around the microspheres, resulting in the temperature not reaching the expected level. In Comparative Example 4, no photosensitizer was added, resulting in no significant temperature change.

[0120] In one embodiment of the present invention, a VX2 tumor animal model experiment was conducted using New Zealand rabbits. Eighty adult New Zealand rabbits of equal weight were selected, with half males and half females, and divided into 5 groups. VX2 tumor tissue blocks were surgically implanted directly into the kidneys of the New Zealand rabbits, with the tumor size strictly controlled (1 mm). 3 -2mm 3The first group of rabbits was implanted with microspheres prepared in Example 1. The position of the silver nanoshells on the surface of the microspheres was observed using CT scans to ensure implantation in the target area. After the rabbits' vital signs stabilized, they were irradiated with near-infrared light (808nm, 1.2W / cm²) for 300 seconds. The second group of rabbits was implanted with microspheres prepared in Comparative Example 1. The position of the silver nanoshells on the surface of the microspheres was observed using CT scans to ensure implantation in the target area. After the rabbits' vital signs stabilized, they were irradiated with near-infrared light (808nm, 1.2W / cm²) for 300 seconds. The third group of rabbits was implanted with microspheres prepared in Comparative Example 2. The location of the silver nanoshells on the surface of the microspheres was observed using CT scans. The microspheres were then implanted into the target area. After the rabbits' vital signs stabilized, they were irradiated with near-infrared light (808nm, 1.2W / cm²) for 300 seconds. The fourth group of rabbits received control product 1, which consisted of embolic particles combined with iodized oil and medication. The iodized oil and medication were injected into the target area, and the location of the iodized oil was observed using CT scans. Embolized particles were used to seal the blurred boundaries of the iodized oil. Control product 1 was PB0500 from Kerui Chi (Shenzhen) Medical Technology Development Co., Ltd. The third group of rabbits did not receive any tumor treatment and served as a blank control group. The animals' diet and activity levels were observed. Rabbits were sacrificed at 1, 2, and 4 weeks post-surgery, with 4 rabbits (half male and half female) sacrificed each time to observe tumor development. The results are shown in Table 2.

[0121] Table 2. Metal nanoparticle loading on embolic microspheres in Example 1 and the control group.

[0122] Please refer to Table 2. In Example 1, the embolization microspheres prepared can be precisely implanted into the target site through autoradiography. Through the synergistic effect of photothermal therapy and drugs, the tumor is rapidly inactivated and tumor recurrence is inhibited. The overall survival rate of New Zealand rabbits at 12 weeks reached 100%. In Comparative Example 1, the prepared embolization microspheres can be precisely implanted into the target site through autoradiography, but no drug loading is performed. The tumor inactivation and tumor recurrence inhibition effects are poor, and the rabbit survival rate decreases at 16 weeks. In Comparative Example 2, the ultrasound process is not performed under ice bath conditions during the preparation of embolization microspheres. The uniformity of the prepared embolization microspheres is worse, and the gelatin structure and grafting rate are affected, reducing the subsequent photothermal therapy and the treatment effect is worse. During treatment, the microspheres can be precisely implanted into the target site through autoradiography. Through the synergistic effect of photothermal therapy and drugs, tumor recurrence is inhibited, but the treatment effect is worse than that of Example 1. In contrast, product 1 used traditional C-Tace treatment, which inhibited tumor growth through drugs and embolization. However, as the drug concentration decreased, the tumor recurred, and the survival rate of the rabbits subsequently decreased rapidly. In the blank control group, no treatment was given to the tumor, and the rapid expansion of the tumor resulted in an extremely low survival rate for the rabbits.

[0123] In one embodiment of the present invention, a laser particle size analyzer combined with SEM is used to analyze the size of the microspheres and observe their surface morphology. Figure 2 This is a scanning electron microscope image of the microspheres prepared in Example 1.

[0124] Table 3 shows the average diameter of the embolic microspheres in Examples 1-3 and Comparative Example 5.

[0125] Please see Figure 2 As shown in Table 3, the embolic microspheres prepared in Example 1 have uniform morphology, reach nanoscale size, and are coated with nano-silver. Comparing Examples 1-3, it can be seen that microspheres of different sizes can be generated by adjusting the power and time of ultrasonic emulsification and ultrasonic crosslinking. In Comparative Example 5, the embolic microspheres obtained by stirring emulsification method are larger in size and have different morphologies. The mainstream microspheres on the market usually adopt stirring emulsification process, which cannot reach the nanoscale, and the size range cannot be accurately calibrated.

[0126] In one embodiment of the present invention, to test the elasticity / compression properties of the embolic microspheres, embolic microspheres from Example 2, Comparative Example 6, and the control product, after being fully swollen with physiological saline, were taken. The embolic microspheres were placed on a smooth glass plate with a micrometer, and the initial diameter of the microspheres was recorded. Then, two glass plates with neat, smooth edges and a thickness greater than the diameter of the microspheres were used to slowly compress the microspheres from both sides, and the maximum compressive deformation of the microspheres was recorded. The percentage of the compressible diameter of the microspheres was calculated. The glass plates that had been used to compress the microspheres were removed, and the time required for the microspheres to return to their spherical shape was recorded. The test results are shown in Table 4.

[0127] Table 4. Elastic / compressible properties of the embolic microspheres in Example 1 and Comparative Example 6

[0128] Please refer to Table 4. The embolic microspheres prepared in Example 2 exhibit excellent maximum compressibility and rapid rebound, ensuring that the microspheres can pass more smoothly through microcatheters smaller than their own diameter and adapt to vascular morphology to the greatest extent, achieving full embolization and adhesion. This also increases the drug release contact area and ensures that the microspheres are not easily broken during compression and rebound. This is because Example 2 uses processes such as ultrasonic foaming and ultrasonic cross-linking, resulting in more voids and a three-dimensional network structure inside the embolic microspheres, thus providing more compression space and elastic support. Comparative Example 6 and Comparative Product 1 have larger dimensions, lower percentage of compressible diameter, and relatively longer rebound times, which are detrimental to the use of embolic microspheres.

[0129] In summary, this invention proposes a plasma-enhanced photothermal embolization microsphere and its preparation method. The resulting embolization microspheres have a high surface loading of nano-metal particles, which allows for stronger X-ray signal absorption by the detector. After conversion by an analog-to-digital converter, clearer CT images are formed, resulting in clearer imaging capabilities and precise delivery of the embolization microspheres to the lesion site. Furthermore, the embolization microspheres obtained by this invention have uniform size and high plasma shell density, thus possessing higher tissue resolution and contrast, as well as lower noise levels and no artifacts. Existing technologies typically graft iodine ions onto the surface of the microspheres. The iodine ions absorb X-rays to produce an imaging effect without affecting drug release, enabling the microspheres to achieve photothermal therapy, which has promising medical applications. Photothermal therapy can be achieved by remotely exciting a light source and using a photosensitizer to generate rapid local heating. Combined with drug therapy, targeted drug delivery can be achieved, significantly inhibiting tumor growth and preventing tumor regeneration. This treatment method can be controlled in both time and space and does not harm normal tissues. Meanwhile, the heat energy generated by photothermal therapy in this invention responds to the thermosensitive properties of gelatin, thereby altering the hydrogen bonding between gelatin molecules, enhancing its solubility, and achieving thermosensitive targeted drug release without causing serious postoperative sequelae. Furthermore, the preparation method of this invention features mild reaction conditions, high controllability, and a relatively fast reaction rate, demonstrating promising prospects for industrial application.

[0130] The above description is merely a preferred embodiment of this application and an explanation of the technical principles used. Those skilled in the art should understand that the scope of the invention involved in this application is not limited to the technical solutions formed by a specific combination of the above-mentioned technical features, but should also cover other technical solutions formed by any combination of the above-mentioned technical features or their equivalent features without departing from the inventive concept. For example, technical solutions formed by replacing the above-mentioned features with technical features with similar functions disclosed in this application (but not limited to) each other.

[0131] Apart from the technical features described in the specification, the other technical features are known to those skilled in the art. To highlight the innovative features of this invention, the other technical features will not be described in detail here.

Claims

1. A method for preparing photothermal therapeutic embolism microspheres with plasma-enhanced imaging, characterized in that, At least the following steps are included: Dissolve gelatin in water to obtain a gelatin solution; An ester modifier is dissolved in water, and acid, initiator, and additives are added under ice bath conditions to obtain a modified solution. The modified liquid is added to the gelatin solution and stirred to obtain an aqueous prepolymer solution; A nucleophilic reagent was added to the aqueous prepolymer solution, and then subjected to ultraviolet irradiation to obtain a first modified aqueous prepolymer solution. A photosensitizer is added to the first modified aqueous prepolymer solution to carry out a grafting reaction, thereby obtaining a second modified aqueous prepolymer solution. The drug is added to the second modified aqueous prepolymer solution and stirred to obtain the third modified aqueous prepolymer solution. The emulsifier is dissolved in the oil phase liquid and heated to a first preset temperature, and stirred to obtain a dispersion. The third modified aqueous prepolymer was placed in an ultrasonic disruptor, and the dispersion was gradually added dropwise under ice bath conditions and first ultrasonic power. Ultrasonic emulsification was carried out for a first preset time to obtain an ultrasonic emulsion. A crosslinking agent is added dropwise to the ultrasonic emulsion, and an ultrasonic crosslinking reaction is carried out under a second ultrasonic power for a second preset time in an ice bath to obtain an intermediate product. The intermediate product is post-processed to obtain the first microspheres; The first microspheres were dispersed in a buffer solution, an adhesive was added and the mixture was stirred for a third preset time. After centrifugation, the second microspheres with an adhesive layer were obtained. The second microsphere is placed in a metal-modified liquid, which undergoes a reduction reaction with the adhesion layer. After centrifugation, embolic microspheres with nano-metal particles attached to the adhesion layer are obtained.

2. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The ester modifier includes at least one of 2-hydroxypropyl acrylate, acrylate, or polyurethane; and / or The acid solution is selected, for example, at least one of hydrochloric acid or nitric acid, and the mass fraction of the acid solution is 10% to 20%; and / or The initiator includes, for example, one or more combinations of cerium ammonium nitrate, ammonium persulfate, or potassium persulfate; and / or The additives include one or a combination of sodium bisulfite, sodium carbonate, or sodium bicarbonate.

3. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The mass ratio of the gelatin to the ester modifier is 1:(1~2); and / or The mass ratio of the ester modifier, the acid, the initiator, and the auxiliary agent is (10~15):(5~10):(0.1~2):(0.5~2).

4. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The reaction temperature of the gelatin solution and the modified liquid is less than 40°C.

5. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The nucleophile includes at least one of ethane-1,2-diamine, ethylenediamine, N-ethylethylenediamine, dimethylethylenediamine, butane-1,4-diamine, or pentane-1,5-diamine, and the mass ratio of the nucleophile to the ester modifier is (1~2):

1.

6. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The ultraviolet irradiation conditions include: the wavelength of the ultraviolet light is 200nm~300nm, the reaction temperature is 45℃~50℃, and the reaction time is 12h~24h.

7. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The photosensitizer includes indocyanine green, and the mass ratio of the gelatin to the photosensitizer is (10~15):1; and / or The reaction conditions for the photosensitizer and the first modified aqueous prepolymer include: a reaction temperature of 30℃~35℃, and a stirring rate of 100r / min~150r / min for 2h~4h.

8. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The drug includes at least one of doxorubicin, epirubicin, irinotecan, or cisplatin-based drugs, and the mass ratio of the gelatin to the drug is (150~250):

1.

9. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The emulsifier comprises one or more of Span 20, Span 80, Tween 20, Tween 80, PEG-40, or PEG-20, and the oil phase liquid comprises low-boiling-point petroleum ether; and / or The first preset temperature is 25℃~35℃.

10. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The first ultrasonic power is 30W~500W, and the first preset time is 15min~30min; and / or The second ultrasonic power is 20W~200W, and the second preset time is 10min~20min; and / or The crosslinking agent includes at least one of glutaraldehyde, formaldehyde, or n-butyraldehyde; and / or The mass ratio of the crosslinking agent to the gelatin is 1:(5~10).

11. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The post-processing includes drying and impurity removal. Drying is performed under vacuum at 35℃~40℃. Impurity removal involves washing with water for injection followed by vacuum drying at 35℃~40℃.

12. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The buffer solution comprises tris(hydroxymethyl)aminomethane hydrochloride, and the concentration of the buffer solution is 0.1 mol / L to 0.15 mol / L; the adhesive comprises at least one of polydopamine, sodium citrate, ethylenediaminetetraacetic acid, or polyvinylpyrrolidone, and the concentration of the buffer solution is 0.5 g / L to 5 g / L, and the volume ratio of the first microsphere to the buffer solution is 1:5 to 20.

13. The method for preparing photothermal therapy embolism microspheres with plasma-enhanced imaging according to claim 1, characterized in that, The metal modification solution includes at least one of silver nitrate solution, chloroauric acid solution or copper sulfate solution, and the concentration of the metal modification solution is 200 μg / ml to 300 μg / ml.

14. A photothermal therapy microsphere for embolism with plasma-enhanced imaging, characterized in that, The embolization microspheres are obtained by the preparation method according to any one of claims 1-13, wherein the embolization microspheres are microspheres polymerized from gelatin and a crosslinking agent; wherein: the embolization microspheres encapsulate a therapeutic drug, a nucleophilic reagent-modified ester-modified copolymer is grafted onto the surface of the embolization microspheres, and a photosensitizer is grafted onto the groups of the nucleophilic reagent; an adhesion layer is formed on the embolization microspheres, and nano-metal particles are uniformly distributed on the adhesion layer.

15. The photothermal therapy embolism microspheres with enhanced plasma imaging according to claim 14, characterized in that, The nano-metal particles include at least one of nano-silver particles, nano-gold particles, or nano-copper particles, and the loading of the nano-metal particles is 50wt%~60wt%.

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