Degradable monodisperse embolism microsphere loaded with radionuclide and chemotherapeutic drug and preparation method of degradable monodisperse embolism microsphere

Abstract

The invention belongs to the field of biological medicine, and relates to degradable monodisperse embolism microspheres loaded with radionuclides and chemotherapeutic drugs and a preparation method of the degradable monodisperse embolism microspheres. The embolism microspheres are composed of degradable polymer microspheres with negative charges, radionuclides and chemotherapeutic drugs with positive charges. Radionuclides are connected to the degradable polymer microspheres through chemical bonds, and chemotherapeutic drugs with positive charges are loaded on the degradable polymer microspheres through electrostatic adsorption; the embolism microsphere is spherical, the particle size is 20-100 microns, and the variable coefficient of the particle size does not exceed 10%; the base material of the degradable polymer microspheres is formed by photo-initiation polymerization of two different photopolymerization macromolecules. The embolism microsphere provided by the invention can realize in-vivo chemoradiotherapy synergistic treatment, in-vivo development and in-vivo degradability, and has excellent monodispersity at the same time.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biological medicine, and relates to degradable monodisperse embolization microspheres loaded with radionuclides and chemotherapeutic drugs and a preparation method thereof. BACKGROUND

[0002] Liver cancer is a serious malignant tumor, and its early symptoms are not obvious, so patients are often in the middle and late stages when they are found. Traditional treatment methods have problems such as poor prognosis and poor efficacy, and embolization therapy provides a new choice for liver cancer treatment. Embolization therapy injects embolic agents into blood vessels near tumor tissues through minimally invasive means, blocks the blood supply of tumor tissues, and "starves" tumor cells to achieve the purpose of treating cancer. In clinical practice, radionuclides or chemotherapeutic drugs can be used for radiotherapy at the same time as embolization therapy to further enhance the therapeutic effect.

[0003] The microspheres loaded with radionuclides or chemotherapeutic drugs on the market are generally non-degradable, which is not conducive to secondary embolization, and may cause permanent damage to normal organs if ectopic embolization occurs. At the same time, the non-degradable drug-loaded embolization microspheres are difficult to completely release the drugs loaded therein, so the drug utilization is also low. At present, some patents have disclosed degradable embolization microspheres that can achieve drug loading, but most of these embolization microspheres are not directly visible, which makes it difficult to evaluate during and after the operation, and the size uniformity of these embolization microspheres is poor, which is easy to cause mis-embolization and affect the safety of use.

[0004] Combining drug-loaded embolization microspheres with internal radiotherapy can achieve the synergistic treatment of chemotherapy and radiotherapy based on embolization microspheres, which is expected to improve the treatment effect on tumors and alleviate the problems of drug resistance and side effects of single chemotherapy. In addition, the use of therapeutic radionuclides that can release gamma rays can also make the embolization microspheres visible during and after the operation, improving the safety of the operation process. Therefore, it is very meaningful to provide a degradable monodisperse embolization microsphere loaded with radionuclides and chemotherapeutic drugs for clinical use. SUMMARY

[0005] In view of the problems of non-direct visibility and non-uniform size of the existing degradable drug-loaded embolization microspheres, the present application provides a degradable monodisperse embolization microsphere loaded with radionuclides and chemotherapeutic drugs and a preparation method thereof, to achieve the synergistic treatment of radiotherapy and chemotherapy in vivo based on embolization microspheres, realize the in-vivo visualization and degradability of embolization microspheres, and improve the monodispersity of embolization microspheres.

[0006] To achieve the above-mentioned purposes, the technical solutions adopted by the present application are as follows:

[0007] The application discloses a degradable monodisperse embolism microsphere loaded with a radionuclide and a chemotherapy drug, which is composed of a negatively charged degradable polymer microsphere, a radionuclide and a positively charged chemotherapy drug; the radionuclide is connected to the degradable polymer microsphere through a chemical bond, and the positively charged chemotherapy drug is loaded on the degradable polymer microsphere through electrostatic adsorption; the embolism microsphere is spherical, with a particle size of 20-100 microns, and the coefficient of variation of the particle size of the embolism microsphere is not more than 10%.

[0008] The base material of the degradable polymer microsphere is formed by photo-induced polymerization of a photo-polymerized high molecule, and the photo-polymerized high molecule is composed of component A and component B; the component A is at least one of methacrylated gelatin and methacrylated silk fibroin, and the component B is at least one of methacrylated chondroitin sulfate and methacrylated sodium alginate.

[0009] In the technical scheme of the above-mentioned degradable monodisperse embolism microsphere loaded with a radionuclide and a chemotherapy drug, the mass ratio of the component A to the component B is (3-9):(7-1). Further, by adjusting the mass ratio of the component A to the component B, the elasticity of the embolism microsphere can be adjusted; generally, the greater the mass ratio of the component A to the component B, the better the elasticity of the embolism microsphere; in actual application, the elasticity of the embolism microsphere can be adjusted by adjusting the mass ratio of the component A to the component B according to the requirement of embolism treatment.

[0010] In the technical scheme of the above-mentioned degradable monodisperse embolism microsphere loaded with a radionuclide and a chemotherapy drug, the photo-induced polymerization process of the photo-polymerized high molecule is that polymerization of the photo-polymerized high molecule is initiated by applying light in the presence of a photo initiator.

[0011] In the technical scheme of the above-mentioned degradable monodisperse embolism microsphere loaded with a radionuclide and a chemotherapy drug, the negatively charged degradable polymer microsphere refers to that the degradable polymer microsphere is negatively charged due to deprotonation of a carboxyl group in physiological saline.

[0012] In the technical scheme of the above-mentioned degradable monodisperse embolism microsphere loaded with a radionuclide and a chemotherapy drug, the positively charged chemotherapy drug is a chemotherapy drug positively charged in physiological saline, and the positively charged chemotherapy drug includes doxorubicin hydrochloride, irinotecan hydrochloride or epirubicin.

[0013] In the technical scheme of the above-mentioned degradable monodisperse embolism microsphere loaded with a radionuclide and a chemotherapy drug, the radionuclide is preferably iodine-131, iodine-129 or iodine-125.

[0014] In the technical scheme of the above degradable monodisperse embolism microspheres loaded with radionuclides and chemotherapeutic drugs, the radioactivity specific activity of the embolism microspheres can be adjusted according to actual application requirements, and the radioactivity specific activity of the embolism microspheres is preferably controlled to be 0.1-10 mCi / mg.

[0015] In the technical scheme of the above degradable monodisperse embolism microspheres loaded with radionuclides and chemotherapeutic drugs, preferably, the coefficient of variation of the particle size of the embolism microspheres is not more than 5%.

[0016] The application further provides a preparation method of the above degradable monodisperse embolism microspheres loaded with radionuclides and chemotherapeutic drugs, comprising the following steps:

[0017] (1) preparing an inner phase fluid, an outer phase fluid and a collection solution

[0018] The inner phase fluid is prepared by dissolving a photoinitiator in water to obtain a photoinitiator solution and dissolving a photopolymer in the photoinitiator solution to obtain the inner phase fluid; in the inner phase fluid, the mass ratio of water, the photopolymer and the photoinitiator is 1:(0.08-0.2):(0.0005-0.0025);

[0019] The outer phase fluid is prepared by dissolving an oil-soluble surfactant in an oily solvent to obtain the outer phase fluid; in the outer phase fluid, the mass ratio of the oily solvent and the oil-soluble surfactant is 1:(0.01-0.1);

[0020] The collection solution is prepared by dissolving an oil-soluble surfactant in an oily solvent to obtain the outer phase fluid; in the outer phase fluid, the mass ratio of the oily solvent and the oil-soluble surfactant is 1:(0.01-0.1);

[0021] (2) preparing monodisperse degradable polymer microspheres

[0022] The inner phase fluid, the outer phase fluid and the collection solution are input into a microfluidic device to prepare monodisperse water-in-oil emulsions, and the water-in-oil emulsions are subjected to light irradiation to initiate polymerization of the photopolymer in the water-in-oil emulsions, so that the water-in-oil emulsions are solidified to obtain the monodisperse degradable polymer microspheres, which are then washed;

[0023] (3) radionuclide labeling

[0024] The washed monodisperse degradable polymer microspheres are subjected to radionuclide labeling to obtain the radionuclide-labeled monodisperse degradable polymer microspheres;

[0025] (4) drug loading

[0026] The radionuclide-labeled monodisperse degradable polymer microspheres are soaked in a solution of the positively charged chemotherapeutic drug, the microspheres are allowed to adsorb the positively charged chemotherapeutic drug sufficiently, and solid-liquid separation is performed to obtain the degradable monodisperse embolism microspheres loaded with the radionuclide and the chemotherapeutic drug.

[0027] In step (4) of the technical solution of the preparation method, the solution of the positively charged chemotherapeutic drug is a physiological saline solution of the positively charged chemotherapeutic drug.

[0028] In the technical solution of the preparation method, the concentration of the positively charged chemotherapeutic drug in the solution of the positively charged chemotherapeutic drug in step (4) is preferably 1-5 mg·mL -1 .

[0029] In step (4) of the technical solution of the preparation method, the soaking time of the radionuclide-labeled monodisperse degradable polymer microspheres in the solution of the positively charged chemotherapeutic drug is determined according to the loading amount of the positively charged chemotherapeutic drug in actual application. The specific soaking time is related to the type of the negatively charged chemotherapeutic drug, the concentration of the solution of the negatively charged chemotherapeutic drug, the matrix material of the radionuclide-labeled monodisperse degradable polymer microspheres, etc. For example, the radionuclide-labeled monodisperse degradable polymer microspheres can be soaked in the solution of the positively charged chemotherapeutic drug until the positively charged chemotherapeutic drug in the microspheres reaches an electrostatic adsorption equilibrium state. Generally, the soaking time of the radionuclide-labeled monodisperse degradable polymer microspheres in the solution of the positively charged chemotherapeutic drug can be controlled to be 1-8 h.

[0030] In step (3) of the technical solution of the preparation method, the washed monodisperse degradable polymer microspheres can be labeled with a radionuclide by using an existing conventional labeling method. A feasible labeling method is to label the washed monodisperse degradable polymer microspheres with radionuclides iodine-131, iodine-129 or iodine-125 by using the chloramine-T method.

[0031] In the technical solution of the preparation method, the photoinitiator can be lithium phenyl 2,4,6-trimethylbenzoyl phosphinate (LAP) or 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone (Irgacure 2959).

[0032] In the technical solution of the preparation method, the oily solvent can be n-octanol, liquid paraffin or vegetable oil. A feasible vegetable oil includes soybean oil.

[0033] In the above preparation method, the oil-soluble surfactant can be polyricinoleate (PGPR), oleic acid diethanolamide, Span20, Span40, Span60, Span80, or Tween85.

[0034] In the above preparation method, step (2) of preparing monodisperse biodegradable polymer microspheres can use a conventional microfluidic device for preparing monoemulsions, such as a primary capillary microfluidic device. A feasible microfluidic device structure is as follows: Figure 1 As shown, it includes an injection tube, a connecting tube, and a collection tube, and is used in conjunction with an injection pump. The injection tube is made of a cylindrical glass capillary tube, with its tail drawn into a conical shape, i.e., its tail is tapered. The collection tube is a cylindrical glass capillary tube. The connecting tube is a square glass tube with a square through hole in its center. The tail of the injection tube is inserted into the head of the collection tube and connected through the connecting tube. The injection tube, connecting tube, and collection tube are arranged coaxially.

[0035] In the above preparation method, in step (2), when preparing monodisperse biodegradable polymer microspheres, the inner diameter of the conical orifice of the microfluidic device injection tube and the flow rates of the inner and outer phase fluids jointly affect the particle size of the monodisperse biodegradable polymer microspheres. By adjusting the inner diameter of the conical orifice of the microfluidic device injection tube and the flow rates of the inner and outer phase fluids, the particle size of the monodisperse biodegradable polymer microspheres can be adjusted, thereby adjusting the particle size of the final prepared embolization microspheres. Typically, the inner diameter of the conical orifice of the microfluidic device injection tube does not exceed 20 μm; for example, the inner diameter of the conical orifice of the injection tube can typically be 15~20 μm. At the same time, in step (2), the flow rate of the inner phase fluid is controlled to be 50~300 μL / h, and the flow rate of the outer phase fluid is 1~10 mL / h.

[0036] In the above preparation method, the elastic properties, degradation properties, and swelling properties of monodisperse biodegradable polymer microspheres can be adjusted by regulating the type and concentration of photopolymerizable polymers in the internal phase fluid, adjusting the light conditions applied in step (2), and adjusting the polymerization reaction time, according to the needs of actual applications. Generally, the water-in-oil emulsion can be solidified by controlling the polymerization reaction time in step (2). For example, the polymer reaction time in step (2) can be controlled to be 1~5 min.

[0037] Compared with the prior art, the technical solution of the present invention can produce the following beneficial technical effects:

[0038] 1. This invention provides a biodegradable monodisperse embolization microsphere loaded with a radionuclide and a chemotherapeutic drug. The microsphere comprises negatively charged biodegradable polymer microspheres, a radionuclide, and a positively charged chemotherapeutic drug. The radionuclide is chemically bonded to the biodegradable polymer microspheres, and the positively charged chemotherapeutic drug is electrostatically adsorbed onto the microspheres. Because the matrix material of the embolization microsphere is a biodegradable polymer, it is biodegradable in vivo, facilitating secondary embolization and the release of the loaded drug. Since the embolization microsphere is labeled with the radionuclide iodine-131, iodine-129, or iodine-125, it is visualized under digital subtraction angiography (DSA) or computed tomography (CT), enabling in vivo visualization of the embolization microsphere and facilitating intraoperative and postoperative monitoring and evaluation. Because the embolization microsphere is loaded with a chemotherapeutic drug, it allows for synergistic radiotherapy and chemotherapy in vivo, improving the therapeutic effect on tumors and alleviating the problems of drug resistance and toxic side effects associated with single-agent chemotherapy. In addition, the embolization microspheres have uniform morphology, good sphericity, and good monodispersity. The coefficient of variation of their particle size does not exceed 10%, which is beneficial for predicting the trajectory of the microspheres and avoids the problem of accidental embolization.

[0039] 2. The present invention also provides a method for preparing the above-mentioned embolization microspheres. The production process of this method is simple and can realize the continuous production of embolization microspheres. At the same time, the method has good adjustability and controllability. By adjusting the flow rate of each phase fluid and the conical size of the injection tube and the diameter of the collection tube of the microfluidic device, the size of the embolization microspheres can be flexibly and precisely controlled. The mechanical properties of the embolization microspheres can be adjusted by changing the type and proportion of photopolymer polymers in the inner phase fluid, which can well meet the diverse treatment needs in clinical practice. Attached Figure Description

[0040] Figure 1 This is a schematic diagram of the structure of the primary capillary microfluidic device used in this invention. In the diagram, 1-injection tube, 2-connecting tube, and 3-collection tube.

[0041] Figure 2 These are optical microscope images of polyGM-CSM microspheres prepared under different flow rates of external phase fluids in Example 1.

[0042] Figure 3 Figure a shows the curve of the diameter of the polyGM-CSM microspheres prepared in Example 1 as a function of the external phase fluid flow rate. Figure 3 Figure b shows the coefficient of variation of the diameter of polyGM-CSM microspheres under the corresponding flow rate conditions.

[0043] Figure 4 Figure a is the preparation of Example 1. 131 The curve showing the encapsulation efficiency of I-polyGM-CSM microspheres for doxorubicin hydrochloride as a function of drug concentration and time.Figure 4 Figure b shows the curve of drug loading as a function of drug concentration and time.

[0044] Figure 5 Figure a shows the drug-loaded material prepared in Example 1 based on the polyGM-CSM microspheres obtained in the sixth group of experiments. 131 Optical images of I-polyGM-CSM microspheres. Figure 5 Figure b shows the corresponding drug loading. 131 Fluorescence image of I-polyGM-CSM microspheres.

[0045] Figure 6 Figure a shows the sample prepared in Example 2. 131 The curve showing the encapsulation efficiency of I-polyGM-CSM microspheres for doxorubicin hydrochloride as a function of drug concentration and time. Figure 6 Figure b shows the curve of drug loading as a function of drug concentration and time.

[0046] Figure 7 Figure a shows the drug-loaded material prepared in Example 2 based on the polyGM-CSM microspheres obtained in the sixth group of experiments. 131 Optical images of I-polyGM-CSM microspheres. Figure 7 Figure b shows the corresponding drug loading. 131 Fluorescence image of I-polyGM-CSM microspheres.

[0047] Figure 8 Figure a shows the product prepared in Example 3. 131 The curve showing the encapsulation efficiency of I-polyGM-CSM microspheres for doxorubicin hydrochloride as a function of drug concentration and time. Figure 8 Figure b shows the curve of drug loading as a function of drug concentration and time.

[0048] Figure 9 Figure a shows the drug-loaded material prepared in Example 2 based on the polyGM-CSM microspheres obtained in the sixth group of experiments. 131 Optical images of I-polyGM-CSM microspheres. Figure 9 Figure b shows the corresponding drug loading. 131 Fluorescence image of I-polyGM-CSM microspheres.

[0049] Figure 10 Figure a shows different drug loading methods. 131 Morphological changes of I-polyGM-CSM microspheres during extrusion-rebound process Figure 10 Figure b shows different drug loading methods. 131 Force-displacement curves of I-polyGM-CSM microspheres during extrusion. Figure 10 Figure c is based on force-displacement curves to calculate different drug loading levels. 131 Young's modulus of I-polyGM-CSM microspheres. Detailed Implementation

[0050] The following examples further illustrate the biodegradable monodisperse embolic microspheres loaded with radionuclides and chemotherapeutic drugs, and their preparation method, as described in this invention. It should be noted that the following examples are only for further illustration of this invention and should not be construed as limiting the scope of protection of this invention. Any non-essential improvements and adjustments made to this invention by those skilled in the art based on the above description are still within the scope of protection of this invention.

[0051] In the following embodiments, the microfluidic device used is a single-stage capillary microfluidic device, the structural schematic of which is shown in the figure. Figure 1 As shown, it includes an injection tube 1, a connecting tube 2, and a collection tube 3, and is used in conjunction with an injection pump. The relevant dimensional information of the microfluidic device used in Example 1 is as follows:

[0052] Injection tube 1 is made by drawing the tail of a cylindrical glass capillary tube (outer diameter 960 μm, inner diameter 500 μm) into a conical shape using a needle puller, and then sanding the conical tip to a flat end with an inner diameter of approximately 20 μm. Collection tube 3 is made of a cylindrical glass capillary tube (outer diameter 960 μm, inner diameter 500 μm) with both ends sanded flat. Connecting tube 2 is a square glass tube with both ends sanded flat, and a square through-hole with dimensions of 1.0 × 1.0 mm is provided in the center. Injection tube 1, connecting tube 2, and collection tube 3 are ultrasonically cleaned in anhydrous ethanol and dried before assembly: the tail of injection tube 1 is inserted into the head of collection tube 3 and connected by connecting tube 2. All three are coaxial and fixed to a glass slide with AB glue. The inlet ends of injection tube 1 and connecting tube 2 are fixed with AB glue to a steel tube and a flat-ended needle for connection to the injection pump, and the non-inlet ends are sealed with AB glue.

[0053] Example 1

[0054] In this embodiment, preparation 131 I-labeled monodisperse drug-loaded polymethacrylamide gelatin-methacrylamide chondroitin sulfate microspheres (drug-loaded) 131 I-polyGM-CSM microspheres), the steps are as follows:

[0055] (1) Preparation of internal phase, external phase fluid and collection liquid

[0056] Preparation of the inner phase fluid: The photoinitiator lithium phenyl 2,4,6-trimethylbenzoylphosphonate (LAP) was added to deionized water and dissolved in a water bath at 50 °C to obtain a photoinitiator solution. Methacrylamide gelatin (GelMA, with a double bond substitution degree of 90%) and chondroitin sulfate methacrylamide (ChSMA) were added to the photoinitiator solution and dissolved in a water bath at 50 °C. The solution was filtered to obtain the inner phase fluid. The mass ratio of deionized water, GelMA, ChSMA and LAP in the inner phase fluid was 1:0.03:0.07:0.0025.

[0057] Preparation of external phase fluid: Dissolve polyricinoleate (PGPR) in soybean oil to obtain external phase fluid; the mass ratio of soybean oil to PGPR in external phase fluid is 1:0.05.

[0058] Preparation of the collection solution: The collection solution is the same as the external phase fluid.

[0059] (2) Preparation of monodisperse polyGM-CSM microspheres

[0060] The structure adopted is as follows Figure 1 The diagram shows a first-stage capillary microfluidic device. At 40 °C, the internal phase fluid is injected into the injection tube 1 of the microfluidic device using a syringe pump, and the external phase fluid is injected into the collection tube 3 of the microfluidic device using a syringe pump. A monodisperse W / O emulsion is formed in the collection tube 3. The W / O emulsion is collected in a container filled with the collection liquid. It is first prepolymerized by irradiation with blue light for 30 s, and then irradiated with ultraviolet light for 1 min to initiate the polymerization of GelMA and ChSMA in the W / O emulsion, yielding monodisperse polyGM-CSM microspheres.

[0061] The collected liquid on the surface of the polyGM-CSM microspheres was removed by washing with isopropanol, and the washed polyGM-CSM microspheres were then vacuum dried at 40°C.

[0062] This step involves seven sets of experiments. In each set of experiments, the flow rate of the internal phase fluid is controlled at 100 μL / h. In the first to seventh sets of experiments, the flow rate of the external phase fluid is controlled at 1, 2, 3, 4, 5, 6, and 7 mL / h, respectively.

[0063] (3) Radionuclide labeling

[0064] The polyGM-CSM microspheres dried after washing step (2) were subjected to the chloramine-T method. 131 The I mark, the specific operation is as follows:

[0065] At room temperature, 8 mg of each group of polyGM-CSM microspheres prepared in each experiment were placed in PE tubes, and 200 μL of PBS buffer was added to each tube for thorough dispersion; then approximately 0.6 mCi of Na+ was added to each tube. 131 The solution and 100 μL of 20 mg / mL chloramine-T solution were reacted with shaking at room temperature for 5 min, and then allowed to stand for 30 min. The mixture was then centrifuged at 3000 rpm for 3 min, and the supernatant was discarded. The mixture was then washed with physiological saline by centrifugation to remove unreacted components. 131 I. This step is repeated 4 times to obtain... 131 I-labeled monodisperse polyGM-CSM microspheres (monodisperse) 131 I-polyGM-CSM microspheres).

[0066] The monodisperse microspheres prepared based on the polyGM-CSM microspheres obtained in the sixth group of experiments were tested. 131 I-polyGM-CSM microspheres 131 The I-labeling rate was approximately 69.50%.

[0067] (4) Drug load

[0068] Doxorubicin hydrochloride was dissolved in physiological saline to obtain doxorubicin hydrochloride concentrations of 1 mg / mL. -1 2.5 mg / mL -1 5 mg·mL -1 Doxorubicin hydrochloride solution. Take 10 mg of the solution prepared in step (3) of each experimental group. 131 I-polyGM-CSM microspheres were added to 2 mL or more of three different concentrations of doxorubicin hydrochloride solutions, shaken for 1 min, and then allowed to stand for 8 h to allow the drug to be loaded onto the surface via electrostatic adsorption. 131 Solid-liquid separation is performed on I-polyGM-CSM microspheres, and the resulting solid phase is the monodisperse drug-loaded phase. 131 I-polyGM-CSM microspheres.

[0069] For step (3), the monodisperse microspheres prepared based on the polyGM-CSM microspheres obtained in the sixth group of experiments were prepared. 131 For I-polyGM-CSM microspheres, 100 μL of supernatant was aspirated at 0.5, 1, 2, 4 and 8 h after standing in this step, and the absorbance of the supernatant was measured at a wavelength of 490 nm using an ELISA reader. The encapsulation efficiency and drug loading were calculated using the standard curve of doxorubicin hydrochloride at the corresponding time.

[0070] Figure 2 These are optical microscope images of polyGM-CSM microspheres prepared under different external phase fluid flow rates in this embodiment. The images clearly show that the polyGM-CSM microspheres prepared in each experiment have good size uniformity.

[0071] Figure 3 Figure a shows the curve of the diameter of the polyGM-CSM microspheres prepared in this embodiment as a function of the external phase fluid flow rate. Figure 3 Figure b shows the coefficient of variation (CV) of the diameter of polyGM-CSM microspheres under the corresponding flow rate conditions. Figure 3 It can be seen that the CV value of the diameter of the polyGM-CSM microspheres prepared under different external phase fluid flow conditions in this embodiment does not exceed 5%, indicating that the polyGM-CSM microspheres have good monodispersity.

[0072] Figure 4 Figure a is the one prepared in this embodiment. 131 The curve showing the encapsulation efficiency of I-polyGM-CSM microspheres for doxorubicin hydrochloride as a function of drug concentration and time. Figure 4Figure b shows the curve of drug loading changing with drug concentration and time. Figure 4 It can be seen that step (3) uses the polyGM-CSM microspheres obtained in the sixth group of experiments to prepare monodisperse... 131 I-polyGM-CSM microspheres at 1 mg·mL -1 2.5 mg·mL -1 5 mg·mL -1 When the drug was allowed to stand in the doxorubicin hydrochloride solution for 30 min, the encapsulation efficiencies reached 95.37%, 97.16%, and 88.44%, respectively, with drug loadings of 16.02%, 32.70%, and 46.93%. After standing for 8 h, the encapsulation efficiencies reached 96.54%, 97.91%, and 97.24%, respectively, with drug loadings of 16.08%, 32.90%, and 48.99%, respectively. This indicates... 131 I-polyGM-CSM microspheres can efficiently load doxorubicin hydrochloride.

[0073] Figure 5 Figure a shows the drug-loaded material prepared in this embodiment based on the polyGM-CSM microspheres obtained in the sixth group of experiments. 131 Optical images of I-polyGM-CSM microspheres. Figure 5 Figure b shows the corresponding drug loading. 131 Fluorescent images of I-polyGM-CSM microspheres. The color and fluorescence properties of the optical spectrum indicate successful loading of doxorubicin hydrochloride.

[0074] Example 2

[0075] In this embodiment, a drug-loaded preparation is performed. 131 I-PolyGM-CSM microspheres, the steps are as follows:

[0076] (1) Preparation of internal phase, external phase fluid and collection liquid

[0077] Preparation of the inner phase fluid: Add the photoinitiator LAP to deionized water and dissolve it in a water bath at 50 °C to obtain a photoinitiator solution. Add GelMA (with a double bond substitution degree of 90%) and ChSMA to the photoinitiator solution and dissolve them in a water bath at 50 °C. Filter to obtain the inner phase fluid. The mass ratio of deionized water, GelMA, ChSMA, and LAP in the inner phase fluid is 1: 0.05: 0.05: 0.0025.

[0078] Preparation of external phase fluid: Dissolve PGPR in soybean oil to obtain external phase fluid; the mass ratio of soybean oil to PGPR in external phase fluid is 1:0.05.

[0079] Preparation of the collection solution: The collection solution is the same as the external phase fluid.

[0080] (2) Preparation of monodisperse polyGM-CSM microspheres

[0081] The structure adopted is as follows Figure 1 The first-stage capillary microfluidic device is shown. At 40 °C, the internal phase fluid is injected into the injection tube 1 of the microfluidic device using a syringe pump, and the external phase fluid is injected into the collection tube 3 of the microfluidic device using a syringe pump. A monodisperse W / O emulsion is formed in the collection tube 3. The W / O emulsion is collected in a container filled with the collection liquid. It is first prepolymerized by irradiation with blue light for 30 s, and then irradiated with ultraviolet light for 1 min to initiate W / O emulsion polymerization, yielding monodisperse polyGM-CSM microspheres.

[0082] The collected liquid on the surface of the polyGM-CSM microspheres was removed by washing with isopropanol, and the washed polyGM-CSM microspheres were then vacuum dried at 40°C.

[0083] This step involves seven sets of experiments. In each set of experiments, the flow rate of the internal phase fluid is controlled at 100 μL / h. In the first to seventh sets of experiments, the flow rate of the external phase fluid is controlled at 1, 2, 3, 4, 5, 6, and 7 mL / h, respectively.

[0084] (3) Radionuclide labeling

[0085] The polyGM-CSM microspheres dried after washing step (2) were subjected to the chloramine-T method. 131 The I mark, the specific operation is as follows:

[0086] At room temperature, 8 mg of each group of polyGM-CSM microspheres prepared in each experiment were placed in PE tubes, and 200 μL of PBS buffer was added to each tube for thorough dispersion; then approximately 0.6 mCi of Na+ was added to each tube. 131 The solution and 100 μL of 20 mg / mL chloramine-T solution were reacted with shaking at room temperature for 5 min, and then allowed to stand for 30 min. The mixture was then centrifuged at 3000 rpm for 3 min, and the supernatant was discarded. The mixture was then washed with physiological saline by centrifugation to remove unreacted components. 131 I. This step is repeated 4 times to obtain monodisperse samples. 131 I-polyGM-CSM microspheres.

[0087] The test was conducted using monodisperse polyGM-CSM microspheres prepared based on the results of the sixth group of experiments. 131 I-polyGM-CSM microspheres 131 The I-labeling rate was approximately 72.87%.

[0088] (4) Drug load

[0089] Doxorubicin hydrochloride was dissolved in physiological saline to obtain doxorubicin hydrochloride concentrations of 1 mg / mL. -1 2.5 mg / mL -1 5 mg·mL-1 Doxorubicin hydrochloride solution. Take 10 mg of the solution prepared in each experimental group. 131 I-polyGM-CSM microspheres were added to 2 mL or more of three different concentrations of doxorubicin hydrochloride solutions, shaken for 1 min, and then allowed to stand for 8 h to allow the drug to be loaded onto the surface via electrostatic adsorption. 131 Solid-liquid separation is performed on I-polyGM-CSM microspheres, and the resulting solid phase is the monodisperse drug-loaded phase. 131 I-polyGM-CSM microspheres.

[0090] For step (3), the monodisperse microspheres prepared based on the polyGM-CSM microspheres obtained in the sixth group of experiments were prepared. 131 For I-polyGM-CSM microspheres, 100 μL of supernatant was aspirated at 0.5, 1, 2, 4 and 8 h after standing in this step, and the absorbance of the supernatant was measured at a wavelength of 490 nm using an ELISA reader. The encapsulation efficiency and drug loading were calculated using the standard curve of doxorubicin hydrochloride at the corresponding time.

[0091] Figure 6 Figure a is the one prepared in this embodiment. 131 The curve showing the encapsulation efficiency of I-polyGM-CSM microspheres for doxorubicin hydrochloride as a function of drug concentration and time. Figure 6 Figure b shows the curve of drug loading changing with drug concentration and time. Figure 6 It can be seen that step (3) uses the polyGM-CSM microspheres obtained in the sixth group of experiments to prepare monodisperse... 131 I-polyGM-CSM microspheres at 1 mg·mL -1 2.5 mg·mL -1 5 mg·mL -1 When the drug was allowed to stand in the doxorubicin hydrochloride solution for 30 min, the encapsulation efficiencies reached 94.31%, 95.65%, and 88.49%, respectively, with drug loadings of 15.87%, 32.35%, and 46.95%. After standing for 8 h, the encapsulation efficiencies reached 96.22%, 98.06%, and 95.93%, respectively, with drug loadings of 16.02%, 32.78%, and 48.60%, respectively. This indicates... 131 I-polyGM-CSM microspheres can efficiently and rapidly load doxorubicin hydrochloride.

[0092] Figure 7 Figure a shows the drug-loaded material prepared in this embodiment based on the polyGM-CSM microspheres obtained in the sixth group of experiments. 131 Optical images of I-polyGM-CSM microspheres. Figure 7 Figure b shows the corresponding drug loading. 131 Fluorescent images of I-polyGM-CSM microspheres. The color and fluorescence properties of the optical spectrum indicate successful loading of doxorubicin hydrochloride.

[0093] Example 3

[0094] In this embodiment, a drug-loaded preparation is performed. 131 I-PolyGM-CSM microspheres, the steps are as follows:

[0095] (1) Preparation of internal phase, external phase fluid and collection liquid

[0096] Preparation of the inner phase fluid: LAP was added to deionized water and dissolved in a water bath at 50 °C to obtain a photoinitiator solution. GelMA (with a double bond substitution degree of 90%) and ChSMA were added to the photoinitiator solution and dissolved in a water bath at 50 °C. The solution was then filtered to obtain the inner phase fluid. The mass ratio of deionized water, GelMA, ChSMA and LAP in the inner phase fluid was 1: 0.07: 0.03: 0.0025.

[0097] Preparation of external phase fluid: Dissolve PGPR in soybean oil to obtain external phase fluid; the mass ratio of soybean oil to PGPR in external phase fluid is 1:0.05.

[0098] Preparation of the collection solution: The collection solution is the same as the external phase fluid.

[0099] (2) Preparation of monodisperse polyGM-CSM microspheres

[0100] The structure adopted is as follows Figure 1 The first-stage capillary microfluidic device is shown. At 40 °C, the internal phase fluid is injected into the injection tube 1 of the microfluidic device using a syringe pump, and the external phase fluid is injected into the collection tube 3 of the microfluidic device using a syringe pump. A monodisperse W / O emulsion is formed in the collection tube 3. The W / O emulsion is collected in a container filled with the collection liquid. It is first prepolymerized by irradiation with blue light for 30 s, and then irradiated with ultraviolet light for 1 min to initiate W / O emulsion polymerization, yielding monodisperse polyGM-CSM microspheres.

[0101] The collected liquid on the surface of the polyGM-CSM microspheres was removed by washing with isopropanol, and the washed polyGM-CSM microspheres were then vacuum dried at 40°C.

[0102] This step involves seven sets of experiments. In each set of experiments, the flow rate of the internal phase fluid is controlled at 100 μL / h. In the first to seventh sets of experiments, the flow rate of the external phase fluid is controlled at 1, 2, 3, 4, 5, 6, and 7 mL / h, respectively.

[0103] (3) Radionuclide labeling

[0104] The polyGM-CSM microspheres dried after washing step (2) were subjected to the chloramine-T method. 131 The I mark, the specific operation is as follows:

[0105] At room temperature, 8 mg of each group of polyGM-CSM microspheres prepared in each experiment were placed in PE tubes, and 200 μL of PBS buffer was added to each tube for thorough dispersion; then approximately 0.6 mCi of Na+ was added to each tube. 131 The solution and 100 μL of 20 mg / mL chloramine-T solution were reacted with shaking at room temperature for 5 min, and then allowed to stand for 30 min. The mixture was then centrifuged at 3000 rpm for 3 min, and the supernatant was discarded. The mixture was then washed with physiological saline by centrifugation to remove unreacted components. 131 I. This step is repeated 4 times to obtain monodisperse samples. 131 I-polyGM-CSM microspheres.

[0106] The test was conducted using monodisperse polyGM-CSM microspheres prepared based on the results of the sixth group of experiments. 131 I-polyGM-CSM microspheres 131 The I-labeling rate was approximately 78.47%.

[0107] (4) Drug load

[0108] Doxorubicin hydrochloride was dissolved in physiological saline to obtain doxorubicin hydrochloride concentrations of 1 mg / mL. -1 2.5 mg / mL -1 5 mg·mL -1 Doxorubicin hydrochloride solution. Take 10 mg of the solution prepared in each experimental group. 131 I-polyGM-CSM microspheres were added to 2 mL or more of three different concentrations of doxorubicin hydrochloride solutions, shaken for 1 min, and then allowed to stand for 8 h to allow the drug to be loaded onto the surface via electrostatic adsorption. 131 Solid-liquid separation is performed on I-polyGM-CSM microspheres, and the resulting solid phase is the monodisperse drug-loaded phase. 131 I-polyGM-CSM microspheres.

[0109] For step (3), the monodisperse microspheres prepared based on the polyGM-CSM microspheres obtained in the sixth group of experiments were prepared. 131 For I-polyGM-CSM microspheres, 100 μL of supernatant was aspirated at 0.5, 1, 2, 4 and 8 h after standing in this step, and the absorbance of the supernatant was measured at a wavelength of 490 nm using an ELISA reader. The encapsulation efficiency and drug loading were calculated using the standard curve of doxorubicin hydrochloride at the corresponding time.

[0110] Figure 8 Figure a is the one prepared in this embodiment. 131 The curve showing the encapsulation efficiency of I-polyGM-CSM microspheres for doxorubicin hydrochloride as a function of drug concentration and time. Figure 8 Figure b shows the curve of drug loading changing with drug concentration and time. Figure 8It can be seen that step (3) uses the polyGM-CSM microspheres obtained in the sixth group of experiments to prepare monodisperse... 131 I-polyGM-CSM microspheres at 1 mg·mL -1 2.5 mg·mL -1 5 mg·mL -1 When the drug was allowed to stand in the doxorubicin hydrochloride solution for 30 min, the encapsulation efficiency reached 92.50%, 92.59%, and 82.31%, respectively, with drug loadings of 15.61%, 31.64%, and 45.14%. After standing for 8 h, the encapsulation efficiency reached 95.09%, 96.46%, and 89.45%, respectively, with drug loadings of 15.83%, 32.37%, and 46.53%, respectively. This indicates... 131 I-polyGM-CSM microspheres can efficiently and rapidly load doxorubicin hydrochloride.

[0111] Figure 9 Figure a shows the drug-loaded material prepared in this embodiment based on the polyGM-CSM microspheres obtained in the sixth group of experiments. 131 Optical images of I-polyGM-CSM microspheres. Figure 9 Figure b shows the corresponding drug loading. 131 Fluorescent images of I-polyGM-CSM microspheres. The color and fluorescence properties of the optical spectrum indicate successful loading of doxorubicin hydrochloride.

[0112] Example 4

[0113] In this embodiment, the drug-loaded samples prepared in Examples 1-3 were tested. 131 The elasticity of I-polyGM-CSM microspheres.

[0114] Drug-loaded materials prepared based on the polyGM-CSM microspheres obtained in the sixth group of experiments in Examples 1-3 were respectively taken. 131 Elasticity tests were performed on I-polyGM-CSM microspheres. During the tests, the drug-loaded microspheres prepared in each embodiment were used... 131 I-poly(GM-CSM) microspheres were placed in a quartz glass sample chamber. Using a solid glass probe, the microspheres were compressed to approximately 60% of their maximum compression ratio. The probe was then withdrawn at maximum speed. The morphological changes of the microspheres during the compression-springback process, the force-displacement curves during compression, and the Young's modulus were recorded. The results are as follows: Figure 10 As shown.

[0115] Figure 10 Figure a shows the drug-loaded part. 131 Morphological changes of I-polyGM-CSM microspheres during extrusion-rebound process Figure 10 Figure b shows the force-displacement curve during the extrusion process. Figure 10 Figure c is the drug loading calculated based on the force-displacement curve. 131Young's modulus values ​​of I-polyGM-CSM microspheres. (Based on...) Figure 10 It can be seen that the drug-loaded materials prepared in Examples 1-3 based on the polyGM-CSM microspheres obtained in the sixth group of experiments are effective. 131 I-polyGM-CSM microspheres all exhibit good elastic properties. Furthermore, the elasticity of the microspheres increases with the increase of the gelatin component content. This indicates that the method of the present invention can adjust the elasticity of the prepared microspheres by controlling the ratio of photopolymerized polymers in the internal phase fluid. In practical applications, the method of the present invention can prepare microspheres with suitable elasticity according to different embolization treatment purposes, flexibly adapting to different tumor vascular environments and embolization treatment needs.

[0116] Example 5

[0117] In this embodiment, preparation 131 I-labeled monodisperse drug-loaded polymethacrylamide gelatin-methacrylamide alginate microspheres (drug-loaded) 131 I-polyGM-AM microspheres), the steps are as follows:

[0118] (1) Preparation of internal phase, external phase fluid and collection liquid

[0119] Preparation of the internal phase fluid: LAP was added to deionized water and dissolved in a water bath at 50 °C to obtain a photoinitiator solution. GelMA (with a double bond substitution degree of 90%) and sodium methacryloyl alginate (AlgMA) were added to the photoinitiator solution and dissolved in a water bath at 50 °C. The solution was then filtered to obtain the internal phase fluid. The mass ratio of deionized water, GelMA, AlgMA, and LAP in the internal phase fluid was 1: 0.04: 0.04: 0.0005.

[0120] Preparation of external phase fluid: Dissolve PGPR in soybean oil to obtain external phase fluid; the mass ratio of soybean oil to PGPR in external phase fluid is 1:0.1.

[0121] Preparation of the collection solution: The collection solution is the same as the external phase fluid.

[0122] (2) Preparation of monodisperse polyGM-AM microspheres

[0123] The structure adopted is as follows Figure 1 The diagram shows a first-stage capillary microfluidic device. At 40 °C, the internal phase fluid is injected into the injection tube 1 of the microfluidic device using a syringe pump, and the external phase fluid is injected into the collection tube 3 of the microfluidic device using a syringe pump. A monodisperse W / O emulsion is formed in the collection tube 3. The W / O emulsion is collected in a container filled with the collection liquid. It is first prepolymerized by irradiation with blue light for 30 s, and then irradiated with ultraviolet light for 1 min to initiate W / O emulsion polymerization, yielding monodisperse polyGM-AM microspheres.

[0124] The collected liquid on the surface of the polyGM-AM microspheres was removed by washing with isopropanol, and the washed polyGM-AM microspheres were then vacuum dried at 40 °C.

[0125] In this step, the flow rate of the internal phase fluid is controlled at 50 μL / h, and the flow rate of the external phase fluid is controlled at 1 mL / h.

[0126] (3) Radionuclide labeling

[0127] The polyGM-AM microspheres dried after washing step (2) were subjected to the chloramine-T method. 131 The I mark, the specific operation is as follows:

[0128] Place 8 mg of the polyGM-AM microspheres prepared in step (2) into a PE tube at room temperature, add 200 μL of PBS buffer, and disperse thoroughly; then add approximately 0.6 mCi of Na 131 The solution and 100 μL of 20 mg / mL chloramine-T solution were reacted with shaking at room temperature for 5 min, and then allowed to stand for 30 min. The mixture was then centrifuged at 3000 rpm for 3 min, and the supernatant was discarded. The mixture was then washed with physiological saline by centrifugation to remove unreacted components. 131 I. This step is repeated 4 times to obtain... 131 I-labeled monodisperse polyGM-AM microspheres (monodisperse) 131 I-polyGM-AM microspheres).

[0129] (4) Drug load

[0130] Doxorubicin hydrochloride was dissolved in physiological saline to obtain a doxorubicin hydrochloride concentration of 5 mg / mL. -1 Doxorubicin hydrochloride solution. Take 10 mg of the solution prepared in step (3). 131 I-polyGM-AM microspheres were added to 2 mL of doxorubicin hydrochloride solution, shaken for 1 min, and then allowed to stand for 8 h to allow the drug to be loaded onto the electrolyte via electrostatic adsorption. 131 Solid-liquid separation is performed on I-polyGM-AM microspheres, and the resulting solid phase is the monodisperse drug-loaded phase. 131 I-polyGM-AM microspheres.

[0131] Example 6

[0132] In this embodiment, preparation 131 I-labeled monodisperse drug-loaded polymethacrylamide silk fibroin-methacrylamide alginate microspheres (drug-loaded) 131 I-poly-SM-AM microspheres), the steps are as follows:

[0133] (1) Preparation of internal phase, external phase fluid and collection liquid

[0134] Preparation of the inner phase fluid: LAP was added to deionized water and dissolved in a water bath at 50 °C to obtain a photoinitiator solution. Methacrylated silk fibroin (SilMA) and methacrylated sodium alginate (AlgMA) were added to the photoinitiator solution and dissolved in a water bath at 50 °C. The solution was then filtered to obtain the inner phase fluid. The mass ratio of deionized water, SilMA, AlgMA, and LAP in the inner phase fluid was 1:0.18:0.02:0.0015.

[0135] Preparation of external phase fluid: Dissolve PGPR in soybean oil to obtain external phase fluid; the mass ratio of soybean oil to PGPR in external phase fluid is 1:0.01.

[0136] Preparation of the collection solution: The collection solution is the same as the external phase fluid.

[0137] (2) Preparation of monodisperse poly(SM-AM) microspheres

[0138] The structure adopted is as follows Figure 1 The first-stage capillary microfluidic device is shown. At 40 °C, the internal phase fluid is injected into the injection tube 1 of the microfluidic device using a syringe pump, and the external phase fluid is injected into the collection tube 3 of the microfluidic device using a syringe pump. A monodisperse W / O emulsion is formed in the collection tube 3. The W / O emulsion is collected in a container filled with the collection liquid, then prepolymerized by irradiation with blue light for 30 s, followed by initiation of W / O emulsion polymerization by irradiation with ultraviolet light for 1 min, yielding monodisperse poly(SM-AM) microspheres.

[0139] The collected liquid on the surface of the poly-SM-AM microspheres was removed by washing with isopropanol, and the washed poly-SM-AM microspheres were then vacuum dried at 40 °C.

[0140] In this step, the flow rate of the internal phase fluid is controlled at 300 μL / h, and the flow rate of the external phase fluid is controlled at 10 mL / h.

[0141] (3) Radionuclide labeling

[0142] The polySM-AM microspheres dried after washing step (2) were subjected to the chloramine-T method. 131 The I mark, the specific operation is as follows:

[0143] Place 8 mg of the polySM-AM microspheres prepared in step (2) into a PE tube at room temperature, add 200 μL of PBS buffer, and disperse thoroughly; then add approximately 0.6 mCi of Na 131 The solution and 100 μL of 20 mg / mL chloramine-T solution were reacted with shaking at room temperature for 5 min, and then allowed to stand for 30 min. The mixture was then centrifuged at 3000 rpm for 3 min, and the supernatant was discarded. The mixture was then washed with physiological saline by centrifugation to remove unreacted components. 131I. This step is repeated 4 times to obtain... 131 I-labeled monodisperse poly(SM-AM) microspheres (monodisperse) 131 I-poly-SM-AM microspheres).

[0144] (4) Drug load

[0145] Doxorubicin hydrochloride was dissolved in physiological saline to obtain a doxorubicin hydrochloride concentration of 5 mg / mL. -1 Doxorubicin hydrochloride solution. Take 10 mg of the solution prepared in step (3). 131 I-poly-SM-AM microspheres were added to 2 mL of doxorubicin hydrochloride solution, shaken for 1 min, and then allowed to stand for 8 h to allow the drug to be loaded onto the electrolyte via electrostatic adsorption. 131 Solid-liquid separation is performed on I-poly(SM-AM) microspheres, and the resulting solid phase is the monodisperse drug-loaded phase. 131 I-poly-SM-AM microspheres.

Claims

1. A biodegradable monodisperse embolic microsphere loaded with a radionuclide and a chemotherapeutic drug, characterized in that, The embolization microspheres are composed of negatively charged biodegradable polymer microspheres, radioactive nuclides, and positively charged chemotherapeutic drugs. The radioactive nuclides are chemically bonded to the biodegradable polymer microspheres, and the positively charged chemotherapeutic drugs are electrostatically adsorbed onto the biodegradable polymer microspheres. The embolization microspheres are spherical with a particle size of 20–100 μm, and the coefficient of variation of the particle size does not exceed 10%. The matrix material of the biodegradable polymer microspheres is formed by photopolymerization of photopolymers. The photopolymers are composed of component A and component B. Component A is at least one of methacrylamide gelatin and methacrylamide silk fibroin, and component B is at least one of methacrylamide chondroitin sulfate and methacrylamide sodium alginate.

2. The biodegradable monodisperse embolic microspheres loaded with radionuclides and chemotherapeutic drugs according to claim 1, characterized in that, The mass ratio of component A to component B is (3~9):(7~1).

3. The biodegradable monodisperse embolic microspheres loaded with radionuclides and chemotherapeutic drugs according to claim 2, characterized in that, The elasticity of the embolization microspheres can be adjusted by changing the mass ratio of component A to component B.

4. The biodegradable monodisperse embolic microspheres loaded with radionuclides and chemotherapeutic agents according to any one of claims 1 to 3, characterized in that, Positively charged chemotherapy drugs are those that carry a positive charge in physiological saline. Positively charged chemotherapy drugs include doxorubicin hydrochloride, irinotecan hydrochloride, or epirubicin.

5. The biodegradable monodisperse embolic microspheres loaded with radionuclides and chemotherapeutic agents according to any one of claims 1 to 3, characterized in that, The radioactive nuclides are iodine-131, iodine-129, or iodine-125.

6. A method for preparing biodegradable monodisperse embolic microspheres loaded with radionuclides and chemotherapeutic agents as described in any one of claims 1 to 5, characterized in that, Includes the following steps: (1) Preparation of internal phase, external phase fluid and collection liquid Preparation of the inner phase fluid: Dissolve the photoinitiator in water to obtain a photoinitiator solution, and dissolve the photopolymer in the photoinitiator solution to obtain the inner phase fluid; in the inner phase fluid, the mass ratio of water, photopolymer, and photoinitiator is 1:(0.08~0.2):(0.0005~0.0025). Preparation of external phase fluid: Dissolve the oil-soluble surfactant in an oily solvent to obtain the external phase fluid; in the external phase fluid, the mass ratio of oily solvent to oil-soluble surfactant is 1:(0.01~0.1). Preparation of the collection solution: Dissolve the oil-soluble surfactant in an oily solvent to obtain the external phase fluid; in the external phase fluid, the mass ratio of the oily solvent to the oil-soluble surfactant is 1:(0.01~0.1). (2) Preparation of monodisperse biodegradable polymer microspheres An internal phase fluid, an external phase fluid, and a collection liquid are fed into a microfluidic device to prepare a monodisperse water-in-oil emulsion. Light is applied to the water-in-oil emulsion to initiate a polymerization reaction of the photopolymerizable polymers in the emulsion. The emulsion is then solidified to obtain monodisperse biodegradable polymer microspheres, which are then washed. (3) Radionuclide labeling The washed monodisperse biodegradable polymer microspheres were labeled with radionuclides to obtain radionuclide-labeled monodisperse biodegradable polymer microspheres. (4) Drug load Radionuclide-labeled monodisperse biodegradable polymer microspheres are immersed in a solution of positively charged chemotherapeutic drugs, allowing the microspheres to fully adsorb the positively charged chemotherapeutic drugs. Solid-liquid separation is then performed to obtain biodegradable monodisperse embolization microspheres loaded with radionuclides and chemotherapeutic drugs.

7. The method for preparing biodegradable monodisperse embolic microspheres loaded with radionuclides and chemotherapeutic drugs according to claim 6, characterized in that, In step (2), the flow rate of the internal phase fluid is controlled to be 50~300 μL / h, and the flow rate of the external phase fluid is 1~10 mL / h.

8. The method for preparing biodegradable monodisperse embolic microspheres loaded with radionuclides and chemotherapeutic drugs according to claim 6 or 7, characterized in that, In step (4), the solution of the positively charged chemotherapy drug is a physiological saline solution of the positively charged chemotherapy drug.

9. The method for preparing biodegradable monodisperse embolic microspheres loaded with radionuclides and chemotherapeutic drugs according to claim 6, characterized in that, In step (4), the concentration of the positively charged chemotherapeutic drug in the solution is 1-5 mg / mL. -1 .

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