Microneedle patch loaded with sorafenib and copper-doped Prussian blue nano material and application of microneedle patch in in-situ triple-negative breast cancer treatment

Abstract

The invention discloses a microneedle patch loaded with a sorafenib and copper-doped Prussian blue nano material and application of the microneedle patch in in-situ triple-negative breast cancer treatment. The sorafenib and the copper-doped Prussian blue nano material are loaded in a needle body of the microneedle patch. The microneedle patch can accurately deliver nanoparticles and sorafenib to tumor tissues, the chemical kinetics effect is enhanced through an efficient and mild photothermal therapy, the ferroptosis of triple negative breast cancer cells is enhanced through ferroptosis induced by the nanoparticles and sorafenib in cooperation with drugs, then cell death is induced, and the curative effect is improved. And a brand-new and promising treatment method is provided for in-situ triple-negative breast cancer treatment.

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 because it lacks conventional therapeutic targets, including estrogen, progesterone, and human epidermal growth factor receptor 2 receptors, and its treatment options are relatively limited. Existing treatments include surgery, chemotherapy, and radiotherapy, but they have many limitations such as low bioavailability, systemic toxicity, and poor targeting. Therefore, it is imperative to develop new therapeutic strategies in the treatment of triple-negative breast cancer to improve efficacy and reduce side effects. In recent years, nanoparticles have been widely used in chemodynamic therapy, photothermal therapy, sonodynamic therapy, and photodynamic therapy due to their unique size and excellent physicochemical properties, showing great potential in the study of triple-negative breast cancer.

[0003] Ferroptosis is a new type of cell death that is different from traditional apoptosis, necrosis and other programmed cell death. Its core feature is the accumulation of lipid peroxides (LPO) caused by the peroxidation of cell membrane phospholipids, which leads to cell membrane rupture and cell death. Therefore, inducing ferroptosis can show the potential to overcome tumor multidrug resistance. Various clinical drugs on the market, such as RSL3, Erastin and sorafenib (SRF), have been studied as ferroptosis inducers. The Journal of Chemical Engineering (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 inhibits glutathione (GSH)-related proteins and thus reduces the synthesis of glutathione. When the level of glutathione decreases, the activity of glutathione peroxidase 4 (GPX4) decreases, and lipid peroxidation cannot be effectively removed, resulting in the accumulation of intracellular lipid peroxides, 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 cause 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 United States 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 excessive inflammation caused by traditional photothermal heating limit 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 effective combined synergistic treatment of triple-negative breast cancer. "Advanced Science" (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 reactions, thereby indirectly affecting the function of glutathione peroxidase 4, resulting in lipid peroxides that cannot be effectively reduced, accumulating and inducing cell membrane damage and ferroptosis, which is expected to be used 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 aggravating 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 application thereof in in situ treatment of triple-negative breast cancer. The technical problem to be solved is: constructing a transdermal drug delivery system to achieve 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 firstly 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 by 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] Further, 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. 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.

[0009] Furthermore, the concentration of 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 in a pyramid shape, and the height of each needle in the needle array can be set as required 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 nanomaterials, comprising the following steps:

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

[0013] The degradable polymer is dissolved in deionized water, and then sorafenib and copper-doped Prussian blue nanomaterials are added, and stirred at room temperature in the dark for 12-24 hours to obtain a needle body 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, vacuumed, dried, and then demolded 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 administration to treat in situ triple-negative breast cancer, and mild photothermal (≤42°C) is combined during the treatment process. The present invention constructs a microneedle patch loaded with sorafenib and copper-doped Prussian blue nanomaterials in a soluble polymer microneedle drug release system, and achieves the treatment of in situ triple-negative breast cancer by co-inducing ferroptosis based on the synergistic effect of iron / copper ions and sorafenib.

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

[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 products have 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 by 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, which directly leads to reduced resistance of cells 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 the activity of GPX4 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 in 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, demonstrating better therapeutic effects. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

[0025] Figure 4 This is a bright field image of the microneedle patch prepared in Example 1 taken under ultra-depth 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] Fig. 9 The flow cytometry results of each group of microtargets on 4T1 cells in Example 4;

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

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

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

[0034] Fig.13 These are the results of lipid peroxidation measurement of 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 on the premise of the technical solution of the present invention, and a detailed implementation method and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiment.

[0036] The preparation method of the copper-doped Prussian blue nanoparticles used in the following examples is as follows: 1584 mg potassium ferrocyanide and 36 g polyvinyl pyrrolidone are added to 360 mL water for full dissolution, and then 300 μL of a 36% hydrochloric acid solution is added and magnetically stirred for 1 h. The resulting yellow mixture is heated in an oil bath at 80° C. for 24 hours, washed (first washed three times with deionized water, then washed once with anhydrous ethanol), and then freeze-dried to obtain solid Prussian blue nanoparticles, which are stored at room temperature. The prepared Prussian blue nanoparticles (20 mg) are then placed in 8 mL water containing 27 mg sodium citrate, and polyvinyl pyrrolidone (100 mg) is added thereto. After full ultrasonic dissolution, 8.8 mg of copper acetate is added, and the resulting blue solution is stirred at room temperature for 24 hours, washed (first washed three times with deionized water, then washed once with anhydrous ethanol), and then freeze-dried to obtain solid copper-doped Prussian blue nanoparticles, which are 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, stir for 24h in the dark, and form a transparent and uniform colloidal mixture. Then use a pipette to drop the colloidal mixture onto the microneedle mold, and then put it into a vacuum box for vacuum treatment until the air is completely extracted, so that the colloidal mixture is filled into the micropores of the needle body of the microneedle mold, remove the excess outside the micropores, and then add 1.5g / mL of PVP solution, and then put it into a vacuum box for vacuum treatment until the air is completely extracted, and then put the mold into a 40°C oven to dry overnight in the dark, and finally gently peel the formed microneedles from the mold to obtain a microneedle patch (referred to 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] Weigh 0.5g of hyaluronic acid, 0.15g of copper-doped Prussian blue nanomaterials and 0.015g of sorafenib and add them to 10mL of deionized water and stir for 24h in the dark to form a uniform colloidal mixture. Then use a pipette to drop the colloidal mixture onto the microneedle mold, and then put it into a vacuum box for vacuum treatment until the air is completely extracted, so that the colloidal mixture is filled into the micropores of the needle body of the microneedle mold, remove the excess outside the micropores, and then add 1.5g / mL of PVP solution, and then put the mold into a 40°C oven to dry overnight in the dark, and finally gently peel the formed microneedle from the mold to obtain a microneedle patch (referred to 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. 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 as determined by UV and ICP.

[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 The force and displacement images of Cu-PB+SRF@MN prepared in Example 1 and HA@MN prepared in Comparative Example 1 are shown in Figure 1. The test method is: with the needle array part of the microneedle facing upward, pressure is applied from top to bottom to test the displacement of the microneedle under different pressures. It can be seen from the figure that the mechanical properties of the microneedle are greatly 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 tested using 808 nm and 1 W / cm 2 The laser was used to illuminate the needle array part, and the photothermal images were recorded at different irradiation times. It can be seen from the figure that the photothermal performance of the microneedle was greatly enhanced by the introduction of nanomaterials and drugs, and the highest temperature of 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 and stir for 24h in the dark to form a uniform colloidal mixture. Then use a pipette to drop the colloidal mixture onto the microneedle mold, and then put it into a vacuum box for vacuum treatment until the air is completely extracted, so that the colloidal mixture is filled into the micropores of the needle body of the microneedle mold, remove the excess outside the micropores, and then add 1.5g / mL of PVP solution, and then put the mold into a 40℃ oven to dry overnight in the dark, and finally gently peel the formed microneedles 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] Weigh 0.5g of hyaluronic acid and 0.15g of copper-doped Prussian blue nanomaterials and add them to 10mL of deionized water and stir for 24h in the dark to form a uniform colloidal mixture. Then use a pipette to drop the colloidal mixture onto the microneedle mold, and then put it into a vacuum box for vacuum treatment until the air is completely extracted, so that the colloidal mixture is filled into the micropores of the needle body of the microneedle mold, remove the excess outside the micropores, and then add 1.5g / mL of PVP solution, and then put the mold into a 40°C oven to dry overnight in the dark, and finally gently peel the formed microneedles from the mold to obtain a microneedle patch (referred to 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 groups of experiments were set up: 1 for the control microneedle group (-), 2 for the control microneedle group (+), 3 for the sorafenib microneedle group (-), 4 for the copper-doped Prussian blue microneedle group (-), 5 for the copper-doped Prussian blue microneedle group (+), 6 for the sorafenib and copper-doped Prussian blue microneedle group (-), and 7 for the sorafenib and copper-doped Prussian blue microneedle group (+). In the groups, (-) represents no light exposure, and (+) represents light exposure.

[0058] After 4T1 cells were revived, they were cultured until they filled the cell bottle and were in the logarithmic growth phase, then plates were plated, and each group of materials (corresponding to groups 3, 4, 6, and 7) were added after overnight culture. After incubation for 24 hours, cell viability tests were performed. Figure 8The effect of the concentration change of the functional components in the microneedle (the amount of sorafenib microneedle added is quantified by sorafenib; the amount of copper-doped Prussian blue microneedle added is quantified by copper-doped Prussian blue; the amount of sorafenib and copper-doped Prussian blue microneedle added is measured by the total amount of sorafenib and copper-doped Prussian blue) in the cell system on the viability of 4T1 cells. It can be seen that compared with SRF@MN and Cu-PB@MN alone, Cu-PB+SRF@MN has a significantly improved tumor cell killing effect under mild light.

[0059] After 4T1 cells were revived, they were cultured until they filled the cell bottle and were in the logarithmic growth phase, and then plates were plated. After overnight culture, 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), and incubated for 24 hours. After the incubation was completed, PI and FITC dyes were added for co-staining, and incubated for 30 minutes. Flow cytometry was performed on a cell analysis system. The results are shown in the following table. Fig. 9 As shown in the figure, the cell survival rate in groups 1 to 5 is higher, indicating that the degree of induced apoptosis is lower. Groups 6 and 7 have a higher killing effect on cells, indicating that the prepared microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials can effectively induce tumor cell apoptosis under mild photothermal conditions and have the strongest killing effect, proving that it has a significant therapeutic effect on 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] The mice were randomly divided into groups: 1 for the control microneedle group (-), 2 for the control microneedle group (+), 3 for the sorafenib microneedle group (-), 4 for the copper-doped Prussian blue microneedle group (-), 5 for the copper-doped Prussian blue microneedle group (+), 6 for the sorafenib and copper-doped Prussian blue microneedle group (-), and 7 for the sorafenib and copper-doped Prussian blue microneedle group (+). In the groups, (-) represents no light exposure, and (+) represents light exposure. There were 5 mice in each group. The modeling method was to inject 4T1 cells into the fourth pair of breasts on the right side of the mouse through an insulin needle to construct an in situ triple-negative breast cancer model. The day when the model was successfully constructed was day 0. The treatment method was: the microneedle patch was pressed to puncture the skin to reach the lesion site, and the pressing treatment was maintained for 5 minutes. The photothermal group applied 808nm near-infrared light while pressing (controlling the microneedle rising temperature to be about 42°C). Treatment was once every two days, for a total of two times.

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

[0064] Sorafenib microneedle group: the hyaluronic acid microneedles containing only sorafenib in Example 2 were administered to the modeled mice;

[0065] Copper-doped Prussian blue microneedle group: The hyaluronic acid microneedles containing only copper-doped Prussian blue nanomaterials of Example 3 were administered to the modeled mice;

[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] Fig.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 the tumor size of other groups after treatment.

[0068] Fig.11 HE staining of tumor tissues dissected from each treatment group in this embodiment. As can be seen from the figure, the number of blue cell nuclei in groups 1 to 5 is large and complete, indicating that tumor cell necrosis is less. Groups 6 to 7 loaded with sorafenib and copper-doped Prussian blue nanomaterials all have varying degrees of necrosis, indicating that the prepared microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials can effectively cause tumor cell necrosis under mild photothermal conditions, and have the strongest killing effect, proving that it has a significant therapeutic effect on triple-negative breast cancer.

[0069] Fig.12 This is a GPX4 staining diagram of the tumor tissue dissected and removed from each treatment group in this embodiment. As can be seen from the figure, compared with the green fluorescence in groups 1 to 2, groups 3 to 6 have different degrees of green fluorescence reduction, indicating that both sorafenib and copper-doped Prussian blue nanomaterials alone have a certain consumption of GPX4. However, group 7 containing sorafenib and copper-doped Prussian blue nanomaterials under mild light has the strongest GPX4 consumption ability, resulting in the least green fluorescence, indicating that the prepared microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials can effectively lead to a reduction in GPX4 under mild light, proving that it has a significant therapeutic effect on triple-negative breast cancer.

[0070] Fig.13The lipid peroxide concentrations measured in the tumor tissues of each treatment group in this example can be seen from the figure: the lipid peroxide concentrations in groups 1 to 5 are relatively low, indicating that the degree of induced ferroptosis is relatively low. The lipid peroxide concentrations in groups 6 to 7 are relatively high, indicating that the prepared microneedles loaded with sorafenib and copper-doped Prussian blue nanomaterials can effectively cause tumor cell necrosis under mild photothermal conditions, and have the strongest ability to induce ferroptosis, proving that they have a significant therapeutic effect on 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 protection scope of the present invention.

Claims

1. A microneedle patch containing sorafenib and copper-doped Prussian blue nanomaterials, characterized in that: 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 by 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 containing sorafenib and copper-doped Prussian blue nanomaterials 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 copper-doped Prussian blue nanomaterials 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 containing sorafenib and copper-doped Prussian blue nanomaterials according to claim 1, characterized in that: Each needle in the needle array is in a pyramid shape.

6. A method for preparing a microneedle patch containing sorafenib and copper-doped Prussian blue nanomaterials as claimed in 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; The degradable polymer is dissolved in deionized water, and then sorafenib and copper-doped Prussian blue nanomaterials are added, and stirred at room temperature in the dark for 12-24 hours to obtain a needle body 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, vacuumed, dried, and then demolded 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 nanomaterials as claimed in 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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