Preparation method of a smart nano-chemotherapeutic drug and its application in hyperthermic perfusion therapy of abdominal metastatic tumors

Abstract

The present invention provides a method for preparing an intelligent nano-chemotherapeutic drug. The nano-chemotherapeutic drug prepared by the present invention is small in size and has an antioxidant effect. After drug loading, it alleviates the kidney damage caused by chemotherapy drugs in peritoneal hyperthermic perfusion therapy; it has a photothermal conversion effect, and can convert light energy into heat energy through NIR irradiation, and realize non-invasive targeted heating treatment of tumor nodules inside the abdominal cavity after peritoneal hyperthermic perfusion therapy, and exerts a secondary enhanced killing effect on heat-tolerant tumor cells; it can respond to the weak acidity of the tumor microenvironment, form a self-assembly structure, and transform from a highly dispersed state close to small molecules to an aggregated state of micron size, and accurately enrich in the tumor site to exert subsequent therapeutic effects. This material will effectively solve the limitations of large kidney burden, cell thermal tolerance, and large toxic side effects in peritoneal hyperthermic perfusion chemotherapy of abdominal tumors such as colorectal cancer and ovarian cancer, and is of great significance for realizing accurate treatment of abdominal metastases and improving patient prognosis.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular relates to an intelligent nano-chemotherapeutic drug, a preparation method thereof, and an application thereof in hot perfusion treatment of abdominal metastatic tumors. Background Art

[0002] Cancer has become the leading cause of death worldwide. In recent years, cancer treatment has made great progress, but local infiltration and distant metastasis of malignant tumors still pose a great threat to patients' survival. Among them, metastatic peritoneal carcinoma is a type of intra-abdominal metastatic tumor formed by the metastasis of cancer cells through the blood route to the peritoneum or direct implantation and growth of the peritoneum. Patients have rapid disease progression, poor prognosis, short survival, high mortality, and great difficulty in clinical treatment. Therefore, combined treatment measures are often needed to prolong patient survival.

[0003] At present, the clinical treatment of abdominal metastases is mainly chemotherapy, supplemented by other treatment options such as surgery, radiotherapy, targeted therapy or immunotherapy. However, due to the presence of a certain number of free tumor cells (peritoneal free cancer cells, PFCC) and metastatic nodules less than 3mm in the abdominal cavity, surgery cannot completely remove them. In addition, the existence of the physiological plasma-peritoneal barrier limits the accumulation of effective drug concentrations in the abdominal cavity after systemic administration, resulting in poor chemotherapy effects and poor patient prognosis. In response to the problem of weak chemotherapy response and poor treatment prognosis of abdominal metastases, a treatment method combining surgical treatment with local treatment, namely peritoneal hyperthermic perfusion therapy, has been developed clinically.

[0004] Hyperthermic peritoneal perfusion therapy refers to the process of circulating a constant-temperature heated chemotherapy solution into the peritoneal cavity through a catheter for a certain period of time after the cytoreduction surgery (CRS) removes part of the visible tumor on the peritoneal surface and in the upper and lower abdominal organs. The synergistic sensitization effect of heating and chemotherapy and the flushing effect of the circulating perfusion of the therapeutic fluid can effectively remove the residual cancer cells and tiny tumor foci in the peritoneal cavity.

[0005] However, under continuous heat shower, tumor cells are stimulated by the high temperature of the environment, overexpress heat shock proteins, and develop heat tolerance; and the chemotherapy drugs used for perfusion have no targeting specificity for tumors, resulting in a decrease in the tumor killing effect in the later stage of heat perfusion and an increase in systemic toxicity during the treatment process. Summary of the invention

[0006] In view of this, the technical problem to be solved by the present invention is to provide an intelligent nano-chemotherapeutic drug with a smaller size, photothermal conversion efficiency and targeting to the tumor site, improve its preparation method and its application in thermal perfusion treatment of abdominal metastatic tumors.

[0007] The present invention provides a method for preparing an intelligent nano-chemotherapeutic drug, comprising the following steps:

[0008] S1) ammonium molybdate is mixed with water to obtain an ammonium molybdate solution;

[0009] Mixing sodium dihydrogen phosphate with water to obtain a sodium dihydrogen phosphate solution;

[0010] S2) ammonium molybdate solution is mixed with sodium dihydrogen phosphate solution, and stirred until colorless to obtain a mixed solution;

[0011] S3) mixing the mixed solution with a reducing agent, and after the reaction, adding an alcohol solvent for precipitation to obtain nanoparticles; the reducing agent is selected from sodium ascorbate and / or ascorbic acid derivatives;

[0012] S4) mixing the nanoparticles with chemotherapy drugs in water to obtain smart nano chemotherapy drugs.

[0013] Preferably, the concentration of the ammonium molybdate solution is 0.1 to 1 mol / L.

[0014] The concentration of the sodium dihydrogen phosphate solution is 0.1-0.5 mol / L.

[0015] Preferably, the molar ratio of ammonium molybdate to sodium dihydrogen phosphate is (40-60):1.

[0016] Preferably, the reducing agent is selected from sodium L-ascorbate and / or L-ascorbic acid;

[0017] The chemotherapy drug is selected from one or more of mitomycin C, cisplatin and 5-fluorouracil.

[0018] Preferably, the reducing agent is added in the form of a reducing agent solution; the mass concentration of the reducing agent solution is 100 to 200 mg / mL;

[0019] The volume ratio of the mixed solution to the reducing agent solution is (3-10):1;

[0020] The mass ratio of the nanoparticles to the chemotherapeutic drug is (40-60):1.

[0021] Preferably, the mixing speed in step S2) is 1000-2000 rpm;

[0022] In the step S3), the reaction is continued until a blue-black color appears, and an alcohol solvent is added to precipitate;

[0023] The alcohol solvent is ethanol.

[0024] Preferably, the particle size of the nanocomposite is less than 10 nm.

[0025] The present invention also provides an intelligent nano-chemotherapeutic drug prepared by the above preparation method.

[0026] The present invention also provides an application of the intelligent nano-chemotherapeutic drug prepared by the above-mentioned preparation method in the preparation of drugs for intraperitoneal hyperthermic perfusion therapy.

[0027] The present invention also provides a method for preparing nanoparticles, comprising the following steps:

[0028] S1) ammonium molybdate is mixed with water to obtain an ammonium molybdate solution;

[0029] Mixing sodium dihydrogen phosphate with water to obtain a sodium dihydrogen phosphate solution;

[0030] S2) ammonium molybdate solution is mixed with sodium dihydrogen phosphate solution, and stirred until colorless to obtain a mixed solution;

[0031] S3) mixing the mixed solution with a reducing agent, and after the reaction, adding an alcohol solvent for precipitation to obtain nanoparticles; the reducing agent is selected from sodium ascorbate and / or ascorbic acid derivatives.

[0032] The present invention provides a method for preparing an intelligent nano-chemotherapeutic drug, comprising the following steps: S1) mixing ammonium molybdate with water to obtain an ammonium molybdate solution; mixing sodium dihydrogen phosphate with water to obtain a sodium dihydrogen phosphate solution; S2) mixing the ammonium molybdate solution with the sodium dihydrogen phosphate solution, stirring until colorless, to obtain a mixed solution; S3) mixing the mixed solution with a reducing agent, reacting, adding an alcohol solvent for precipitation, to obtain nanoparticles; the reducing agent is selected from sodium ascorbate and / or ascorbic acid derivatives; S4) mixing the nanoparticles with a chemotherapeutic drug in water to obtain an intelligent nano-chemotherapeutic drug. Compared with the prior art, the intelligent nano-chemotherapeutic drug prepared by the present invention has the following advantages:

[0033] 1) The material is small in size and easy to metabolize: Ultra-small nanoparticles (≤10nm) are difficult to be recognized and cleared by phagocytes and the reticuloendothelial system, and can easily pass through the kidney's filtration system and be metabolized and excreted from the body. Transmission electron microscopy (TEM) images show that the diameter of this smart nano-chemotherapeutic drug is less than 10nm, indicating that this smart nano-chemotherapeutic drug is easy to metabolize;

[0034] 2) High photothermal conversion efficiency: This smart nano-chemotherapeutic drug is exposed to near-infrared light (NIR, 1.5W / cm2) at 808nm in the near-infrared region (NIR I). 2 ) for 10 min, and according to the temperature change under this condition, the photothermal conversion efficiency was calculated to be 26.68%, which shows that this intelligent nano-chemotherapeutic drug system has good photothermal conversion efficiency;

[0035] 3) Acidic self-assembly performance: The intelligent nano-chemotherapeutic drug was treated under weak acid conditions. The results showed that as the pH decreased, the surface charge distribution of the material gradually decreased, and the hydrated particle size of the material gradually increased, which indicated that the intelligent nano-chemotherapeutic drug would self-assemble under weak acid conditions;

[0036] 4) Significant killing effect on heat-tolerant cells: Under physiological conditions, the acidified smart nano-chemotherapeutic drugs and mitomycin C were co-incubated with heat-tolerant colorectal cancer cells and irradiated with laser. The cell killing effect of the smart nano-chemotherapeutic drugs was significantly higher than that of mitomycin C, indicating that the smart nano-chemotherapeutic drugs prepared by the present invention can effectively kill heat-tolerant cancer cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The infrared (IR) spectrum of the MoNs nano drug carrier and the drug-loaded MoNs@MyC nanocomposite in Example 1;

[0038] Figure 2 High-resolution elemental analysis positioning (HTEM-mapping) image of the MoNs@MyC nanocomposite in Example 1;

[0039] Figure 3 is a transmission electron microscopy (TEM) image of the MoNs@MyC nanocomposite in Example 1;

[0040] Figure 4 is the ultraviolet spectrum (UV) of the MoNs@MyC nanocomposite in Example 1;

[0041] Figure 5 The photothermal conversion efficiency data of the MoNs@MyC nanocomposite in Example 1;

[0042] Figure 6 The Zeta potential change diagram and dynamic light scattering (DLS) diagram of the MoNs@MyC nanocomposite in Example 1;

[0043] Figure 7 This is a diagram showing the killing effect of MoNs, mitomycin C and MoNs@MyC nanocomplexes in Example 1 on heat-resistant CT26 cells after light treatment;

[0044] Figure 8 The dynamic light scattering diagram of the smart nano-chemotherapeutic drug obtained at different rotation speeds in the embodiment;

[0045] Fig. 9 This is a diagram of the surface charge distribution-Zeta potential of the smart nano-chemotherapeutic drug obtained at different rotation speeds in the embodiment. DETAILED DESCRIPTION

[0046] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0047] The invention provides a method for preparing an intelligent nano-chemotherapeutic drug, comprising the following steps: S1) mixing ammonium molybdate with water to obtain an ammonium molybdate solution; mixing sodium dihydrogen phosphate with water to obtain a sodium dihydrogen phosphate solution; S2) mixing the ammonium molybdate solution with the sodium dihydrogen phosphate solution, stirring until colorless, to obtain a mixed solution; S3) mixing the mixed solution with a reducing agent, reacting, adding an alcohol solvent for precipitation, to obtain nanoparticles; the reducing agent is selected from sodium ascorbate and / or ascorbic acid derivatives; S4) mixing the nanoparticles with a chemotherapeutic drug in water to obtain an intelligent nano-chemotherapeutic drug.

[0048] The present invention has no particular limitation on the sources of all raw materials, and any raw materials available on the market can be used.

[0049] Ammonium molybdate is mixed with water to obtain an ammonium molybdate solution; in a specific embodiment provided by the present invention, the ammonium molybdate may be ammonium molybdate tetrahydrate ((NH4)6Mo7O 24 ·4H2O); the water may be double deionized water (ddH2O); the concentration of the ammonium molybdate solution is 0.1-1 mol / L, more preferably 0.3-0.8 mol / L, more preferably 0.4-0.6 mol / L, and most preferably 0.5 mol / L.

[0050] Sodium dihydrogen phosphate is mixed with water to obtain a sodium dihydrogen phosphate solution; in a specific embodiment provided by the present invention, the sodium dihydrogen phosphate can be sodium dihydrogen phosphate dodecahydrate (NaH2PO4·12H2O); the water can be doubly deionized water (ddH2O); the concentration of the sodium dihydrogen phosphate solution is 0.1-0.5 mol / L, more preferably 0.2-0.4 mol / L, more preferably 0.25-0.3 mol / L, and most preferably 0.292 mol / L.

[0051] The ammonium molybdate solution is mixed with the sodium dihydrogen phosphate solution, and stirred until colorless to obtain a mixed solution; in a specific embodiment provided by the present invention, the sodium dihydrogen phosphate solution is preferably slowly dripped into the ammonium molybdate solution for mixing; the molar ratio of the ammonium molybdate to the sodium dihydrogen phosphate is preferably (40-60):1, more preferably (45-55):1, and more preferably 50:1; the rotation speed of the mixing is preferably 1000-2000rpm, more preferably 1200-2000rpm, more preferably 1400-1800rpm, more preferably 1500-1700rpm, and most preferably 1600rpm; the mixing is preferably carried out at room temperature. The two compounds of ammonium molybdate and sodium dihydrogen phosphate form a molybdenum-based Keggin-type anionic metal oxoate by self-assembly.

[0052] The mixed solution is mixed with a reducing agent, and after the reaction, an alcohol solvent is added for precipitation to obtain nanoparticles; the reducing agent is sodium ascorbate and / or an ascorbic acid derivative, which can reduce molybdenum (Mo) from a VI oxidation state to a V oxidation state; in a specific embodiment provided by the present invention, the reducing agent is preferably L-sodium ascorbate and / or L-ascorbic acid; the reducing agent is preferably added in the form of a reducing agent solution; the mass concentration of the reducing agent solution is preferably 100-200 mg / mL, more preferably 120-180 mg / mL, more preferably 140-160 mg / mL, and most preferably 150 mg / mL; the volume ratio of the mixed solution to the reducing agent solution is preferably (3-10):1, more preferably (4-10):1, and more preferably (5-10):1; in a specific embodiment provided by the present invention The reaction is preferably carried out until a blue-black color appears, and an alcohol solvent is added for precipitation; the alcohol solvent can be an alcohol solvent well known to those skilled in the art, and there is no special limitation. In the present invention, ethanol is preferably used; the volume ratio of the added volume of the alcohol solvent to the mixed solution is (3-10):1, more preferably (4-8):1; in a specific embodiment provided by the present invention, after precipitation, centrifugation, washing, and freeze-drying are preferably performed to obtain nanoparticles; the washing is preferably performed using an alcohol solvent and water, more preferably ethanol and double deionized water (ddH2O); the vacuum degree of the freeze-drying is preferably 10-20 Pa, more preferably 10-18 Pa, more preferably 12-16 Pa, and most preferably 14 Pa; the freeze-drying temperature is preferably -20°C to -40°C, more preferably -25°C to -35°C, and more preferably -30°C.

[0053] The nanoparticles are mixed with chemotherapeutic drugs in water to obtain smart nano chemotherapeutic drugs. In a specific embodiment provided by the present invention, the chemotherapeutic drugs include but are not limited to one or more of mitomycin C, cisplatin and 5-fluorouracil. The mass ratio of the nanoparticles to the chemotherapeutic drugs is preferably (40-60):1, more preferably (45-55):1, and more preferably 50:1. The mixing is preferably carried out at room temperature. The mixing time is preferably 10-30 hours, more preferably 15-30 hours, and more preferably 20-30 hours. The most preferred time is 24 hours; after mixing, the nanocomposite is preferably centrifuged, washed, and freeze-dried to obtain the nanocomposite; the washing preferably uses an alcohol solvent and water, and more preferably uses ethanol and double deionized water (ddH2O); the vacuum degree of the freeze-drying is preferably 10-20Pa, more preferably 10-18Pa, more preferably 12-16Pa, and most preferably 14Pa; the freeze-drying temperature is preferably -20℃ to -40℃, more preferably -25℃ to -35℃, and more preferably -30℃; the particle size of the nanocomposite is preferably less than 10nm.

[0054] The nano-chemotherapeutic drugs prepared by the present invention are small in size and have an antioxidant effect. After drug loading, they alleviate the kidney damage caused by chemotherapy drugs in peritoneal hyperthermic perfusion therapy; they have a photothermal conversion effect, and can convert light energy into heat energy through NIR irradiation, and realize non-invasive targeted heating treatment of tumor nodules inside the abdominal cavity after peritoneal hyperthermic perfusion therapy, and play a secondary enhanced killing effect on heat-tolerant tumor cells; they can respond to the weak acidity of the tumor microenvironment, form a self-assembly structure, and transform from a highly dispersed state close to small molecules to an aggregated state of micron size, and accurately enrich in the tumor site to play a subsequent therapeutic effect. It can be seen that the intelligent nano-chemotherapeutic drugs provided by the present invention will effectively solve the limitations of large kidney burden, cell thermal tolerance, and large toxic side effects in peritoneal hyperthermic perfusion chemotherapy of abdominal tumors such as colorectal cancer and ovarian cancer, and are of great significance for realizing accurate treatment of abdominal metastases and improving patient prognosis. .

[0055] The present invention also provides a nano-chemotherapeutic drug prepared by the above method, wherein the smart nano-chemotherapeutic drug is specifically formed by a complex of molybdenum nanoparticles and chemotherapeutic drugs; the particle size of the smart nano-chemotherapeutic drug is preferably less than 10 nm.

[0056] The present invention also provides an application of the intelligent nano-chemotherapeutic drug prepared by the above method in the preparation of chemotherapy drugs for peritoneal hyperthermic perfusion.

[0057] In the present invention, the intraperitoneal hyperthermic perfusion chemotherapy may specifically be intraperitoneal hyperthermic perfusion chemotherapy for intraperitoneal tumors such as colorectal cancer and ovarian cancer.

[0058] The present invention also provides a method for preparing nanoparticles, comprising the following steps: S1) mixing ammonium molybdate with water to obtain an ammonium molybdate solution; mixing sodium dihydrogen phosphate with water to obtain a sodium dihydrogen phosphate solution; S2) mixing the ammonium molybdate solution with the sodium dihydrogen phosphate solution, stirring until colorless, to obtain a mixed solution; S3) mixing the mixed solution with a reducing agent, reacting, adding an alcohol solvent for precipitation, to obtain nanoparticles; the reducing agent is selected from sodium ascorbate and / or ascorbic acid derivatives.

[0059] Specifically, the steps S1) to S3) are the same as described above and will not be repeated here.

[0060] To further illustrate the present invention, an intelligent nano-chemotherapeutic drug provided by the present invention, a preparation method thereof, and an application thereof in the hot perfusion treatment of abdominal metastatic tumors are described in detail below in conjunction with embodiments.

[0061] The reagents used in the following examples are all commercially available.

[0062] Example 1

[0063] In the embodiment, the preparation method of the MoNs nano drug carrier comprises the following steps:

[0064] Step 1: (NH4)6Mo7O 24 ·4H2O (ammonium molybdate tetrahydrate) was dissolved in 10 mL ddH2O to prepare a solution (concentration 0.5 mol / L). NaH2PO4·12H2O (sodium dihydrogen phosphate dodecahydrate) was dissolved in 10 mL H2O to prepare a solution (concentration 0.292 mol / L).

[0065] Step 2: Slowly drop NaH2PO4·12H2O solution into 10mL of (NH4)6Mo7O in a molar ratio of 50:1 between ammonium molybdate and sodium dihydrogen phosphate. 24 ·4H2O solution, at room temperature, stir on a magnetic stirrer at 1600 rpm until colorless.

[0066] Step 3: Add 2 mL of L-sodium ascorbate solution (concentration 150 mg / mL), stir until a blue-black color appears, add 80 mL of C2H5OH to precipitate MoNs, wash with ethanol and ddH2O, collect by centrifugation, and freeze-dry (vacuum degree 14 Pa, temperature -30°C) to obtain nanoparticles recorded as MoNs dry powder.

[0067] Step 4: MoNs dry powder and mitomycin C were dispersed in 10 mL ddH2O at a mass ratio of 500 mg:10 mg, stirred at room temperature for 24 h, collected by centrifugation, washed with ethanol and ddH2O for multiple times, and freeze-dried (vacuum degree 14 Pa, temperature -30 ° C) to obtain smart nano-chemotherapeutic drugs recorded as MoNs@MyC dry powder.

[0068] The chemical composition of MoNs and MoNs@MyC was characterized by infrared spectroscopy, and the infrared spectra were shown in Figure 2. Figure 1 As shown by Figure 1 It can be seen that drug loading does not affect the basic structure of MoNs.

[0069] The distribution of each element in the MoNs@MyC nanocomposite was further characterized by high-resolution element analysis positioning (HTEM-mapping), and the high-resolution element analysis positioning (HTEM-mapping) diagram was obtained as shown in the figure. Figure 2 As shown by Figure 2 It can be seen that the positions of each element correspond one to one, which further illustrates that MoNs are successfully synthesized.

[0070] The particle size and morphology of the MoNs@MyC nanocomposite were characterized using a transmission electron microscope, and the transmission electron microscope (TEM) image was as follows: Figure 3 As shown by Figure 3 It can be found that the particle size is uniform and all are less than 10 nm.

[0071] The UV spectrum of MoNs@MyC nanocomposite was characterized by UV-visible-near infrared spectrophotometer, and its UV spectrum (UV) was obtained as shown in the figure Figure 4 As shown by Figure 4 It can be seen that MoNs@MyC exhibits significant ultraviolet absorption at 750-850nm.

[0072] Figure 5 The nanoparticles were exposed to 808 nm laser (NIR, 1 W / cm 2 ) Photothermal conversion efficiency data after 10 min of irradiation, including the UV absorption values ​​of MoNs@MyC solutions with different concentrations ( Figure 5 A) Heating curve of MoNs@MyC ( Figure 5 B), heating-cooling cycle curve ( Figure 5 C), and Lnθ-time photothermal conversion efficiency curve ( Figure 5 D).

[0073] The dynamic light scattering test was used to determine the hydrated particle size of MoNs@MyC under different pH conditions to further determine whether the material synthesis was successful and whether it had self-assembly properties. The Zeta potential change graph and dynamic light scattering graph (DLS) were obtained as shown in the figure. Figure 6 As shown by Figure 6 The results show that as the pH becomes smaller, the hydrated particle size of the material gradually increases, indicating that the material aggregates under weakly acidic conditions.

[0074] Colorectal cancer cells (CT26) were cultured in 24-well plates, with 1×10 5 Each well contained 1 mL of R1640 culture medium. After the cells were cultured in the incubator for 24 hours, the original culture medium was aspirated and 1 mL of fresh R1640 culture medium containing 500 mg / mL MoNs, 10 mg / mL MyC, and 500 mg / mL MoNs@MyC was added to the experimental groups respectively. After incubation for 12 hours, the cells were illuminated using a laser (NIR, 1 W / cm 2 ) for 5 min, and 4 hours later, the cell viability was tested using the AM / PI kit. Figure 7 A is the fluorescence imaging image. Figure 7 B is a statistical chart. The results show that there is no significant difference in the killing effect of each group without light. After 5 minutes of light exposure, the killing effect of MoNs@MyC is significantly improved by 28% compared with MyC, which indicates that MoNs@MyC can significantly kill colorectal cancer cells that have become heat-resistant after light exposure.

[0075] By changing the stirring speed in step 2 to 800 rpm and 400 rpm respectively, the hydrated particle size of the smart nano-chemotherapeutic drug is obtained by dynamic light scattering test, such as Figure 8 As shown; Test the surface charge distribution of smart nano-chemotherapeutic drugs - Zeta potential size, such as Fig. 9 As shown. Figure 8 and Fig. 9 It can be seen that the faster the stirring speed is, the faster the added sodium dihydrogen phosphate dodecahydrate can react with the ammonium molybdate tetrahydrate, and quickly nucleate in a short period of time to form a large number of nanomaterials with uniform and small particle sizes.

[0076] In summary, the smart nano-chemotherapeutic drug MoNs@MyC provided by the present invention can be applied to intraperitoneal hyperthermic perfusion chemotherapy. The prepared smart nano-chemotherapeutic drug MoNs@MyC has the characteristics of small size, high photothermal conversion efficiency and acid-responsive self-assembly, which can effectively solve the problems of kidney burden, cellular thermal tolerance and large toxic side effects in the drug metabolism process in the current intraperitoneal hyperthermic perfusion chemotherapy, and can effectively improve the therapeutic effect of intraperitoneal hyperthermic perfusion chemotherapy and improve the patient's prognosis.

[0077] 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 method for preparing an intelligent nano-chemotherapeutic drug, characterized in that: The following steps are involved: S1) mixing ammonium molybdate with water to obtain an ammonium molybdate solution; Mixing sodium dihydrogen phosphate with water to obtain a sodium dihydrogen phosphate solution; S2) mixing the ammonium molybdate solution and the sodium dihydrogen phosphate solution, stirring until colorless, to obtain a mixed solution; the molar ratio of the ammonium molybdate to the sodium dihydrogen phosphate is (40-60):1; S3) mixing the mixed solution with a reducing agent, and after reaction, adding an alcohol solvent for precipitation to obtain nanoparticles; the reducing agent is selected from L-sodium ascorbate and / or L-ascorbic acid; S4) mixing the nanoparticles with a chemotherapeutic drug in water to obtain an intelligent nano-chemotherapeutic drug; The chemotherapeutic drug is selected from mitomycin C.

2. The preparation method according to claim 1, characterized in that: The concentration of the ammonium molybdate solution is 0.1-1 mol / L; The concentration of the sodium dihydrogen phosphate solution is 0.1-0.5 mol / L.

3. The preparation method according to claim 1, characterized in that: The reducing agent is added in the form of a reducing agent solution; the mass concentration of the reducing agent solution is 100-200 mg / mL; The volume ratio of the mixed solution to the reducing agent solution is (3-10):1; The mass ratio of the nanoparticles to the chemotherapy drug is (40-60):

1.

4. The preparation method according to claim 1, characterized in that: The mixing speed in step S2) is 1000-2000 rpm; In step S3), the reaction is continued until a blue-black color appears, and an alcohol solvent is added to precipitate; The alcohol solvent is ethanol.

5. The preparation method according to claim 1, characterized in that: The particle size of the intelligent nano-chemotherapeutic drug is less than 10 nm.

6. The intelligent nano-chemotherapeutic drug prepared by any one of the preparation methods of claims 1 to 5.

7. Use of the intelligent nano-chemotherapeutic drug prepared by any one of the preparation methods of claims 1 to 5 in the preparation of drugs for intraperitoneal hyperthermic perfusion therapy.

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