Microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials and its application in the treatment of in situ triple-negative breast cancer

Abstract

The present invention discloses a microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials and its use in the in situ treatment of triple-negative breast cancer. The microneedle patch contains sorafenib and copper-doped Prussian blue nanomaterials within its needles. The microneedle patch can precisely deliver nanoparticles and sorafenib to tumor tissue, enhancing the chemokinetic effect through efficient and gentle photothermal therapy. The synergistic drug-induced ferroptosis of triple-negative breast cancer cells enhances ferroptosis, further inducing cell death. This provides a novel and promising treatment approach for in situ triple-negative breast cancer.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical device preparation, and specifically relates to a microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials, a preparation method thereof, and an application thereof in the treatment of in situ triple-negative breast cancer. Background Art

[0002] Currently, triple-negative breast cancer (TNBC) is considered an uncontrollable type of breast cancer due to the lack of conventional therapeutic targets, including estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2), resulting in relatively limited treatment options. Existing treatments include surgery, chemotherapy, and radiotherapy, but they suffer from numerous limitations, including low bioavailability, systemic toxicity, and poor targeting. Therefore, developing novel therapeutic strategies to improve efficacy and reduce side effects in the treatment of TNBC is imperative. In recent years, nanoparticles, due to their unique size and excellent physicochemical properties, have been widely used in chemodynamic therapy, photothermal therapy, sonodynamic therapy, and photodynamic therapy, showing great potential in the research of TNBC.

[0003] Ferroptosis is a novel, iron-dependent cell death pathway distinct from most other programmed cell death pathways, such as apoptosis and necrosis. Its core characteristic is the peroxidation of cell membrane phospholipids, leading to the accumulation of lipid peroxides (LPO), which in turn causes cell membrane rupture and cell death. Therefore, inducing ferroptosis has the potential to overcome multidrug resistance in tumors. Currently, various clinical drugs on the market, such as RSL3, Erastin, and sorafenib (SRF), have been studied as ferroptosis inducers. The Chemical Engineering Journal (Chemical Engineering Journal, Vol. 488, 2024, p. 150831) reported a modified iron-based mesoporous polydopamine (MPDA), called S@M-EF (Sorafenib@MPDA-EGCG-Fe), in which Sorafenib is a protein kinase inhibitor that reduces the synthesis of glutathione (GSH) by inhibiting glutathione (GSH)-related proteins. When glutathione levels decrease, the activity of glutathione peroxidase 4 (GPX4) decreases, and it is unable to effectively remove lipid peroxidation, resulting in the accumulation of lipid peroxides in cells, and ultimately inducing ferroptosis. However, the regulatory mechanism of ferroptosis is complex and involves the interaction of multiple signaling pathways. Sorafenib alone cannot effectively activate some necessary pathways, thereby limiting the occurrence of ferroptosis, and large-scale systemic administration can bring serious side effects such as diarrhea, rash, and hair loss. Therefore, it is necessary to explore new strategies such as combination therapy and targeted drug delivery to improve efficacy and reduce toxic side effects. Prussian blue (PB), as an antidote approved by the U.S. Food and Drug Administration (USFDA) for the treatment of poisoning by radioactive elements such as thallium, has been shown to have outstanding biosafety and has become a triple-negative breast cancer treatment drug with great clinical transformation prospects. However, the weak glutathione consumption capacity, low drug delivery efficiency, and excessively high traditional photothermal heating that causes inflammation have limited the use of Prussian blue in the treatment of triple-negative breast cancer. Therefore, there is an urgent need to develop a new Prussian blue drug delivery system to achieve a combined synergistic and effective treatment of triple-negative breast cancer. Advanced Science (Vol. 32, 2020, p. 2000542) reported a copper-rich Prussian blue nanodrug for the treatment of breast cancer by disulfiram in situ toxicity and photothermal anti-tumor amplification. Among them, iron-based nanoparticles can consume glutathione by regulating iron ion levels and Fenton reaction, thereby indirectly affecting the function of glutathione peroxidase 4, resulting in lipid peroxides that cannot be effectively reduced, accumulate and induce cell membrane damage and ferroptosis, and are expected to serve as a new type of ferroptosis inducer. In addition, studies have shown that exogenous copper can increase the ubiquitination of glutathione peroxidase 4, which can directly inactivate glutathione peroxidase 4 and inhibit its function, making it unable to clear excessive lipid peroxides and exacerbating the development of ferroptosis.

[0004] In summary, by combining copper / iron-based nanoparticles with clinical ferroptosis inducers, not only can the side effects of clinical drugs be reduced, but it can also help improve the efficacy of ferroptosis-based triple-negative breast cancer treatment. Summary of the Invention

[0005] The present invention provides a microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials and its application in the in situ treatment of triple-negative breast cancer. The technical problem to be solved is: to construct a transdermal drug delivery system to achieve the synergistic induction of ferroptosis by sorafenib and copper-doped Prussian blue nanomaterials, thereby treating triple-negative breast cancer.

[0006] In order to solve the technical problem, the present invention adopts the following technical solution:

[0007] The present invention first discloses a microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials, which is characterized in that: the microneedle patch comprises a backing layer and a needle array arranged on the backing layer; the backing layer and the needle array are both formed from an aqueous solution of a degradable polymer, and sorafenib and copper-doped Prussian blue nanomaterials are loaded in the aqueous solution of the degradable polymer used to form the needle array.

[0008] Furthermore, the degradable polymers used in the backing layer and the needle array are each independently selected from at least one of hyaluronic acid, polyvinyl pyrrolidone, and polyvinyl alcohol. The concentration of the degradable polymer in the aqueous solution used to form the backing layer is 1-3 g / mL, and the concentration of the degradable polymer in the aqueous solution used to form the needle array is 0.01-0.05 g / mL.

[0009] Furthermore, the concentration of the copper-doped Prussian blue nanomaterial in the aqueous solution of the degradable polymer used to form the needle array is 10-20 mg / mL, and the concentration of sorafenib is 1-2 mg / mL.

[0010] Furthermore, each needle in the needle array is pyramid-shaped, and the height of each needle in the needle array can be set as needed to ensure that it can directly act on the lesion site.

[0011] The present invention also discloses a method for preparing the microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterial, comprising the following steps:

[0012] dissolving a degradable polymer in deionized water to obtain a backing layer solution;

[0013] Dissolve the degradable polymer in deionized water, add sorafenib and copper-doped Prussian blue nanomaterials, and stir in the dark at room temperature for 12-24 hours to obtain a needle mixture;

[0014] The needle body mixture is filled into the needle body micropores of the microneedle mold, the excess part outside the micropores is removed, and then the backing layer solution is added above the micropores. Vacuum and dry, and then the mold is removed to obtain a microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials.

[0015] The microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials obtained by the present invention can be used for transdermal drug delivery to treat in situ triple-negative breast cancer, combined with mild photothermal therapy (≤42°C) during the treatment process. The present invention constructs a microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials using a soluble polymer microneedle drug delivery system. Based on the synergistic effect of iron / copper ions and sorafenib, it achieves the treatment of in situ triple-negative breast cancer by co-inducing ferroptosis.

[0016] Compared with the prior art, the beneficial effects of the present invention are embodied in:

[0017] 1. The present invention prepares soluble microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials for the first time. The preparation method is simple, the reaction conditions are mild, the obtained product has uniform morphology, and the production cost is low, which is suitable for industrial scale-up production.

[0018] 2. The microneedles loaded with sorafenib (SRF) and copper-doped Prussian blue (Cu-PB) nanomaterials prepared in the present invention can achieve rapid dissolution and accurately deliver Cu-PB and SRF to tumor tissues through transdermal administration, achieving more accurate drug release, smaller dosage, and better biocompatibility.

[0019] 3. The microneedles prepared by the present invention can release Cu 2+ Ubiquitination of GPX4 renders it inactive, directly leading to a decrease in the cell's resistance to oxidative stress.

[0020] 4. The microneedles prepared by the present invention can release Fe 3+ and Cu 2+ The generation of ·OH through Fenton / Fenton-like reaction and endogenous H2O2, and the released SRF inhibiting the production of GSH, indirectly reduce GPX4 activity and induce oxidative stress, which synergizes with the ferroptosis caused by the increase of highly toxic ·OH, ultimately leading to enhanced ferroptosis and inducing cell death.

[0021] 5. The microneedles prepared by the present invention can locally release sorafenib and Fe 3+ and Cu 2+ Ions not only significantly reduce the dosage and toxic side effects of sorafenib, but also synergistically induce cell ferroptosis, showing better therapeutic effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1This is a transmission electron microscope image of the copper-doped Prussian blue nanomaterial prepared in the example;

[0023] Figure 2 is the X-ray diffraction pattern of the copper-doped Prussian blue nanomaterial prepared in the embodiment;

[0024] Figure 3 This is an optical image of the microneedle prepared in Example 1;

[0025] Figure 4 This is a bright field image of the microneedle patch prepared in Example 1 obtained by ultra-depth-of-field microscopy;

[0026] Figure 5 This is a scanning electron microscope image of the microneedle prepared in Example 1;

[0027] Figure 6 Force and displacement images of the microneedles prepared in Example 1 and Comparative Example 1;

[0028] Figure 7 Near-infrared thermal images of the microneedles prepared in Example 1 and Comparative Example 1

[0029] Figure 8 The effect of each group of microneedles on 4T1 cell viability as the concentration of the functional components in the cell system changes in Example 4;

[0030] Figure 9 The flow cytometry results of each group of microtargets on 4T1 cells in Example 4 are shown;

[0031] Figure 10 The volume change curves of tumor tissues dissected from each treatment group in Example 5;

[0032] Figure 11 These are H&E staining images of tumor tissues dissected from each treatment group in Example 5;

[0033] Figure 12 GPX4 staining images of tumor tissues dissected from each treatment group in Example 5;

[0034] Figure 13 These are the results of lipid peroxidation determination of the tumor tissues dissected from each treatment group in Example 5. DETAILED DESCRIPTION

[0035] The following is a detailed description of an embodiment of the present invention. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process. However, the protection scope of the present invention is not limited to the following embodiment.

[0036] The copper-doped Prussian blue nanoparticles used in the following examples were prepared as follows: 1584 mg of potassium ferricyanide and 36 g of polyvinyl pyrrolidone were added to 360 mL of water and thoroughly dissolved. 300 μL of 36% hydrochloric acid solution was then added and magnetically stirred for 1 hour. The resulting yellow mixture was heated in an 80°C oil bath for 24 hours, washed (three times with deionized water and once with anhydrous ethanol), and then lyophilized to obtain solid Prussian blue nanoparticles, which were stored at room temperature. The prepared Prussian blue nanoparticles (20 mg) were then placed in 8 mL of water containing 27 mg of sodium citrate, and polyvinyl pyrrolidone (100 mg) was added. After thorough ultrasonic dissolution, 8.8 mg of copper acetate was added. The resulting blue solution was stirred at room temperature for 24 hours, washed (three times with deionized water and once with anhydrous ethanol), and then lyophilized to obtain solid copper-doped Prussian blue nanoparticles, which were stored at room temperature. Figure 1 This is a transmission electron microscope image of the prepared copper-doped Prussian blue nanomaterial. It can be clearly seen from the image that the nanomaterial has uniform size. Figure 2 This is the X-ray diffraction pattern of the prepared copper-doped Prussian blue nanoparticles. It can be seen from the figure that copper doping does not change the crystal phase of Prussian blue.

[0037] Comparative Example 1

[0038] This comparative example prepares a pure hyaluronic acid microneedle patch without sorafenib and copper-doped Prussian blue nanomaterials:

[0039] Weigh 0.5g of hyaluronic acid and add it to 10mL of deionized water in the dark and stir for 24h to form a transparent and uniform colloidal mixture. Then use a pipette to add the colloidal mixture dropwise to the microneedle mold, and then place it in a vacuum box for vacuum treatment until the air is completely extracted. Fill the colloidal mixture into the micropores of the needle body of the microneedle mold, remove the excess part outside the micropores, and then add 1.5g / mL of PVP solution. Then place it in a vacuum box for vacuum treatment until the air is completely extracted. Then place the mold in a 40°C oven in the dark and dry overnight. Finally, gently peel the formed microneedles from the mold to obtain a microneedle patch (denoted as HA@MN).

[0040] Example 1

[0041] In this example, a hyaluronic acid microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials was prepared:

[0042] 0.5 g of hyaluronic acid, 0.15 g of copper-doped Prussian blue nanomaterial, and 0.015 g of sorafenib were weighed and added to 10 mL of deionized water in the dark and stirred for 24 h to form a uniform colloidal mixture. The colloidal mixture was then added dropwise to the microneedle mold using a pipette, and then placed in a vacuum chamber for evacuation until the air was completely removed. The colloidal mixture was filled into the micropores of the microneedle mold. The excess outside the micropores was removed, and then 1.5 g / mL of PVP solution was added. The mold was then placed in a 40°C oven in the dark and dried overnight. Finally, the formed microneedles were gently peeled off from the mold to obtain a microneedle patch (denoted as Cu-PB+SRF@MN).

[0043] Multiple microneedle patches were prepared repeatedly according to the above method, and then dissolved in 1 mL of deionized water respectively. After UV and ICP determination, the concentration of copper-doped Prussian blue nanomaterials in water was 100-200 μg / mL, and the concentration of sorafenib was 5-10 μg / mL.

[0044] Figure 3 This is an optical picture of the microneedles prepared in Example 1. It can be seen from the picture that the microneedle patch is a 12*12 array, and its corresponding backing layer is a circle with a diameter of 1 cm.

[0045] Figure 4 This is a bright field side view of the microneedle prepared in Example 1 under an ultra-depth microscope (Easyzoom ultra-depth microscope). It can be seen from the figure that the microneedle has a sharp needle tip.

[0046] Figure 5 This is a scanning electron microscope image (ZEISS Gemini SEM 300 field emission scanning electron microscope) of the microneedle prepared in Example 1. The overall appearance of the microneedle can be clearly seen from the image.

[0047] Figure 6 These force and displacement images show the Cu-PB+SRF@MN prepared in Example 1 and the HA@MN prepared in Comparative Example 1. The test method involved applying downward pressure with the microneedle array facing upward, and measuring the displacement of the microneedles under varying pressures. The images demonstrate that the mechanical properties of the microneedles are significantly enhanced by the introduction of nanomaterials and drugs.

[0048] Figure 7 The near-infrared thermal images of Cu-PB+SRF@MN prepared in Example 1 and HA@MN prepared in Comparative Example 1 were obtained by using a near-infrared thermal imager with a wavelength of 808 nm and a wavelength of 1 W / cm 2 The laser illuminated the microneedle array and recorded photothermal images at different exposure times. The images show that the photothermal performance of the microneedles was greatly enhanced by the introduction of nanomaterials and drugs, and the maximum temperature of the Cu-PB+SRF@MN never exceeded 42°C.

[0049] Example 2

[0050] In this example, a hyaluronic acid microneedle patch containing only sorafenib was prepared:

[0051] Weigh 0.5g of hyaluronic acid and 0.015g of sorafenib and add them to 10mL of deionized water in the dark and stir for 24h to form a uniform colloidal mixture. Then use a pipette to add the colloidal mixture dropwise to the microneedle mold, and then place it in a vacuum box for vacuum treatment until the air is completely extracted. The colloidal mixture is filled into the micropores of the needle body of the microneedle mold. The excess outside the micropores is removed, and then 1.5g / mL of PVP solution is added. The mold is then placed in a 40°C oven in the dark and dried overnight. Finally, the formed microneedles are gently peeled off from the mold to obtain a microneedle patch (denoted as SRF@MN).

[0052] Example 3

[0053] This example prepares a hyaluronic acid microneedle patch containing only copper-doped Prussian blue nanomaterials:

[0054] 0.5g of hyaluronic acid and 0.15g of copper-doped Prussian blue nanomaterial were weighed and added to 10mL of deionized water in the dark and stirred for 24h to form a uniform colloidal mixture. The colloidal mixture was then added dropwise to the microneedle mold using a pipette, and then placed in a vacuum oven for evacuation until the air was completely removed. The colloidal mixture was filled into the micropores of the microneedle mold. The excess outside the micropores was removed, and then 1.5g / mL of PVP solution was added. The mold was then placed in a 40°C oven to dry in the dark overnight. Finally, the formed microneedles were gently peeled off from the mold to obtain a microneedle patch (denoted as Cu-PB@MN).

[0055] Example 4

[0056] In this example, the in vitro cell experiment of the microneedles prepared in the above example was carried out according to the following steps:

[0057] Seven experimental groups were set up: 1: control microneedle group (-), 2: control microneedle group (+), 3: sorafenib microneedle group (-), 4: copper-doped Prussian blue microneedle group (-), 5: copper-doped Prussian blue microneedle group (+), 6: sorafenib and copper-doped Prussian blue microneedle group (-), and 7: sorafenib and copper-doped Prussian blue microneedle group (+). Within the groups, (-) represents no light exposure, and (+) represents light exposure.

[0058] After reviving, the 4T1 cells were cultured until they filled the cell flask and were in the logarithmic growth phase. The cells were plated and cultured overnight. The materials of each group (corresponding to groups 3, 4, 6, and 7) were added and incubated for 24 hours. Cell viability was then tested. Figure 8The figure shows the effect of varying concentrations of the functional components in the microneedle system (the amount of sorafenib added to the microneedle is quantified as sorafenib; the amount of copper-doped Prussian blue added to the microneedle is quantified as copper-doped Prussian blue; the amount of sorafenib and copper-doped Prussian blue added to the microneedle is measured as the total amount of sorafenib and copper-doped Prussian blue) on 4T1 cell viability. It can be seen that compared to SRF@MN and Cu-PB@MN alone, Cu-PB+SRF@MN has a significantly enhanced tumor cell killing effect under mild light.

[0059] After 4T1 cells were revived and cultured until they filled the cell flask and were in the logarithmic growth phase, they were plated and cultured overnight. Each group of materials was added (the concentration of sorafenib microneedles in the cell system was quantified by sorafenib, which was 5 μg / mL; the concentration of copper-doped Prussian blue microneedles in the cell system was quantified by copper-doped Prussian blue, which was 100 μg / mL; the concentration of sorafenib and copper-doped Prussian blue microneedles in the cell system was measured by the total amount of sorafenib and copper-doped Prussian blue, which was 100 μg / mL). The cells were incubated for 24 h. After the incubation was completed, PI and FITC dyes were added for co-staining. The cells were incubated for 30 min and flow cytometry was performed on a cell analysis system. The results are shown in the figure. Figure 9 As shown in the figure, the cell survival rates in groups 1 to 5 were higher, indicating a lower degree of induced apoptosis. Groups 6 and 7 had a higher cell-killing effect, indicating that the prepared microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials can effectively induce tumor cell apoptosis under mild photothermal conditions, with the strongest killing effect, demonstrating its significant therapeutic effect against triple-negative breast cancer.

[0060] Example 5

[0061] This example tests the therapeutic effect of the microneedles prepared in the above example on triple-negative breast cancer according to the following steps:

[0062] Mice were randomly divided into the following groups: 1 (control microneedle group (-), 2 (control microneedle group (+), 3 (sorafenib microneedle group (-), 4 (copper-doped Prussian blue microneedle group (-), 5 (copper-doped Prussian blue microneedle group (+), 6 (sorafenib and copper-doped Prussian blue microneedle group (-), and 7 (sorafenib and copper-doped Prussian blue microneedle group (+)). (In each group, (-) represents no light exposure, and (+) represents light exposure.) Five mice were assigned to each group. An orthotopic triple-negative breast cancer model was established by injecting 4T1 cells into the fourth pair of right mammary glands of mice via an insulin needle. The day the model was successfully established was designated Day 0. Treatment consisted of applying pressure to the skin with a microneedle patch to reach the lesion site, maintaining pressure for 5 minutes. For the photothermal group, 808nm near-infrared light was applied simultaneously with pressure (controlling the microneedle temperature rise to approximately 42°C). Treatments were given every two days for a total of two treatments.

[0063] Control microneedle group: pure hyaluronic acid microneedles of Comparative Example 1 were administered to model mice;

[0064] Sorafenib microneedle group: The model mice were administered with hyaluronic acid microneedles containing only sorafenib as described in Example 2;

[0065] Copper-doped Prussian blue microneedle group: The model mice were administered with hyaluronic acid microneedles containing only copper-doped Prussian blue nanomaterials as described in Example 3;

[0066] Sorafenib and copper-doped Prussian blue microneedle group: The hyaluronic acid microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials of Example 1 were administered to the modeled mice.

[0067] Figure 10 The volume change curves of tumor tissues in each treatment group in this embodiment are shown in FIG. As can be seen from the figure, compared with groups 1 to 6, the tumor size of group 7 is much smaller than that of the tumors in the other groups after treatment.

[0068] Figure 11 HE staining of dissected tumor tissue from each treatment group in this example. As can be seen from the figure, groups 1-5 show a high number of intact blue nuclei, indicating less tumor cell necrosis. Groups 6-7, loaded with sorafenib and copper-doped Prussian blue nanomaterials, all showed varying degrees of necrosis. This demonstrates that the prepared microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials can effectively induce tumor cell necrosis under gentle photothermal conditions, demonstrating the strongest killing effect, demonstrating their significant therapeutic efficacy against triple-negative breast cancer.

[0069] Figure 12 Figure 4 shows GPX4 staining of dissected tumor tissue from each treatment group in this example. As can be seen, compared to the green fluorescence in Groups 1 and 2, Groups 3 to 6 all showed varying degrees of reduction in green fluorescence, indicating that both sorafenib and the copper-doped Prussian blue nanomaterials alone depleted GPX4 to some extent. However, Group 7, containing both sorafenib and the copper-doped Prussian blue nanomaterials, exhibited the strongest GPX4 depletion under mild illumination, resulting in the least green fluorescence. This demonstrates that the prepared microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials can effectively reduce GPX4 under mild illumination, demonstrating their significant therapeutic efficacy against triple-negative breast cancer.

[0070] Figure 13The lipid peroxide concentrations measured in tumor tissue from each treatment group in this example are shown in the figure. Groups 1-5 had lower lipid peroxide concentrations, indicating a lower degree of ferroptosis induction. Groups 6-7 had higher lipid peroxide concentrations, indicating that the prepared microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials can effectively induce tumor cell necrosis under mild photothermal conditions, demonstrating the strongest ability to induce ferroptosis, demonstrating a significant therapeutic effect against triple-negative breast cancer.

[0071] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials, characterized by: The microneedle patch includes a backing layer and a needle array arranged on the backing layer; the backing layer and the needle array are both formed from an aqueous solution of a degradable polymer, and the aqueous solution of the degradable polymer used to form the needle array is loaded with sorafenib and copper-doped Prussian blue nanomaterials.

2. The microneedle patch containing sorafenib and copper-doped Prussian blue nanomaterials according to claim 1, characterized in that: The degradable polymers used in the backing layer and the needle array are independently selected from at least one of hyaluronic acid, polyvinyl pyrrolidone and polyvinyl alcohol.

3. The microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterial according to claim 1 or 2, characterized in that: The concentration of the degradable polymer in the aqueous solution of the degradable polymer used to form the backing layer is 1-3 g / mL, and the concentration of the degradable polymer in the aqueous solution of the degradable polymer used to form the needle array is 0.01-0.05 g / mL.

4. The microneedle patch containing sorafenib and copper-doped Prussian blue nanomaterials according to claim 1, characterized in that: The concentration of the copper-doped Prussian blue nanomaterial in the aqueous solution of the degradable polymer used to form the needle array is 10-20 mg / mL, and the concentration of sorafenib is 1-2 mg / mL.

5. The microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials according to claim 1, characterized in that: Each needle in the needle array is pyramid-shaped.

6. A method for preparing a microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials according to any one of claims 1 to 5, characterized in that: The steps include: dissolving a degradable polymer in deionized water to obtain a backing layer solution; Dissolve the degradable polymer in deionized water, add sorafenib and copper-doped Prussian blue nanomaterials, and stir in the dark at room temperature for 12-24 hours to obtain a needle mixture; The needle body mixture is filled into the needle body micropores of the microneedle mold, the excess part outside the micropores is removed, and then the backing layer solution is added above the micropores. Vacuum and dry, and then the mold is removed to obtain a microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials.

7. Use of the microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterial according to any one of claims 1 to 5 in the preparation of a drug for transdermal administration to treat in situ triple-negative breast cancer.

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