Pickering nanosheet encapsulation layer for surfactant-free cancer drug delivery

Abstract

This invention discloses a Pickering nanosheet encapsulation layer for surfactant-free cancer drug delivery, belonging to the field of cancer drug delivery technology. The encapsulation layer uses octadecyl-functionalized monolayer zirconium phosphate (ZrP-C18) nanosheets as a Pickering emulsifier, forming a dense nanobarrier on the surface of the hydrophobic chemotherapy drug docetaxel (DTX) core through an emulsification-diffusion-evaporation method. This invention eliminates traditional toxic molecular surfactants and organic solvents. The ZrP-C18 nanosheets impart excellent colloidal stability to the drug-loaded nanoparticles through interfacial congestion effects, while simultaneously achieving controlled sustained drug release. This encapsulation layer allows the drug-loaded particles to be efficiently internalized by taxane-resistant cancer cells, bypassing drug resistance mechanisms, without significant hemolytic effects and exhibiting excellent blood compatibility. This invention provides a new solution for surfactant-free delivery of hydrophobic cancer chemotherapy drugs, applicable to the treatment of various cancers such as ovarian cancer and breast cancer, and has promising clinical translation prospects.

Description

Technical Field

[0001] This invention relates to the field of cancer drug delivery technology, specifically a Pickering nanosheet encapsulation layer for surfactant-free cancer drug delivery. Background Technology

[0002] Cancer is a major global public health challenge, and chemotherapy is one of the core methods of clinical oncology treatment. However, the clinical application of hydrophobic chemotherapy drugs such as docetaxel is limited by problems such as low bioavailability and high systemic toxicity. Nanocarrier technology provides a way to solve these problems. Currently, most mainstream nanocarrier systems use molecular surfactants or synthetic polymers to stabilize solid drug nanoparticles. However, these stabilizers have the drawbacks of poor mechanical stability and biological inertness.

[0003] Molecular surfactants are difficult to completely remove from formulations, which can easily cause severe hypersensitivity reactions and hemolysis. Furthermore, traditional drug delivery systems require the use of toxic organic solvents such as DMSO and ethanol as co-solvents, which further exacerbates systemic toxicity. In addition, traditional formulations also have the problems of drug aggregation and uncontrollable release, resulting in a significant decrease in therapeutic efficacy in taxane-resistant cancer cells.

[0004] Therefore, there is an urgent need to develop a Pickering coating with ZrP-based two-dimensional nanosheets as the core, which can eliminate the need for traditional toxic surfactants and organic solvents, achieve stable, low-toxicity, and controllable delivery of hydrophobic chemotherapy drugs, and solve the problem of drug uptake by drug-resistant cancer cells. Summary of the Invention

[0005] The purpose of this section is to outline some aspects of the embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0006] In view of the problems existing in the Pickering nanosheet encapsulation layers for surfactant-free cancer drug delivery described above and / or in existing ones, the present invention is proposed.

[0007] Therefore, the purpose of this invention is to provide a Pickering nanosheet encapsulation layer for surfactant-free cancer drug delivery, achieving low-toxicity, stable, and controllable delivery of hydrophobic chemotherapy drugs, while improving drug uptake and therapeutic efficacy in drug-resistant cancer cells.

[0008] To address the aforementioned technical problems, according to one aspect of the present invention, the present invention provides the following technical solution: A Pickering nanosheet coating layer for surfactant-free cancer drug delivery, wherein the coating layer uses functionalized zirconium phosphate nanosheets as a Pickering emulsifier and self-assembles on the surface of hydrophobic chemotherapeutic drug particles to form a dense nanobarrier; wherein the functionalized zirconium phosphate nanosheets are ZrP-C18 nanosheets obtained by hydrophobic modification with octadecyl isocyanate, and are Janus-type or Gemini-type monolayer nanosheets.

[0009] As a preferred embodiment of the Pickering nanosheet encapsulation layer for surfactant-free cancer drug delivery described in this invention, the hydrophobic chemotherapy drug is docetaxel, and the average hydrodynamic diameter of the DTX-ZrP-NP drug-loaded nanoparticles formed by the encapsulation layer and docetaxel is 220±7.3 nm, with a particle size distribution range of 200-270 nm.

[0010] As a preferred embodiment of the Pickering nanosheet coating for surfactant-free cancer drug delivery described in this invention, the ZrP-C18 nanosheet has a zeta potential of -50.8±4.6mV, which enables the composite drug-loaded nanoparticles coated with the coating to achieve a zeta potential of approximately -20mV. This achieves colloidal stability through electrostatic repulsion, and no significant aggregation is observed after resuspending in deionized water for 24 hours.

[0011] As a preferred embodiment of the Pickering nanosheet coating for surfactant-free cancer drug delivery described in this invention, the ZrP-C18 nanosheets are arranged in a curved and overlapping manner on the surface of the drug particles, forming a dense nanobarrier that can inhibit molecular diffusion by more than 80%, thereby achieving controlled sustained release of the drug.

[0012] A preferred embodiment of a method for preparing a Pickering nanosheet coating for surfactant-free cancer drug delivery includes the following steps: S1, synthesizing layered zirconium phosphate (ZrP) solid powder using a reflux method; S2, subjecting ZrP to a hydrophobic modification reaction with octadecyl isocyanate, followed by exfoliation and lyophilization to obtain ZrP-C18 nanosheets; S3, using ZrP-C18 nanosheets as a Pickering emulsifier, enabling the ZrP-C18 nanosheets to self-assemble on the surface of hydrophobic chemotherapeutic drug particles via an emulsification-diffusion-evaporation method to form a Pickering nanosheet coating.

[0013] As a preferred embodiment of the method for preparing a Pickering nanosheet coating for surfactant-free cancer drug delivery according to the present invention, the specific process of ZrP synthesis by reflux in step S1 is as follows: 6g of zirconium oxychloride octahydrate is mixed with 50mL of 12M phosphoric acid, placed in a 100mL round-bottom flask and refluxed in an oil bath at 94℃ for 24h. The reaction product is washed three times with deionized water, dried in an oven, and ground to obtain ZrP fine powder.

[0014] As a preferred embodiment of the method for preparing a Pickering nanosheet coating for surfactant-free cancer drug delivery according to the present invention, in step S2, the process parameters of the hydrophobic modification reaction are as follows: the molar ratio of ZrP to octadecyl isocyanate is 10:1, and the reaction is carried out under a nitrogen atmosphere at 90°C with magnetic stirring for 24 hours; after the reaction product is washed three times with methanol and dried in an oven at 70°C, it is exfoliated at room temperature in deionized water with tetrabutylammonium hydroxide at a molar ratio of 1:1 to obtain a single-layer ZrP-C18 nanosheet suspension, which is then freeze-dried to obtain solid ZrP-C18 nanosheets.

[0015] As a preferred embodiment of the method for preparing a Pickering nanosheet coating for surfactant-free cancer drug delivery according to the present invention, the specific operation of the emulsification-diffusion-evaporation method in step S3 includes an emulsification step: dissolving the hydrophobic chemotherapy drug docetaxel in ethyl acetate to form an organic phase with a concentration of 1.25 mg / mL, mixing the organic phase with an aqueous phase containing ZrP-C18 nanosheets at an oil / water volume ratio of 1:10, magnetically stirring at 600 rpm for 30 min, and then ultrasonically emulsifying with an 8W power probe for 1 min to form a Pickering emulsion.

[0016] As a preferred embodiment of the method for preparing a Pickering nanosheet coating for surfactant-free cancer drug delivery according to the present invention, in step S3, the emulsification-diffusion-evaporation method further includes diffusion and evaporation steps: the Pickering emulsion is diluted with an equal volume of deionized water, and stirred with the lid open for 3 hours at 800 rpm in a fume hood to allow the ethyl acetate to fully evaporate, and the ZrP-C18 nanosheets self-assemble on the surface of the drug particles to form a dense coating layer.

[0017] As a preferred embodiment of the method for preparing a Pickering nanosheet coating for surfactant-free cancer drug delivery according to the present invention, in step S3, after evaporation, the resulting suspension is directly freeze-dried without prior washing, the material recovery rate is close to quantitative, and after drying, drug-loaded particles with a Pickering nanosheet coating are obtained.

[0018] Compared with the prior art, the beneficial effects of the present invention are: 1. The coating layer of this invention uses biocompatible ZrP-C18 nanosheets as the core, eliminating the need for traditional molecular surfactants and toxic organic solvents. The prepared drug-loaded particles do not have a significant hemolytic effect even at high concentrations under physiological pH, completely solving the problems of hemolysis and hypersensitivity reactions in traditional formulations, and exhibiting excellent blood compatibility.

[0019] 2. The coating layer formed by ZrP-C18 nanosheets endows the drug-loaded particles with excellent colloidal stability through the dual effects of interfacial congestion and electrostatic repulsion. The drug-loaded particles have a narrow particle size distribution and show no obvious aggregation after 24 hours of resuspension in water, effectively solving the technical problem of easy aggregation of hydrophobic drugs.

[0020] 3. The encapsulation layer is a dense nanobarrier structure that can inhibit molecular diffusion by more than 80%, effectively preventing premature release of drugs in systemic circulation, achieving controlled and sustained drug release, and maintaining continuous therapeutic pressure at the tumor site.

[0021] 4. The drug-loaded particles coated with this coating can be efficiently internalized by taxane-resistant ovarian cancer cells through endocytosis, bypassing the drug resistance mechanism of cancer cells. At high concentrations, it shows excellent therapeutic effects on drug-resistant ovarian cancer, sensitive ovarian cancer, and breast cancer. Attached Figure Description

[0022] To more clearly illustrate the technical solutions of the embodiments of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and detailed embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0023] Figure 1 Interfacial assembly and morphological characterization of surfactant-free Pickering nanocarriers: 1a: Schematic diagram of the preparation of the coating layer using the emulsification-diffusion-evaporation strategy: 1b: A scanning electron microscope (SEM) image of DTX-ZrP-NP stabilized on ZrP nanosheets; 1c: Dynamic light scattering DLS particle size distribution diagram of DTX-ZrP-NP; 1d: SEM image of fluorescein-labeled PLGA nanoparticles; 1e: DLS particle size distribution of fluorescein-labeled PLGA nanoparticles.

[0024] Figure 2 Diagram showing internalization and cell compatibility in taxane-resistant SKOV3TR cells: 2a: A fluorescence microscope comparison image of cells incubated in serum-free culture medium; 2b: Fluorescence micrograph of cells incubated with 50 μg / mL fluorescein-labeled PLGA-ZrP particles; 2c: Mean fluorescence intensity (MFI) plot of cells quantified by flow cytometry; 2d: Percentage of fluorescein-positive cells in the cell population; 2e: Graph showing the results of cell viability assay.

[0025] Figure 3 Diagram illustrating the dose-dependent cytotoxicity and nanobarrier release mechanism: 3a: The cell viability assay results of DTX-ZrP-NP, free DTX, and blank ZrP nanosheets in SKOV3TR cells; 3b: This figure shows the cell viability assay results of the above samples in SKOV3sens cells; 3c: This is a graph showing the cell viability assay results of the above samples in SUM159 breast cancer cells; 3d: Schematic diagram of the nano-barrier controlled release mechanism.

[0026] Figure 4 This diagram illustrates the compatibility and electrostatic stabilization effects of isolated blood.

[0027] Figure 5 Mechanical mechanisms of 2D nanobarriers: Interfacial congestion and diffusion control diagram: 5a: Macroscopic visualization of the diffusion of Rhodamine BRhB from chloroform droplets into the aqueous phase; 5b: Time-resolved fluorescence microscopy image of the oil / water interface; 5c: UV-Vis absorption spectrum of RhB.

[0028] In the above figures, the error bars all represent standard deviations; Figure 5 The scale in b is 500 μm. Detailed Implementation

[0029] The present invention will be further described in detail below with reference to specific embodiments. In this embodiment, docetaxel is used as a hydrophobic chemotherapy drug to prepare a ZrP-C18 nanosheet coating layer and verify its performance. The scope of protection of the present invention is not limited to the following embodiments.

[0030] Experimental materials Docetaxel (DTX) was purchased from Shaanxi Spetech High-Tech Industry Co., Ltd.; zirconium oxychloride octahydrate, 85% phosphoric acid, ethyl acetate, and tetrabutylammonium hydroxide were purchased from Fisher Scientific; anhydrous toluene and 8% octadecyl isocyanate were purchased from Sigma-Aldrich; polylactic acid-glycolic acid copolymer (PLGA), 40 kDa, was purchased from Evonik; and NHS-fluorescein was purchased from Thermo Scientific.

[0031] Experimental instruments: FD-1A-50 freeze dryer, FACSCalibur flow cytometer, SEM scanning electron microscope, DLS dynamic light scattering instrument, microplate reader, fluorescence microscope, magnetic stirrer, ultrasonic probe, etc.

[0032] Example 1: Synthesis of ZrP Layered zirconium phosphate (ZrP) was synthesized by reflux method: 6 g of zirconium oxychloride octahydrate (ZrOCl2・8H2O) was weighed and added to a 100 mL round-bottom flask with 50 mL of 12 M phosphoric acid. After thorough mixing, the mixture was placed in an oil bath at 94 °C and refluxed for 24 h. After the reaction was completed, the product was washed three times with deionized water to remove unreacted raw materials. The washed product was then dried in an oven. After drying, the ZrP solid was collected, ground into a fine powder using a mortar and pestle, and sealed for later use.

[0033] Example 2: Preparation of ZrP-C18 Pickering Emulsifier Hydrophobic modification: The ZrP fine powder prepared in Example 1 was dried overnight in an oven to completely remove residual moisture; the dried ZrP microcrystals were suspended in anhydrous toluene in a three-necked flask equipped with a magnetic stir bar, and the flask was immersed in a 90°C preheated oil bath. Nitrogen gas was purged into the flask for 10 min to remove oxygen; at the same time, octadecyl isocyanate ODI was dissolved in anhydrous toluene, and the ODI solution was slowly added to the three-necked flask under a nitrogen atmosphere, controlling the molar ratio of ZrP to ODI to be 10:1; after the addition was complete, nitrogen gas was purged for another 20 min, and then the nitrogen purging was stopped. The reaction was carried out at 90°C with magnetic stirring for 24 h; after the reaction was completed, the product was washed three times with methanol to remove unreacted ODI, and then dried overnight in a 70°C oven to obtain hydrophobically modified ZrP-C18 particles.

[0034] Peeling and freeze-drying: The above ZrP-C18 particles were reacted with tetrabutylammonium hydroxide (TBA) + OH - The ZrP-C18 nanosheets were dispersed in deionized water at a 1:1 molar ratio and exfoliated by magnetic stirring at room temperature to obtain Janus-type and Gemini-type monolayer ZrP-C18 nanosheet suspensions. The suspensions were then transferred to lyophilization bottles and freeze-dried to obtain solid ZrP-C18 nanosheets, i.e., Pickering emulsifier, which were sealed for later use.

[0035] Example 3: Preparation of Pickering nanosheet coating ZrP-C18 nanosheet coatings were prepared on docetaxel surfaces using an emulsification-diffusion-evaporation method. Specific steps included: Organic phase preparation: Weigh 0.025 g DTX, dissolve it in 2 mL ethyl acetate (EA), place it in a glass vial and sonicate for 5 min to ensure complete dissolution of DTX, forming a DTX-EA organic phase with a concentration of 1.25 mg / mL; Aqueous phase preparation: Take 100 μL of 5 wt% ZrP-C18 nanosheet suspension, add it to 20 mL of deionized water, and mix evenly with magnetic stirring to obtain an aqueous phase containing Pickering emulsifier; Emulsification: The DTX-EA organic phase was added dropwise to the above aqueous phase at an oil / water volume ratio of 1:10 under magnetic stirring at 600 rpm. After the addition was complete, the mixture was stirred at a constant temperature for 30 min. Then, the mixture was ultrasonically emulsified for 1 min using an 8W probe ultrasonic instrument to form a milky white DTX / EAPickering emulsion. At this time, ZrP-C18 nanosheets initially self-assembled at the oil-water interface. Diffusion and evaporation: Add 20 mL of deionized water to the above Pickering emulsion for dilution, transfer the diluted emulsion to a beaker, and stir magnetically at 800 rpm for 3 h in a fume hood with the lid off to allow the ethyl acetate to fully evaporate. The droplets in the emulsion gradually shrink into dense drug particles, and ZrP-C18 nanosheets further self-assemble on the surface of the drug particles to form a dense Pickering nanosheet coating layer. Freeze-drying collection: The suspension after evaporation was directly transferred to a freeze-drying bottle and freeze-dried using a freeze dryer. No pre-washing was required. The material recovery rate after drying was close to quantitative, and DTX-ZrP-NP drug-loaded particles with ZrP-C18 nanosheet coatings on the surface were collected.

[0036] Example 4: Performance Verification of the Encapsulation Layer Morphology and particle size characterization: The morphology of DTX-ZrP-NP was observed by SEM. The results showed that the particles had regular morphology and were tightly coated with ZrP-C18 nanosheets. The particle size was measured by DLS. The particle size distribution of DTX-ZrP-NP was 200-270 nm, with an average diameter of 220±7.3 nm, which is comparable to the lateral size of ZrP-C18 nanosheets. After resuspending DTX-ZrP-NP in deionized water, there was no obvious aggregation after 24 h, indicating excellent colloidal stability.

[0037] Internalization and compatibility verification: Taxane-resistant ovarian cancer cells SKOV3TR were internalized at 2×10⁻⁶ cells / cells. 5Cells were seeded per well in 6-well plates and cultured for 48 hours. The medium was then replaced with serum-free medium containing 50 μg / mL fluorescein-labeled PLGA-ZrP particles and incubated for 1 hour. After washing and trypsin digestion, flow cytometry showed high mean fluorescence intensity (MFI) and a large proportion of fluorescein-positive cells. Fluorescence microscopy revealed obvious intracellular green fluorescence, demonstrating that the drug-loaded particles coated with the coating layer could be efficiently internalized by drug-resistant cancer cells. Cell viability assays showed that the cell viability of cells treated with ZrP-C18 nanosheets was close to 100%, proving that the coating layer of this invention is non-cytotoxic.

[0038] Controlled-release performance verification: Using Rhodamine B as a model drug, the controlled-release effect of the coating layer was verified using a chloroform / water two-phase system. The results showed that without ZrP-C18 nanosheets, RhB rapidly diffused into the aqueous phase within 1 hour, while the coating layer formed by ZrP-C18 nanosheets could significantly inhibit RhB diffusion. Moreover, the diffusion inhibition effect increased with the increase of ZrP-C18 concentration, and the molecular outflow could be inhibited by more than 80%, which proved that the coating layer has excellent controllable sustained-release performance and can effectively prevent premature drug release.

[0039] Blood compatibility verification: In vitro hemolysis test was performed using healthy rat red blood cells. DTX-ZrP-NP was prepared into PBS suspensions of 1, 5, and 40 μg / mL and incubated with diluted red blood cells. DTX dissolved in Tween 80 / ethanol was used as a control. The results showed that the hemolysis rate of DTX-ZrP-NP at all concentrations was <1%, which was negligible. However, the hemolysis rate of DTX formulation with Tween 80 / ethanol carrier reached 8.14±1.97% and 33.15±5.91% at medium and high concentrations, respectively. This proves that the coating layer of the present invention can completely solve the hemolysis problem of traditional formulations and has excellent blood compatibility.

[0040] Example 5: Preparation of coating layer for fluorescein-labeled PLGA nanoparticles To verify the versatility of the preparation method of the present invention, fluorescein-conjugated PLGA nanoparticles were prepared and coated with a coating layer. The preparation process was completely consistent with that in Example 3: 0.025g of fluorescein-conjugated PLGA was dissolved in 2mL of ethyl acetate, and the subsequent emulsification, diffusion, volatilization, and lyophilization steps were the same as those for the preparation of DTX-ZrP-NP. The prepared PLGA-ZrP nanoparticles had an average diameter of 255±33nm and a particle size distribution of 200-350nm. The ZrP-C18 nanosheet coating layer on the particle surface had a dense structure and excellent stability, proving that the coating layer preparation method of the present invention is suitable for the surface coating of various hydrophobic drugs / carriers.

[0041] The above specific embodiments are merely preferred embodiments of the present invention and are not intended to limit the technical solutions of the present invention. Any modifications, equivalent substitutions, improvements, etc., made without departing from the technical principles and inventive concept of the present invention should be included within the protection scope of the present invention.

Claims

1. A Pickering nanosheet encapsulation layer for surfactant-free cancer drug delivery, characterized in that, The coating layer uses functionalized zirconium phosphate nanosheets as a Pickering emulsifier to self-assemble on the surface of hydrophobic chemotherapy drug particles to form a dense nanobarrier; the functionalized zirconium phosphate nanosheets are ZrP-C18 nanosheets obtained by hydrophobic modification with octadecyl isocyanate, and are Janus-type or Gemini-type monolayer nanosheets.

2. The Pickering nanosheet encapsulation layer for surfactant-free cancer drug delivery according to claim 1, characterized in that, The hydrophobic chemotherapy drug is docetaxel. The average hydrodynamic diameter of the DTX-ZrP-NP drug-loaded nanoparticles formed by the coating layer and docetaxel is 220±7.3nm, and the particle size distribution range is 200-270nm.

3. The Pickering nanosheet encapsulation layer for surfactant-free cancer drug delivery according to claim 2, characterized in that, The ZrP-C18 nanosheets have a zeta potential of -50.8±4.6mV, which makes the zeta potential of the composite drug-loaded nanoparticles coated with this coating reach about -20mV. Colloidal stability is achieved through electrostatic repulsion, and no obvious aggregation is observed after 24 hours of resuspension in deionized water.

4. The Pickering nanosheet encapsulation layer for surfactant-free cancer drug delivery according to claim 3, characterized in that, The ZrP-C18 nanosheets are arranged in a curved and overlapping manner on the surface of the drug particles, forming a dense nanobarrier that can inhibit molecular diffusion by more than 80%, thus achieving controlled and sustained release of the drug.

5. A method for preparing the Pickering nanosheet coating layer according to any one of claims 1-4, characterized in that, Includes the following steps: S1. Layered zirconium phosphate (ZrP) solid powder was synthesized by reflux method; S2. ZrP was hydrophobically modified with octadecyl isocyanate, and ZrP-C18 nanosheets were obtained by exfoliation and freeze-drying; S3. Using ZrP-C18 nanosheets as Pickering emulsifier, ZrP-C18 nanosheets were self-assembled on the surface of hydrophobic chemotherapy drug particles through emulsification-diffusion-volatilization method to form a Pickering nanosheet coating layer.

6. The preparation method according to claim 5, characterized in that, In step S1, the specific process for synthesizing ZrP by reflux is as follows: 6g of zirconium oxychloride octahydrate is mixed with 50mL of 12M phosphoric acid and placed in a 100mL round-bottom flask. The mixture is refluxed in an oil bath at 94℃ for 24h. The reaction product is washed three times with deionized water, dried in an oven, and then ground to obtain ZrP fine powder.

7. The preparation method according to claim 5, characterized in that, In step S2, the process parameters for the hydrophobic modification reaction are as follows: the molar ratio of ZrP to octadecyl isocyanate is 10:1, and the reaction is carried out under a nitrogen atmosphere at 90℃ with magnetic stirring for 24 hours; after the reaction product is washed three times with methanol and dried in an oven at 70℃, it is exfoliated at room temperature in deionized water with tetrabutylammonium hydroxide at a molar ratio of 1:1 to obtain a single-layer ZrP-C18 nanosheet suspension, which is then freeze-dried to obtain solid ZrP-C18 nanosheets.

8. The preparation method according to claim 5, characterized in that, In step S3, the specific operation of the emulsification-diffusion-evaporation method includes the emulsification step: dissolving the hydrophobic chemotherapy drug docetaxel in ethyl acetate to form an organic phase with a concentration of 1.25 mg / mL, mixing the organic phase with an aqueous phase containing ZrP-C18 nanosheets at an oil / water volume ratio of 1:10, magnetically stirring at 600 rpm for 30 min, and then ultrasonically emulsifying with an 8W power probe for 1 min to form a Pickering emulsion.

9. The preparation method according to claim 8, characterized in that, In step S3, the emulsification-diffusion-evaporation method also includes diffusion and evaporation steps: the Pickering emulsion is diluted with an equal volume of deionized water, and stirred with the lid open for 3 hours at 800 rpm in a fume hood to allow the ethyl acetate to fully evaporate, and the ZrP-C18 nanosheets self-assemble on the surface of the drug particles to form a dense coating layer.

10. The preparation method according to claim 9, characterized in that, In step S3, after evaporation, the resulting suspension is directly freeze-dried without prior washing, and the material recovery rate is close to quantitative. After drying, drug-loaded particles with a Pickering nanosheet coating are obtained.

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