2-dipyridyl ketone benzothiazole hydrazone copper complex-deferritran nanoparticle, and preparation method and application thereof

Abstract

The application provides a 2-dipyridyl ketone benzothiazole hydrazone copper complex-deironing protein nanoparticle and a preparation method and application thereof, and belongs to the technical field of antitumor drugs. The 2-hydrazine benzothiazole and 2-dipyridyl ketone are dissolved in methanol, stirred, refluxed and rotary evaporated under reduced pressure to obtain a ligand, the ligand is reacted with copper nitrate to obtain a 2-dipyridyl ketone benzothiazole hydrazone copper complex, and the 2-dipyridyl ketone benzothiazole hydrazone copper complex is reacted with deironing protein to generate a 2-dipyridyl ketone benzothiazole hydrazone copper complex-deironing protein nanoparticle. The 2-dipyridyl ketone benzothiazole hydrazone copper complex and the 2-dipyridyl ketone benzothiazole hydrazone copper complex-deironing protein nanoparticle prepared by the application can effectively treat malignant brain tumors and have small side effects.

Description

Technical Field

[0001] This invention relates to the field of antitumor drug technology, and in particular to a 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticle, its preparation method, and its application. Background Technology

[0002] Brain tumors are a common but heterogeneous type of intracranial tumor. Malignant brain tumors are among the most aggressive and deadly cancers in all age groups, especially in adolescents, where they are the most common cancer and a leading cause of cancer-related death. Currently, the standard treatment for malignant gliomas is surgical resection followed by radiotherapy and temozolomide chemotherapy; however, its efficacy is very limited, with a median survival of less than 1.5 years after diagnosis. Copper complexes have been widely synthesized and used in anti-tumor research, but they exhibit heterogeneity in their application to brain tumors. Existing research mainly focuses on designing and synthesizing mononuclear or binuclear copper complexes, but there are no reports of trinuclear copper complexes being used to treat malignant brain tumors. Furthermore, the blood-brain barrier prevents more than 98% of drugs from reaching the tumor site. Summary of the Invention

[0003] In view of this, in order to solve the above problems, the purpose of this invention is to provide a 2-dipyridyl ketone benzothiazole hydrazone copper complex and deferritin nanoparticles, as well as their preparation method and application.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0005] This invention provides a 2-dipyridyl ketone benzothiazole hydrazone copper complex, the structural formula of which is shown in Formula I:

[0006]

[0007] This invention also provides a method for preparing the 2-dipyridyl ketone benzothiazole hydrazone copper complex, comprising the following steps:

[0008] (1) Dissolve 2-hydrazinobenzothiazole and 2-dipyridyl ketone in methanol and stir to obtain mixture 1; the molar ratio of 2-hydrazinobenzothiazole and 2-dipyridyl ketone is 0.5 to 2:1, and the ratio of 2-hydrazinobenzothiazole to methanol is 5 mol: 35 to 45 mL;

[0009] (2) Add glacial acetic acid to the mixture 1 and reflux to obtain mixture 2; the volume ratio of glacial acetic acid to methanol is 1:38-42.

[0010] (3) The mixture 2 was subjected to rotary evaporation under reduced pressure to obtain a solid powder, which is the ligand;

[0011] (4) Mix the ligand, copper nitrate and methanol, seal after vacuuming; place at 57-62℃ for 11-13h, collect the precipitated black crystals, which are the 2-dipyridyl ketone benzothiazole hydrazone copper complex.

[0012] The molar ratio of the ligand to copper nitrate is 1:0.8 to 1.2.

[0013] Preferably, the stirring temperature is 20-30°C and the stirring time is 1.5-2.5 hours.

[0014] Preferably, the reflux temperature is 63-67°C, the reflux speed is 200-500 rpm, and the reflux time is 5.5-6.5 h.

[0015] Preferably, the temperature of the vacuum rotary evaporation is 45-55°C, the rotation speed of the vacuum rotary evaporation is 50-100 rpm, and the vacuum degree of the vacuum rotary evaporation is 0.08-0.12 MPa.

[0016] Preferably, the ratio of the ligand to methanol is 0.1 mol: 4-6 mL.

[0017] This invention also provides a method for preparing 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles, comprising the following steps:

[0018] (1) The 2-dipyridyl ketone benzothiazole copper hydrazone complex was prepared into a solution and mixed with deferrin, and the pH was adjusted to 1.8-2.2;

[0019] (2) Stir in an ice bath for 13-17 minutes and adjust the pH to 7-8;

[0020] (3) Continue stirring for 1.5 to 2 hours, add PBS and then ultrafilter to obtain 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles.

[0021] Preferably, the concentration of the 2-dipyridyl ketone benzothiazole hydrazone copper complex solution is 0.7–1.2 mg / mL, and the mass ratio of the 2-dipyridyl ketone benzothiazole hydrazone copper complex to deferritin is 0.5–1.5:10.

[0022] The present invention also provides 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles prepared by the above preparation method.

[0023] The present invention also provides the application of the 2-dipyridyl ketone benzothiazole hydrazone copper complex and the 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferrin nanoparticles in the preparation of drugs for treating brain tumors.

[0024] By adopting the above technical solution, the present invention has the following beneficial effects: The structural formula of the 2-dipyridyl ketone benzothiazole hydrazone copper complex synthesized in this invention is disclosed for the first time in this invention. It can effectively inhibit the growth of brain tumor cells, and the therapeutic effect of the 2-dipyridyl ketone benzothiazole hydrazone copper complex is superior to that of the existing brain tumor treatment drug temozolomide; the 2-dipyridyl ketone benzothiazole hydrazone copper complex prepared in this invention, together with deferritin nanoparticles, has the ability to cross the blood-brain barrier, and can effectively treat malignant brain tumors with few side effects. The preparation reaction of the 2-dipyridyl ketone benzothiazole hydrazone copper complex and the 2-dipyridyl ketone benzothiazole hydrazone copper complex with deferritin nanoparticles in this invention is mild, simple to operate, low in cost, and suitable for large-scale industrial production. Attached Figure Description

[0025] Figure 1 The structural formula is for a copper complex of 2-dipyridyl ketone benzothiazole hydrazone;

[0026] Figure 2 Schematic diagram of the crystal structure of the copper 2-dipyridyl ketone benzothiazole hydrazone complex;

[0027] Figure 3 Scanning electron microscope image of 2-dipyridyl ketone benzothiazole copper hydrazone complex nanoparticles;

[0028] Figure 4 The average tumor weight of mice in each group after treatment;

[0029] Figure 5 Sections of mouse tumors;

[0030] Figure 6 The average body weight change of mice in each group during the treatment process. Detailed Implementation

[0031] This invention provides a 2-dipyridyl ketone benzothiazole hydrazone copper complex, the structural formula of which is shown in Formula I:

[0032]

[0033] The present invention also provides a method for preparing the 2-dipyridyl ketone benzothiazole hydrazone copper complex, comprising the following steps:

[0034] (1) Dissolve 2-hydrazinobenzothiazole and 2-dipyridyl ketone in methanol and stir to obtain mixture 1; the molar ratio of 2-hydrazinobenzothiazole and 2-dipyridyl ketone is 0.5 to 2:1, and the ratio of 2-hydrazinobenzothiazole to methanol is 5 mol: 35 to 45 mL;

[0035] (2) Add glacial acetic acid to the mixture 1 and reflux to obtain mixture 2; the volume ratio of glacial acetic acid to methanol is 1:38-42.

[0036] (3) The mixture 2 was subjected to rotary evaporation under reduced pressure to obtain a solid powder, which is the ligand;

[0037] (4) Mix the ligand, copper nitrate and methanol, seal after vacuuming; place at 57-62℃ for 11-13h, collect the precipitated black crystals, which are the 2-dipyridyl ketone benzothiazole hydrazone copper complex.

[0038] The molar ratio of the ligand to copper nitrate is 1:0.8 to 1.2.

[0039] In this invention, 2-hydrazinobenzothiazole and 2-dipyridyl ketone are dissolved in methanol and stirred to obtain mixture 1. The molar ratio of 2-hydrazinobenzothiazole to 2-dipyridyl ketone in this invention is 0.5–2:1, more preferably 0.8–1.7:1, and more preferably 1:1. The ratio of 2-hydrazinobenzothiazole to methanol in this invention is 5 mol: 35–45 mL, more preferably 5 mol: 38–42 mL, and more preferably 5 mol: 40 mL. In this invention, the reaction temperature of 2-hydrazinobenzothiazole and 2-dipyridyl ketone is preferably 20–30°C, more preferably 22–27°C, and more preferably 25°C. The stirring time is 1.5–2.5 h, more preferably 1.7–2.3 h, and more preferably 2 h.

[0040] In this invention, glacial acetic acid is added to mixture 1 and refluxed to obtain mixture 2; the volume ratio of glacial acetic acid to methanol is 1:38-42, more preferably 1:39-41, and even more preferably 1:40. The reflux temperature is 63-67°C, more preferably 64-66°C, and even more preferably 65°C; the reflux speed is 200-500 rpm, more preferably 300-400 rpm, and even more preferably 350 rpm; the reflux reaction time is 5.5-6.5 h, and even more preferably 6 h.

[0041] In this invention, the mixture 2 is subjected to vacuum rotary evaporation. The rotation speed of the vacuum rotary evaporation is 50-100 rpm, more preferably 70-90 rpm, and even more preferably 80 rpm; the temperature of the vacuum rotary evaporation is 45-55℃, more preferably 48-52℃, and even more preferably 50℃; the vacuum degree of the vacuum rotary evaporation is 0.08-0.12 MPa, more preferably 0.09-0.11 MPa, and even more preferably 0.1 MPa. After vacuum rotary evaporation, a pale yellow powder is obtained. The pale yellow powder is washed with methanol solution and dried to obtain the ligand; the number of washings is 2-4 times, more preferably 3 times; the drying temperature is 63-67℃, more preferably 64-66℃, and even more preferably 65℃; the drying time is 1-2 hours, and even more preferably 1.5 hours.

[0042] After obtaining the ligand, the ligand and copper nitrate are added to methanol. The molar ratio of the ligand to copper nitrate is 1:0.8–1.2, more preferably 1:0.9–1.1:1, and even more preferably 1:1. The ratio of the ligand to methanol is 0.1 mol:4–6 mL, more preferably 0.1 mol:4.5–5.5 mL, and even more preferably 0.1 mol:5 mL. The reaction of the ligand and copper nitrate is preferably carried out in a glass test tube. After evacuation, the test tube is sealed at high temperature. The sealed test tube is then heated, and the precipitated black crystals are 2-dipyridyl ketone benzothiazole hydrazone copper complex. The heating temperature is 57–62°C, more preferably 58–61°C, and even more preferably 60°C. The heating time is 11–13 h, and even more preferably 12 h. The heating is preferably carried out in an oven.

[0043] This invention also provides a method for preparing 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles, comprising the following steps:

[0044] (1) Prepare a solution of the 2-dipyridyl ketone benzothiazole copper hydrazone complex, mix it with deferrin, and adjust the pH to 1.8-2.2;

[0045] (2) Stir in an ice bath for 13-17 minutes and adjust the pH to 7-8;

[0046] (3) Continue stirring for 1.5 to 2 hours, add PBS and then ultrafilter to obtain 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles.

[0047] The concentration of the 2-dipyridyl ketone benzothiazole hydrazone copper complex solution of the present invention is 0.7–1.2 mg / mL, more preferably 0.8–1.1 mg / mL, and even more preferably 1 mg / mL. The pH value is preferably adjusted to 1.8–2.2, and even more preferably 2, using a 1 mol / L HCl solution. The mass ratio of the 2-dipyridyl ketone benzothiazole hydrazone copper complex to deferritin is 0.5–1.5:10, more preferably 0.8–1.2:10, and even more preferably 1:10. After adjusting the pH value, stirring is performed under ice bath conditions, and the pH value is adjusted to 7–8 after stirring. The stirring time is 13–17 min, more preferably 14–16 min, and even more preferably 15 min. The pH value is preferably adjusted to 7–8, and even more preferably 7.5, using a 1 mol / L NaOH solution. After adjusting the pH value, stirring continues at a temperature of 22–28°C, more preferably 24–26°C, and even more preferably 25°C; at a stirring speed of 90–110 rpm, more preferably 95–105 rpm, and even more preferably 100 rpm; and for a stirring time of 1.5–2 h, more preferably 100–110 min, and even more preferably 105 min. After stirring, PBS is added for ultrafiltration at a speed of 2800–3200 rpm, more preferably 2900–3100 rpm, and even more preferably 3000 rpm; for an ultrafiltration time of 8–12 min, more preferably 9–11 min, and even more preferably 10 min. Ultrafiltration is preferably performed in an ultrafiltration tube, with a molecular weight cutoff of 10,000 Da. After ultrafiltration, 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles are obtained.

[0048] The present invention also provides the application of the 2-dipyridyl ketone benzothiazole hydrazone copper complex and the 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferrin nanoparticles in the preparation of drugs for treating brain tumors.

[0049] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0050] The deferritin described in this invention was purchased from Sigma-Aldrich. Unless otherwise specified, the other reagents can be purchased through conventional channels.

[0051] Example 1

[0052] I. Preparation of the 2-dipyridyl ketone benzothiazole hydrazone copper complex:

[0053] 1. Dissolve 5 mmol of 2-hydrazinobenzothiazole and 5 mmol of 2-dipyridyl ketone in 40 mL of methanol and stir at 25 °C for 2 h;

[0054] 2. Add 1 mL of glacial acetic acid to the above mixed solution and reflux at 65°C and 300 rpm for 6 hours;

[0055] 3. The powder was obtained by rotary evaporation under reduced pressure at 80 rpm, 50 °C and 0.1 MPa. The powder was washed three times with a small amount of methanol solution and dried at 63 °C for 1.5 h to obtain the ligand.

[0056] 4. Take a 20 mL glass test tube, weigh 0.1 mmol of ligand and 0.1 mmol of copper nitrate, add 5 mL of methanol, evacuate, and seal at high temperature;

[0057] 5. When the sealed glass test tube is placed in an oven at 60°C and heated for 12 hours, black crystals will precipitate, which is the 2-dipyridyl ketone benzothiazole copper hydrazone complex.

[0058] II. Preparation of 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles

[0059] 1. Prepare a solution of 2-dipyridyl ketone benzothiazole copper hydrazone with a concentration of 1 mg / mL, and take 1 mL of this solution for later use;

[0060] 2. Add 10 mg of deferritin to the above solution and adjust the pH to 2.0 with 1 mol / L HCl solution;

[0061] 3. Stir in an ice bath for 15 minutes, then add 1 mol / L NaOH solution to adjust the pH to 7.5.

[0062] 4. Stir at 100 rpm and 22°C for 2 h, transfer to a Millipore ultrafiltration tube (molecular weight cutoff 10,000 Da), add 1 mL PBS and ultrafilter at 3000 rpm for 10 min to obtain 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles.

[0063] Example 2

[0064] 1. Dissolve 5 mmol of 2-hydrazinobenzothiazole and 10 mmol of 2-dipyridyl ketone in 45 mL of methanol and stir at 20 °C for 1.5 h;

[0065] 2. Add 1.3 mL of glacial acetic acid to the above mixed solution and reflux at 63°C for 200 rpm for 5.5 h;

[0066] 3. The powder was obtained by rotary evaporation under reduced pressure at 50 rpm, 45 °C and 0.08 MPa. The powder was washed three times with a small amount of methanol solution and dried at 65 °C for 1 h to obtain the ligand.

[0067] 4. Take a 20 mL glass test tube, weigh 0.1 mmol of ligand and 0.08 mmol of copper nitrate, add 4 mL of methanol, evacuate, and seal at high temperature;

[0068] 5. When the sealed glass test tube is placed in an oven at 57°C and heated for 11 hours, black crystals will precipitate, which is the 2-dipyridyl ketone benzothiazole copper hydrazone complex.

[0069] II. Preparation of 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles

[0070] 1. Prepare a solution of 2-dipyridyl ketone benzothiazole copper hydrazone with a concentration of 0.7 mg / mL, and take 1 mL of this solution for later use;

[0071] 2. Add 14 mg of deferritin to the above solution and adjust the pH to 1.8 with 1 mol / L HCl solution;

[0072] 3. Stir in an ice bath for 13 minutes, then add 1 mol / L NaOH solution to adjust the pH to 7.0.

[0073] 4. Stir at 100 rpm and 25°C for 1.5 h, transfer to a Millipore ultrafiltration tube (molecular weight cutoff 10,000 Da), add 1 mL PBS and ultrafilter at 2800 rpm for 8 min to obtain 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles.

[0074] Example 3

[0075] 1. Dissolve 5 mmol of 2-hydrazinobenzothiazole and 2.5 mmol of 2-dipyridyl ketone in 35 mL of methanol and stir at 30 °C for 2.5 h;

[0076] 2. Add 0.8 mL of glacial acetic acid to the above mixed solution and reflux at 67°C for 500 rpm for 6.5 h;

[0077] 3. The powder was obtained by rotary evaporation under reduced pressure at 100 rpm, 55 °C and 0.12 MPa. The powder was washed three times with a small amount of methanol solution and dried at 67 °C for 2 h to obtain the ligand.

[0078] 4. Take a 20 mL glass test tube, weigh 0.1 mmol of ligand and 0.12 mmol of copper nitrate, add 6 mL of methanol, evacuate, and seal at high temperature;

[0079] 5. When the sealed glass test tube is placed in an oven at 62°C and heated for 13 hours, black crystals will precipitate, which is the 2-dipyridyl ketone benzothiazole copper hydrazone complex.

[0080] II. Preparation of 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles

[0081] 1. Prepare a solution of 2-dipyridyl ketone benzothiazole copper hydrazone with a concentration of 1.2 mg / mL, and take 1 mL of this solution for later use;

[0082] 2. Add 8 mg of deferritin to the above solution and adjust the pH to 2.2 with 1 mol / L HCl solution;

[0083] 3. Stir in an ice bath for 17 minutes, then add 1 mol / L NaOH solution to adjust the pH to 8.0.

[0084] 4. Stir at 110 rpm and 28°C for 110 min, transfer to a Millipore ultrafiltration tube (molecular weight cutoff 10,000 Da), add 1 mL PBS and ultrafilter at 3200 rpm for 12 min to obtain 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles.

[0085] Experimental Example 1

[0086] Elemental analysis was performed on the ligand prepared in Example 1. The measured values ​​were: C, 65.31; H, 3.90; N, 21.05; S, 9.74; the theoretical values ​​were: C, 65.24; H, 3.95; N, 21.13; S, 9.67. The chemical formula is C1. 18 H 13 N5S was used to analyze the ligand using mass spectrometry, and the result was 330.38 [MH]. + Yield = (actual yield / theoretical yield) × 100%. The weight of the ligand obtained in Example 1 was 1.49 g, with a yield of 90%.

[0087] Elemental and mass spectrometric analyses were performed on the 2-dipyridyl ketone benzothiazole hydrazone copper complex prepared in Example 1. The results were as follows: Theoretical values: C, 39.33; H, 2.20; N, 17.84; S, 5.83. Measured values: C, 39.39; H, 2.23; N, 17.80; S, 5.78. The chemical formula is C2. 36 H 24 Cu3N 14 O 12 S2, mass spectrometry analysis result is 1098.40 [MH] + .

[0088] Diffraction data were obtained using a single-crystal diffractometer, and the crystal structure of the copper complex in Example 1 was analyzed using OLEX 2 software, such as... Figure 2 As shown.

[0089] The 2-dipyridyl ketone benzothiazole hydrazone copper complex obtained in Example 1 weighed 95.65 mg, with a yield of 87%.

[0090] The 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles prepared in Example 1 were examined using scanning electron microscopy. The results were as follows: Figure 3 As shown, the average particle size of the 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles is 15.3 nm.

[0091] Experimental Example 2: In vitro antitumor activity assay of 2-dipyridyl ketone benzothiazole hydrazone copper complex and its deferriprotein nanoparticles.

[0092] In vitro cytotoxicity experiments were conducted using malignant brain tumor cell lines U87MG and U-373MG, which were purchased from ATCC (American Center for Type Culture Collection, Manassas, VA, USA).

[0093] MTT assay (thiazolyl blue test):

[0094] U87MG and U-373MG cells were respectively loaded at 5×10 4 Add 180 μL of cells per mL to a 96-well plate and culture in DMEM at 37°C with 5% CO2 for 18 h.

[0095] In the first group, 20 μL of 2-dipyridyl ketone benzothiazole copper hydrazone complexes of different concentrations were added to each well, so that the final concentrations in the culture medium were 0.2, 0.4, 0.8, 1.2, and 1.6 μM, respectively.

[0096] In the second group, 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles were added to each well, with final concentrations in the culture medium of 0.2, 0.4, 0.8, 1.2, and 1.6 μM, respectively.

[0097] The third group had temozolomide added to the culture medium to achieve final concentrations of 20, 30, 40, 50, and 60 μM, respectively.

[0098] Continue culturing for 48 hours, then add 10 μL of 5 mg / mL MTT staining agent and incubate for 4 hours. Slowly remove all liquid, then add 100 μL of dimethyl sulfoxide to dissolve. Measure the absorbance using a microplate reader at 570 nm / 630 nm dual wavelengths and calculate the IC50. 50 The values ​​are shown in Table 1.

[0099] Table 1. IC50 of different compounds on U87MG and U-373MG cell lines 50 value

[0100]

[0101] IC 50 The value (μM) indicates the inhibitory activity against cancer cells; the lower the value, the better the inhibitory activity. Table 1 shows the IC50 values ​​of the 2-dipyridyl ketone benzothiazole copper complex against U87MG cells for malignant brain tumor cell lines U87MG and U-373MG. 50 The value is lower than that of temozolomide, indicating that the 2-dipyridyl ketone benzothiazole hydrazone copper complex has better anti-brain tumor activity than temozolomide; moreover, the anti-brain tumor activity is even better when the 2-dipyridyl ketone benzothiazole hydrazone copper complex is prepared into deferritin nanoparticles.

[0102] Experimental Example 3: In vivo antitumor activity assay of 2-dipyridyl ketone benzothiazole hydrazone copper complex and its deferriprotein nanoparticles in mice.

[0103] Take 20 mice aged 6-8 weeks and administer 1×10 6 U87MG cells were introduced into the left hemisphere of mice to establish a human glioma tumor model expressing orthogonal luciferase. The growth of the heterogeneous gliomas was monitored using an in vitro luminescence imaging system (IVIS). The mice were divided into four groups: experimental group 1, experimental group 2, control group, and positive control group, with five mice in each group.

[0104] In the experimental group, mice were injected with 2-dipyridyl ketone benzothiazole copper hydrazone complex (1 mg / kg) via the tail vein;

[0105] In Experiment 2, mice were injected via tail vein with 2-dipyridyl ketone benzothiazole hydrazone copper complex-aferritin nanoparticles (containing 1 mg / kg of 2-dipyridyl ketone benzothiazole hydrazone copper complex);

[0106] The control group received the same volume of physiological saline.

[0107] The positive control group was injected with temozolomide at a dose of 1 mg / kg.

[0108] The mice were injected every two days for a total of 14 days. They were weighed on days 0, 4, 8, 12, and 16 of treatment. The changes in mouse weight are shown below. Figure 6 As shown.

[0109] After treatment, the mouse tumors were removed and weighed, and the results were as follows: Figure 4 As shown; mouse tumors were sectioned, and the damage to tumor cells was observed using hematoxylin and eosin (H&E) staining. The results are as follows. Figure 5 As shown.

[0110] Figure 4The results showed that, compared with the control group, the tumor weight was significantly reduced after treatment with the 2-dipyridyl ketone benzothiazole copper hydrazone complex, especially in the 2-dipyridyl ketone benzothiazole copper hydrazone complex-aferritin nanoparticle treatment group, where the tumor weight was much lower than that in the control group and even lower than that in the temozolomide group. H&E staining revealed extensive damage to the tumor sites after treatment with the 2-dipyridyl ketone benzothiazole copper hydrazone complex-aferritin nanoparticles. Figure 5 The 2-dipyridyl ketone benzothiazole copper complex-deferrin nanoparticles showed that the damaged area was larger than that of the temozolomide group, indicating that the 2-dipyridyl ketone benzothiazole copper complex-deferrin nanoparticles can effectively cross the blood-brain barrier and achieve the treatment of malignant brain tumors.

[0111] During treatment, changes in mouse body weight are an important indicator of drug toxicity. Compared with the control group, mice in the 2-dipyridyl ketone benzothiazole copper hydrazone complex-deferrin nanoparticle treatment group did not show a significant decrease in body weight. Figure 6 The 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferrin nanoparticles showed a significant decrease in toxicity, while the temozolomide group showed a significant decrease, indicating that the 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferrin nanoparticles have fewer toxic side effects.

[0112] As can be seen from the above embodiments, the present invention provides a 2-dipyridyl ketone benzothiazole hydrazone copper complex and a 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferrin nanoparticles, both of which can effectively treat malignant brain tumors with few side effects.

[0113] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A 2-dipyridyl ketone benzothiazole hydrazone copper complex, characterized in that, The structural formula of the 2-dipyridyl ketone benzothiazole hydrazone copper complex is shown in Formula I: Equation I.

2. The method for preparing the 2-dipyridyl ketone benzothiazole hydrazone copper complex according to claim 1, characterized in that, Includes the following steps: (1) Dissolve 2-hydrazinobenzothiazole and 2-dipyridyl ketone in methanol and stir to obtain mixture 1; the molar ratio of 2-hydrazinobenzothiazole and 2-dipyridyl ketone is 0.5~2:1, and the ratio of 2-hydrazinobenzothiazole to methanol is 5mmol:35~45mL; (2) Mix the mixture 1 with glacial acetic acid and reflux to obtain mixture 2; the volume ratio of glacial acetic acid to methanol is 1:38~42; (3) The mixture 2 was subjected to rotary evaporation under reduced pressure to obtain a solid powder, which is the ligand; (4) Mix the ligand, copper nitrate and methanol, seal after vacuuming; place at 57~62℃ for 11~13h, collect the precipitated black crystals, which are the 2-dipyridyl ketone benzothiazole hydrazone copper complex; The molar ratio of the ligand to copper nitrate is 1:0.8~1.

2.

3. The preparation method according to claim 2, characterized in that, The stirring temperature is 20~30℃, and the stirring time is 1.5~2.5h.

4. The preparation method according to claim 2, characterized in that, The reflux temperature is 63~67℃, the reflux speed is 200~500 rpm, and the reflux time is 5.5~6.5h.

5. The preparation method according to claim 2, characterized in that, The temperature of the vacuum rotary evaporation is 45~55℃, the rotation speed is 50~100 rpm, and the vacuum degree is 0.08~0.12 MPa.

6. According to the preparation method of claim 2, the ratio of the ligand to methanol is 0.1 mmol: 4~6 mL.

7. A method for preparing 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles, characterized in that, Includes the following steps: (1) The 2-dipyridyl ketone benzothiazole copper hydrazone complex of claim 1 is prepared into a solution and mixed with deferrin, and the pH value is adjusted to 1.8~2.2; (2) Stir in an ice bath for 13-17 minutes and adjust the pH to 7-8; (3) Continue stirring for 1.5-2 hours, add PBS and then ultrafilter to obtain 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles.

8. The preparation method according to claim 7, characterized in that, The concentration of the 2-dipyridyl ketone benzothiazole hydrazone copper complex solution is 0.7~1.2 mg / mL, and the mass ratio of the 2-dipyridyl ketone benzothiazole hydrazone copper complex to deferritin is 0.5~1.5:

10.

9. 2-Dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles prepared by the preparation method according to claim 7 or 8.

10. The use of the 2-dipyridyl ketone benzothiazole hydrazone copper complex of claim 1 or the 2-dipyridyl ketone benzothiazole hydrazone copper complex-deferroprotein nanoparticles of claim 9 in the preparation of a medicament for treating brain tumors.

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