Multifunctional microsphere for tumor chemoradiotherapy embolism treatment and imaging as well as preparation method and application of multifunctional microsphere

Abstract

The invention provides a multifunctional microsphere for tumor chemoradiotherapy embolism treatment and imaging and a preparation method and application thereof.According to the multifunctional microsphere, a polylactic acid-glycolic acid copolymer serves as a framework material, a small molecule medicine is entrapped in the multifunctional microsphere, and surface modification and radionuclide labeling are conducted at the same time; the small molecular medicine is prepared from one or more of icaritin, icariin, lecimod, imiquimod, motod, visamod and tilamod, and preferably, the icaritin and the lecimod are selected; the surface modification is performed by adopting tyramine or tyrosine polypeptide; the radionuclides include 123I, 125I, and 131 I, preferably 131 I. The preparation process and equipment of the multifunctional microsphere are simple, the cost is low, chemotherapy drugs and immunologic adjuvants are entrapped at the same time, radionuclides are marked, hepatic artery embolism treatment, 131I long-term local nuclide treatment and combined treatment of local chemotherapy and immunoregulation are achieved, and meanwhile the SPECT / CT imaging in-vivo tracing function of the multifunctional microsphere is achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a multifunctional microsphere used for tumor radiochemoembolization treatment and imaging, and a preparation method and application thereof. Background Art

[0002] Embolization therapy is a commonly used local treatment for tumors. For tumors with specific blood vessels, it can effectively block tumor nutrients to "starve" the tumor. In recent years, combining embolization therapy with chemotherapy, radiotherapy and other treatments can improve the anti-tumor effect. Among them, radioembolization therapy (transarterial radioembolization, TARE) for liver cancer is a treatment method that delivers radionuclide-labeled embolic agents to the tumor site of liver cancer patients through the hepatic artery, emits continuous high-dose radiation to the tumor, and avoids the normal liver tissue from being affected by radiation. Commonly used TARE embolic agents in clinical practice are and All are yttrium-90 (Yttrium-90, 90 TARE therapy is an important means of downstaging for patients with unresectable liver cancer, especially those with portal vein tumor thrombus, due to its powerful tumor reduction and portal vein revascularization effects. Existing TARE embolic agents have failed to achieve multimodal treatment combining immunomodulation with embolization, chemotherapy, and radionuclide therapy, and some existing microspheres are non-degradable microspheres, making it difficult to avoid postoperative complications caused by permanent vascular occlusion.

[0003] In order to improve the biocompatibility of microspheres and meet the needs of multiple clinical embolization treatments, more and more degradable materials are being developed for the preparation of drug-loaded microspheres. Polylactic-co-glycolic acid (PLGA) is a commonly used degradable synthetic material that can be used as a good carrier for drug delivery and sustained release. In preclinical studies, it can encapsulate chemotherapy drugs to prepare multifunctional microspheres for the treatment of hepatic artery embolism. Therapeutic radionuclide iodine-131 (Iodine-131, 131 I) is an ideal internal irradiation nuclide that can emit beta rays, with a median penetration depth of 0.4mm, and has a certain therapeutic effect on tumors. Studies have shown that radiotherapy and chemotherapy can induce immunogenic cell death in tumor cells, express damage-related pattern molecules, induce dendritic cell activation and recruit tumor-infiltrating lymphocytes to stimulate anti-tumor immunity. The use of drug delivery systems can not only release the above drugs in a fixed and quantitative manner at the tumor site, but also achieve a combination of multiple treatment methods to enhance the therapeutic effect.

[0004] Based on the above problems, the present invention adopts biodegradable materials to prepare combined drug-loaded microspheres encapsulating anti-tumor drugs and immunomodulators, and labels therapeutic nuclides on the surface of the microspheres to achieve embolization therapy, local nuclide therapy, local chemotherapy and immunomodulation combined therapy, and at the same time realize the in vivo tracing function of microsphere SPECT / CT imaging. Summary of the invention

[0005] The present invention provides a multifunctional microsphere for tumor radiochemoembolization treatment and imaging and a preparation method and application thereof. The multifunctional microsphere preparation process and equipment are simple and the cost is low. The multifunctional microsphere can be loaded with chemotherapy drugs and immune adjuvants and labeled with radionuclides, thus realizing hepatic artery embolization treatment, 131 ICombined treatment of long-term local radionuclide therapy, local chemotherapy and immunomodulation, while realizing the in vivo tracing function of SPECT / CT imaging of multifunctional microspheres.

[0006] The technical solution adopted by the present invention to achieve the above-mentioned purpose is: a multifunctional microsphere for tumor radiochemoembolization treatment and imaging, wherein the multifunctional microsphere uses polylactic acid-glycolic acid copolymer as a skeleton material, encapsulates small molecule drugs inside, and simultaneously performs surface modification and radionuclide labeling; the structural formula of the polylactic acid-glycolic acid copolymer is shown in Formula 1; the small molecule drug includes one or more of icariin, icariin, resiquimod, imiquimod, motomod, visamod and tiramod, preferably icariin and resiquimod; the surface modification is surface modification using tyramine or tyrosine polypeptide; the radionuclide includes 123 I. 125 I and 131 1, preferably 131 I;

[0007]

[0008] The molecular weight ratio of the lactic acid monomer to the glycolic acid monomer is 50:50, and the total molecular weight of the copolymer is 3000-30000 Da.

[0009] Preferably, the drug loading amount of icariin in the multifunctional microspheres is 5-10%, and the drug loading amount of resiquimod is 2-8%.

[0010] Preferably, the particle size of the multifunctional microspheres is 20-40 μm, 40-70 μm and 70-100 μm, preferably 40-70 μm.

[0011] Preferably, the labeling rate of radionuclides in the multifunctional microspheres is 60-70%.

[0012] The present invention also provides a method for preparing the multifunctional microspheres, comprising the following steps:

[0013] S1. preparing a dichloromethane solution of poly(lactic acid)-co-glycolic acid and a dichloromethane solution of a small molecule drug;

[0014] S2. Mixing the dichloromethane solution of the polylactic acid-glycolic acid copolymer of S1 and the dichloromethane solution of the small molecule drug to obtain a mixed solution, adding the mixed solution dropwise to a 17-88 type polyvinyl alcohol aqueous solution, and stirring to form an emulsion; stirring at room temperature in the dark until the dichloromethane evaporates, and forming microspheres are observed under a microscope; washing the microspheres with ultrapure water, sieving through a sieve, and freeze-drying to obtain drug-loaded microspheres;

[0015] S3. Weigh 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide and dissolve them in 0.01 M PBS to obtain a mixed solution, suspend the drug-loaded microspheres of S2 in the mixed solution to obtain a drug-loaded microsphere-PBS suspension, dissolve tyramine or tyrosine polypeptide in dimethyl sulfoxide, and then add it dropwise to the drug-loaded microsphere-PBS suspension, react at room temperature in the dark for 24 hours, during which the microspheres are placed on a seesaw shaker to keep the microspheres suspended, washed with ultrapure water, and freeze-dried to obtain surface-modified drug-loaded microspheres;

[0016] S4. The surface-modified drug-loaded microspheres of S3 were suspended in 0.01M PBS, and the PBS was discarded by centrifugation to obtain the surface-modified drug-loaded microspheres for standby use; Na 131 I solution is added to the chloramine-T PBS solution, mixed and the surface-modified drug-loaded microspheres are added, gently shaken to suspend, placed in a 30-40° C. metal bath, and kept shaking for 20-40 minutes, and then the surface-modified drug-loaded microspheres are washed with PBS to obtain the multifunctional microspheres.

[0017] Preferably, the mass ratio of the lactic acid-glycolic acid copolymer in the dichloromethane solution of the polylactic acid-glycolic acid copolymer in S1 to the small molecule drug in the dichloromethane solution of the small molecule drug is (5-10):1.

[0018] Preferably, the molar ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxysuccinimide, tyramine or tyrosine polypeptide in S3 is (3-5):(3-5):1, and the molar ratio of tyramine or tyrosine polypeptide and polylactic acid-co-glycolic acid-carboxyl contained in the drug-loaded microspheres is (1-5):1.

[0019] Preferably, the concentration of the chloramine-T PBS solution in S4 is 5-20 mg / mL.

[0020] Preferably, the surface-modified drug-loaded microspheres, Na 131 The mass volume ratio of I solution and chloramine-T PBS solution is (10-20) mg: (10-50) μL: 10 μL.

[0021] The present invention also provides the use of the multifunctional microspheres in tumor embolization, combined radiotherapy and chemotherapy, and simultaneous single-photon emission computed tomography (SPECT).

[0022] Compared with the prior art, the at least one technical solution adopted in the embodiments of this specification can achieve the following beneficial effects:

[0023] (1) The preparation process and equipment of the multifunctional microspheres of the present invention are simple and low in cost. The particle size of the microspheres is 48.59±7.24 μm, which is suitable for hepatic artery embolization treatment. The microspheres are round in shape and uniform in size.

[0024] (2) The multifunctional microspheres of the present invention can be 131 IμSPECT / CT imaging can be used for long-term tracking. 131 I can monitor the enrichment of microspheres in the tumor site and examine the distribution of microspheres in the liver, thus realizing the study of the spatiotemporal distribution of microspheres after hepatic artery injection;

[0025] (3) The multifunctional microspheres of the present invention simultaneously encapsulate chemotherapeutic drugs and immune adjuvants and are labeled with radionuclides, thus achieving hepatic artery embolization therapy, 131 ICombined treatment of long-term local radionuclide therapy, local chemotherapy and immunomodulation, while realizing the in vivo tracing function of SPECT / CT imaging of multifunctional microspheres. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on the drawings without paying creative work.

[0027] Figure 1 The figure is a flow chart of the preparation of multifunctional microspheres;

[0028] Figure 2 Optical microscopic images of BLANK-MS, R848-MS, ICT-MS and ICT / R848-MS, with a scale of 50 μm;

[0029] Figure 3 This is a scanning electron micrograph of ICT / R848-MS, with a scale bar of 20 μm;

[0030] Figure 4 is the particle size distribution diagram of ICT / R848-MS;

[0031] Figure 5 for 131 Analysis of drug loading and encapsulation efficiency of ICT and R848 in I-ICT / R848-MS

[0032] Figure 6 The infrared spectra of Tyr-Pent, PLGA-MS and PLGA-MS-Tyr-Pent are shown in Figure 1. The arrows indicate the characteristic peaks of the benzene ring.

[0033] Figure 7 The results of H NMR spectra of PLGA-MS (A), Tyr-Pent (B) and PLGA-MS-Tyr-Pent (C) are shown. The arrows indicate the characteristic peaks of Tyr-Pent.

[0034] Figure 8 for 131 I-ICT / R848-MS and free 131 Radio-TLC scanning result diagram of I;

[0035] Fig. 9 for 31 I-ICT / R848-MS in PBS and FBS for 15 days 131 I Stability test result diagram;

[0036] Fig.10 The rats in each treatment group were analyzed before treatment, 1d, 5d and 10d after treatment. 18 F-FDGμPET / CT imaging results;

[0037] Fig.11 For each treatment group 18 F-FDG SUV max Statistical analysis chart of * p<0.05, *** p<0.001;

[0038] Fig.12 Figure 2 is an analysis of immune cells in the tumor site, where (A) is the CD4 + T cells, CD8 + T cells and CD25 + FOXP3 + Flow cytometry results of Treg cells (B) CD8 + T cell percentage, CD8 + T cells / CD4 + T cell ratio, Treg cell ratio and CD8 + Statistical analysis of the ratio of T cells / Treg cells, where **p<0.01, *** p<0.001 (compared with the control group);

[0039] Fig.13 The analysis diagram of immune cells in the spleen, where (A) is CD4 + T cells, CD8 + T cells and CD25 + FOXP3 + Flow cytometry results of Treg cells (B) CD8 + T cell percentage, CD8 + T cells / CD4 + T cell ratio and CD8 + Statistical analysis of the ratio of T cells / Treg cells; * p<0.05; ** p<0.01; *** p<0.001 (compared with the control group);

[0040] Fig.14 The analysis diagram of immune cells in lymph nodes, where (A) is CD80 + CD86 + (B) is the statistical analysis of the proportion of mature DC cells, where ** p<0.01, *** p<0.001 (compared with the control group);

[0041] Fig.15 The results of H&E staining of the heart, liver, spleen, lung, and kidney of tumor-bearing rats after treatment, where the scale bar is 200 μm;

[0042] Fig.16 This is the blood routine test and liver and kidney function test results of tumor-bearing rats after treatment;

[0043] Fig.17 for 131 SPECT / CT imaging effect diagram of I-ICT / R848-MS. DETAILED DESCRIPTION

[0044] The embodiments of the present application are described in detail below with reference to the accompanying drawings.

[0045] The following describes the implementation methods of the present application through specific examples, and those skilled in the art can easily understand other advantages and effects of the present application from the contents disclosed in this specification. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. The present application can also be implemented or applied through other different specific implementation methods, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present application. It should be noted that, in the absence of conflict, the following embodiments and the features in the embodiments can be combined with each other. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without making creative work belong to the scope of protection of the present application.

[0046] Example 1

[0047] A multifunctional microsphere for tumor radiochemoembolization therapy and imaging, the preparation steps of which are as follows:

[0048] S1. Weigh 100 mg of polylactic acid-glycolic acid copolymer PLGA-COOH (total molecular weight of 10,000) and dissolve it in 2.5 mL of dichloromethane to obtain a dichloromethane solution of polylactic acid-glycolic acid copolymer; weigh 10 mg of icariin (ICT) and 10 mg of resiquimod (R848) and dissolve them in a mixed solution of 2.5 mL of dichloromethane and 20 μL of dimethyl sulfoxide to obtain a dichloromethane solution of small molecule drugs;

[0049] S2. The dichloromethane solution of the polylactic acid-glycolic acid copolymer of S1 and the dichloromethane solution of the small molecule drug are mixed to obtain a mixed solution, 100 mL of a 0.5% 17-88 polyvinyl alcohol aqueous solution is taken into a beaker, and a magnetic stirrer is placed at a speed of 700 rpm, and the mixed solution is dropped into the beaker to form an emulsion, and the mixture is stirred at room temperature in the dark for 12 h until the dichloromethane evaporates, and the formed microspheres are observed under a microscope. The microspheres are washed with ultrapure water for 3 times, sieved through a sieve, and freeze-dried to obtain drug-loaded microspheres ICT / R848-MS;

[0050] S3. Weigh 2.90 mg (15 μmol) 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1.75 mg (15 μmol) N-hydroxysuccinimide and dissolve them in 2 mL 0.01 M PBS to obtain a mixed solution, suspend 20 mg of ICT / R848-MS (containing 2 μmol PLGA-COOH) described in S2 in the mixed solution to obtain a drug-loaded microsphere-PBS suspension, dissolve 2.50 mg (3 μmol) tyrosine pentapeptide (Tyr-Pent) in 50 μL dimethyl sulfoxide, and then add it dropwise to the drug-loaded microsphere-PBS suspension, react at room temperature in the dark for 24 h, during which the microspheres are placed on a seesaw shaker to keep the microspheres suspended, wash three times with ultrapure water, and lyophilize to obtain surface-modified drug-loaded microspheres ICT / R848-MS-Tyr-Pent;

[0051] S4. The ICT / R848-MS-Tyr-Pent of S3 was suspended in 0.01M PBS, and the PBS was discarded by centrifugation. The obtained ICT / R848-MS-Tyr-Pent was set aside; Na 131 I solution (20 mCi / mL) was added to a 10 mg / mL chloramine-TPBS solution, mixed and added with the ICT / R848-MS-Tyr-Pent, and gently vibrated to suspend. Among them, ICT / R848-MS-Tyr-Pent, Na 131 The mass volume ratio of I solution and chloramine-T PBS solution is 20 mg: 10 μL: 10 μL, and the mixture is placed in a 37°C metal bath and shaken for 40 minutes. The ICT / R848-MS-Tyr-Pent is then washed with PBS, and the radioactivity in the supernatant is measured until the radioactivity in the supernatant is less than 1 μCi, thereby obtaining the multifunctional microspheres. 131 I-ICT / R848-MS.

[0052] Example 2

[0053] A multifunctional microsphere for tumor radiochemoembolization and imaging, the preparation process is the same as that of Example 1, except that in step S1, the mass of polylactic acid-glycolic acid copolymer is 140 mg, the mass of icariin (ICT) is 10 mg, and the mass of resimod (R848) is 10 mg, in step S3, the molar ratio of tyrosine pentapeptide and polylactic acid-glycolic acid copolymer-carboxyl contained in ICT / R848-MS is 1:1, in step S4, the concentration of chloramine-T PBS solution is 5 mg / mL, ICT / R848-MS-Tyr-Pent, Na 131 The mass volume ratio of I solution and chloramine-T PBS solution was 20 mg:10 μL:10 μL, the metal bath temperature was 30°C, and the PBS washing time was 20 min.

[0054] Example 3

[0055] A multifunctional microsphere for tumor radiochemoembolization and imaging, the preparation process is the same as that of Example 1, except that in step S1, the mass of polylactic acid-glycolic acid copolymer is 160 mg, the mass of icariin (ICT) is 10 mg, and the mass of resimod (R848) is 10 mg; in step S3, the molar ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxysuccinimide and tyrosine pentapeptide is 3:3:1, and the molar ratio of tyrosine pentapeptide to polylactic acid-glycolic acid copolymer-carboxyl contained in ICT / R848-MS is 4:1; in step S4, the concentration of chloramine-T PBS solution is 15 mg / mL, and the concentration of ICT / R848-MS-Tyr-Pent, Na 131 The mass volume ratio of I solution and chloramine-T PBS solution was 10 mg:10 μL:10 μL, the metal bath temperature was 40°C, and the PBS washing time was 30 min.

[0056] Example 4

[0057] A multifunctional microsphere for tumor radiochemoembolization and imaging, the preparation process is the same as that of Example 1, except that in step S1, the mass of polylactic acid-glycolic acid copolymer is 160 mg, the mass of icariin (ICT) is 8 mg, and the mass of resimod (R848) is 8 mg; in step S3, the molar ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxysuccinimide and tyrosine pentapeptide is 4:4:1, the molar ratio of tyrosine pentapeptide and polylactic acid-glycolic acid copolymer-carboxyl contained in ICT / R848-MS is 5:1, and in step S4, the concentration of chloramine-T PBS solution is 20 mg / mL, ICT / R848-MS-Tyr-Pent, Na 131 The mass volume ratio of I solution and chloramine-T PBS solution was 10 mg:20 μL:10 μL.

[0058] The ICT / R848-MS prepared above was observed by optical microscope, scanning electron microscope, particle size distribution analysis, 131 The drug loading and encapsulation efficiency of ICT and R848 in I-ICT / R848-MS were analyzed. 131 I-ICT / R848-MS is used to analyze whether the surface of the tyrosine pentapeptide is successfully modified. 131 I-ICT / R848-MS 131 I labeling rate was analyzed. 131The in vitro stability of I-ICT / R848-MS was analyzed. The results showed that the microspheres were uniform in size and round in shape under optical microscopy and scanning electron microscopy ( Figure 2 , Figure 3 ); the particle size of the microspheres is distributed in the range of 25 to 70 μm ( Figure 4 ); the drug loading and encapsulation efficiency of ICT were 9.00±0.92% and 89.58±3.48%, respectively, and the drug loading and encapsulation efficiency of R848 were 5.41±0.46% and 54.48±2.16%, respectively. The in vitro drug release results showed that both drugs had good sustained release effects ( Figure 5 ); IR and H-NMR spectra both proved that the microspheres successfully modified the tyrosine pentapeptide ( Figure 6 , Figure 7 ); 131 I-ICT / R848-MS 131 The I labeling rate was 62.71±0.86%, and the radiochemical purity reached 99.72±0.23% ( Figure 8 ); The results of in vitro stability experiments showed that ( Fig. 9 ), 131 I-ICT / R848-MS can maintain more than 90% radiochemical purity in PBS and more than 60% radiochemical purity in FBS at 15 days, with good stability.

[0059] Example 5 131 Study on the therapeutic effect of I-ICT / R848-MS

[0060] In the rat orthotopic hepatocellular carcinoma model, control group (CTRL), BLANK-MS group (TAE), 131 I-MS group (TARE), R848-MS group (TAIE), ICT-MS group (TACE) and 131 In vivo therapeutic efficacy study of I-ICT / R848-MS group (TARICE) was conducted by small animal 18 F-FDGμPET / CT was used to evaluate the efficacy, and tumor cells in the TARICE group were observed. 18 F-FDG uptake was significantly lower than that of other groups, showing a strong anti-tumor effect ( Fig.10 , Fig.11 ); flow cytometry was then used to detect and analyze immune cells in tumors, spleens, and lymph nodes, proving that the TARICE group was the most effective in increasing the infiltration of cytotoxic T cells in tumors and reducing Treg cells, reversing their strong inhibitory effect on cytotoxic T cells, restoring the tumor-killing ability of CTL, and improving the body's anti-tumor immune response ( Fig.12 , Fig.13 and Fig.14). By performing H&E staining on the important organs of rats, such as heart, liver, spleen, lung, and kidney, and testing blood routine and liver and kidney function, it was proved that BLANK-MS, 131 I-MS, R848-MS, ICT-MS and 131 Biosafety of I-ICT / R848-MS ( Fig.15 and Fig.16 ).

[0061] Example 6 131 Study on the Development Effect of I-ICT / R848-MS

[0062] right 131 Small animal μSPECT / CT imaging and biodistribution experiments were performed on rats injected with I-ICT / R848-MS: The multifunctional microspheres were resuspended in 1.5% carboxymethylcellulose saline solution and the functional microspheres were concentrated to 20 mg / mL (containing 131 I1.2mCi / mL), take rats with orthotopic liver cancer model, insert hepatic artery catheter under surgical microscope, connect syringe to hepatic artery catheter, draw appropriate amount of multifunctional microsphere suspension, slowly inject through hepatic artery catheter, inject 400μL per rat. After injection, flush the hose with saline, slowly withdraw the catheter and restore blood supply to the common hepatic artery. Measure the radioactivity in the syringe and hose before and after injection to calculate the injection dose. 131 At 4h, 24h, and 168h after I-ICT / R848-MS, CT scans for 10min and SPECT scans for 50min were performed under isoflurane anesthesia. Images were reconstructed using Scivis HiSPECT software and analyzed using Bioscan InVivoScope software. Fig.17 Knowable 131 The effect of I-ICT / R848-MS at the tumor site was long-lasting.

[0063] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable ordinary technicians in the field to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made based on the essence of the content of the present invention should be included in the protection scope of the present invention.

Claims

1. A multifunctional microsphere for tumor radiotherapy, chemotherapy, embolization and imaging, characterized in that: The multifunctional microspheres use polylactic acid-glycolic acid copolymer as a skeleton material, encapsulate small molecule drugs inside, and are simultaneously surface modified and radionuclide labeled; the structural formula of the polylactic acid-glycolic acid copolymer is shown in Formula 1; the small molecule drugs include one or more of icariin, icariin, resiquimod, imiquimod, motomod, visamod and tiramod, preferably icariin and resiquimod; the surface modification is surface modification using tyramine or tyrosine polypeptide; the radionuclide includes 123 I. 125 I and 131 1, preferably 131 I; The molecular weight ratio of the lactic acid monomer to the glycolic acid monomer is 50:50, and the total molecular weight of the copolymer is 3000-30000 Da.

2. The multifunctional microsphere according to claim 1, characterized in that: The drug loading amount of icariin in the multifunctional microspheres is 5-10%, and the drug loading amount of resiquimod is 2-8%.

3. The multifunctional microsphere according to claim 1, characterized in that: The particle size of the multifunctional microspheres is 20-40 μm, 40-70 μm and 70-100 μm, preferably 40-70 μm.

4. The multifunctional microsphere according to claim 1, characterized in that: The labeling rate of the radioactive nuclide of the multifunctional microsphere is 60-70%.

5. A method for preparing multifunctional microspheres as claimed in claim 1, characterized in that: The following steps are involved: S1. preparing a dichloromethane solution of poly(lactic acid)-co-glycolic acid and a dichloromethane solution of a small molecule drug; S2. Mixing the dichloromethane solution of the polylactic acid-glycolic acid copolymer of S1 and the dichloromethane solution of the small molecule drug to obtain a mixed solution, adding the mixed solution dropwise to a 17-88 type polyvinyl alcohol aqueous solution, and stirring to form an emulsion; stirring at room temperature in the dark until the dichloromethane evaporates, and forming microspheres are observed under a microscope; washing the microspheres with ultrapure water, sieving through a sieve, and freeze-drying to obtain drug-loaded microspheres; S3. Weigh 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide and dissolve them in 0.01 M PBS to obtain a mixed solution, suspend the drug-loaded microspheres of S2 in the mixed solution to obtain a drug-loaded microsphere-PBS suspension, dissolve tyramine or tyrosine polypeptide in dimethyl sulfoxide, and then add it dropwise to the drug-loaded microsphere-PBS suspension, react at room temperature in the dark for 24 hours, during which the microspheres are placed on a seesaw shaker to keep the microspheres suspended, washed with ultrapure water, and freeze-dried to obtain surface-modified drug-loaded microspheres; S4. The surface-modified drug-loaded microspheres of S3 were suspended in 0.01M PBS, and the PBS was discarded by centrifugation to obtain the surface-modified drug-loaded microspheres for standby use; Na 131 I solution is added to the chloramine-T PBS solution, mixed and the surface-modified drug-loaded microspheres are added, gently shaken to suspend, placed in a 30-40° C. metal bath, and kept shaking for 20-40 minutes, and then the surface-modified drug-loaded microspheres are washed with PBS to obtain the multifunctional microspheres.

6. The preparation method according to claim 5, characterized in that: The mass ratio of the lactic acid-glycolic acid copolymer in the dichloromethane solution of the polylactic acid-glycolic acid copolymer in S1 to the small molecule drug in the dichloromethane solution of the small molecule drug is (5-10):

1.

7. The preparation method according to claim 5, characterized in that: The molar ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxysuccinimide, tyramine or tyrosine polypeptide in S3 is (3-5):(3-5):1, and the molar ratio of tyramine or tyrosine polypeptide to polylactic acid-co-glycolic acid-carboxyl contained in the drug-loaded microspheres is (1-5):

1.

8. The preparation method according to claim 5, characterized in that: The concentration of the chloramine-T PBS solution in S4 is 5-20 mg / mL.

9. The preparation method according to claim 5, characterized in that: The surface modified drug-loaded microspheres, Na 131 The mass volume ratio of I solution and chloramine-T PBS solution is (10-20) mg: (10-100) μL: 10 μL.

10. Use of the multifunctional microspheres according to any one of claims 1 to 4 in tumor embolization, combined radiochemotherapy, and simultaneous single photon emission computed tomography.

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