A paclitaxel nanomaterial for treating breast cancer drug resistance, its preparation method and application

Abstract

The present invention discloses a paclitaxel nanomaterial for anti-breast cancer drug resistance and its preparation method and application, belonging to the field of nanomedicine technology. The nanomedicine for treating breast cancer disclosed by the present invention uses hyaluronic acid-modified iron metal organic framework MIL-100 (Fe) as a drug delivery carrier, loaded with paclitaxel and iFSP1, and the preparation method is simple. The paclitaxel nanomaterial for anti-breast cancer drug resistance of the present invention can improve the therapeutic effect of paclitaxel on breast cancer, and also shows good therapeutic effect on breast cancer resistant to paclitaxel.

Description

Technical Field

[0001] The invention belongs to the technical field of nano-drugs, and specifically relates to a paclitaxel nano-material for resisting breast cancer drug resistance, and a preparation method and application thereof. Background Art

[0002] Breast cancer is the most common female malignancy in the world and one of the main causes of cancer death in women. In recent years, as the most common cancer in Chinese women, the incidence and mortality of breast cancer in my country have been increasing year by year, and the age of onset is tending to be younger, which seriously endangers the health of Chinese women.

[0003] Paclitaxel (PTX) is one of the most widely used natural anticancer chemotherapy drugs and is often used as a first-line treatment for breast cancer. Due to the physical property that paclitaxel itself is insoluble in water, paclitaxel is mainly dissolved in a composite solvent of polyoxyethylene castor oil and anhydrous ethanol in clinical practice. Due to its low bioavailability, advanced nanotechnology is used to prepare paclitaxel liposomes and paclitaxel-albumin-bound complexes for use. At present, the only manufacturer of paclitaxel liposomes for injection in the domestic market is Luye Pharma, and the domestic manufacturers of paclitaxel-albumin include Shijiazhuang Pharmaceutical Group, Hengrui Group, Qilu Pharmaceutical, and Kelun Pharmaceutical. However, the therapeutic effect of paclitaxel in clinical applications is limited by its hydrophobicity, high toxicity, and lack of targeting. In addition, as a first-line anticancer drug, paclitaxel has been found to be resistant in a variety of cancer patients, including breast cancer patients, and is also one of the main causes of death related to treatment failure. The main solutions currently include P-glycoprotein (P-gp) inhibitors, proteasome inhibitors, ibrutinib or Chinese medicines such as baicalin and curcumin combined with paclitaxel to reverse paclitaxel resistance. Therefore, the development of paclitaxel-resistant anti-tumor drugs is an urgent problem to be solved. Summary of the invention

[0004] The purpose of the present invention is to provide a paclitaxel nanomaterial for anti-breast cancer resistance and its preparation method and application, which can improve the disadvantage of poor water solubility of paclitaxel, improve its tumor accumulation and bioavailability, and avoid its toxicity; secondly, a paclitaxel nanomaterial with stable structure and controllable particle size can be obtained. In addition, the nano drug externally connected with hyaluronic acid has the characteristics of actively targeting the CD44 receptor of breast cancer cells, thereby improving the accumulation of drugs in tumors. In addition, the iFSP in the nano drug can overcome the paclitaxel resistance of tumor cells by using the iron death mechanism, thereby also having a therapeutic effect on paclitaxel-resistant tumors.

[0005] To achieve the above-mentioned purpose, the present invention provides a paclitaxel nanomaterial for resisting breast cancer resistance, comprising a drug delivery carrier and paclitaxel (PTX) and FSP1 inhibitor (iFSP1) loaded on the carrier; the carrier is an iron-based metal organic framework (MIL-100(Fe)) modified with functionalized hyaluronic acid.

[0006] Furthermore, the loading amount of paclitaxel is 13-15%, and the loading amount of the FSP1 inhibitor is 2-4%.

[0007] Furthermore, the iron-based metal organic framework is a prismatic crystal with a particle size of 200 to 300 nm.

[0008] Furthermore, the present invention also provides a method for preparing a paclitaxel nanomaterial that is resistant to breast cancer drug resistance, comprising the following steps:

[0009] (1) Synthesis of PEGylated hyaluronic acid

[0010] The hyaluronic acid solution was mixed with NHS and EDC, and NH2-PEG-NH2 was added under stirring. After the reaction was completed, the hyaluronic acid was dialyzed and freeze-dried to obtain functionalized hyaluronic acid.

[0011] (2) Loading paclitaxel and FSP1 inhibitor

[0012] The iron-based metal organic framework was co-dissolved with paclitaxel and FSP1 inhibitor in an organic solution, and the nanomaterial HA-PEG-MIL-100@PTX / iFSP1 (HPM@Pi) was prepared after centrifugation and re-suspending with functionalized hyaluronic acid.

[0013] The mass ratio of the iron-based metal-organic framework to the functionalized hyaluronic acid is 1:2.

[0014] Furthermore, the concentration of the hyaluronic acid solution is 0.005 g / mL, the pH value is 9.0, and in the solution after mixing in step (1), the mass ratio of hyaluronic acid, NHS, EDC and NH2-PEG-NH2 is 10:25 to 30:30 to 45:20.

[0015] Furthermore, the reaction time of step (1) is 24 hours, and the dialysis conditions are: MWCO is 3500Da, and the dialysis time is 24 hours.

[0016] Furthermore, the mass ratio of the iron-based metal organic framework to paclitaxel and the FSP1 inhibitor is 5:1:0.1-0.3.

[0017] Furthermore, step (2) specifically includes the following process:

[0018] The iron-based metal organic framework, paclitaxel and FSP1 inhibitor were co-dissolved in an organic solution, and after ultrasonication for 30 minutes, the solution was stirred at room temperature until the volume was 1 / 4 of the original solution. Deionized water was added dropwise to continue evaporation to obtain an aqueous solution environment, and the stirring was continued for 24 hours.

[0019] The solution was recovered and the precipitate was collected by centrifugation, and the precipitate was resuspended with functionalized hyaluronic acid, stirred continuously for 24 hours, dialyzed, and freeze-dried to obtain the product.

[0020] Furthermore, the iron-based metal organic framework is prepared by the following method:

[0021] Add ferric chloride hexahydrate, potassium fluoride and nitric acid into water, then add trimesic acid and mix well, and react at 120°C for 24 hours to obtain the product.

[0022] Furthermore, the molar mass ratio of ferric chloride hexahydrate, potassium fluoride, nitric acid and trimesic acid is 3:3:3:2.

[0023] The invention also discloses the application of the above-mentioned paclitaxel nano material for resisting breast cancer drug resistance in the preparation (treatment) of breast cancer medicine.

[0024] Furthermore, the breast cancer is drug-resistant breast cancer.

[0025] In summary, the present invention has the following advantages:

[0026] 1. Metal-organic framework materials (MOFs) are a type of coordination polymer with adjustable pore size, highly stable structure and high specific surface area, which gives it a clear advantage in drug carriers. MIL-100 (Fe), a series of materials from the Lavahill framework (MIL) series, is a type of MOF. Compared with other metal ions, it is non-toxic and the raw materials are cheap and readily available. It also exhibits good drug loading performance, controlled release performance of molecules and imaging performance in terms of drug carriers. Therefore, the present invention uses MIL-100 (Fe) modified with surface hyaluronic acid as a drug delivery carrier, and then co-loads PTX and iFSP1 on the carrier to form a new type of nanomedicine, which has the advantages of high targeting, low toxicity and high anti-cancer efficiency.

[0027] 2. The anti-breast cancer resistant paclitaxel nanomaterial prepared by the present invention uses functionalized HA-modified MIL-100 (Fe) as a drug delivery system, which can actively target the surface of breast cancer cells, increase the accumulation of drugs in tumor cells, and improve drug absorption and efficacy.

[0028] 3. The anti-breast cancer resistant paclitaxel nanomaterial prepared by the present invention has the advantages of good biocompatibility, high drug loading, good safety, and tumor microenvironment response.

[0029] 4. When the paclitaxel-containing nanomaterial prepared by the present invention is used to prepare drugs for treating breast cancer, that is, when it is subsequently used to treat breast cancer, paclitaxel and iFSP1 can be released in drug-resistant tumor cells. The released drugs synergistically kill tumor cells, including tumor cells resistant to paclitaxel, through apoptosis and ferroptosis pathways, respectively. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Transmission electron microscope (TEM) image.

[0031] in, Figure 1 a is the transmission electron microscope (TEM) image of the prepared MIL-100(Fe), Figure 1 b is the transmission electron microscopy (TEM) image of the prepared HPM@Pi;

[0032] Figure 2 Dynamic light scattering (DLS) images of MIL-100(Fe) and HPM@Pi;

[0033] Figure 3 is the potential distribution diagram of MIL-100(Fe) and HPM@Pi;

[0034] Figure 4 is the infrared spectrum of HA-PEG-NH2;

[0035] Figure 5 is the UV spectrum of HPM@Pi;

[0036] Figure 6 is the infrared spectrum of HPM@Pi;

[0037] Figure 7 High performance liquid chromatography (HPLC) graph and standard curve for detecting HPM@Pi drug PTX;

[0038] Figure 8 High performance liquid chromatography (HPLC) graph and standard curve for detecting HPM@Pi drug iFSP1;

[0039] Fig. 9 is the relative release amount of PTX and iFSP1 in different GSH value environments;

[0040] Fig.10 is the hemolysis rate of HPM@Pi with different concentrations in blood measured by MIL-100(Fe);

[0041] Fig.11 The toxicity of different concentrations of HPM@Pi to paclitaxel-resistant cells MDA-MB-231 / PTX;

[0042] Fig.12The toxicity of different materials to paclitaxel-resistant cells MDA-MB-231 / PTX at the same concentration;

[0043] Fig.13 The phagocytosis of HPM@Pi and PM@Pi after administration of paclitaxel-resistant cells MDA-MB-231 / PTX after staining with rhodamine B;

[0044] Fig.14 The phagocytic activity of HPM@Pi stained with rhodamine B after administration of paclitaxel-resistant cell line MDA-MB-231 / PTX and endothelial cells HUVEC. DETAILED DESCRIPTION

[0045] The principles and features of the present invention are described below in conjunction with the examples, which are only used to explain the present invention and are not intended to limit the scope of the present invention. If no specific conditions are specified in the examples, the conditions are carried out according to conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0046] Example 1

[0047] This embodiment provides a paclitaxel nanomaterial for preventing and treating breast cancer, which is prepared by the following method:

[0048] (1) Synthesis of iron-based metal-organic frameworks

[0049] Weigh 420 mg (2 mmol) of trimesic acid (1,3,5-BTC), 811 mg (3 mmol) of ferric chloride hexahydrate (FeCl3·6H2O), and 174 mg (3 mmol) of potassium fluoride (KF).

[0050] First, add the water-insoluble BTC into the polytetrafluoroethylene liner. Then, dissolve the weighed FeCl3·6H2O and KF in 20 mL of water and add 3 mmol of nitric acid dropwise.

[0051] The solution was added to the liner and stirred thoroughly with BTC for 30 min. The liner was moved into a hydrothermal synthesis reactor and placed in an oven at 120°C for 24 h to obtain an orange product.

[0052] The obtained product was washed three times with 50 mL of water and 50 mL of anhydrous ethanol respectively, and finally dried under vacuum at 50° C. to obtain an orange solid product.

[0053] (2) Synthesis of PEG-functionalized HA

[0054] HA (10 mg), NHS (28.75 mg) and EDC (38.8 mg) were mixed with 2 mL of phosphate buffer solution (pH=9) and stirred at room temperature for 30 min.

[0055] Then, 20 mg of NH2-PEG-NH2 was added to the above mixture, and stirring was continued for 24 h.

[0056] The crude HA-PEG-NH2 was purified by dialysis (MWCO: 3500Da) for 24 hours. The dialyzed solution was recovered and freeze-dried to obtain a white granular solid, which was PEG-functionalized HA.

[0057] (3) Co-loading of paclitaxel and iFSP nanodrugs

[0058] 10 mg of MIL-100(Fe), 2 mg of PTX and 0.4 mg of iFSP1 were co-dissolved in 5 mL of methanol solution.

[0059] After ultrasonic treatment for 30 minutes, the solution was stirred at room temperature until the volume of the original solution reached 1 / 4, deionized water was added dropwise to continue evaporation to replace the aqueous solution environment and stirred for 24 hours, and the recovered solution was centrifuged to collect the precipitate (10 minutes, 10000 rpm).

[0060] The precipitate was resuspended with 10 mL of HA-PEG-NH2 aqueous solution (2 mg / mL) and stirred for 24 h. After dialyzed overnight (MWCO: 10000 Da), the recovered solution was freeze-dried to obtain an orange solid, which was the nanomaterial (drug) HA-PEG-MIL-100@PTX / iFSP1, abbreviated as HPM@Pi.

[0061] The TEM and DLS images of the orange solid product obtained in step (1) of Example 1 are as follows: Figure 1 As shown in a and 2, it can be seen that it has a prismatic crystal morphology, a particle size of about 203nm, and a potential of about -41mV ( Figure 3 ).

[0062] The infrared spectrum of the white granular solid obtained in step (2) of Example 1 is as follows: Figure 4 As shown, the formation of amide bonds indicated that PEG-functionalized HA was successfully prepared.

[0063] The TEM and DLS images of HPM@Pi prepared in Example 1 are as follows: Figure 1 b and Figure 2 As shown, it can be seen that the nano drug HPM@Pi has an irregular prismatic shape and a particle size of about 312nm. At the same time, it can be seen from the UV spectrum ( Figure 5), the HPM@Pi nanomaterial showed the characteristic peak of iFSP1 at around 280nm, indicating that iFSP1 was successfully loaded. Figure 6 The infrared results showed that the HPM@Pi group contained characteristic infrared peaks of each drug group, indicating that PTX was successfully loaded and HA-PEG-NH2 was successfully connected. The quality of the drug loaded in the nanoparticles was determined by high performance liquid chromatography (HPLC). Figure 7 and Figure 8 As shown in the figure, the calculation formula of drug loading rate is: drug loading rate (%) = (weight of loaded PTX or iFSP1) / (total weight of nanodrug)×100.

[0064] The calculation showed that the drug loading rate of PTX was 13.8% and that of iFSP1 was 2.3%.

[0065] Example 2

[0066] This embodiment provides a paclitaxel nanomaterial for preventing and treating breast cancer, which is prepared by the following method:

[0067] (1) Synthesis of iron-based metal-organic frameworks

[0068] Weigh 420 mg (2 mmol) of trimesic acid (1,3,5-BTC), 811 mg (3 mmol) of ferric chloride hexahydrate (FeCl3·6H2O), and 174 mg (3 mmol) of potassium fluoride (KF).

[0069] First, add the water-insoluble BTC into the polytetrafluoroethylene liner. Then, dissolve the weighed FeCl3·6H2O and KF in 20 mL of water and add 3 mmol of nitric acid dropwise.

[0070] The solution was added to the liner and stirred thoroughly with BTC for 30 min. The liner was moved into a hydrothermal synthesis reactor and placed in an oven at 120°C for 24 h to obtain an orange product.

[0071] The obtained product was washed three times with 50 mL of water and 50 mL of anhydrous ethanol respectively, and finally dried under vacuum at 50° C. to obtain an orange solid product.

[0072] (2) Synthesis of PEG-functionalized HA

[0073] HA (10 mg), NHS (30 mg) and EDC (40 mg) were mixed with 2 mL of phosphate buffer solution (pH = 9) and stirred at room temperature for 30 min.

[0074] Then, 20 mg of NH2-PEG-NH2 was added to the above mixture, and stirring was continued for 24 h.

[0075] The crude HA-PEG-NH2 was purified by dialysis (MWCO: 3500Da) for 24 hours. The dialyzed solution was recovered and freeze-dried to obtain a white granular solid, which was PEG-functionalized HA.

[0076] (3) Load

[0077] 10 mg of MIL-100(Fe), 2 mg of PTX and 0.5 mg of iFSP1 were co-dissolved in 5 mL of methanol solution.

[0078] After ultrasonic treatment for 30 minutes, the solution was stirred at room temperature until the volume of the original solution reached 1 / 4, deionized water was added dropwise to continue evaporation to replace the aqueous solution environment and stirred for 24 hours, and the recovered solution was centrifuged to collect the precipitate (10 minutes, 10000 rpm).

[0079] The precipitate was resuspended with 10 mL of HA-PEG-NH2 aqueous solution (2 mg / mL) and stirred for 24 h. After dialyzed overnight (MWCO: 10000 Da), the recovered solution was freeze-dried to obtain an orange solid, which was the nanodrug HA-PEG-MIL-100@PTX / iFSP1, abbreviated as HPM@Pi.

[0080] In this embodiment, the drug loading rate of PTX is 14.1%, and the drug loading rate of iFSP1 is 3.0%.

[0081] Example 3

[0082] This embodiment provides a paclitaxel nanomaterial for preventing and treating breast cancer, which is prepared by the following method:

[0083] (1) Synthesis of iron-based metal-organic frameworks

[0084] Weigh 420 mg (2 mmol) of trimesic acid (1,3,5-BTC), 811 mg (3 mmol) of ferric chloride hexahydrate (FeCl3·6H2O), and 174 mg (3 mmol) of potassium fluoride (KF).

[0085] First, add the water-insoluble BTC into the polytetrafluoroethylene liner. Then, dissolve the weighed FeCl3·6H2O and KF in 20 mL of water and add 3 mmol of nitric acid dropwise.

[0086] The solution was added to the liner and stirred thoroughly with BTC for 30 min. The liner was moved into a hydrothermal synthesis reactor and placed in an oven at 120°C for 24 h to obtain an orange product.

[0087] The obtained product was washed three times with 50 mL of water and 50 mL of anhydrous ethanol respectively, and finally dried under vacuum at 50° C. to obtain an orange solid product.

[0088] (2) Synthesis of PEG-functionalized HA

[0089] HA (10 mg), NHS (25.6 mg) and EDC (40.2 mg) were mixed with 2 mL of phosphate buffer solution (pH = 9) and stirred at room temperature for 30 min.

[0090] Then, 20 mg of NH2-PEG-NH2 was added to the above mixture, and stirring was continued for 24 h.

[0091] The crude HA-PEG-NH2 was purified by dialysis (MWCO: 3500Da) for 24 hours. The dialyzed solution was recovered and freeze-dried to obtain a white granular solid, which was PEG-functionalized HA.

[0092] (3) Load

[0093] 10 mg of MIL-100(Fe), 2 mg of PTX and 0.6 mg of iFSP1 were co-dissolved in 5 mL of methanol solution.

[0094] After ultrasonic treatment for 30 minutes, the solution was stirred at room temperature until the volume of the original solution reached 1 / 4, deionized water was added dropwise to continue evaporation to replace the aqueous solution environment and stirred for 24 hours, and the recovered solution was centrifuged to collect the precipitate (10 minutes, 10000 rpm).

[0095] The precipitate was resuspended with 10 mL of HA-PEG-NH2 aqueous solution (2 mg / mL) and stirred for 24 h. After dialyzed overnight (MWCO: 10000 Da), the recovered solution was freeze-dried to obtain an orange solid, which was the nanodrug HA-PEG-MIL-100@PTX / iFSP1, abbreviated as HPM@Pi.

[0096] In this embodiment, the drug loading rate of PTX is 13.2%, and the drug loading rate of iFSP1 is 2.4%.

[0097] Test Example 1

[0098] HPM@Pi obtained in Example 1 was used to prepare the nanodrug in order to evaluate the GSH-responsive release characteristics of PTX and iFSP1 in the nanodrug.

[0099] The nano drug was prepared into an aqueous solution, and 1 mL of the sample was placed in a dialysis bag with a MWCO of 1000 Da. Then, the dialysis bag was immersed in a normal pH environment (pH = 7.4) with or without GSH (2, 4, 8 mM) and shaken at 37°C. The PTX and iFSP1 contents in 1 mL of buffer outside the dialysis bag at different time intervals were measured by HPLC.

[0100] like Fig. 9As shown in the figure, at the same time interval, the release of PTX and iFSP1 increased with the increase of GSH concentration. In the same pH environment solution, GSH increased the release of PTX and iFSP1 from nanomedicine.

[0101] Test Example 2

[0102] The HPM@Pi obtained in Example 1 was used to detect the hemolytic reaction of the nanodrug. Whole blood was obtained from healthy mice using the eyeball blood sampling method, collected in an anticoagulant tube containing sodium citrate, and evenly shaken and centrifuged (3000rpm, 15min) to obtain red blood cells. The red blood cell solution diluted to 5% was incubated with 1% Triton X-100 (TrionX-100) and nanodrugs of different concentrations (5μg / mL, 10μg / mL, 20μg / mL, 40μg / mL, 80μg / mL, 160μg / mL) for 12h, and then centrifuged (3000rpm, 15min). The absorbance at 405nm was detected by an enzyme marker. The stability of the nanodrug in different media (H2O, PBS, DMEM, RPMI-1640 and Plasma) was detected. Fig.10 As shown in the figure, the hemolysis degree of HPM@Pi material is positively correlated with the concentration of nanomaterials, but the hemolysis rate is low even at the highest administration concentration, indicating that HPM@Pi has good biocompatibility.

[0103] Test Example 3

[0104] The MDA-MB-231 / PTX cells used in this experimental example and the following experimental examples are all paclitaxel-resistant cells.

[0105] MDA-MB-231 / PTX cells were plated in a 96-well plate so that each well contained approximately 4 × 10 3 cells, cultured for 12 h, at 0, 2.5, 5, 10, 20, 40 μg mL -1 HPM@Pi was administered to MDA-MB-231 / PTX cells at a concentration of PTX, and the cells were cultured for 24 h, washed with PBS, and CCK-8 detection solution (v / v: 10%) without fetal bovine serum (FBS) was added, and the cells were cultured at 37°C for another 1-2 h before detection. Cell viability was measured at 450 nm using an ELISA analyzer. Fig.11 As shown, HPM@Pi has a killing effect on the drug-resistant cell line MDA-MB-231 / PTX, and the toxicity increases in a concentration-dependent manner.

[0106] MDA-MB-231 / PTX cells were plated in a 96-well plate so that each well contained approximately 4 × 10 3 cells, cultured for 12 h, at 20 μg mL -1 of PTX and 3.3 μg mL -1Different drugs (PTX, HPM@PTX, HPM@iFSP1, HPM@Pi) were given at different iFSP1 concentrations, and the cells were cultured for 24 h. The cells were washed with PBS, and CCK-8 detection solution (v / v: 10%) without fetal bovine serum (FBS) was added. The cells were cultured for another 1-2 h at 37°C, and the cell viability was measured at 450 nm using an enzyme-labeled analyzer. Fig.12 As shown in the figure, compared with PTX at the same concentration, HPM@Pi has a stronger killing effect on the drug-resistant cell line MDA-MB-231 / PTX.

[0107] Test Example 4

[0108] MDA-MB-231 / PTX cells were plated on confocal plates so that each plate contained approximately 2×10 3 The cells were cultured for 12 h and washed with PBS. HPM@Pi and PM@Pi labeled with rhodamine B were administered for 12 h, washed with PBS, and DAPI was added to stain the cells. The stain was washed with PBS and examined using a confocal microscope.

[0109] MDA-MB-231 / PTX cells and HUVEC cells were placed on confocal plates so that each plate contained approximately 2×10 3 The cells were cultured for 12 h, washed with PBS, and then HPM@Pi labeled with rhodamine B was administered for 12 h. The cells were washed with PBS, and DAPI was added to stain the cells. The stain was washed with PBS and examined using a confocal microscope.

[0110] like Fig.13 As shown in the figure, there is a significant fluorescence difference after HPM@Pi and PM@Pi were administered to tumor cells, indicating that HPM@Pi is more easily internalized by cells; and after HPM@Pi was administered to different cells, normal cells showed a more obvious fluorescence intensity than cancer cells ( Fig.14 ), the above can successfully prove the targeting of HA to tumor cells.

[0111] Although the specific implementation of the present invention is described in detail in conjunction with the drawings, it should not be understood as limiting the scope of protection of this patent. Within the scope described in the claims, various modifications and variations that can be made by those skilled in the art without creative work still fall within the scope of protection of this patent.

Claims

1. A paclitaxel nanomaterial for resisting breast cancer drug resistance, characterized in that: It comprises a carrier and paclitaxel and a FSP1 inhibitor loaded on the carrier; the loading amount of the paclitaxel is 13-15%, and the loading amount of the FSP1 inhibitor is 2-4%; the carrier is an iron-based metal organic framework modified with functionalized hyaluronic acid; and the FSP1 inhibitor is iFSP1; The preparation method of the paclitaxel nanomaterial is as follows: (1) Synthetic PEGylated hyaluronic acid The hyaluronic acid solution was mixed with NHS and EDC, and NH2-PEG-NH2 was added under stirring. After the reaction was completed, the hyaluronic acid was dialyzed and freeze-dried to obtain functionalized hyaluronic acid. (2) Loading paclitaxel and FSP1 inhibitor The iron-based metal organic framework, paclitaxel and FSP1 inhibitor were co-dissolved in an organic solution, centrifuged, reacted with functionalized hyaluronic acid, and dialyzed to obtain a nano drug; The mass ratio of the iron-based metal organic framework to the functionalized hyaluronic acid is 1:

2.

2. The paclitaxel nanomaterial for resisting breast cancer drug resistance according to claim 1, characterized in that: The iron-based metal organic framework is a prismatic crystal with a particle size of 200-300 nm.

3. The method for preparing the anti-breast cancer drug-resistant paclitaxel nanomaterial according to claim 1 or 2, characterized in that: The following steps are involved: (1) Synthetic PEGylated hyaluronic acid The hyaluronic acid solution was mixed with NHS and EDC, and NH2-PEG-NH2 was added under stirring. After the reaction was completed, the hyaluronic acid was dialyzed and freeze-dried to obtain functionalized hyaluronic acid. (2) Loading paclitaxel and FSP1 inhibitor The iron-based metal organic framework, paclitaxel and FSP1 inhibitor were co-dissolved in an organic solution, centrifuged, reacted with functionalized hyaluronic acid, and dialyzed to obtain a nano drug; The mass ratio of the iron-based metal organic framework to the functionalized hyaluronic acid is 1:

2.

4. The method for preparing the paclitaxel nanomaterial for resisting breast cancer drug resistance according to claim 3, characterized in that: The concentration of the hyaluronic acid solution is 0.005 g / mL, and the pH value is 9. In the solution after mixing in step (1), the mass ratio of hyaluronic acid, NHS, EDC and NH2-PEG-NH2 is 10:25~30:30~45:

20.

5. The method for preparing the paclitaxel nanomaterial for resisting breast cancer drug resistance according to claim 3, characterized in that: The reaction time of step (1) is 20-30 h, and the dialysis conditions are: MWCO is 3500 Da, and the dialysis time is 20-30 h.

6. The method for preparing the paclitaxel nanomaterial for resisting breast cancer drug resistance according to claim 1, characterized in that: The mass ratio of the iron-based metal organic framework to paclitaxel and FSP1 inhibitor is 5:1:0.1-0.3; The iron-based metal organic framework is prepared by the following method: Add ferric chloride hexahydrate, potassium fluoride and nitric acid into water, then add trimesic acid and mix well, and react at 110-130℃ for 20-30h to obtain; The molar mass ratio of the ferric chloride hexahydrate, potassium fluoride, nitric acid and trimesic acid is 3:3:3:

2.

7. The method for preparing the paclitaxel nanomaterial with drug resistance against breast cancer according to claim 1, characterized in that: Step (2) specifically includes the following process: The iron-based metal organic framework, paclitaxel and FSP1 inhibitor were co-dissolved in an organic solution, and then stirred at room temperature until the volume of the original solution was 1 / 4 after ultrasonic treatment for 20-40 minutes. Deionized water was added dropwise to obtain an aqueous solution environment after continued evaporation, and the stirring was continued for 20-30 hours. The solution was recovered and the precipitate was collected by centrifugation, and the precipitate was resuspended with functionalized hyaluronic acid, and stirred continuously for 20 to 30 hours, dialyzed, and freeze-dried to obtain the product.

8. Use of the paclitaxel nanomaterial against breast cancer drug resistance as claimed in claim 1 or 2 in the preparation of breast cancer drugs.

9. The use according to claim 8, characterized in that The breast cancer is drug-resistant breast cancer.

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