Polyurethane complex, polyurethane complex micelle, and preparation and application thereof

Abstract

The present invention relates to a polyurethane complex, polyurethane complex micelles, and their preparation and application. The polyurethane complex is a complex of a polyurethane containing an oxime-carbamate group and a metal ion. The polyurethane complex and an organic solvent are mixed, then added dropwise to water under stirring, and then dialyzed after stirring to obtain the polyurethane complex micelles. The polyurethane complex micelles of the present invention are simple to prepare and stable. The pH-responsive polyurethane micelles complexing the metal ions have a tumor-killing effect. The pH-responsive function ensures the controlled release of the metal ions in the body, thereby improving in vivo safety.

Description

Technical Field

[0001] The present invention belongs to the field of polymer materials, and in particular relates to a polyurethane complex, a polyurethane complex micelle, and preparation and application thereof. Background Art

[0002] Polymer micelles are a common drug carrier with the advantages of a wide drug loading range, good tissue permeability, long retention time, stable structure, and easy targeting. Polyurethane can be synthesized by fully selecting building blocks (polyols, diisocyanates or polyisocyanates and chain extenders) with suitable physicochemical and biological properties. By flexibly integrating various functions into a single macromolecule through molecular structure design, it is easy to prepare various functional polyurethane micelles. However, there are relatively few studies on polyurethane micelles, and a complete understanding of the degradation, metabolism and therapeutic effects of polyurethane in the body has not yet been achieved. There are few studies on the controlled drug release of polyurethane micelles. In most cases, the drug is released in a sudden burst, and the therapeutic effect is poor. Therefore, it is necessary to design polyurethane micelles with stimulus responsiveness. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a polyurethane complex, a polyurethane complex micelle and the preparation and application thereof. The blank polyurethane structure in the polyurethane complex is a polyurethane containing an oxime-carbamate group.

[0004] The present invention provides a polyurethane complex, the structure of which is shown below:

[0005] ,or

[0006] ;

[0007] Wherein R1 is the remaining group after polyethylene glycol is dehydroxylated;

[0008] R2 is the remaining group after the diisocyanate is stripped of the diisocyanate group;

[0009] R3 is the remaining group after removing the hydroxyl group from polycaprolactone diol;

[0010] R4 is the remaining group after fluorescein is dehydroxylated;

[0011] M is a metal ion;

[0012] x=10-1000; y=10-1000; z=10-1000.

[0013] Preferably, the diisocyanate includes one or more of aromatic diisocyanate and aliphatic diisocyanate.

[0014] The aromatic diisocyanate includes diphenylmethane diisocyanate; the aliphatic diisocyanate includes one or more of hexamethylene diisocyanate and isophorone diisocyanate.

[0015] Preferably, the molecular weight of the polyethylene glycol is 500-5000.

[0016] Preferably, the molecular weight of the polycaprolactone diol is 500-5000.

[0017] Preferably, the metal ion is at least one of ferric ion, ferrous ion, copper ion, magnesium ion, zinc ion, nickel ion and cobalt ion.

[0018] The present invention provides a method for preparing a polyurethane complex, comprising:

[0019] (1) Under protective gas conditions, polymer diol, diisocyanate, catalyst, and organic solvent are mixed and reacted, and then a dimethylglyoxime solution is added, reacted, purified, and dried to obtain an amphiphilic polyurethane; wherein the polymer diol is polycaprolactone diol and polyethylene glycol;

[0020] (2) The amphiphilic polyurethane, metal salt and organic solvent are mixed, evaporated at room temperature and then vacuumed to obtain a polyurethane complex.

[0021] The polymer diol in step (1) is the polymer diol after water removal.

[0022] In step (1), after the polymer diol is dehydrated, a diisocyanate dissolved in an organic solvent and a catalyst are added under protective gas conditions at 60-80°C for 3-4 hours, and then a solution containing dimethylglyoxime is added and the reaction is continued overnight under a protective gas atmosphere.

[0023] The protective gas in step (1) is nitrogen.

[0024] The purification in step (1) is to add the reaction mixture dropwise into diethyl ether to remove the solvent and unreacted small molecules, precipitate the reactant, and then continue to dissolve the reactant in an organic solvent, continue to add dropwise into diethyl ether to precipitate and wash away impurities, and repeat the operation 1 to 3 times.

[0025] Preferably, the diisocyanate in step (1) includes one or more of aromatic diisocyanate and aliphatic diisocyanate.

[0026] The aromatic diisocyanate includes diphenylmethane diisocyanate; the aliphatic diisocyanate includes one or more of hexamethylene diisocyanate and isophorone diisocyanate.

[0027] Preferably, the molecular weight of the polyethylene glycol in step (1) is 500-5000;

[0028] Preferably, the molecular weight of the polycaprolactone diol in step (1) is 500-5000;

[0029] Preferably, the catalyst in step (1) includes one or more of dibutyltin dilaurate, stannous octoate, and triethylamine;

[0030] Preferably, the organic solvent in steps (1) and (2) includes one or more of tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetone.

[0031] Preferably, the dimethylglyoxime solution in step (1) is a dimethylglyoxime solution, or a mixture of dimethylglyoxime and fluorescein monomer; wherein the solvent containing the dimethylglyoxime solution comprises one or more of tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetone.

[0032] The fluorescein monomers include one or more of fluorescein isothiocyanate, rhodamine, and anthocyanin.

[0033] The fluorescein isothiocyanate class includes fluorescein isothiocyanate ester; the rhodamine class includes tetraethylrhodamine; and the anthocyanin class includes trimethine cyanine dye.

[0034] Preferably, the metal salt in step (2) includes one or more of ferric salts, ferrous salts, copper salts, magnesium salts, zinc salts, nickel salts, and cobalt salts.

[0035] Preferably, in step (1), the molar ratio of diisocyanate, polymer diol and dimethylglyoxime is a:b:c, wherein b is 1-10, c is 1-10, and a=b+c;

[0036] Preferably, the amount of the catalyst added in step (1) is 0.1-0.5% of the total mass of the polymer diol, dimethylglyoxime and diisocyanate.

[0037] Preferably, the molar ratio of polycaprolactone diol to polyethylene glycol in step (1) is a:b, wherein a is 1-100 and b is 1-100.

[0038] Preferably, in step (2), the molar ratio of the metal ion to dimethylglyoxime in the metal salt is 0.1:1 to 1:1.

[0039] In step (2), the mixture is evaporated at room temperature overnight; and the mixture is vacuumed in an oven for 12-24 hours.

[0040] The present invention provides a micelle containing the polyurethane complex.

[0041] The invention provides a method for preparing micelles, which comprises: mixing the polyurethane complex and an organic solvent, then adding the mixture dropwise into water under stirring, and dialyzing the mixture after stirring to obtain micelles.

[0042] Preferably, the mass ratio of the polyurethane complex to the organic solvent is 1:10-1:100.

[0043] The polyurethane complex is a block material of a polyurethane complex.

[0044] Preferably, the organic solvent comprises one or more of ethanol, isopropanol, acetone, chloroform, dichloromethane, ethyl acetate, and tetrahydrofuran;

[0045] Preferably, the dialysis has a molecular weight cut-off of 500-14000 Da and a dialysis time of 36-72 h.

[0046] The concentration of the micelles is 1-10 mg / mL.

[0047] Furthermore, for example, the preparation of micelles: the polyurethane block complexing metal ions is dissolved in an organic solvent, and slowly added dropwise into deionized water under vigorous stirring. After stirring for 3-5 hours, it is transferred to a dialysis bag (molecular weight cutoff 3500 Da) for dialysis. The water is changed regularly during the period. After 36-48 hours, pH-responsive polyurethane micelles complexing metal ions are obtained.

[0048] The present invention provides an application of the polyurethane complex in the preparation of anti-tumor drugs.

[0049] The present invention provides an application of the polyurethane complex in combination with RT in the preparation of anti-tumor drugs.

[0050] The polyurethane micelles of the present invention can complex metal ions and release them responsively in an acidic environment, while having excellent stability and biocompatibility, releasing metal ions, inducing ferroptosis and cooperating with radiotherapy to effectively treat tumors.

[0051] The polyurethane complex micelles of the present invention are simple to prepare and stable. The pH-responsive polyurethane micelles that complex metal ions have a tumor-killing effect. The pH-responsive function ensures the controlled release of metal ions in the body, thereby improving in vivo safety.

[0052] Beneficial effects

[0053] This invention prepares an amphiphilic polyurethane capable of complexing with metal ions and produces pH-responsive polyurethane micelles via a solvent evaporation method. The polyurethane complexing the metal ions slowly releases the ions, and this release is accelerated by stimulation from the acidic environment of the tumor. The released metal ions can disrupt the ionic balance within the tumor, thereby inducing tumor cell death. This allows for the safe delivery of hydrophobic drugs in vivo, with precise release at the tumor site. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 Schematic diagram of the synthesis process of fluorescent polyurethane capable of complexing metal ions and the iron coordination process; R1 is the remaining group after PEG removes the hydroxyl group; R2 is the remaining group after IPDI removes the diisocyanate group; R3 is the remaining group after PCL-diol removes the hydroxyl group; R4 is the remaining group after FITC removes the hydroxyl group; x = 10-1000; y = 10-1000; z = 10-1000;

[0055] Figure 2 Schematic diagram of Fourier transform infrared spectra of PCE, PCEF and PCEF@Fe prepared in Example 1 and Example 2;

[0056] Figure 3 Fluorescence emission spectra of polyurethane PCE micelles, blank fluorescent polyurethane PCEF micelles and fluorescent polyurethane PCEF@Fe micelles complexed with ferrous ions;

[0057] Figure 4 The SEM images of blank fluorescent polyurethane PCEF micelles and fluorescent polyurethane PCEF@Fe micelles complexed with ferrous ions;

[0058] Figure 5 The particle size distribution diagram of blank fluorescent polyurethane PCEF micelles and fluorescent polyurethane PCEF@Fe micelles complexed with ferrous ions;

[0059] Figure 6 is the potential of blank fluorescent polyurethane PCEF micelles and fluorescent polyurethane PCEF@Fe micelles complexed with ferrous ions;

[0060] Figure 7 is the particle size of blank fluorescent polyurethane PCEF micelles and fluorescent polyurethane PCEF@Fe micelles complexed with ferrous ions in different pH solvents;

[0061] Figure 8 Study on the acidic response release behavior of fluorescent polyurethane PCEF@Fe micelles complexed with ferrous ions;

[0062] Figure 9Ferrous iron probe staining and statistical analysis of OMM2.3 and A375 cells; Note: P < 0.05 indicates statistically significant differences; asterisks indicate statistically significant differences: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001;

[0063] Figure 10 Images of tumors isolated after treatment and statistical analysis of tumor volume and weight during the experimental process; Note: P < 0.05 indicates statistically significant differences, and asterisks indicate statistically significant differences: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001;

[0064] Figure 11 Representative images of H&E, Ki67, and Tunel staining of xenografts.

[0065] Figure 12 Schematic diagram of the formation of fluorescent polyurethane PCEF@Fe micelles that complex ferrous ions. DETAILED DESCRIPTION

[0066] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the appended claims of the application.

[0067] raw material:

[0068] Polycaprolactone diol (3000 g / mol) was purchased from Shandong Jiaying Chemical Technology Co., Ltd.; polyethylene glycol (2000 g / mol) was purchased from J&K Chemical Technology Co., Ltd.; diacetyl dioxime and ferrous chloride were purchased from Sinopharm Chemical Reagent Co., Ltd.; fluorescein isothiocyanate and isophorone diisocyanate were purchased from Adamas Reagent Co., Ltd.

[0069] Related tests:

[0070] Structural characterization: The structure of the cross-linked polyurethane before and after synthesis was characterized by Fourier transform infrared spectroscopy (FTIR). The attenuated total reflectance (ATR) accessory was used for testing, with a scan frequency of 32 times and a wavelength scanning range of 4000–400 cm -1 , with a spectral resolution of 4 cm -1 .

[0071] The fluorescence emission spectra of polyurethane micelles and fluorescent polyurethane were tested using a steady-state transient fluorescence spectrometer.

[0072] The morphology of the iron-complexed polyurethane micelles was observed using a scanning electron microscope (SEM) at a voltage of 15 kV.

[0073] Zeta potential and hydrodynamic particle size were measured using an Andon Paar nanoparticle size and zeta potential analyzer. All samples were dispersed in water (1 mg / mL) before measurement.

[0074] The micelles were dispersed in deionized water, phosphate buffer solutions with different pH values ​​(PBS, pH 7.4, pH 6.5), and citrate buffer solution (SSC, pH 5.0), and their particle sizes were measured using a nanoparticle size analyzer.

[0075] Ferrous ion release from PCEF@Fe micelles was studied under different conditions. A 5 mL solution of PCEF@Fe micelles (10 mg / mL) was placed in a dialysis bag (MWCO = 500 Da). The dialysis bag was then placed in 50 mL of PBS buffer at different pH values ​​(pH 5.0 and pH 7.4) for sustained release. The entire system was maintained in a thermostatic shaker at 37°C. At each time point, 2 mL of the external phase buffer medium was sampled. 2 mL of fresh buffer was then added. The ferrous ion content in the buffer was determined using inductively coupled plasma optical emission spectrometry. Three replicates were performed for each sample.

[0076] Biological characterization: intracellular Fe 2+ Detection of Fe in living cells 2+ The level of Fe in living cells was detected using orange iron dye (Gold, Japan, F374). 2+ Briefly, the indicated cells were seeded at a density of 5 × 10^4 cells per well in a 12-well plate and treated with 1 mL of complete medium. OMM2.3 and A375 cells were washed three times with serum-free medium and then treated with a serum-free medium solution containing 1 µmol / L iron orange reagent. After incubation in a conventional incubator for 30 minutes, intracellular Fe 2+ (Ex: 561 nm, Em: 570-620 nm).

[0077] Animal experimentation: This study was conducted with the approval of the Institutional Animal Care and Use Committee of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Healthy female BALB / c nude mice (4 weeks old, 17-19 g) were obtained from Shanghai Jihui Laboratory Animal Care Co., Ltd. and maintained in a specific pathogen-free animal room. During the experiment, these nude mice had unrestricted access to food and water. A suspension of A375 cells (25 × 10^5 cells / mL) prepared in PBS was injected into the right back of the mice (0.1 mL / mouse). After tumors reached a volume of approximately 100 mm^3, the mice were randomly divided into six groups. Mice were intravenously injected with PBS, PCEF, or PCEF@Fe, followed by 5 Gy of gamma irradiation of the tumor site and subsequent intravenous injection. Treatments were administered weekly for two cycles. Tumor size was measured every three days over a 12-day period. At the end of the experiment, all mice were sacrificed, and tumors from each group were removed, measured, weighed, and fixed in formalin. Tumor volume was calculated using the formula 0.5 × longest diameter × shortest diameter.

[0078] Xenograft tumor tissue sections were fixed in formalin, dehydrated, embedded in paraffin, and sectioned. Tumor sections were stained with hematoxylin and eosin, Ki67, and TUNEL according to standard protocols. Images were obtained using a light microscope.

[0079] Example 1

[0080] Polycaprolactone diol (9 g) and polyethylene glycol (3 g) were placed in a three-necked flask. The reaction flask was placed in an oil bath at 110°C and vacuum-dried for 2 h. The oil bath temperature was lowered to 60°C and a nitrogen balloon was inserted to maintain a vacuum environment. Isophorone diisocyanate (2.0007 g) and dibutyltin dilaurate (0.073 g, 0.5 wt%) dissolved in THF were added to the reaction system, and the reaction was continued for 4 h. Subsequently, dimethylglyoxime (0.5226 g) dissolved in tetrahydrofuran was added. The reaction was continued overnight. A nitrogen atmosphere was maintained throughout the reaction. After the reaction, the reaction product was added dropwise to diethyl ether to remove the solvent and unreacted small molecules, resulting in a white precipitate. The white precipitate was then dissolved in tetrahydrofuran and added dropwise to diethyl ether to precipitate and wash away impurities. The operation was repeated twice, and the white reactant was dried in a vacuum oven at 50 °C for 12 h to obtain amphiphilic polyurethane (PCE).

[0081] Dissolve 0.1 g of polyurethane bulk in 4 mL of tetrahydrofuran and slowly add it dropwise to 20 mL of deionized water under vigorous stirring. After stirring for 4 hours, transfer the solution to a dialysis bag (molecular weight cutoff 3500 Da) and dialyze for 48 hours to obtain blank polyurethane micelles, changing the water regularly.

[0082] Example 2

[0083] The only difference between Example 2 and Example 1 is that fluorescein isothiocyanate monomer (0.1469 g, 1 wt %) is added during the dimethylglyoxime reaction step to synthesize fluorescent polyurethane (PCEF).

[0084] Dissolve 0.1 g of fluorescent polyurethane monolith in 4 mL of tetrahydrofuran and slowly add it dropwise to 20 mL of deionized water under vigorous stirring. After stirring for 4 hours, transfer the mixture to a dialysis bag (molecular weight cutoff 3500 Da) and dialyze for 48 hours to obtain fluorescent polyurethane micelles, changing the water regularly.

[0085] Example 3

[0086] The fluorescent polyurethane material (0.679 g) obtained in Example 2 and ferrous chloride (0.00267 g) were dissolved in acetone, poured into a polytetrafluoroethylene mold, evaporated at room temperature for 12 h, and then placed in a 50°C oven under vacuum for 24 h to obtain a fluorescent polyurethane complexed with metal ferrous ions (PCEF@Fe).

[0087] Dissolve 0.1 g of the ferrous ion-complexed fluorescent polyurethane monolith in 4 mL of tetrahydrofuran and, under vigorous stirring, slowly add it dropwise to 20 mL of deionized water. After stirring for 4 hours, transfer the monolith to a dialysis bag (molecular weight cutoff 3500 Da) and dialyze for 48 hours to obtain the ferrous ion-complexed fluorescent polyurethane micelles. The water was changed regularly during the dialyzation process.

[0088] Test Case

[0089] like Figure 2 The Fourier transform infrared spectrum shown, 956.5 cm -1 The peak at 3380.6 cm corresponds to the NO stretching peak in diacetyl oxime. -1 and 1735.6 cm -1 The stretching vibration peaks of the NH bond and C=O bond in the carbamate group correspond to the successful synthesis of polyurethane materials containing dimethylglyoxime groups. -1 No characteristic peak of isocyanate group was found at , indicating that isophorone diisocyanate has completely participated in the reaction.

[0090] like Figure 3 Shown are the fluorescence emission spectra of the three micellar solutions. It can be seen from the figure that Examples 2 and 3 are fluorescent polyurethane micelles with a maximum emission wavelength of 519 nm, while the non-fluorescent polyurethane micelles of Example 1 emit no light in the 480-700 nm range. This demonstrates that the fluorescent group has been successfully incorporated into the polyurethane micelles, allowing their use as fluorescent probes.

[0091] like Figure 4Shown are scanning electron microscopy images of blank fluorescent polyurethane micelles and fluorescent polyurethane micelles complexed with ferrous ions. It can be seen that the micelle morphology is spherical, and the fluorescent polyurethane micelles were successfully synthesized.

[0092] like Figure 5 and Figure 6 Shown are the particle size distribution and potential of blank fluorescent polyurethane micelles and fluorescent polyurethane micelles complexed with ferrous ions. The hydrodynamic sizes of the two micelles are 228.2 ± 2.4 nm and 155.4 ± 14.1 nm, respectively. Both micelles exhibit a negative charge.

[0093] like Figure 7 The following figure shows the particle size of two fluorescent polyurethane micelles in solutions with different pH values. It can be seen that the micelle size remains essentially unchanged in neutral and weakly acidic environments. However, in an acidic environment (pH = 5.0), the particle size increases. This is because the oxime bond in the polyurethane is a reversible and dynamically acid-labile bond, allowing the formation of a pH-responsive polymer. This demonstrates the successful preparation of pH-responsive polyurethane micelles.

[0094] like Figure 8 The figure shows the release of ferrous ions from fluorescent polyurethane micelles complexed with ferrous ions in PBS buffers at different pH values. It can be seen that the micelles slowly release ferrous ions under acidic conditions, while in neutral environments, only a very small amount of ferrous ions is released. This further demonstrates the pH-responsive release capability of the polyurethane micelles.

[0095] like Figure 9 The figure shows the ferrous ion probe staining and statistical analysis of OMM2.3 and A375 cells. In OMM2.3 and A375 cell lines, the combined treatment of RT and PCEF@Fe micelles significantly increased the intracellular ferrous ion level compared to RT alone, indicating successful ferrous ion release.

[0096] like Figure 10 Shown are images of isolated tumors after treatment and statistical analysis of tumor volume and weight during the experimental period. After combined treatment with PCEF@Fe micelles and RT, the tumor growth rate was significantly inhibited, and the size and weight of the tumor were significantly reduced.

[0097] like Figure 11 Representative images of HE staining, Ki67 staining, and TUNEL staining of xenografts are shown. It can be seen that the attenuation of Ki67 signal and the enhancement of TUNEL signal in tumor tissues of the PCEF@F micelle and RT combination group indicate that their proliferation is slowed and cell killing is effective.

[0098] like Figure 12 Shown is a schematic diagram of the formation of fluorescent polyurethane PCEF@Fe micelles complexed with ferrous ions.

Claims

1. A micelle, characterized in that The micelles are prepared from polyurethane complexes; The structure of the polyurethane complex is shown below: Wherein R1 is the remaining group after polyethylene glycol is dehydroxylated; R2 is the remaining group after the diisocyanate is stripped of the diisocyanate group; R3 is the remaining group after removing the hydroxyl group from polycaprolactone diol; R4 is the remaining group after fluorescein is dehydroxylated; M is a metal ion; x=10-1000; y=10-1000; z=10-1000.

2. The micelle according to claim 1, characterized in that The diisocyanate includes one or more of aromatic diisocyanate and aliphatic diisocyanate; The molecular weight of the polyethylene glycol is 500-5000; The molecular weight of the polycaprolactone diol is 500-5000; The metal ion is at least one of ferric ion, ferrous ion, copper ion, magnesium ion, zinc ion, nickel ion and cobalt ion.

3. The micelle according to claim 1, characterized in that A method for preparing a polyurethane complex comprises: (1) Under protective gas conditions, a polymer diol, a diisocyanate, a catalyst, and an organic solvent are mixed and reacted, and then a dimethylglyoxime solution is added, reacted, purified, and dried to obtain a polyurethane; wherein the polymer diol is polycaprolactone diol and polyethylene glycol; (2) Mixing polyurethane, metal salt and organic solvent, volatilizing at room temperature and then vacuuming to obtain a polyurethane complex.

4. The micelle according to claim 3, characterized in that The diisocyanate in step (1) includes one or more of aromatic diisocyanate and aliphatic diisocyanate; The molecular weight of the polyethylene glycol in step (1) is 500-5000; The molecular weight of the polycaprolactone diol in step (1) is 500-5000; The catalyst in step (1) includes one or more of dibutyltin dilaurate, stannous octoate, and triethylamine; The organic solvent in steps (1) and (2) includes one or more of tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetone; The dimethylglyoxime solution in step (1) is a dimethylglyoxime solution, or a mixture of dimethylglyoxime and fluorescein monomer; The metal salt in step (2) includes one or more of ferric salts, ferrous salts, copper salts, magnesium salts, zinc salts, nickel salts, and cobalt salts.

5. The micelle according to claim 3, characterized in that In step (1), the molar ratio of diisocyanate, polymer diol and dimethylglyoxime is a:b:c, wherein b is 1-10, c is 1-10, and a=b+c; The amount of the catalyst added in step (1) is 0.1 to 0.5% of the total mass of the polymer diol, dimethylglyoxime and diisocyanate; and the molar ratio of the metal ion in the metal salt to dimethylglyoxime in step (2) is 0.1:1 to 1:

1.

6. A method for preparing the micelle according to claim 1, comprising: The polyurethane complex and the organic solvent are mixed, then added dropwise into water under stirring, and then dialyzed after stirring to obtain micelles.

7. The preparation method according to claim 6, characterized in that: The mass ratio of the polyurethane complex to the organic solvent is 1:10-1:100; The organic solvent includes one or more of ethanol, isopropanol, acetone, chloroform, dichloromethane, ethyl acetate, and tetrahydrofuran; The dialysis has a molecular weight cut-off of 500-14000 Da and a dialysis time of 36-72 h.

8. Use of the micelle according to claim 1 in the preparation of anti-tumor drugs.

9. Use of the micelle according to claim 1 in combination with RT in the preparation of anti-tumor drugs.

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