Tumor microenvironment responsive nanoparticles for precise treatment of non-invasive central nervous system lymphoma and preparation method and application thereof

Abstract

The present invention provides a tumor microenvironment responsive nanoparticle for the precise treatment of non-invasive central nervous system lymphoma and its preparation method and application, belonging to the field of nanomedicine technology. The present invention dissolves carboplatin in water, dissolves pyrazine-quinoxaline in N, N-dimethylformamide, mixes the two for solvent thermal reaction, and collects the product by centrifugation after completion to obtain carboplatin nanoparticles; 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride and cysteine ​​hydrochloride are sequentially added to the dextran solution to perform condensation reaction to obtain thiolated dextran; the carboplatin nanoparticles are mixed with the thiolated dextran, dissolved in water for coupling reaction, and washed and dried after the reaction to obtain nanoparticles Pt-NPs@Glucan. The Pt-NPs@Glucan of the present invention can effectively inhibit the growth of central nervous system lymphoma, reduce the spread of cancer cells, and reduce mortality.

Description

Technical Field

[0001] The present invention belongs to the technical field of nanomedicine, and in particular relates to a tumor microenvironment responsive nanoparticle for precise treatment of non-invasive central nervous system lymphoma, and a preparation method and application thereof. Background Art

[0002] Central nervous system lymphoma (CNSL) is an extremely aggressive disease, accounting for 4% of intracranial malignancies, with an incidence of approximately 7 / 1 million. Untreated CNSL patients develop rapidly, with an average survival of only about 1.5 months. Current clinical treatments mainly include: (1) high-dose chemotherapy: mainly high-dose methotrexate and rituximab combination therapy; (2) intrathecal injection of drugs: mainly methotrexate (MTX), cytarabine (Ara-C), dexamethasone (DXM) and rituximab; (3) cranial or cerebrospinal fluid radiotherapy, mainly whole brain radiotherapy (WBRT) combined with chemotherapy; (4) autologous stem cell transplantation (ASCT); and (5) CD19-targeted chimeric antigen receptor (CAR-T) cell therapy. However, chemotherapy based on high-dose methotrexate is still the first-line clinical treatment option. Although it has achieved certain efficacy in disease control, its adverse reactions and limitations cannot be ignored. Some targeted drugs are still needed to improve patient survival and reduce peripheral side effects.

[0003] As a type of brain tumor, CNSL, like most central nervous system diseases, is affected by the blood-brain barrier (BBB), resulting in poor therapeutic effects of chemotherapy drugs and low patient survival rates. The BBB is a complex cellular structure that separates the blood from the brain parenchyma. Its integrity and perfect functionality are essential to prevent neurotoxic plasma components and pathogens from entering the brain, but the low permeability of the BBB also represents a huge obstacle for brain tumors. The key point is the presence of active efflux transporters (AETs) on the BBB, and most AETs belong to the ATP-binding cassette protein (ABC) superfamily, including P-glycoprotein, multidrug resistance-associated protein 1, and breast cancer resistance protein. Exogenous molecules, including most chemotherapeutic drugs, are pumped out by AETs.

[0004] However, during the progression of brain tumors, due to the destruction of the BBB, some non-targeted drugs will also passively accumulate in brain tumors. However, in clinical trials, this passive accumulation method has not shown obvious effects, nor has it added any significant benefits. From a clinical point of view, the several methods currently used can prolong the survival rate of patients to a certain extent, but the recurrence rate and mortality rate are still very high, and the prognosis is poor. The reason is that the existence of the blood-brain barrier (BBB) ​​makes it difficult for anticancer drugs to enter the brain. And due to poor targeting, the accumulation of drugs in non-target tissues can also lead to serious side effects, such as reduced white blood cell levels, skin damage, hair loss, and gastrointestinal reactions.

[0005] The development of nano drug delivery systems, which has attracted much attention, is expected to improve the targeting of drugs to tumor cells and reduce the side effects of drugs on the periphery. According to the characteristics of brain tumor formation and development at different stages, there are currently three strategies for targeted drug delivery of brain tumors: trans-blood-brain barrier (BBB) ​​transport, trans-blood-brain tumor barrier (BBTB) transport, and delivery using the high permeability and retention effect (EPR effect) of solid tumors. The nano drug delivery carriers that have been widely studied include liposomes, solid lipid nanoparticles, polymer micelles, dendrimers, carbon nanotubes, polymer nanoparticles, magnetic nanoparticles, etc. However, these treatment methods are usually invasive, such as intravenous injection, in situ injection into the tumor, etc., and these methods are often accompanied by increased patient fear, pain at the injection site, the need to go to the outpatient clinic or hospital for treatment, safety issues, etc., as well as compliance issues caused by inconvenient administration and increased treatment costs.

[0006] Therefore, there is an urgent need to provide a non-invasive, highly targeted nanoparticle to provide technical support for the precise treatment of central nervous system lymphoma. Summary of the invention

[0007] In view of this, the purpose of the present invention is to provide a tumor microenvironment responsive nanoparticle for the precise treatment of non-invasive central nervous system lymphoma and a preparation method and application thereof, so as to solve the problems of existing drugs having strong invasiveness, poor targeting and strong side effects.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] The invention provides a nanoparticle Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma. The nanoparticle Pt-NPs@Glucan is obtained by combining carboplatin nanoparticles and thiolated dextran through a Pt-S bond.

[0010] Preferably, the mass ratio of the carboplatin nanoparticles to the thiolated dextran is 0.5-2:0.5-2.

[0011] The present invention also provides a method for preparing the nanoparticles Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma, comprising the following steps:

[0012] 1) dissolving carboplatin in water and pyrazine-quinoxaline in N,N-dimethylformamide, mixing the two for solvothermal reaction, and collecting the product by centrifugation after the reaction to obtain carboplatin nanoparticles;

[0013] 2) adding 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride and cysteine ​​hydrochloride to the dextran solution in sequence to carry out a condensation reaction to obtain thiolated dextran;

[0014] 3) Mixing the carboplatin nanoparticles with the thiolated dextran, dissolving them in water for coupling reaction, and after the reaction, washing and drying to obtain nanoparticles Pt-NPs@Glucan.

[0015] Preferably, in step 3), the mass ratio of the carboplatin nanoparticles to the thiolated dextran is 0.5-2:0.5-2;

[0016] The mass volume ratio of the carboplatin nanoparticles to water is 1 g: 130-170 mL.

[0017] Preferably, the reaction temperature in step 3) is 20-30°C, and the reaction time is 18-30h;

[0018] The drying temperature is 30-40° C.; the drying time is 8-16 hours.

[0019] Preferably, in step 1), the mass ratio of carboplatin to pyrazine-quinoxaline is 0.5-2:0.5-2.

[0020] Preferably, the reaction temperature in step 1) is 160-200° C., the reaction time is 5-7 h, stirring is performed during the reaction, and the stirring speed is 400-500 rpm.

[0021] Preferably, in step 2), the mass ratio of 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride to dextran is 1:(1-2); the mass ratio of cysteine ​​hydrochloride to dextran is (2-4):1.

[0022] Preferably, in step 2), after adding 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride, the mixture is stirred at a speed of 500-700 rpm for 0.5-1.5 h; after adding cysteine ​​hydrochloride, the mixture is stirred at a speed of 500-700 rpm for 20-30 h in the dark.

[0023] The present invention also provides the use of the nanoparticles Pt-NPs@Glucan or the nanoparticles Pt-NPs@Glucan prepared by the preparation method in the preparation of a drug for treating central nervous system lymphoma.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The present invention combines carboplatin nanoparticles with thiolated dextran through a Pt-S bond to obtain Pt-NPs@Glu nanoparticles, which can respond to the tumor microenvironment to release carboplatin, and at the same time synergize with the immune-related functions of dextran to be used for non-invasive and precise treatment of central nervous system lymphoma, which can effectively inhibit tumor growth, reduce the spread of cancer cells, and reduce mortality. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a schematic diagram of the preparation principle of the nanoparticles Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma of the present invention;

[0027] Figure 2 are scanning electron microscopy images and transmission electron microscopy images of Pt-NPs@Glucan prepared in Example 1;

[0028] Figure 3 It is the UV-vis image of Pt-NPs@Glucan prepared in Example 1 before and after incubation in the tumor microenvironment;

[0029] Figure 4 is the mass spectrum of Pt-NPs@Glucan prepared in Example 1 after incubation in a tumor microenvironment;

[0030] Figure 5 It is the fluorescence image of drugs in various tissues and organs after oral administration;

[0031] Figure 6 The figures are the weight changes and survival curves of mice in the Control group, Pt-NPs group, Glucan group, Pt-NPs+free Glucan group and Pt-NPs@Glucan group during the experiment (A is the weight change graph of mice in each group, and B is the survival curve graph of mice in each group). DETAILED DESCRIPTION

[0032] The present invention provides a nanoparticle Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma, wherein the nanoparticle Pt-NPs@Glucan is obtained by combining carboplatin nanoparticles with thiolated dextran through a Pt-S bond. In the present invention, the mass ratio of the carboplatin nanoparticles to the thiolated dextran is preferably 0.5-2:0.5-2, and more preferably 0.8-1.5:0.8-1.5.

[0033] The present invention also provides a method for preparing the nanoparticles Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma, comprising the following steps:

[0034] 1) dissolving carboplatin in water and pyrazine-quinoxaline in N,N-dimethylformamide, mixing the two for solvothermal reaction, and collecting the product by centrifugation after the reaction to obtain carboplatin nanoparticles;

[0035] 2) adding 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride and cysteine ​​hydrochloride to the dextran solution in sequence to carry out a condensation reaction to obtain thiolated dextran;

[0036] 3) Mixing the carboplatin nanoparticles with the thiolated dextran, dissolving them in water for coupling reaction, and after the reaction, washing and drying to obtain nanoparticles Pt-NPs@Glucan.

[0037] In the present invention, carboplatin is dissolved in water, pyrazine-quinoxaline is dissolved in N,N-dimethylformamide, the two are mixed for a solvothermal reaction, and the product is collected by centrifugation after the reaction to obtain carboplatin nanoparticles. The concentration of carpa in water is preferably 2-4 mg / mL, and more preferably 2.5-3.5 mg / mL; the concentration of pyrazine-quinoxaline in N,N-dimethylformamide is preferably 0.5-1.5 mg / mL, and more preferably 0.8-1.2 mg / mL; the mass ratio of carboplatin to pyrazine-quinoxaline is preferably 0.5-2:0.5-2, and more preferably 0.8-1.5:0.8-1.5; the solvothermal reaction is preferably carried out in an oil bath, and the reaction temperature is preferably 160-200°C, and more preferably 17 0~190℃; the reaction time is preferably 5~7h, more preferably 5.5~6.5h; stirring is performed during the reaction, and the stirring speed is preferably 400~500rpm, more preferably 420~480rpm; after collecting the product, washing and drying are performed, and the washing is preferably 2 times of deionized water washing and 1 time of anhydrous ethanol washing; the drying is preferably vacuum drying; the drying temperature is preferably 50~70℃, more preferably 55~65℃; the drying time is preferably 8~16h, more preferably 10~14h.

[0038] In the present invention, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride and cysteine ​​hydrochloride are sequentially added to the glucan solution to carry out a condensation reaction to obtain thiolated glucan. The glucan is extracted from yeast cell walls, and the concentration of the glucan solution is preferably 4 to 6 mg / mL, and more preferably 4.5 to 5.5 mg / mL; the mass ratio of the 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride to the glucan is preferably 1:(1 to 2), and more preferably 1:(1.2 to 1.8); after adding 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride, the mixture is stirred at a speed of 500 to 700 rpm for 0.5 to 1.5 h; the speed is preferably The stirring speed is preferably 550-650rpm, and the stirring time is preferably 0.8-1.2h; the mass ratio of cysteine ​​hydrochloride to dextran is preferably (2-4):1, and further preferably (2.5-3.5):1; after adding cysteine ​​hydrochloride, stirring is carried out at a speed of 500-700rpm for 20-30h under light-proof conditions; the speed is preferably 550-650rpm, and the stirring time is preferably 22-28h; after the reaction is completed, dialysis is carried out, and the dialysis conditions are preferably alkaline conditions, and the solution obtained after dialysis is freeze-dried and stored.

[0039] In the present invention, the carboplatin nanoparticles are mixed with the thiolated dextran, dissolved in water for coupling reaction, and after the reaction is completed, washed and dried to obtain nanoparticles Pt-NPs@Glucan. The mass ratio of the carboplatin nanoparticles to the thiolated dextran is preferably 0.5-2:0.5-2, and more preferably 0.8-1.5:0.8-1.5; the mass volume ratio of the carboplatin nanoparticles to water is preferably 1g:130-170mL, and more preferably 1g:140-160mL, and the water is preferably deionized water; the reaction temperature is preferably 20-30°C, and more preferably 22-28°C; the reaction time is preferably 18-30h, and more preferably 20-28h; the washing is preferably deionized water centrifugal washing, and the drying is preferably vacuum drying; the drying temperature is preferably 30-40°C, and more preferably 32-38°C; the drying time is preferably 8-16h, and more preferably 10-14h.

[0040] The present invention also provides the use of the nanoparticles Pt-NPs@Glucan or the nanoparticles Pt-NPs@Glucan prepared by the preparation method in the preparation of a drug for treating central nervous system lymphoma.

[0041] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0042] Example 1

[0043] The preparation method of the nanoparticles Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma of the present invention is as follows:

[0044] (1) Preparation of carboplatin nanoparticles

[0045] Take 15 mg of carboplatin and dissolve it in 3 mL of deionized water by ultrasonic. Take 15 mg of pyrazine-quinoxaline and dissolve it in 15 mL of N, N-dimethylformamide. Mix the two and react at 180°C with a speed of 500 rpm for 6 hours. After the reaction, centrifuge and wash with deionized water and anhydrous ethanol in turn. After washing, centrifuge and discard the supernatant, retain the precipitate, and place the precipitate in a vacuum drying oven at 60°C for 12 hours.

[0046] (2) Thiolation treatment of dextran

[0047] Dissolve 1 g of dextran in 100 mL of deionized water, add 1.4 g of 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM) to the solution, stir at 600 rpm for 1 h, add 0.35 g of cysteine ​​hydrochloride and keep stirring for 24 h in dark. After the reaction is completed, transfer the reaction solution into a dialysis bag and dialyze in alkaline deionized water, changing the water every 4 h.

[0048] (3) Preparation of Pt-NPs@Glucan

[0049] 1 g of carboplatin nanoparticles was mixed with 1 g of thiolated dextran, dissolved in 150 mL of deionized water, reacted at 25°C for 24 h, centrifuged and washed with deionized water three times, and finally transferred to a 37°C vacuum drying oven for drying for 12 h.

[0050] The preparation principle of the nanoparticles Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma of the present invention is as follows: Figure 1As shown, carboplatin nanoparticles are combined with thiolated dextran through a Pt-S bond to obtain Pt-NPs@Glucan. Dextran can target the intestinal epithelial fold cells (M cells) of the intestine. When Pt-NPs@Glucan is taken orally, the nanoparticles can pass through the dense mucosal epithelium and target M cells to enter the body. After the endocytosis process of macrophages around the intestine, Pt-NPs@Glucan eventually crosses the blood-brain barrier with the homing effect of macrophages to reach the central nervous system lymphoma site. Carboplatin is released to kill cancer cells under the action of highly reactive oxygen in the tumor microenvironment. In addition, dextran as an immune adjuvant can be paired with antigens released by some tumors killed by carboplatin, effectively activating the systemic immune system to limit the potential cancer of tumor spread.

[0051] Example 2

[0052] The Pt-NPs@Glucan prepared in Example 1 was characterized by scanning electron microscopy, transmission electron microscopy and UV-spectrophotometer.

[0053] Experimental results: Figure 2 and 3 As shown. Figure 2 The scanning electron microscopy image shows that the prepared Pt-NPs@Glucan has a particle size of about 200 nm and a spherical shape. Figure 3 As shown in the UV-Vis spectrophotometer, the nanoparticles can effectively release carboplatin after incubation in the tumor microenvironment.

[0054] Example 3

[0055] The prepared Pt-NPs@Glucan was subjected to in vitro experiments.

[0056] 30% H2O2 was diluted with PBS to a concentration of 100 μM and a volume of 10 mL. 20 mg Pt-NPs@Glucan was weighed and fully suspended. After shaking in a shaker at 37°C for 24 h, the supernatant was centrifuged and freeze-dried in a vacuum freeze dryer to remove the solvent. The resulting powder was subjected to mass spectrometry.

[0057] Experimental results: From Figure 4 The mass spectrum shown in the figure shows that Pt-NPs@Glucan can release carboplatin under the conditions of high reactive oxygen species simulating the tumor microenvironment.

[0058] Example 4

[0059] Verification of Pt-NPs@Glucan's ability to target brain tumors

[0060] Construction of in situ central nervous system lymphoma model: Balb / c mice with the same weight and similar growth status were selected and fasted for 12 hours before surgery. They were anesthetized by intraperitoneal injection of 0.5% sodium pentobarbital. An incision of about 1 cm was made on the skin of the top of the mouse head, and the mucosa on the surface of the skull was corroded with 30% hydrogen peroxide. A brain stereotaxic instrument was used to drill a hole in the right front part of the mouse brain. Each mouse was injected with 5uL, 4*10 7 After the injection, the incision of the mouse brain was sutured with absorbable sutures. After the operation, the mice were observed to be normal and then raised in separate cages. The mice were observed within 24 hours.

[0061] Central nervous system lymphoma model mice were selected and orally gavaged with Pt-NPs@Glucan labeled with cy5.5, and in vitro tissue imaging was performed.

[0062] Experimental results: Figure 5 As shown in the figure, the drug can enter the brain tumor site at 4 hours and accumulate in the subsequent time, indicating that Pt-NPs@Glucan can pass through the blood-brain barrier and target the brain tumor site and accumulate.

[0063] Example 5

[0064] Treatment of orthotopic CNS lymphoma mouse models

[0065] 25 mice of the in situ central nervous system lymphoma mouse model successfully constructed in Example 4 were randomly divided into a control group, a carboplatin group, a carboplatin nanoparticle group, a carboplatin nanoparticle + Glucan group, and a Pt-NPs@Glucan group, with 5 mice in each group. The control group was treated with normal saline; the carboplatin group was treated with carboplatin orally at 10 mg / kg for 3 consecutive days; the carboplatin nanoparticle group was treated with the prepared carboplatin nanoparticles orally at 10 mg / kg for 3 consecutive days; the carboplatin nanoparticle + Glucan group was treated with the prepared carboplatin nanoparticles and thiolated dextran orally at 10 mg / kg for 3 consecutive days; the Pt-NPs@Glucan group was treated with the prepared Pt-NPs@Glucan orally at 10 mg / kg for 3 consecutive days. The body weight and survival curve of mice in each group were recorded every other day after treatment.

[0066] Experimental results: Figure 6 As shown. Figure 6 As shown in A, the weight of mice in the Pt-NPs@Glucan group grew steadily, while the weight of mice in other groups decreased. This indicates that the growth of in situ central nervous system lymphoma will cause mice to lose weight too quickly, and the use of Pt-NPs@Glucan nanoparticles can significantly inhibit the growth of in situ central nervous system lymphoma and reduce the degree of weight loss in mice. Figure 6As can be seen from B, the survival rate of mice in the Pt-NPs@Glucan group was significantly improved compared with mice in other groups, indicating that treatment with Pt-NPs@Glucan nanoparticles can significantly reduce cancer mortality.

[0067] It can be seen from the above examples that the nanoparticles for treating central nervous system lymphoma of the present invention that precisely non-invasively specifically respond to the tumor microenvironment can effectively treat in situ central nervous system lymphoma, inhibit the growth and spread of tumors, and reduce cancer mortality.

[0068] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A nanoparticle Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma, characterized in that: The nanoparticles Pt-NPs@Glucan are obtained by combining carboplatin nanoparticles with thiolated dextran via a Pt-S bond; The mass ratio of the carboplatin nanoparticles to the thiolated dextran is 0.5-2:0.5-2; The method for preparing the nanoparticles Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma comprises the following steps: 1) dissolving carboplatin in water and pyrazine-quinoxaline in N,N-dimethylformamide, mixing the two for solvothermal reaction, and collecting the product by centrifugation after the reaction to obtain carboplatin nanoparticles; 2) Adding 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride and cysteine ​​hydrochloride to the dextran solution in sequence to carry out a condensation reaction to obtain thiolated dextran; 3) mixing the carboplatin nanoparticles with the thiolated dextran, dissolving them in water for coupling reaction, and after the reaction, washing and drying to obtain nanoparticles Pt-NPs@Glucan; Step 3) The reaction temperature is 20-30°C and the reaction time is 18-30h; Step 3) The drying temperature is 30-40° C. and the drying time is 8-16 hours.

2. The method for preparing the nanoparticles Pt-NPs@Glucan for treating non-invasive central nervous system lymphoma according to claim 1, characterized in that: The following steps are involved: 1) dissolving carboplatin in water and pyrazine-quinoxaline in N,N-dimethylformamide, mixing the two for solvothermal reaction, and collecting the product by centrifugation after the reaction to obtain carboplatin nanoparticles; 2) Adding 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride and cysteine ​​hydrochloride to the dextran solution in sequence to carry out a condensation reaction to obtain thiolated dextran; 3) The carboplatin nanoparticles are mixed with the thiolated dextran, dissolved in water for coupling reaction, and after the reaction is completed, washed and dried to obtain nanoparticles Pt-NPs@Glucan.

3. The preparation method according to claim 2, characterized in that: In step 3), the mass ratio of the carboplatin nanoparticles to the thiolated dextran is 0.5-2:0.5-2; The mass volume ratio of the carboplatin nanoparticles to water is 1 g: 130-170 mL.

4. The preparation method according to claim 2, characterized in that: In step 3), the reaction temperature is 20-30°C and the reaction time is 18-30h; The drying temperature is 30-40° C. and the drying time is 8-16 hours.

5. The preparation method according to claim 2, characterized in that: The mass ratio of carboplatin to pyrazine-quinoxaline in step 1) is 0.5-2:0.5-2.

6. The preparation method according to claim 2, characterized in that: The reaction temperature in step 1) is 160-200° C., the reaction time is 5-7 hours, stirring is performed during the reaction, and the stirring speed is 400-500 rpm.

7. The preparation method according to claim 2, characterized in that: The mass ratio of 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride to dextran in step 2) is 1:(1-2); the mass ratio of cysteine ​​hydrochloride to dextran is (2-4):

1.

8. The preparation method according to claim 2, characterized in that: In step 2), 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride is added, and the mixture is stirred at a speed of 500-700 rpm for 0.5-1.5 h; and cysteine ​​hydrochloride is added, and the mixture is stirred at a speed of 500-700 rpm for 20-30 h in a dark environment.

9. Use of the nanoparticles Pt-NPs@Glucan according to claim 1 or the nanoparticles Pt-NPs@Glucan prepared by the preparation method according to any one of claims 2 to 8 in the preparation of a drug for treating central nervous system lymphoma.

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