Preparation method and application of a nanomedicine for deep endometriosis

Abstract

This invention relates to the field of biomedical technology, and in particular to a method for preparing and applying a nanomedicine for treating deep endometriosis. The method involves mixing ferrous ammonium sulfate, trisodium citrate, and polyethyleneimine, then adding thioacetamide and triethanolamine via a solvothermal reaction to obtain two-dimensional iron sulfide nanosheets. Dopamine hydrochloride is then added and stirred at room temperature in anhydrous ethanol to obtain polydopamine-coated iron sulfide (FP). FP is then mixed with larotrectinib and anhydrous ethanol to obtain the nanomedicine FPL for treating deep endometriosis. The synthesis method of this invention is simple and highly operable; the product is stable and reproducible; FPL exhibits good biocompatibility and biodegradability. After entering the microenvironment of deep endometriosis lesions, it can responsively release larotrectinib, effectively inhibiting the Trk signaling pathway and significantly reducing the degree of nerve infiltration; simultaneously, the anti-inflammatory effect of the FP carrier alleviates the local inflammatory response, jointly inhibiting lesion progression.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a method for preparing and applying a nanomedicine for treating deep endometriosis. Background Technology

[0002] Deep infiltrating endometriosis (DE) is a gynecological disease that seriously affects the quality of life of women of reproductive age. It is characterized by endometrial glands and stroma infiltrating deeper than 5 mm into the subperitoneal region, commonly found in the rectovaginal septum, uterosacral ligaments, intestines, and urinary system. DE not only causes symptoms such as chronic pelvic pain, deep dyspareunia, and infertility, but also exhibits significant nerve infiltration, meaning that ectopic lesions often invade and grow along the distribution of pelvic nerves, leading to increased nerve fiber density and neurogenic inflammation, further exacerbating pain and lesion progression. This nerve infiltration is closely related to the high expression of neurotrophic factors (such as NGF) and their receptor Trk, and is one of the important reasons for the difficulty in treating DE and its high recurrence rate.

[0003] In recent years, nanomaterials have seen rapid development in the medical field, particularly demonstrating great potential in targeted therapy for diseases. Due to their unique physicochemical properties, such as controllable size distribution, responsive release characteristics, and ease of surface functionalization, nanomaterials have become ideal drug delivery carriers. In the treatment of deep endometriosis (DE), nanomaterials offer unique advantages. First, nanoparticles can accumulate in ectopic endometrial tissue through the abnormally proliferating vascular network and enhanced vascular permeability in the lesion area. Second, DE lesions exhibit a unique inflammatory microenvironment, characterized by acidic pH, elevated reactive oxygen species (ROS) levels, and high expression of specific matrix metalloproteinases (MMPs). This microenvironment can intelligently trigger the degradation of nanomaterials and precisely release active ingredients, thereby enhancing the targeted therapeutic effect on ectopic endometrial cells while reducing toxic side effects on normal tissues.

[0004] There are currently no reports on the use of iron sulfide nanosheets coated with polydopamine and loaded with larotrectinib for the treatment of deep endometriosis. Larotrectinib, as a highly selective Trk inhibitor, can effectively block the NGF / Trk signaling pathway at the lesion site, inhibiting the proliferation, invasion, and nerve infiltration of ectopic endometrial stromal cells, providing a new approach for targeted therapy of this disease. Therefore, developing a nanomedicine system that can simultaneously target nerve infiltration and the inflammatory microenvironment to achieve synergistic therapy is of great significance for solving the challenges of DE treatment. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a method for preparing and applying a nanomedicine for treating deep endometriosis. The preparation method provided by this invention is simple and highly operable. The prepared nanomedicine, through the loading of larotrectinib, effectively inhibits the Trk signaling pathway, significantly reduces the degree of nerve infiltration in the lesions, and thereby inhibits the survival and proliferation of endometrial stromal cells. Simultaneously, the FP nanocarrier itself possesses excellent anti-inflammatory properties, effectively alleviating the inflammatory response at the DE lesion site and reducing pain symptoms. This dual-functional synergistic effect achieves effective treatment for deep endometriosis, and the preparation process is stable, which is beneficial for clinical application.

[0006] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a method for preparing a nanomedicine for deep endometriosis, comprising the following steps: (1) Dissolve ferrous ammonium sulfate and trisodium citrate in ethylene glycol to obtain solution A, dissolve polyethyleneimine in ethylene glycol to obtain solution B, add solution B to solution A, and stir the reaction at room temperature to obtain a mixture; (2) Thioacetamide solution was added to the mixture, and then triethanolamine was added dropwise. The mixture was stirred at room temperature. After stirring, a solvothermal reaction was carried out. After the reaction was completed, the product was centrifuged and washed to obtain two-dimensional iron sulfide (FeS) nanosheets.

[0007] (3) The iron sulfide nanosheets obtained in step (2) are mixed with dopamine hydrochloride in anhydrous ethanol, stirred at room temperature, and centrifuged and washed after the reaction is completed to obtain iron sulfide (FeS@PDA, FP) nanomaterials coated with polydopamine (in FP, iron sulfide is inside and polydopamine is outside).

[0008] (4) The polydopamine-coated iron sulfide nanomaterials obtained in step (3) are mixed with larotrectinib and anhydrous ethanol to obtain polydopamine-coated iron sulfide-larotrectinib nanocomposite (FeS@PDA-Lar nanocomposite, abbreviated as FPL), which is also a nanomedicine for deep endometriosis.

[0009] Furthermore, in step (1), the ratio of ferrous ammonium sulfate, trisodium citrate, and ethylene glycol in solution A is 0.6 mmol: 0.2 mmol: 15 mL; the ratio of polyethyleneimine and ethylene glycol in solution B is 500 mg: 5 mL; and the ratio of the volume of ethylene glycol in solution A to the volume of ethylene glycol in solution B is 3:1.

[0010] Furthermore, in step (1), the stirring is magnetic stirring with a rotation speed of 800 rpm; the stirring reaction time is 2 h.

[0011] Furthermore, in step (2), the concentration of the thioacetamide solution is 0.05M; the ratio of the amount of ferrous ammonium sulfate added to the thioacetamide solution and triethanolamine is 0.6 mmol: 15 mL: 2 mL; the stirring is magnetic stirring at a speed of 800 rpm, and the stirring reaction time is 1~10 min.

[0012] Furthermore, in step (2), the temperature of the solvothermal reaction is 200℃ and the time is 24 h; the centrifugation speed is 14000 rpm and the time is 10 min; the washing is three times with anhydrous ethanol.

[0013] Furthermore, in step (3), the ratio of the amount of iron sulfide nanosheets, dopamine hydrochloride and anhydrous ethanol added is 1 mg: 1 mg: 2 mL.

[0014] Furthermore, in step (3), the stirring is magnetic stirring at a speed of 400 rpm; the stirring reaction time is 10 h; the centrifugation speed is 14000 rpm and the time is 10 min; and the washing is washing twice with deionized water.

[0015] Furthermore, in step (4), the ratio of the polydopamine-coated iron sulfide nanomaterials to larotrectinib and anhydrous ethanol is 1 mg:1 mg:2 mL; the mixing is carried out under stirring for 6 hours; after stirring, centrifugation and washing are also included, and the centrifugation conditions include: a rotation speed of 14,000 rpm and a time of 10 minutes; washing is performed with anhydrous ethanol twice.

[0016] The present invention also provides a nanomedicine for treating deep endometriosis prepared by the preparation method described in the above technical solution.

[0017] The present invention also provides the application of the anti-deep endometriosis nanomedicine described in the above technical solution in the preparation of drugs for treating deep endometriosis.

[0018] Compared with the prior art, the beneficial effects of the present invention are: This invention develops a polydopamine-coated iron sulfide-larotinib nanocomposite (FeS@PDA-Lar, abbreviated as FPL). This composite is responsively degraded in the microenvironment of deep endometriosis (DE), gradually releasing its active components. Larotinib, as a highly selective Trk inhibitor, effectively blocks the NGF / Trk signaling pathway, significantly inhibiting nerve infiltration in the lesion area, thereby suppressing the proliferation and invasion of endometrial stromal cells. Simultaneously, the FeS@PDA carrier can scavenge overexpressed reactive oxygen species (ROS) at the lesion site, regulate inflammatory factor levels, downregulate the pro-inflammatory factor IL-6 and upregulate the anti-inflammatory factor IL-10, thereby alleviating local inflammatory responses and pain symptoms. The synergistic effect of these two components remodels the DE microenvironment, achieving effective inhibition and clearance of ectopic endometrial cells, providing a novel treatment strategy for deep endometriosis.

[0019] Therefore, the FeS@PDA-Lar nanocomposite demonstrates significant potential in the treatment of deep endometriosis, providing a novel therapeutic strategy that combines microenvironmental responsiveness with synergistic effects across multiple mechanisms. This composite effectively inhibits the Trk signaling pathway via larotrectinib, significantly reducing nerve infiltration, while simultaneously modulating the inflammatory microenvironment through the FeS@PDA carrier. This dual mechanism synergistically inhibits the proliferation and survival of ectopic endometrial cells. Benefiting from its enrichment effect at the lesion site and its specific action on the disease microenvironment, this nanomedicine effectively inhibits ectopic lesions while having minimal impact on normal tissues, showing broad application prospects as a treatment for deep endometriosis. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the embodiments will be briefly described below.

[0021] Figure 1 Transmission electron microscopy image of iron sulfide nanosheets (FeS); Figure 2 Transmission electron microscopy image of iron sulfide nanomaterials (FeS@PDA, FP) coated with polydopamine; Figure 3 The hydrated particle size of the prepared FeS and FP nanomaterials is shown. Figure 4 The zeta potentials of the prepared FeS, FP, FPL and larotrectinib standards; Figure 5 The scavenging effect of FPL nanosheets at different concentrations on two free radicals (PTIO and DPPH); Figure 6 The concentration uptake of the prepared FPL nanosheets; Figure 7The effect of different concentrations of FPL nanosheets prepared on the growth of neurites in PC12 cells; Figure 8 To investigate the effect of PC12 cell supernatant pretreated with different concentrations of FPL nanosheets on the viability of endometrial stromal cells; Figure 9 To investigate the effect of PC12 cell supernatant pretreated with different concentrations of FPL nanosheets on the migration ability of endometrial stromal cells; Figure 10 Fluorescence images of ROS removal from FPL nanosheets at different concentrations; Figure 11 To investigate the anti-inflammatory effects of different concentrations of FPL nanosheets. Detailed Implementation

[0022] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that, unless otherwise specified, the following embodiments and features described therein can be combined with each other.

[0023] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0024] As described in the background section, the clinical treatment of deep endometriosis (DE) currently faces multiple challenges, including significant nerve infiltration, persistent pain symptoms, complex inflammatory microenvironment, and easy recurrence. Existing drugs have limitations such as insufficient targeting, short local retention time, and difficulty in simultaneously intervening in neural and inflammatory pathways.

[0025] Based on this, the purpose of this invention is to provide a polydopamine-coated iron sulfide-loaded larotrectinib nanomaterial, its preparation method, and its application for treating deep endometriosis. This invention uses ferrous ammonium sulfate and thioacetamide as raw materials to prepare two-dimensional iron sulfide nanosheets (FeS) through stirring and solvothermal reaction. Subsequently, polydopamine (PDA) is coated onto the surface of these nanosheets to form a composite carrier (FP), and finally, the Trk inhibitor larotrectinib (Lar) is loaded to obtain the target nanomedicine (FPL). This material has a simple and highly operable synthesis method, good biocompatibility and microenvironment responsiveness, and can release larotrectinib at the lesion site of deep endometriosis to inhibit nerve infiltration. Simultaneously, it utilizes FP to regulate the inflammatory microenvironment, achieving dual-pathway intervention of nerves and inflammation, thereby effectively inhibiting the proliferation of ectopic endometrial cells, relieving pain, and reducing the risk of recurrence.

[0026] To enable those skilled in the art to better understand the technical solution of this application, the technical solution of this application will be described in detail below with reference to specific embodiments.

[0027] The test materials used in the embodiments of this invention are all conventional test materials in the art and can be purchased through commercial channels.

[0028] Example 1: Preparation of two-dimensional iron sulfide nanosheets Solution A was prepared by dissolving 0.6 mmol of ferrous ammonium sulfate and 0.2 mmol of trisodium citrate in 15 mL of ethylene glycol. Solution B was prepared by dissolving 500 mg of polyethyleneimine (PEI) in 5 mL of ethylene glycol. Solution B was then added to solution A, and the mixture was reacted at room temperature with magnetic stirring at 800 rpm for 2 h to obtain a final mixture. Subsequently, 15 mL of 0.05 M thioacetamide solution was added to the mixture, followed by 2 mL of triethanolamine. The mixture was then reacted at room temperature with magnetic stirring at 800 rpm for 5 min. After stirring, the entire mixture was transferred to an autoclave and heated at 200 °C for 24 h. Finally, the mixture was collected by centrifugation at 14000 rpm for 10 min and washed three times with anhydrous ethanol to obtain two-dimensional iron sulfide nanosheets (FeS).

[0029] Example 2: Preparation of polydopamine-coated iron sulfide material 1 mg of iron sulfide nanosheets and 1 mg of dopamine hydrochloride were dissolved in 2 mL of anhydrous ethanol and stirred at 400 rpm for 10 h at room temperature. The resulting product was centrifuged at 14000 rpm for 10 min, the supernatant was discarded and the precipitate was collected and washed twice with deionized water to obtain the final iron sulfide material coated with polydopamine, namely FeS@PDA (FP).

[0030] Example 3: Preparation of iron sulfide-larotinib nanocomposite coated with polydopamine (i.e., nanomedicine for deep endometriosis).

[0031] 1 mg of FP (based on the mass of iron sulfide) and 1 mg of larotrectinib were added to 2 ml of anhydrous ethanol and stirred for 6 h. Then, the mixture was collected by centrifugation at 14000 rpm for 10 min and washed twice with anhydrous ethanol to obtain the iron sulfide-larotrectinib nanocomposite coated with polydopamine, namely FeS@PDA-Lar nanocomposite, abbreviated as FPL.

[0032] Experimental Example 1 Material property analysis (1) Observation by transmission electron microscopy Dissolve an appropriate amount of FeS nanosheets in anhydrous ethanol to prepare a 1 mg / mL solution. Use a pipette to add 20 μL of the solution onto a copper grid. Dry the solution to prepare a transmission electron microscope (TEM) sample and observe it using a TEM.

[0033] The results are as follows Figure 1 The iron sulfide prepared as shown is in the shape of two-dimensional thin sheets with a particle size of about 100 nm.

[0034] Dissolve an appropriate amount of FP material in anhydrous ethanol to prepare a 1 mg / mL solution. Use a pipette to add 20 μL of the solution to a copper grid. Dry the sample to prepare it for transmission electron microscopy (TEM) detection and observe it using a TEM.

[0035] The results are as follows Figure 2 The polydopamine-coated iron sulfide prepared as shown is in the shape of a two-dimensional sheet with a particle size of about 100-120 nm.

[0036] (2) Dynamic Light Scattering Analyzer (DLS) Test: Ethanol dispersions containing 30 μg of FeS and FP were taken separately, centrifuged to remove the supernatant, and resuspended in 1 mL of pure water to prepare dispersions of 30 μg / mL. The hydrated particle size of FeS and FP was measured using a dynamic light scattering analyzer (DLS). The results are as follows: Figure 3 As shown, the results indicate that the hydrated particle size of FeS nanomaterials is approximately 125 nm, and the hydrated particle size of FP nanomaterials is approximately 169 nm.

[0037] (3) Prepare ethanol dispersions of FeS, FP, FPL, and larotrectinib standards to a concentration of 30 μg / mL, and measure the zeta potential of each sample using a dynamic light scattering analyzer (DLS). The results are as follows: Figure 4As shown, the results indicate that the zeta potential of FeS nanosheets is approximately 23.65 mV, that of FP nanosheets is approximately 18.39 mV, that of larotrectinib standard is approximately -9.46 mV, and that of FPL nanosheets is approximately 9.59 mV.

[0038] (4) Take an appropriate amount of ethanol dispersion of FPL nanosheets, centrifuge to remove the supernatant, and resuspend in pure water to prepare dispersions of different concentrations for later use. In the DPPH experiment, a 0.2 mg / mL DPPH ethanol solution was prepared in advance. Then, 0 μg / mL, 0.5 μg / mL, 1 μg / mL and 2 μg / mL FPL nanosheets were mixed with 2 mL of DPPH solution and reacted for 30 minutes. Subsequently, the absorbance at 519 nm was measured by UV-Vis spectroscopy, and the DPPH free radical scavenging rate (%) was calculated as follows: 对照 -A 样品 ) / A 对照 ]×100%, where A 对照 A represents the absorbance of the 0 μg / mL FPL group at 519 nm. 样品 The absorbance at 519 nm was measured for different concentrations of FPL. In the PTIO experiment, a PTIO solution of approximately 0.05 mg / mL was prepared using PBS buffer. FPL nanosheets of 0 μg / mL, 1.25 μg / mL, 2.5 μg / mL, and 5 μg / mL were mixed with 2 mL of PTIO solution and incubated at room temperature for 2 hours. The absorbance at 557 nm was then measured using UV-Vis spectroscopy. The PTIO radical scavenging rate (%) was calculated as follows: = [(A 对照 -A 样品 ) / A 对照 ]×100%, where A 对照 A represents the absorbance of the 0 μg / mL FPL group at 557 nm. 样品 The absorbance at 557 nm is for different concentrations of FPL. Figure 5 As shown, the results indicate that FPL nanosheets have a good ability to scavenge DPPH and PTIO free radicals, and this ability is concentration-dependent.

[0039] (5) such as Figure 6 As shown, FPL (Cy 5.5 modified) was co-incubated with pheochromocytoma (PC12) cells at concentrations of 0 µg / ml, 10 µg / ml, and 40 µg / ml for 4 hours, and the uptake of the nanomaterial by the cells was detected using a fluorescence inverted microscope. The results showed that the fluorescence captured by the microscope gradually increased with increasing concentration, indicating that the prepared FPL can be effectively taken up by nerve cells in a concentration-dependent manner.

[0040] (6) For example Figure 7 As shown, FPL nanosheets (resuspended in PBS) were co-incubated with PC12 cells pre-incubated with nerve growth factor (NGF) for 12 hours at concentrations of 0 µg / ml, 1.25 µg / ml, 2.5 µg / ml, 5 µg / ml, and 10 µg / ml for 6 hours. The effect of FPL nanosheets on neurite growth was examined using an inverted microscope. The results showed that with increasing concentration, the length of PC12 cell neurites gradually shortened, indicating that the prepared FPL could effectively inhibit the growth of nerve cell neurites in a concentration-dependent manner.

[0041] (7) For example Figure 8 As shown, FPL nanosheets were incubated with PC12 cells pre-incubated with nerve growth factor (NGF) for 12 hours at concentrations of 0 µg / ml, 1.25 µg / ml, 2.5 µg / ml, 5 µg / ml, 10 µg / ml, 20 µg / ml, and 40 µg / ml for 6 hours. The cell supernatant was then centrifuged and collected. The supernatant of each concentration was mixed 1:1 with DMEM complete medium to prepare a mixed culture medium, which was added to endometrial stromal cells and incubated for 24 hours. The mixed culture medium was then removed, and medium containing 5 mg / ml MTT was added and reacted for 4 hours. Finally, DMSO was added and the reaction was carried out on a shaker for 15 minutes. The absorbance of the cells at each concentration was measured using a microplate reader, and cell viability was calculated and plotted. The results showed that cell viability gradually decreased with increasing concentration, demonstrating that FPL nanosheets can inhibit the upregulation of endometrial stromal cell viability by activated PC12 supernatant in a concentration-dependent manner.

[0042] (8) such as Figure 9 As shown, FPL nanosheets (resuspended in PBS) were incubated with PC12 cells pre-incubated with nerve growth factor (NGF) for 12 hours at concentrations of 0 µg / ml, 1.25 µg / ml, 2.5 µg / ml, 5 µg / ml, and 10 µg / ml for 6 hours. The cell supernatant was then collected by centrifugation, and the supernatant of each concentration was mixed 1:1 with normal complete culture medium for later use. Endometrial stromal cells were then cultured at a rate of 1*10... 5 FPL nanosheets were seeded per well into migration chambers. After 12 hours of growth, the chambers were removed, and a pre-prepared mixture was added. Images were taken at 0, 24, and 48 hours of culture. The results showed that FPL nanosheets could inhibit the effect of activated PC12 supernatant on the migration of endometrial stromal cells in a concentration-dependent manner.

[0043] (9) such as Figure 10As shown, FPL was co-incubated with lipopolysaccharide-activated endometrial stromal cells at concentrations of 0 µg / ml, 5 µg / ml, and 10 µg / ml for 4 hours. After aspirating the cell supernatant, ROS fluorescent probe solution diluted to 1 / 2000 was added and incubated for 20 minutes. Following removal, the cells were washed three times with PBS. The ability of FPL nanosheets to scavenge reactive oxygen species (ROS) from endometrial stromal cells under inflammatory conditions was detected using an inverted fluorescence microscope. The results showed that the green color, representing ROS levels, gradually weakened with increasing concentration, indicating that the prepared FPL could effectively scavenge ROS generated by endometrial stromal cells under inflammatory conditions in a concentration-dependent manner.

[0044] (10) such as Figure 11 As shown, FPL was co-incubated with lipopolysaccharide-activated endometrial stromal cells at concentrations of 0 µg / ml, 5 µg / ml, and 10 µg / ml for 4 hours. The cell supernatant was then aspirated, cell debris was removed by centrifugation, and the supernatant was collected. The levels of IL-6 and IL-10 in the supernatant were detected using an ELISA kit. The results indicate that FPL can effectively reduce inflammatory factors produced by lipopolysaccharide-induced endometrial stromal cells in a concentration-dependent manner, demonstrating a certain anti-inflammatory effect.

[0045] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing an anti-deep endometriosis nanomedicine, characterized in that, The method comprises the following steps: (1) dissolving ammonium ferrous sulfate and trisodium citrate in ethylene glycol to obtain solution A, dissolving polyethyleneimine in ethylene glycol to obtain solution B, adding solution B to solution A, stirring at room temperature to obtain a mixed solution; (2) adding a thioacetamide solution to the mixed solution, then adding triethanolamine dropwise, stirring at room temperature, performing a solvothermal reaction after the stirring is completed, centrifuging and washing the product after the reaction is completed to obtain two-dimensional iron sulfide nanosheets; (3) mixing the iron sulfide nanosheets prepared in step (2) and dopamine hydrochloride in anhydrous ethanol, stirring at room temperature, centrifuging and washing the product after the reaction is completed to obtain iron sulfide nanomaterials coated with polydopamine; (4) mixing the iron sulfide nanomaterials coated with polydopamine obtained in step (3) with larotrectinib and anhydrous ethanol to obtain iron sulfide-larotrectinib nanocomposites coated with polydopamine, i.e. nanomedicines against deep endometriosis.

2. The production method according to claim 1, characterized by, In step (1), the ratio of the amounts of ammonium ferrous sulfate, trisodium citrate and ethylene glycol added in the solution A is 0.6 mmol:0.2 mmol:15 mL; the ratio of the amounts of polyethyleneimine and ethylene glycol added in the solution B is 500 mg:5 mL; and the ratio of the volume of ethylene glycol in the solution A to the volume of ethylene glycol in the solution B is 3:

1.

3. The production method according to claim 2, characterized by, In step (1), the stirring is magnetic stirring at a speed of 800 rpm, and the stirring reaction is performed for 2 h.

4. The method of claim 1, wherein, In step (2), the concentration of the thioacetamide solution is 0.05 M; the ratio of the amounts of ammonium ferrous sulfate, the thioacetamide solution and triethanolamine added is 0.6 mmol:15 mL:2 mL; the stirring is magnetic stirring at a speed of 800 rpm, and the stirring reaction is performed for 1-10 min.

5. The preparation method according to claim 4, characterized in that, In step (2), the solvothermal reaction is performed at a temperature of 200℃ for 24 h; the centrifugation is performed at a speed of 14000 rpm for 10 min; and the washing is performed with anhydrous ethanol for 3 times.

6. The method of claim 1, wherein, In step (3), the ratio of the amounts of the iron sulfide nanosheets, dopamine hydrochloride and anhydrous ethanol added is 1 mg:1 mg:2 mL.

7. The production method according to claim 6, wherein In step (3), the stirring is magnetic stirring at a speed of 400 rpm for 10 h; the centrifugation is performed at a speed of 14000 rpm for 10min; and the washing is performed with deionized water for 2 times.

8. The production method according to claim 1, characterized by, In step (4), the ratio of the amounts of the iron sulfide nanomaterials coated with polydopamine, larotrectinib and anhydrous ethanol added is 1 mg:1 mg:2 mL; the mixing is performed with stirring, and the stirring is performed for 6 h; After the stirring, centrifugation and washing are further performed, the centrifugation is performed at a speed of 14000 rpm for 10 min; The washing is performed with anhydrous ethanol for 2 times.

9. Nanomedicines against deep endometriosis prepared by the preparation method of any one of claims 1-8.

10. The use of the anti-deep endometriosis nanomedicine of claim 9 for the preparation of a medicament for the treatment of deep endometriosis.

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