Use of polypeptide chain, nanomaterial and preparation method and use thereof, and drug for preventing and / or treating central precocious puberty

Abstract

The present invention belongs to the field of medical technology, and specifically relates to the use of polypeptide chains, nanomaterials and preparation methods and uses thereof, and drugs for preventing and / or treating central precocious puberty. The present invention uses polypeptide chains (Trp7, β-Ala8)-Neurokinin A (4-10) or derivatives thereof to prepare drugs targeting hypothalamic GnRH neurons, and further provides nanomaterials and nasal preparations thereof that can target hypothalamic GnRH neurons and prevent or treat central precocious puberty. The nanomaterials and nasal preparations thereof of the present invention have better preventive and therapeutic effects on CPP, and have good application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to uses of polypeptide chains, nanomaterials and preparation methods and uses thereof, and drugs for preventing and / or treating central precocious puberty. Background Art

[0002] Puberty is a transitional period from childhood to adulthood. It is an important period of physical and mental development for people. It usually occurs between 10 and 18 years old for girls and 12 and 20 years old for boys. Puberty can be divided into three stages, namely early puberty, middle puberty and late puberty. During this process, adolescents will experience physical development and psychological development and transformation, including the appearance of secondary sexual characteristics and other sexual development, physical development, cognitive development, personality development, social development, etc. The age and period when each adolescent enters puberty are different due to factors such as genetics, nutrition and exercise. The sexual development stage is regulated by growth hormone in the hypothalamus-pituitary-gonadal (HPG) axis of the central nervous system. With the improvement of living standards, the onset of human puberty has gradually been advanced, resulting in more and more children experiencing precocious puberty. Central precocious puberty (CPP) is a neurodevelopmental disorder characterized by the premature initiation of sexual development. In CPP, the hypothalamus releases gonadotropin-releasing hormone (GnRH) prematurely, leading to premature activation of the reproductive system. This condition manifests as early development of secondary sexual characteristics, such as breast development in girls before age 8 or enlarged testicles in boys before age 9. In addition, CPP may also lead to accelerated growth, short stature, advanced bone age, obesity, emotional and psychological challenges due to premature physical development, and even an increased risk of cancer and diabetes.

[0003] Currently, GnRH analogs, such as leuprolide acetate and triptorelin, are widely used for the treatment of central precocious puberty disorders by subcutaneous injection. Neurokinin-3 receptors (NK3Rs) are mainly located in the arcuate nucleus (ARC) of the hypothalamus and play an important role in regulating GnRH secretion. There is evidence that the NK3R signaling pathway has an impact on congenital gonadotropin deficiency and the onset of puberty and is associated with accelerating the release of GnRH pulses, thereby triggering the onset of puberty. Notably, a NK3R antagonist, SB222200, has been shown to delay the onset of puberty to some extent when given to animals for treatment. However, due to the challenges of the blood-brain barrier (BBB), tight junctions and metabolic barriers that limit the exchange of substances between the brain and blood, peripheral administration of NK3R antagonists did not significantly affect the onset of puberty.

[0004] Therefore, for the treatment of central precocious puberty, how to deliver drugs to hypothalamic neurons is a key issue to achieve drug efficacy. However, there is no relevant literature report on the targeted delivery of drugs for the treatment of central precocious puberty. Summary of the invention

[0005] In view of the problems of the prior art, the present invention provides a use of a polypeptide chain, a nanomaterial and a preparation method and use thereof, and a drug for preventing and / or treating central precocious puberty.

[0006] Use of polypeptide chain (Trp7, β-Ala8)-Neurokinin A (4-10) or its derivatives in preparing drugs targeting hypothalamic GnRH neurons.

[0007] Preferably, the derivative is (Trp7,β-Ala8)-Neurokinin A(4-10) with cysteine ​​modified at the carbon terminal.

[0008] The present invention also provides a nano material, which is made from raw materials comprising the following components in parts by weight:

[0009] 0.9-1.1 parts of carrier material,

[0010] 0.19-0.21 parts of (Trp7,β-Ala8)-Neurokinin A(4-10) or its derivatives, and 0.11-0.13 parts of active substances for preventing and / or treating central precocious puberty.

[0011] Preferably, it is made of the following raw materials in parts by weight:

[0012] 1 carrier material,

[0013] (Trp7,β-Ala8)-Neurokinin A(4-10) or its derivatives 0.2 parts,

[0014] 0.12 parts of active substance for the prevention and / or treatment of central precocious puberty.

[0015] Preferably, the carrier material is selected from mPEG-PCL;

[0016] and / or, the derivative is (Trp7,β-Ala8)-Neurokinin A(4-10) with cysteine ​​modified at the carbon terminal;

[0017] and / or, the active substance is selected from SB-222200;

[0018] And / or, the particle size of the nanomaterial is 60-100 nm.

[0019] The present invention also provides a method for preparing the above-mentioned nanomaterial, comprising the following steps:

[0020] Step 1, mixing the (Trp7,β-Ala8)-Neurokinin A(4-10) or its derivative with a carrier material for reaction;

[0021] Step 2, adding the active substance, ultrasonically crushing, and separating to obtain.

[0022] Preferably, in step 1, the reaction solvent is N,N-dimethylformamide;

[0023] and / or, in step 1, the pH of the reaction is 6.5-7.5;

[0024] And / or, in step 1, the reaction temperature is 20-30°C;

[0025] And / or, in step 1, the reaction time is 2-3 hours;

[0026] And / or, in step 2, the ultrasonic crushing time is 5-10 min;

[0027] And / or, in step 2, the separation step includes centrifugation, filtration and water washing.

[0028] The present invention also provides the use of the nano material in preparing a drug for preventing and / or treating central precocious puberty.

[0029] The present invention also provides a drug for preventing and / or treating central precocious puberty, which is prepared by using the above nano material as an active ingredient and adding pharmaceutically acceptable auxiliary materials.

[0030] Preferably, it is a preparation for nasal administration, comprising the following raw materials in the following concentrations:

[0031] The above-mentioned nanomaterials have a concentration of 0.95-1 mg / mL based on active substance;

[0032] Acetylcysteine ​​0.71-0.75 mg / mL.

[0033] The present invention applies the polypeptide chain (Trp7, β-Ala8)-Neurokinin A (4-10) to the construction of hypothalamic neuron cell targeted drugs for the first time, thereby providing a nanomaterial with a targeted function on hypothalamic neuron cells for preventing or treating central precocious puberty. Furthermore, in combination with NAC, the present invention provides a nasal administration preparation that can bypass the blood-brain barrier and further promote the above nanomaterial to achieve its targeted administration function.

[0034] Therefore, the beneficial effects of the present invention include: the provided drug has a sustained release function, can effectively pass through the nasal mucosa system to bypass the blood-brain barrier, and can achieve targeted administration to hypothalamic neuronal cells. The drug of the present invention has a good effect on the prevention and treatment of central precocious puberty and has a good application prospect.

[0035] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0036] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The morphology of the two nanoparticles under a transmission electron microscope, where A is the morphology of S@NP and B is the morphology of S@ANP.

[0038] Figure 2 This is the experimental result of the cumulative release rate of the two nanoparticles.

[0039] Figure 3 This is a flow cytometry quantitative analysis of the experimental results of GT1-7 cells' uptake of nanoparticles at different times.

[0040] Figure 4 This is the experimental result of the penetration ability of nanoparticles combined with NAC into calu-3 cells.

[0041] Figure 5 This is the experimental result of body weight of female mice in CPP model treated with nanoparticles after weaning.

[0042] Figure 6 This is the experimental result of nanoparticle treatment on ovarian weight of female mice in CPP model.

[0043] Figure 7 Results of the experiment on vaginal opening time of female mice with CPP model treated with nanoparticles. DETAILED DESCRIPTION

[0044] In the following examples and experimental examples, reagents and raw materials not specifically described are all commercially available products.

[0045] Example 1 Nanomaterials and nasal preparations made therefrom

[0046] 1. Nanomaterials targeting hypothalamic GnRH neurons for the prevention and / or treatment of central precocious puberty:

[0047] The nanomaterial of this embodiment is prepared according to the following method:

[0048] The carbon terminus of the polypeptide chain (Trp7, β-Ala8)-Neurokinin A (4-10) was modified with cysteine ​​(sequence: Asp-Ser-Phe-Trp-β-Ala-Leu-Met-Cys-NH2, this step of synthesis was completed by Nanjing Taopu Biotechnology Co., Ltd.), 200 mg was dissolved in 100 mL of N, N-dimethylformamide, 0.5-1.5 mL of triethylamine was added dropwise to adjust the pH of the solution to 7-7.5 and control pH = 7, and then 1 g of PCL-PEG (PCL 10000 -PEG 3500 -Mal, purchased from Guangzhou Carbon Water Biotechnology Co., Ltd., item number: 80030609-3500) was reacted at room temperature (25°C) for 2 hours to form a nanomaterial PPA with a target head. Then 4 mg of PPA was weighed and dissolved in a mixed solvent of 0.4 ml of dimethyl sulfoxide and acetone (volume ratio of 1:1), and the dissolved PPA was transferred to a centrifuge tube with 5 mL of ultrapure water added in advance, and then 0.4 mg of SB-222200 (concentration of 40 mg / mL) dissolved in a mixed organic solvent (composed of chloroform and methanol in a volume ratio of 2:1) was added, ultrasonically crushed for 5 minutes, and the organic solvent was removed by rotary evaporation, centrifuged at 10000 rpm for 10 minutes, passed through a 0.22 μm membrane, ultrafiltered through an ultrafiltration tube, 5500 rpm, centrifuged for 20 minutes, and washed several times with UP water. The obtained nanomaterial was named S@ANP.

[0049] 2. Nasal administration preparations

[0050] Prepare as follows: 2 mg of nasal mucolytic agent acetylcysteine ​​(NAC) is dissolved in

[0051] 0.133 mL 20XPBS (working concentration is 0.2 M) was prepared into a 15 mg / mL NAC solution, and the NAC solution was isotonic added to the prepared nanomaterial S@ANP suspension (the volume ratio of the NAC solution was 1 / 20, and the concentration of the S@ANP suspension was 1 mg / mL calculated based on SB-222200), and mixed. The resulting nasal administration preparation was named S@ANP+NAC.

[0052] Comparative Example 1

[0053] 1. Nanomaterials:

[0054] The comparative nanomaterial does not include a derivative of the polypeptide chain (Trp7, β-Ala8)-Neurokinin A (4-10), and is prepared as follows:

[0055] The nanomaterial mPEG-PCL (10 mg / ml, purchased from Guangzhou Carbon Biotechnology Co., Ltd., catalog number: 80010402-2k-2k) was dissolved in a mixed organic solvent of chloroform and methanol at a volume ratio of 2:1, and SB-222200 (40 mg / mL) was dissolved in a mixed solvent of dimethyl sulfoxide and methanol at a volume ratio of 2:1. The above two were mixed and the dosage was 10% (4 mg mPEG-PCL + 0.4 mg SB-222200), rotary evaporation for 10 minutes to remove the organic solvent, add 5mL 1X phosphate buffer (7.9g sodium chloride, 0.2g potassium chloride, 0.24g potassium dihydrogen phosphate and 1.8 potassium dihydrogen phosphate, fixed to 1L ultrapure water), water bath ultrasound for 10 minutes hydration, ultrasonic crushing for 5min, 10000rpm, centrifugation for 10 minutes, 0.22μm membrane, ultrafiltration tube ultrafiltration, 5500rpm, 20min centrifugation and then washed three times with ultrapure water. The obtained nanomaterial is named S@NP.

[0056] 2. Nasal administration preparations

[0057] The preparation method is the same as that of Example 1, except that S@ANP is replaced by S@NP. The obtained nasal administration preparation is named S@NP+NAC.

[0058] The technical solution of the present invention is further described below through experiments. In the following experimental examples, the samples S@NP, S@ANP, S@NP+NAC and S@ANP+NAC used were prepared according to the method of Example 1 or Comparative Example 1.

[0059] 3. Nanomaterials Cou6@NP and Cou6@ANP with Cou6 fluorescence labeling

[0060] Preparation of nanomaterial Cou6@ANP: The nanomaterial PPA with a target head (same as in Example 1) was dissolved in a mixed solvent of dimethyl sulfoxide and acetone (1:1 by volume) and transferred to a centrifuge tube with 5 mL of ultrapure water added in advance, and then Cou6 0.4 mg (2 mg / mL in concentration) was dissolved in a mixed organic solvent composed of chloroform and methanol in a volume ratio of 2:1. The ratio of PPA to Cou6 was 10:1. Ultrasonic crushing for 5 min, rotary evaporation to remove the organic solvent, centrifugation at 10000 rpm for 10 minutes, 0.22 μm membrane, ultrafiltration tube ultrafiltration, 5500 rpm, 20 min centrifugation and washing with UP water several times. The obtained nanomaterial was named Cou6@ANP.

[0061] Preparation of Cou6@NP: The nanomaterial mPEG-PCL (same as comparative example 1) was dissolved in a mixed organic solvent with a volume ratio of 2:1 between chloroform and methanol, and 0.4 mg Cou6 (2 mg / mL) of fluorescein was dissolved in a mixed solvent with a volume ratio of 2:1 between dimethyl sulfoxide and methanol, and the above two were mixed, and the dosage ratio of mPEG-PCL and Cou6 was 10:1. Rotary evaporation was performed for 10 minutes to remove the organic solvent, 5 mL of phosphate buffer was added, water bath ultrasound was performed for 10 minutes, ultrasonic crushing was performed for 5 minutes, 10000 rpm, centrifuged for 10 minutes, 0.22 μm membrane was passed, ultrafiltration was performed through an ultrafiltration tube, 5500 rpm, centrifuged for 20 minutes, and then washed three times with ultrapure water. The obtained nanomaterial was named Cou6@NP.

[0062] To ensure that the Cou6@NP and Cou6@ANP nanomaterials have the same cellular uptake properties, we subjected the two nanomaterials to fluorescence detection by microplate reader and quantified Cou6 as nanoparticles with the same fluorescence intensity (excitation wavelength 490-495 nm, emission wavelength 520-530 nm), Cou6@NP and Cou6@ANP.

[0063] Experimental Example 1 Characterization of S@NP and S@ANP Nanomaterials

[0064] Experimental materials: S@NP and S@ANP nanomaterials, UV spectrophotometer, Brookhaven laser particle size analyzer 90Plus, and projection electron microscope.

[0065] Experimental steps: The synthesized nanomaterials were tested for particle size, PDI and ζ-potential using a particle size analyzer; the drug loading and encapsulation efficiency were tested using an ultraviolet spectrophotometer; and the morphology of the two nanomaterials was tested using a transmission electron microscope.

[0066] Experimental results: The results in Table 1 show that the effective particle size, PDI, ζ-potential, drug loading and encapsulation efficiency of the two nanoparticles are similar. Figure 1 The results showed that the nanoparticles were spherical in shape under a transmission electron microscope, with a particle size of 60-100 nm.

[0067] Table 1 Nanoparticle characterization

[0068]

[0069] Experimental Example 2: Detection of Cumulative Release Rate of Nanoparticles by UV Spectrophotometry

[0070] Experimental materials: UV photometer (instrument model: Thermo Fisher GENESYS180)

[0071] Experimental steps: A UV spectrophotometer was used to detect the cumulative release efficiency of the nanomaterials at different time points (1, 3, 6, 9, 18, 24, 36, 48, and 96 hours). The mixed solvent was dimethyl sulfoxide and acetone in a volume ratio of 1:1. The amount of nanomaterials was 0.3-0.4 mL, and the detection wavelength was 322 nm.

[0072] Experimental results: Figure 2 It can be seen that both nanomaterials are sustained-release preparations, with a 96-hour release efficiency of more than 70%.

[0073] Experimental Example 3 Flow cytometry was used to quantitatively analyze the uptake of nanoparticles by GT1-7 cells at different times.

[0074] Experimental materials: GT1-7 cells, purchased from the Cell Bank of the Chinese Academy of Sciences in Shanghai; Beckman Coulter flow cytometer (model Cytomics FC 500)

[0075] Experimental steps: GT1-7 cells in the logarithmic phase were inoculated in 12-well plates. The culture medium was MEM + 10% fetal bovine serum + 1% penicillin and streptomycin antibiotic mixed solution purchased from Gibico Life Technologies, USA. The cell density was 1.5×10 5 Each group had 3 replicate wells. After the cells adhered to the wall, the nanomaterials Cou6@NP and Cou6@ANP labeled with Cou6 fluorescence were added in a cell culture incubator in the dark for 1, 2, and 4 hours. The cell supernatant was discarded, and the cells were washed 3 times with PBS. The cells were digested with 0.25% trypsin (containing 0.02% EDTA solution), resuspended in a flow tube with PBS, and then detected by flow cytometry.

[0076] Experimental results: By comparing the uptake of the two nanomaterials by GT1-7 cells at 1, 2, and 4 hours, it can be seen that the nanomaterial Cou6@ANP with a target head has a stronger uptake ability in GT1-7 cells than the nanomaterial Cou6@NP without a target head. GT1-7 cells can be used to study the effects of drugs on hypothalamic GnRH neuron cells. Therefore, the above experimental results show that after the polypeptide chain (Trp7, β-Ala8)-Neurokinin A (4-10) is used to prepare nanomaterials, the obtained nanomaterials can be better taken up by hypothalamic GnRH neuron cells.

[0077] Experimental Example 4 Fluorescence quantitative detection of the penetration ability of nanoparticles combined with NAC into Calu-3 cells.

[0078] Experimental materials: Calu-3 cells, purchased from the Cell Bank of the Chinese Academy of Sciences in Shanghai, Cou6 fluorescently labeled nanomaterials Cou6@NP, 100 μM NAC (PBS solution), Transwell chamber (Corning, catalog number 3401), full wavelength microplate reader (Infinite M200, Tecan).

[0079] Experimental steps: Calu-3 cells in the logarithmic phase were seeded in a 12-well Transwell chamber at a cell density of 5×10 5 Each group had 3 replicate wells. After the cells were fully grown and the resistance value no longer increased, the Cou6 fluorescently labeled nanomaterial Cou6@NP (a mixture containing 100 μM NAC, diluted in Hanks buffer) was added to the Calu-3 monolayer chamber in the dark. 1 mL of Hanks buffer was added to the lower layer. 100 μL of the lower layer of Hanks buffer was taken at 4, 8, and 12 hours, respectively, and detected by a fluorescence spectrophotometer (Ex=425, Em=490).

[0080] Experimental results: Calu-3 cells were used to simulate the in vitro nasal mucosal system. Cou6@NP combined with NAC (100 μM) could significantly increase the Calu-3 cell penetration efficiency at 4, 8, and 12 hours, indicating that the nanomaterial combined with NAC of the present invention is more conducive to penetrating Calu-3 cells.

[0081] Experimental Example 5 Body weight of female mice in the CPP model treated with nanoparticles.

[0082] Experimental Materials: Female C57BL / 6J pregnant mice (8-32 weeks) were purchased from Chengdu Yaokang Biotechnology Co., Ltd. All animal experiments were performed in accordance with the methods approved by the Experimental Animal Management Committee of Sichuan University. Before and during pregnancy, all dams were fed a control diet (12% fat content). During lactation, dams were fed a high-fat diet (60% fat) or a regular diet. Low-fat diet coarse grains with 6.2% fat, 35.6% carbohydrates, 20.8% protein, and a caloric value of 17.6 kJ / g were obtained from Beijing Keao Xieli Feed Co., Ltd. High-fat diets containing 60% fat, 20% carbohydrates, 20% protein, and 22.0 kJ / g of calories were obtained from Research Diets (Cat. No. D12492); Analytical balance.

[0083] Experimental procedures: After the 21st day of the offspring of C57 female mice, the offspring mice were divided into 6 groups (6 mice in each group): ① the blank group (Con.) was given a low-fat normal diet; ② the model group (HFD) was given a high-fat diet; ③ the S@NP nanoparticle treatment group (HFD+S@NP) was given a high-fat diet; ④ the S@ANP nanoparticle treatment group (HFD+S@ANP) was given a high-fat diet; ⑤ the S@NP+NAC nanoparticle treatment group (HFD+S@NP+NAC group) was given a high-fat diet; ⑥ the S@ANP+NAC nanoparticle treatment group (HFD+

[0084] S@ANP+NAC) were given a high-fat diet. All nanomaterial groups were given nasally, once every 3 days, with a dose of 1 mg / kg (the dose was calculated according to the nanomaterial loaded with SB222200). After the 23rd day after birth, the pups were weighed and dosed every 2 days. After the 28th day, the vaginal opening of the female mice was observed every day and the time of the first vaginal opening was recorded. The vaginal opening was rinsed with saline and smeared and observed microscopically. The time when the female mice were in the first estrus was the onset of puberty. On the 42nd day after birth, the female mice were anesthetized with isoflurane, and plasma and hypothalamic, pituitary, ovarian, and uterine tissues were collected and stored in a refrigerator at -80°C. The ovarian tissues of female mice in each group were weighed.

[0085] Experimental results: By comparing the HFD group and the Con. group, it can be seen that the body weight of female mice in the high-fat diet-induced CPP model was significantly higher than that of the low-fat diet. Further comparison of the differences in body weight of female mice after weaning in the CPP model treated with different types of nanoparticles showed that the four types of nanoparticles, S@NP, S@ANP, S@NP+NAC, and S@ANP+NAC, can all improve the phenomenon of weight gain induced by a high-fat diet.

[0086] According to the records of the ovarian weight of each group of female mice on the 42nd day, it was found that there were significant differences in the ovarian tissue of each group of female mice after treatment and that of the model group. The ovarian tissue of female mice in the S@NP group, S@ANP group, S@NP+NAC group and S@ANP+NAC group were significantly reduced compared with the model group mice, further proving that nanoparticle treatment can significantly improve the quality of ovarian tissue of female mice in the high-fat-induced CPP model.

[0087] Based on the observation of the vaginal opening time of each group of female mice, the results show that all four nanoparticles can improve the timing of early puberty in female mice, and the therapeutic effects of these four nanoparticles are ranked as follows: S@ANP+NAC>S@NP+NAC>S@ANP>S@NP.

[0088] The above experimental results show that the S@ANP nanomaterial provided by the present invention has a better CPP therapeutic effect, and by compounding S@ANP with NAC, the effect of nasal administration can be improved to achieve a better therapeutic effect.

[0089] It can be seen from the above embodiments and experimental examples that the present invention provides a nanomaterial that can target hypothalamic GnRH neuron cells and has good preventive and therapeutic effects on CPP. By combining the nanomaterial with NAC, the present invention further provides a preparation that can bypass the blood-brain barrier by nasal administration, which has better preventive and therapeutic effects on CPP. Therefore, the present invention has a good application prospect.

Claims

1. A nanomaterial, characterized in that: It is made of the following raw materials by weight: 0.9-1.1 parts of carrier material, 0.19-0.21 parts of (Trp7,β-Ala8)-Neurokinin A (4-10) derivative, 0.11-0.13 parts of active substance for the prevention and / or treatment of central precocious puberty; The carrier material is selected from PCL 10000 -PEG 3500 -Mal; The (Trp7, β-Ala8)-Neurokinin A (4-10) derivative is a (Trp7, β-Ala8)-Neurokinin A (4-10) with a carbon-terminal cysteine ​​modification, and the sequence is: Asp-Ser-Phe-Trp-β-Ala-Leu-Met-Cys-NH2; The active substance for preventing and / or treating central precocious puberty is selected from SB-222200.

2. The nanomaterial according to claim 1, characterized in that: It is made of the following raw materials in parts by weight: 1 carrier material, 0.2 parts of (Trp7,β-Ala8)-Neurokinin A (4-10) derivative, 0.12 parts of active substance for the prevention and / or treatment of central precocious puberty.

3. The nanomaterial according to claim 1 or 2, characterized in that: The particle size of the nano material is 60-100 nm.

4. The method for preparing the nanomaterial according to any one of claims 1 to 3, characterized in that: The steps include: Step 1, mixing the (Trp7,β-Ala8)-Neurokinin A (4-10) derivative with a carrier material for reaction; Step 2, adding the active substance for preventing and / or treating central precocious puberty, ultrasonically crushing and separating to obtain.

5. The preparation method according to claim 4, characterized in that: In step 1, the reaction solvent is N,N-dimethylformamide; and / or, in step 1, the pH of the reaction is 6.5-7.5; And / or, in step 1, the reaction temperature is 20-30°C; And / or, in step 1, the reaction time is 2-3 hours; And / or, in step 2, the ultrasonic crushing time is 5-10 min; And / or, in step 2, the separation step includes centrifugation, filtration and water washing.

6. Use of the nanomaterial according to any one of claims 1 to 3 in the preparation of a drug for preventing and / or treating central precocious puberty.

7. A drug for preventing and / or treating central precocious puberty, characterized in that: The nano material is prepared by using the nano material described in any one of claims 1 to 3 as an active ingredient and adding pharmaceutically acceptable auxiliary materials.

8. The drug according to claim 7, characterized in that: It is a nasal preparation, comprising the following raw materials in the following concentrations: The nanomaterial according to any one of claims 1 to 3, wherein the concentration is 0.95 to 1 mg / mL based on the active substance; Acetylcysteine ​​0.71-0.75 mg / mL.

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