Redox response type metal organic framework nano-particles, nano-drug delivery system and construction method of nano-drug delivery system
By performing solvothermal reaction in DMF solution, redox-responsive metal organic frame nanoparticles Fe-MOF-SS is prepared, which solves the problem that existing MOF does not have redox-responsive characteristics, and realizes the nanodrug delivery system in tumor microscopy Targeted and efficient release in the environment improves tumor treatment efficiency and reduces toxic side effects.
Patent Information
- Application Number
- CN202411596554.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-11
- Publication Date
- 2025-02-14
AI Technical Summary
When the existing redox MOF is used in nanodrug delivery systems, the MOF itself does not have redox response characteristics, making it difficult to achieve sufficient drug release and degradation.
Redox-responsive metal organic frame nanoparticles Fe- were prepared by solvothermal reaction in DMF solution using ferric chloride hexahydrate and 2,2'-dithiodibenzoic acid as iron source and organic ligand. MOF-SS and use it in nanodrug delivery systems.
The preparation of redox-responsive metal organic framework nanoparticles has been achieved, with good biocompatibility and safety, and can achieve targeted and efficient drug release in the tumor microenvironment, improving tumor treatment efficiency and reducing toxic side effects.
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Figure CN119431815A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of bio-nanomaterial preparation, and in particular to a redox-responsive metal organic framework nanoparticle, a nano drug delivery system and a construction method thereof. Background Art
[0002] In recent years, nano drug delivery systems have been widely used in disease diagnosis and treatment. Tumor microenvironment responsive nano drug delivery systems, such as pH-responsive, redox-responsive, ROS-responsive, and enzyme-responsive nano drug delivery systems, have attracted widespread attention because they can respond to the special physiological environment in the tumor to achieve targeted drug release. In particular, during the development of tumors, the glutathione concentration in the microenvironment is about 1000 times higher than that in the normal physiological environment. This large concentration difference provides a theoretical basis for the design of redox-responsive drug delivery systems. In recent years, various redox-responsive nano drug delivery systems, such as nano micelles and nano assemblies, have been developed and widely used in tumor treatment, improving the therapeutic effect. However, their low drug content still limits their application.
[0003] Metal organic framework (MOF) is a new type of highly crystalline organic-inorganic hybrid porous material formed by self-assembly with metal ions or metal clusters as the central site and organic ligands. By adjusting the type or preparation conditions of the organic ligand, MOFs with different morphologies and functions can be obtained for anti-tumor drug delivery, and a large specific surface area can greatly increase the drug content (Wuttke, Stefan, et al. "Positioning metal-organic framework nanoparticles within the context of drug delivery-a comparison with mesoporous silica nanoparticles and dendrimers." Biomaterials 123 (2017): 172-183.). However, when the existing redox MOF is used in a nano drug delivery system, it is often wrapped with a redox polymer outside the MOF, and the MOF itself does not have redox response characteristics; it is difficult to achieve sufficient drug release and degradation. Summary of the invention
[0004] In view of the above technical problems, the present invention provides a redox-responsive metal organic framework nanoparticle, which is rod-shaped with a long diameter of 180 to 250 nm. The metal organic framework nanoparticle is a redox metal organic framework nanoparticle Fe-MOF-SS with a nanometer particle size obtained by a solvothermal reaction in a DMF solution using ferric chloride hexahydrate as an iron source, 2,2'-dithiodibenzoic acid as an organic ligand, and sodium hydroxide as a pH regulator.
[0005] Preferably, the metal organic framework nanoparticles are prepared by the following method: dissolving ferric chloride hexahydrate and 2,2'-dithiodibenzoic acid in a mixed solution of DMF and water, adding sodium hydroxide to adjust the pH of the solution, transferring the solution to a polytetrafluoroethylene-lined reactor after ultrasonic dispersion, and conducting a solvent thermal reaction in a closed environment at 60 to 180° C. The product is centrifuged, washed, and dried to obtain a redox-responsive metal organic framework nanomaterial.
[0006] Preferably, the molar ratio of the ferric chloride hexahydrate to 2,2'-dithiodibenzoic acid is 1:(1-3); and the molar amount of the sodium hydroxide is 0.1-1 times the molar amount of the ferric chloride hexahydrate.
[0007] Preferably, the molar ratio of the ferric chloride hexahydrate to 2,2'-dithiodibenzoic acid is 1:1.25; and the molar amount of the sodium hydroxide is 0.6 times the molar amount of the ferric chloride hexahydrate.
[0008] Preferably, the washing uses DMF and anhydrous ethanol.
[0009] The second purpose of the present invention is to provide a nano drug delivery system, which is constructed by using the redox-responsive metal organic framework nanoparticles as a carrier, loading anti-tumor drugs, and then coating with pharmaceutical excipient Poloxamer F127.
[0010] Preferably, the anti-tumor drugs include chemotherapy drugs and immunotherapy drugs.
[0011] Preferably, the chemotherapy drug is at least one of doxorubicin, docetaxel and paclitaxel; and the immunotherapy drug is NLG919.
[0012] Preferably, the chemotherapy drug is doxorubicin.
[0013] The third object of the present invention is to provide a method for constructing the nano drug delivery system, comprising the following steps:
[0014] (1) Redox-responsive metal organic framework nanoparticles, chemotherapeutic drugs and immunotherapeutic drugs are co-dispersed in a methanol solution, ultrasonically dispersed, stirred for 12 to 24 hours, centrifuged, washed, and vacuum dried to obtain drug-loaded D+N@MOF-SS;
[0015] (2) The D+N@MOF-SS and F127 prepared in step (1) were dispersed in deionized water, stirred in the dark for 12 to 24 hours, centrifuged, washed, and freeze-dried to obtain a nano drug delivery system.
[0016] Preferably, the mass ratio of the redox-responsive metal organic framework nanoparticles, chemotherapeutic drugs and immunotherapeutic drugs in step (1) is 1: (0.1-0.8): (0.1-0.5), and the mass ratio of D+N@MOF-SS to F127 in step (2) is 1: (1-5).
[0017] Preferably, the washing in step (1) uses anhydrous methanol and is performed three times; the washing in step (2) uses deionized water; the centrifugal speed in step (2) is 8000-12000 rpm and the time is 5 min.
[0018] Preferably, the centrifugal speed in step (2) is 10000 rpm and the time is 5 min.
[0019] The beneficial effects of the present invention are as follows: (1) The present invention provides a redox-responsive metal organic framework nanoparticle, which is rod-shaped, has good dispersibility, and a long diameter particle size of no more than 200 nm. Compared with the reported metal organic framework materials, the particle size is better controlled; it has good biocompatibility and safety, and also has good adsorption performance. The redox-responsive metal organic framework nanoparticle is used to construct a nano drug delivery system, which is expected to achieve targeted release of anti-tumor drugs, reduce toxic side effects, and improve tumor treatment efficiency;
[0020] (2) The present invention controls the solvothermal reaction process of iron ions and 2,2'-dithiodibenzoic acid by adding sodium hydroxide as a pH regulator, thereby preparing disulfide bond nanorod-like structured redox metal organic framework nanoparticles with redox responsive decomposition; and also provides alkaline ligands to promote the coordination reaction between metal ions and organic ligands, and adjusts the reaction rate and product distribution by adjusting the pH value of the reaction system, thereby efficiently synthesizing high-quality MOF materials.
[0021] (3) The present invention provides a nano drug delivery system, which has long-term stability in a normal physiological environment, improves the circulation time of the nano drug delivery system in the body, and enhances the delivery efficiency, laying a foundation for the application of the nano drug delivery system in the field of tumor treatment; it can be rapidly released in the tumor environment, so that the nano drug delivery system can respond to the tumor microenvironment and achieve targeted and efficient drug release; experimentally verified, the nano drug delivery system has a high inhibition rate on pancreatic cancer cells and has good in vivo anti-tumor ability. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 Transmission electron microscopy (A) and scanning electron microscopy (B) images of the redox-responsive metal organic framework MOF-SS constructed by the present invention, and transmission electron microscopy (C) and scanning electron microscopy (D) images of the constructed nano drug delivery system D+N@MOF-F127.
[0023] Figure 2 Release curves of D+N@MOF-F127 in different buffers.
[0024] Figure 3 In vitro tumor inhibitory effect of D+N@MOF-F127 on PANC-1 cells.
[0025] Figure 4 Internalization of free DOX and D+N@MOF-F127 by PANC-1 cells.
[0026] Figure 5 D+N@MOF-F127 induces ICD effect in vitro.
[0027] Figure 6 In vivo tumor inhibitory effect of D+N@MOF-F127. DETAILED DESCRIPTION
[0028] The specific implementation of the present invention is further described in detail below in conjunction with the accompanying drawings and examples. The following examples are only used to more clearly illustrate the technical solution of the present invention so that those skilled in the art can well understand and utilize the present invention, rather than limiting the scope of protection of the present invention.
[0029] The production processes, experimental methods or detection methods involved in the embodiments and comparative examples of the present invention are all conventional methods in the prior art unless otherwise specified, and their names and / or abbreviations are all conventional names in the field and are very clear and unambiguous in the relevant application fields. Technicians in the field can understand the conventional process steps based on the names and apply the corresponding equipment to implement them according to conventional conditions or the conditions recommended by the manufacturer.
[0030] The various instruments, equipment, raw materials or reagents used in the embodiments of the present invention are not particularly limited in terms of their sources, and are all conventional products that can be purchased through regular commercial channels, or can be prepared according to conventional methods well known to those skilled in the art.
[0031] Glossary:
[0032] Dimethylformamide, abbreviated as DMF, is an organic compound with the chemical formula C 3 H 7 NO is a colorless transparent liquid. It is miscible with water and most organic solvents. It is a commonly used solvent for chemical reactions. It is not only a widely used chemical raw material, but also an excellent solvent with a wide range of uses.
[0033] Docetaxel is an anti-tumor injection, mainly used for chemotherapy, and is abbreviated as DOX in the following examples.
[0034] NLG919 is an oral inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) with potential immunomodulatory and anti-tumor activities.
[0035] F127 is a common nonionic surfactant, and its scientific name is Poloxamer 188. Example 1: Preparation of redox-responsive metal organic framework nanoparticles
[0036] Accurately weigh 1.08g FeCl 3 6H 2 O, 1.624g 2,2'-dithiodibenzoic acid was dispersed in 54mL DMF, mixed with 6mL sodium hydroxide solution (0.4M), ultrasonically treated for 5min, transferred to a 100mL polytetrafluoroethylene-lined reactor, and reacted at 100℃ for 12h. After the reaction was completed, it was naturally cooled to room temperature, and the resulting solution was transferred to a centrifuge tube. The precipitate was collected by centrifugation at 10000rpm for 10min using a high-speed centrifuge, washed 3 times with DMF and anhydrous ethanol respectively, and dried in a vacuum drying oven for 24h, and then taken out to obtain a yellowish-brown nanoparticle powder. The prepared Fe-MOF-SS nanoparticles were characterized by transmission and scanning electron microscopy.
[0037] Figure 1 A and B are images of the redox metal organic framework Fe-MOF-SS observed under transmission and scanning electron microscopes, respectively. The Fe-MOF-SS prepared by adding sodium hydroxide as a solution pH regulator in the present invention is rod-shaped, with an average long diameter of about 200 nm and good monodispersity, and is suitable for use in nano drug delivery systems. It is difficult to obtain the product without adding sodium hydroxide. Figure 1C and 1D are the redox-responsive nanodrug D+N@MOF-F127 observed under transmission and scanning electron microscopy, respectively. The results show that its morphology remains intact after drug loading.
[0038] Example 2: Preparation of Nano-drug Delivery Systems with Different Ratios
[0039] Preparation Example 1:
[0040] Accurately weigh 30 mg of the Fe-MOF-SS nanoparticles prepared in Example 1, disperse them together with 15 mg of DOX and 15 mg of NLG919 in 10 mL of methanol solution, and mix them evenly by ultrasound. React for 24 h under magnetic stirring at room temperature, centrifuge, wash three times with anhydrous methanol, and vacuum dry to prepare 42 mg of D+N@MOF-SS.
[0041] Preparation Example 2
[0042] 30 mg of the Fe-MOF-SS nanoparticles prepared in Example 1 were accurately weighed and dispersed together with 5 mg of DOX and 5 mg of NLG919 in 10 mL of methanol solution. The mixture was dispersed and mixed evenly by ultrasound. The mixture was reacted under magnetic stirring at room temperature for 24 h. The mixture was centrifuged, washed three times with anhydrous methanol, and dried in vacuo to obtain 35 mg of D+N@MOF-SS.
[0043] Preparation Example 3
[0044] 30 mg of the Fe-MOF-SS nanoparticles prepared in Example 1 were accurately weighed and dispersed together with 10 mg of DOX and 15 mg of NLG919 in 10 mL of methanol solution. The mixture was dispersed and mixed evenly by ultrasound. The mixture was reacted under magnetic stirring at room temperature for 24 h. The mixture was centrifuged, washed three times with anhydrous methanol, and dried in vacuo to obtain 38 mg of D+N@MOF-SS.
[0045] Preparation Example 4
[0046] 30 mg of the Fe-MOF-SS nanoparticles prepared in Example 1 were accurately weighed and dispersed together with 10 mg of DOX and 5 mg of NLG919 in 10 mL of methanol solution. The mixture was dispersed and mixed evenly by ultrasound. The mixture was reacted under magnetic stirring at room temperature for 24 h. The mixture was centrifuged, washed three times with anhydrous methanol, and dried in vacuo to obtain 40 mg of D+N@MOF-SS.
[0047] Weigh 10 mg of D+N@MOF-SS and 10 mg of F127 prepared in Preparation Examples 1-4 respectively, disperse them evenly in 4 mL of deionized water, stir them magnetically for 12 h at room temperature in the dark, centrifuge them at 10,000 rpm for 5 min, collect the precipitate, wash it three times with deionized water, and freeze-dry it to obtain 16 mg of D+N@MOF-F127.
[0048] The experimental results show that D+N@MOF-F127 prepared based on Preparation Example 1 has the best effect, so in subsequent experiments, D+N@MOF-F127 prepared based on Preparation Example 1 was used.
[0049] Example 3: Nano drug delivery system
[0050] 1. Preparation
[0051] This experiment was carried out based on D+N@MOF-F127 prepared in Preparation Example 1 in Example 2.
[0052] 2. Drug loading test
[0053] The supernatant was collected and the concentrations of remaining DOX and NLG919 in the supernatant were determined by UV-visible spectrophotometer and HPLC, respectively. The drug loading of D+N@MOF-F127 for DOX and NLG919 was obtained by reduction method, which was 21.02% and 11.72%, respectively, which was attributed to the adsorption effect brought about by the porous structure of MOF itself and electrostatic effect.
[0054] 3. Drug release capacity test
[0055] Accurately weigh 4 portions of the redox metal organic framework nano drug delivery system D+N@MOF-F127 loaded with DOX and NLG919 and place them in a dialysis bag (MWCO: 1000), and place them in 100 ml of phosphate buffer solution of pH 7.4 and pH7.4+10μM GSH, and acetate buffer solution of pH 5.0 and pH 5.0+10μM GSH to simulate the normal physiological environment and tumor microenvironment. Place it in a constant temperature shaking shaker at 37°C, take out 5 ml of dialysate at the set time point to test the release amount, and replenish new buffer solution to maintain a constant volume. Use a UV-visible spectrophotometer to test the absorbance of the dialysate at 485nm to evaluate the release effect of DOX in D+N@MOF-F127 under different environments.
[0056] Figure 2 The DOX release behavior of D+N@MOF-F127 in different buffer solutions is given. The nanodrug delivery system has a low drug leakage rate in a simulated physiological environment (pH 7.4 phosphate buffer solution + 10μM GSH) and has the ability to respond to GSH for rapid release in a simulated tumor environment (pH 5.0 acetate buffer solution + 10μM GSH).
[0057] Example 4: In vitro anti-tumor cell proliferation inhibition experiment
[0058] The present invention uses mouse pancreatic cancer cell PANC-1 as a model and adopts the CCK-8 method to examine the in vitro anti-tumor cell proliferation inhibition effects of different samples.
[0059] 1. Cell Culture
[0060] Human pancreatic cancer cells (PANC-1) were purchased from Shanghai Fuheng Biotechnology Co., Ltd., China, and placed in a 5% CO 2 , and cultured in an incubator at 37°C.
[0061] 2. Cell Viability Test
[0062] The CCK-8 method was used to evaluate the killing effect of the D+N@MOF-F127 nanomedicine on pancreatic cancer. 4 The cells / well were seeded into a 96-well plate, cultured with DMEM medium containing 10% FBS, and incubated in an incubator for 24 hours. The medium in the well plate was aspirated, and an equal volume of DMEM medium containing different equivalent concentrations of free DOX and D+N@MOF-F127 samples was added, and the incubation continued for 48 hours. CCK-8 reagent was added, and the absorbance value at 450nm was measured with a microplate reader.
[0063] from Figure 3 The results of in vitro antitumor experiments show that with the increase of DOX concentration, the survival rate of PANC-1 cells decreased significantly, and the inhibitory effect continued to increase, showing a certain concentration dependence. At the same time, at the same equivalent concentration, D+N@MOF-F127 has a stronger ability to inhibit tumor activity and a lower IC 50 value.
[0064] 3. Cell endocytosis ability test
[0065] PANC-1 (1×10 5 / mL) cells were seeded in a confocal culture dish and incubated with MOF-SS, free DOX, and D+N@MOF-F127 nanoparticles for 6 h at the same equivalent DOX concentration of 0.2 μg / mL. After incubation, the cells were washed with PBS and fixed with 4% paraformaldehyde. The cells were then permeabilized with TritonX-100. After washing, the cell nuclei were dark stained with DAPI for 10 min. Bright field, DOX, and DAPI fluorescence channel images were obtained by confocal laser scanning microscopy.
[0066] DAPI was used to locate the cell nucleus, bright field images were used to locate the cell outline, and red fluorescence was used to locate the distribution of DOX. Figure 4From the results of tumor cell endocytosis, at the same equivalent concentration, cells treated with D+N@MOF-F127 had stronger DOX spontaneous red fluorescence, indicating that D+N@MOF-F127 has a stronger ability to enter cells than free doxorubicin.
[0067] 4. Induced ICD effect test
[0068] For immunofluorescence staining of CRT and HMGB1, PANC-1 cells were cultured with free DOX, DOX+NLG919 and D+N@MOF-F127 (equivalent DOX concentration of 10 μM) at 37°C for 4 h, fixed with 4% paraformaldehyde, permeabilized with 0.1% TritonX-100, blocked with 5% FBS, and stained with anti-CRT primary antibody (66240-1-Ig, purchased from Proteintech) or anti-HMGB1 primary antibody (ab79823, purchased from Abcam), respectively, and then stained with Alexa 594 or 647-conjugated monoclonal secondary antibody (purchased from Proteintech) and DAPI, and imaged under a confocal microscope.
[0069] To evaluate the ATP secretion induced by D+N@MOF-F127, PANC-1 cells were seeded in 24-well plates (5×10 4 cells / well), incubated with free DOX, NLG919, and D+N@MOF-F127 (equivalent DOX concentration was 10 μM) for 24 h, and the supernatant was collected to determine the ATP content using an ATP assay kit.
[0070] from Figure 5 It can be seen that compared with doxorubicin alone, D+N@MOF-F127 loaded with MOF-SS has more significant effects on CRT eversion, HMGB1 extracellular expression and ATP secretion in inducing immunogenic death.
[0071] Example 5. In vivo anti-tumor experimental results
[0072] In this application example, six groups were set up, including control group, MOF-SS group, NLG919 group, DOX group, DOX+NLG919 group and D+N@MOF-F127 group, to further study the in vivo anti-tumor experimental results of the D+N@MOF-F127 nanodrug delivery system.
[0073] 1. Methods
[0074] SPF female C57BL / 6 mice aged 6 to 8 weeks were selected. The tumor tissue of KPC mice was cut into small pieces with a diameter of about 3 mm and subcutaneously implanted into the axilla of C57BL / 6 mice to construct a pancreatic cancer transplant tumor model. The subcutaneous tumor formation was observed, the long and short diameters of the tumor were measured with a vernier caliper, and the tumor volume was calculated for in vivo anti-tumor performance evaluation.
[0075] The tumor-bearing mice were divided into 6 groups, namely control group, MOF-SS group, NLG919 group, DOX group, DOX+NLG919 group and D+N@MOF-F127 group, with 6 mice in each group. The respective solutions were injected into the tail vein of the tumor-bearing mice in each group. The equivalent concentration of DOX was 5.0 mg / kg, the equivalent dose of NLG919 was 2.8 mg / kg, and the dose of MOF-SS was 16.0 mg / kg. The drugs were given once every three days until the experimental endpoint was reached.
[0076] The tumor volume was measured every 2 days, and the changes in tumor volume were recorded. At the same time, the weight changes of tumor-bearing mice were recorded to verify the anti-tumor effectiveness of D+N@MOF-F127 in vivo.
[0077] 2. Results
[0078] Figure 6 a is a picture of tumor-bearing mice 18 days after injection of different materials. It can be seen that compared with the control group, the tumor volumes of mice in the DOX group, DOX+NLG919 group and D+N@MOF-F127 group were significantly reduced, proving that their tumor growth rates had a significant downward trend compared with the control group.
[0079] Figure 6 Figures b and c are the time-dependent changes in tumor weight and volume of tumor-bearing mice in different treatment groups. It can be seen that the tumor volume of tumor-bearing mice in the D+N@MOF-F127 group was significantly smaller than that in the control group injected with PBS, and was also significantly smaller than that in the DOX group and the DOX+NLG919 group, proving that the presence of MOF-SS enhanced the targeted release ability of the drug delivery system, and DOX was effectively delivered to the tumor tissue.
[0080] Figure 6 d is the weight-time curve of tumor-bearing mice after injection of different materials. During the treatment period, the weight of tumor-bearing mice in each group did not fluctuate significantly, and no tumor-bearing mice died during the entire experimental period, which proves that the nano drug delivery system of the present invention has good biocompatibility, does not affect the normal growth of tumor-bearing mice, and will not cause poisoning or death of experimental animals.
[0081] Figure 6e is the HE staining image of the main organs of tumor-bearing mice in different treatment groups. It can be seen that the combination of free doxorubicin and DOX+NLG919 caused obvious organic cardiac lesions, while the main organs of mice treated with D+N@MOF-F127 after loading showed no obvious damage, indicating that the targeted release ability of MOF-SS can significantly reduce the toxic side effects of chemotherapeutic drugs.
[0082] In summary, (1) the present invention provides a redox-responsive metal organic framework nanoparticle, which is rod-shaped, has good dispersibility, and a long diameter particle size of no more than 200 nm. Compared with the reported metal organic framework materials, the particle size is better controlled; it has good biocompatibility and safety, and also has good adsorption performance. The redox-responsive metal organic framework nanoparticle is used to construct a nano drug delivery system, which is expected to achieve targeted release of anti-tumor drugs, reduce toxic side effects, and improve tumor treatment efficiency;
[0083] (2) The present invention controls the solvothermal reaction process of iron ions and 2,2'-dithiodibenzoic acid by adding sodium hydroxide as a pH regulator, thereby preparing disulfide bond nanorod-like structured redox metal organic framework nanoparticles with redox responsive decomposition; and also provides alkaline ligands to promote the coordination reaction between metal ions and organic ligands, and adjusts the reaction rate and product distribution by adjusting the pH value of the reaction system, thereby efficiently synthesizing high-quality MOF materials.
[0084] (3) The present invention provides a nano drug delivery system, which has long-term stability in a normal physiological environment, improves the circulation time of the nano drug delivery system in the body, and enhances the delivery efficiency, laying a foundation for the application of the nano drug delivery system in the field of tumor treatment; it can be rapidly released in the tumor environment, so that the nano drug delivery system can respond to the tumor microenvironment and achieve targeted and efficient drug release; experimentally verified, the nano drug delivery system has a high inhibition rate on pancreatic cancer cells and has good in vivo anti-tumor ability.
[0085] The above embodiments of the present invention do not describe all the details in detail, nor limit the present invention to the above embodiments. Various changes, modifications, substitutions and variations made by ordinary technicians in this field without departing from the principles and purpose of the present invention should be included in the protection scope of the present invention.
Claims
1. A redox-responsive metal organic framework nanoparticle, characterized in that: The metal organic framework nanoparticles are rod-shaped with a long diameter of 180 to 250 nm. The redox metal organic framework nanoparticles Fe-MOF-SS with a nanometer particle size are obtained by a solvothermal reaction in a DMF solution using ferric chloride hexahydrate as an iron source, 2,2'-dithiodibenzoic acid as an organic ligand, and sodium hydroxide as a pH regulator.
2. The redox-responsive metal organic framework nanoparticle according to claim 1, characterized in that: The metal organic framework nanoparticles are prepared by the following method: ferric chloride hexahydrate and 2,2'-dithiodibenzoic acid are dissolved in a mixed solution of DMF and water, sodium hydroxide is added to adjust the pH value of the solution, ultrasonically dispersed uniformly, and then transferred to a polytetrafluoroethylene lined reactor, and a solvent thermal reaction is carried out in a closed environment at 60-180°C. After the product is centrifuged, washed, and dried, a redox responsive metal organic framework nanomaterial is obtained.
3. The redox-responsive metal organic framework nanoparticle according to claim 2, characterized in that: The molar ratio of the ferric chloride hexahydrate to 2,2'-dithiodibenzoic acid is 1:(1-3); the molar amount of the sodium hydroxide is 0.1-1 times the molar amount of the ferric chloride hexahydrate.
4. The redox-responsive metal organic framework nanoparticle according to claim 2, characterized in that: The washing uses DMF and anhydrous ethanol.
5. A nano drug delivery system, characterized in that: The delivery system is constructed by using the redox-responsive metal organic framework nanoparticles described in any one of claims 1 to 4 as a carrier, loading the anti-tumor drug, and then coating it with the pharmaceutical excipient Poloxamer F127.
6. The nano drug delivery system according to claim 5, characterized in that The anti-tumor drugs include chemotherapy drugs and immunotherapy drugs.
7. The nano drug delivery system according to claim 6, characterized in that, The chemotherapy drug is at least one of doxorubicin, docetaxel and paclitaxel; the immunotherapy drug is NLG919.
8. The method for constructing a nano drug delivery system according to any one of claims 5 to 7, characterized in that: The steps include: (1) Redox-responsive metal organic framework nanoparticles, chemotherapeutic drugs and immunotherapeutic drugs are co-dispersed in a methanol solution, ultrasonically dispersed, stirred for 12 to 24 hours, centrifuged, washed, and vacuum dried to obtain drug-loaded D+N@MOF-SS; (2) The D+N@MOF-SS and F127 prepared in step (1) were dispersed in deionized water, stirred in the dark for 12 to 24 hours, centrifuged, washed, and freeze-dried to obtain a nano drug delivery system.
9. The method for constructing a nano drug delivery system according to claim 8, characterized in that: The mass ratio of the redox-responsive metal organic framework nanoparticles, the chemotherapeutic drugs and the immunotherapeutic drugs described in step (1) is 1:(0.1-1):(0.1-1), and the mass ratio of D+N@MOF-SS and F127 described in step (2) is 1:(1-10).
10. The method for constructing a nano drug delivery system according to claim 8, characterized in that: The washing method in step (1) is anhydrous methanol, and the washing is performed three times; the washing method in step (2) is deionized water; the centrifugal speed in step (2) is 8000-12000 rpm, and the time is 5 minutes.