A hollow core-satellite structure nanoparticle and a preparation method thereof

Abstract

The present invention discloses a hollow core-satellite structure nanoparticle, which comprises an inner layer and an outer layer. The inner layer is a hollow mesoporous copper sulfide core (HMCuS); the outer layer is a plurality of "satellite" calcium carbonate nanoparticles (CaCO3) connected to the surface of the copper sulfide core, and their particle size is 50-80 nm; the copper sulfide core is HMCuS with a particle size of 150-300 nm prepared by the sacrificial template method; the outer layer directly adsorbs the generated CaCO3 on the surface of the copper sulfide core by the gas diffusion method. The technical effects of this invention are that the preparation method is simple and feasible, the morphology and particle size of the product are uniform, the stability and dispersibility are good, and the slow release of chemotherapeutic drugs can be achieved, which has great potential application value in the direction of biomedical tumor treatment.

Description

Technical Field

[0001] The present invention relates to the technical field of nanomaterials, and specifically to a hollow core-satellite structure nanoparticle and a preparation method thereof. Background Art

[0002] Cancer seriously threatens the health of all mankind. According to the official website of the World Health Organization, there were approximately 19.3 million new cancer cases worldwide in 2020, and the number of death cases was approximately 10 million. It is estimated that there will be 28.4 million new cancer cases globally in 2040, a 47% increase compared to 2020. Traditional cancer treatment strategies include surgery, chemotherapy, adjuvant radiotherapy, and immunotherapy, etc., which have different technical routes and curative effects. Chemotherapeutic drugs or anti-tumor drugs are usually administered orally or intravenously. These functional molecules usually lack tumor specificity during long-term circulation, resulting in adverse toxicity and side effects on healthy tissues and may activate the immune system. In addition, most therapeutic drugs diffuse into healthy tissues after systemic administration, thereby reducing the bioavailability of the drug at the tumor site and leading to treatment failure. Therefore, many nano-drug delivery systems, such as liposomes, metal nanoparticles, carbon nanocomposites, silica nanoparticles, and polymer nanocapsules, etc., have been developed to actively transport drug molecules and reduce their systemic toxicity in blood circulation. However, premature leakage of the drug before reaching the tumor site remains a major problem in the design of nano-drug delivery systems, which may affect the effective therapeutic concentration required in the tumor area. Therefore, there is an urgent need to develop new strategies to efficiently and accurately deliver anti-tumor drugs to the tumor site in a controllable manner.

[0003] In the latest progress of tumor treatment, nanocarriers that respond to specific tumor microenvironment cues have shown attractive capabilities in targeted drug delivery, thereby reducing systemic side effects. Many biocompatible materials encapsulating drugs can respond to the presence of specific stimuli, including endogenous factors (e.g., pH changes, enzymatic catalysis, or redox gradients) and exogenous factors (e.g., light illumination, temperature changes, ultrasound, or magnetic fields). Nano-calcium carbonate, as a pH-decomposable calcium-based biomineral, has been widely used in the biomedical field due to its excellent biodegradability and biocompatibility.

[0004] As is well known, copper sulfide has been widely used in photothermal therapy and photodynamic therapy due to its high photothermal conversion efficiency, good Fenton-like catalytic activity, simple preparation, low biological toxicity, etc. At the same time, the hollow structure can be used for drug loading and delivery. Combining these functions will provide multiple advantages for cancer treatment. In view of this, amorphous calcium carbonate has been developed and uniformly coated on the surface of hollow copper sulfide nanoparticles. A pH-sensitive photothermal therapy and chemotherapy synergistic nano-drug delivery system is constructed to achieve "zero release" before reaching the tumor microenvironment. The calcium carbonate degrades through the pH change in the tumor environment to start releasing chemotherapy drugs and achieve good therapeutic effects. Summary of the Invention

[0005] The purpose of the present invention is to provide a hollow core-satellite structure nanoparticle and its preparation method to achieve the technical effects proposed in the above background technology.

[0006] To achieve the above purpose, the invention provides the following technical solution: A hollow core-satellite structure nanoparticle, including an inner layer and an outer layer,

[0007] The inner layer is a hollow mesoporous copper sulfide core (HMCuS);

[0008] The outer layer is a plurality of "satellite" calcium carbonate nanoparticles (CaCO3) connected to the surface of the copper sulfide core, with a particle size of 50 - 80 nm;

[0009] The copper sulfide core is HMCuS with a particle size of 150 - 300 nm prepared by the sacrificial template method;

[0010] The outer layer uses the gas diffusion method to directly adsorb the generated CaCO3 on the surface of the copper sulfide core.

[0011] The preparation method of this hollow core-satellite structure nanoparticle specifically includes the following steps:

[0012] Step 1: Add polyvinylpyrrolidone to deionized water and stir magnetically for 5 min until completely dissolved;

[0013] Step 2: Add an aqueous solution of divalent copper salt to the mixed solution obtained in Step 1 and stir for 2 min until evenly blended;

[0014] Step 3: Add an aqueous solution of sodium hydroxide to the mixed solution obtained in Step 2 and stir for 2 min;

[0015] Step 4: Add a hydrazine hydrate solution to the mixed solution obtained in Step 3 and stir for 5 min;

[0016] Step 5: Add a sulfur source to the mixed solution obtained in Step 4, stir at 60 °C for 2 h until the solution turns dark, wash with deionized water and ethanol respectively, and centrifuge to obtain HMCuS;

[0017] Step 6: Add divalent calcium salt to ethanol and stir magnetically until completely dissolved;

[0018] Step 7: Resuspend the HMCuS obtained in Step 5 in 3 ml of ethanol solution, and add the HMCuS ethanol solution to the mixed solution obtained in Step 6 under high-speed stirring, and stir for 5 min;

[0019] Step 8: Place the mixed solution obtained in Step 7 in a desiccator containing ammonium bicarbonate, react fully in an oven at 40 °C for 12 h, wash with ethanol and deionized water, and centrifuge to obtain hollow core-satellite structure nanoparticles HMCuS@CaCO3.

[0020] Preferably, the molecular weight of the polyvinylpyrrolidone in Step 1 is 44000 - 54000; the mass of the polyvinylpyrrolidone in Step 1 is 0.48 g; the volume of deionized water in Step 1 is 50 ml.

[0021] Preferably, the divalent copper salt in Step 2 is one or more of copper(II) chloride dihydrate and copper(II) sulfate pentahydrate; the molar concentration of the divalent copper salt in Step 2 is 0.5 M; the volume of the divalent copper salt aqueous solution in Step 2 is 200 μl.

[0022] Preferably, the pH value of the sodium hydroxide aqueous solution in Step 3 is 9; the volume of the sodium hydroxide aqueous solution in Step 3 is 50 ml.

[0023] Preferably, the mass fraction of the hydrazine hydrate solution in Step 4 is 80 wt%; the volume of the hydrazine hydrate solution in Step 4 is 8 μl.

[0024] Preferably, the sulfur source in Step 5 is sodium sulfide nonahydrate, the molar concentration of the sodium sulfide nonahydrate is 1.33 M; the volume of the sodium sulfide nonahydrate is 400 μl; the centrifugation speed in Step 5 is 11000 rpm, and the centrifugation time is 10 min.

[0025] Preferably, the divalent calcium salt in Step 6 is calcium chloride dihydrate; the mass fraction of ethanol in Step 6 is 95 wt%; the volume of ethanol in Step 6 is 50 ml.

[0026] Preferably, the centrifugation speed in Step 8 is 9000 rpm, and the centrifugation time is 8 min.

[0027] Preferably, the application of HMCuS@CaCO3 as a nano-drug delivery system in biomedical tumor treatment.

[0028] Compared with the prior art, the beneficial effects of the invention are as follows:

[0029] 1. For the hollow core-satellite structure nanoparticles and their preparation method, the core prepared is HMCuS, and the synthesized product has uniform particle size and good dispersibility. The hollow structure can be used to load small molecule drugs.

[0030] 2. For the hollow core-satellite structure nanoparticles and their preparation method, the HMCuS@CaCO3 has the effect of photothermal therapy and can be used for tumor photothermal therapy.

[0031] 3. For the hollow core-satellite structure nanoparticles and their preparation method, the outer layer prepared is CaCO3, which can be slowly decomposed under acidic pH conditions, and the loaded small molecule drugs can be slowly released in the tumor microenvironment.

[0032] 4. For the hollow core-satellite structure nanoparticles and their preparation method, the selected HMCuS and CaCO3 have good biocompatibility and have potential for biomedical applications.

[0033] 5. For the hollow core-satellite structure nanoparticles and their preparation method, the particle synthesis process is simple, the raw materials are simple and easy to obtain, and the equipment requirements are low. Description of the Drawings

[0034] Figure 1 It is a schematic diagram of HMCuS@CaCO3 in the embodiment of the present invention.

[0035] Figure 2 It is a hydrated particle size distribution diagram of HMCuS in the embodiment of the present invention.

[0036] Figure 3 It is a hydrated particle size distribution diagram of HMCuS@CaCO3 in the embodiment of the present invention.

[0037] Figure 4 It is a scanning electron microscope and transmission electron microscope image of HMCuS in the embodiment of the present invention.

[0038] Figure 5 It is a transmission electron microscope image of HMCuS@CaCO3 in the embodiment of the present invention.

[0039] Figure 6 It is a Zeta potential change diagram of CaCO3, HMCuS and HMCuS@CaCO3 in the embodiment of the present invention.

[0040] Figure 7The UV absorption curves of HMCuS and HMCuS@CaCO3 in the embodiments of the present invention.

[0041] Figure 8 The X-ray diffraction pattern of HMCuS in the embodiments of the present invention.

[0042] Figure 9 The nitrogen adsorption-desorption isotherm of HMCuS in the embodiments of the present invention.

[0043] Figure 10 The pore size distribution map of HMCuS in the embodiments of the present invention. Detailed implementation manners

[0044] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0045] The present invention provides a technical solution: with 200 nm HMCuS as the core, HMCuS@CaCO3 with surface-adsorbed CaCO3 is generated by gas diffusion using electrostatic adsorption, see Figure 1 :

[0046] (1) Preparation of HMCuS: Under magnetic stirring at room temperature, 200 μl of an aqueous solution of 0.5 M CuCl2·2H2O was mixed with 50 ml of an aqueous solution containing 0.48 g of PVP-K30 until evenly mixed. After 2 min, 50 ml of NaOH (pH = 9) was added to the above system, and then 8 μl of an 80% hydrazine hydrate solution was added to reduce divalent copper ions to monovalent cuprous ions, obtaining a bright yellow cuprous oxide suspension. After mixing for 5 min, 400 μl of 1.33 M Na2S aqueous solution was added to the suspension, and it was heated with constant shaking at 200 rpm at 60 °C for 2 h. The obtained HMCuS was centrifuged at 11000 rpm for 10 min, washed once with water and ethanol respectively, and then dispersed in 5 ml of ethanol and stored in the refrigerator for later use.

[0047] As Figure 2 can be seen, the hydrodynamic diameter of HMCuS is about 204.5 nm, and the PDI is 0.093.

[0048] As Figure 4 can be seen, the surface of HMCuS has abundant defects, showing an obvious hollow structure, the wall thickness is about 30 - 40 nm, there is no aggregation, and it is evenly dispersed. It can also be clearly seen that there are pores in HMCuS.

[0049] From Figure 7 It can be seen that HMCuS has obvious ultraviolet absorption peaks in both the first and second near-infrared regions, and the absorption originates from the plasma resonance absorption caused by high copper defects on the surface.

[0050] From Figure 8 It can be seen that the X-ray diffraction pattern of HMCuS is most similar to PDF 78-2391 in the standard colorimetric card, belonging to covellite of the hexagonal crystal system.

[0051] From Figure 9 It can be seen that the nitrogen adsorption-desorption curve of HMCuS is a typical type V adsorption isotherm with an H3-type hysteresis loop, without an obvious adsorption plateau. When reaching the saturated vapor pressure, the number of adsorption layers is limited, and the adsorption amount tends to a limit value. At the same time, due to the occurrence of capillary condensation, the isotherm rises rapidly at medium relative pressures and is accompanied by a hysteresis loop; the results show that the specific surface area of HMCuS is 6.5358 m² / g.

[0052] From Figure 10 It can be seen that the average pore diameter of HMCuS is 11.2 nm.

[0053] (2) Preparation of HMCuS@CaCO3: Under high-speed stirring, 5 ml of the HMCuS ethanol concentrate obtained in step (1) was dropped into 50 ml of a 0.1 mg / ml sodium chloride ethanol solution, and stirred for 10 min. Then the above solution was transferred to a dryer containing 5 g of ammonium bicarbonate, and the dryer was heated at 40 °C for 12 h. Centrifuged at 9000 rpm for 10 min and dispersed in a small amount of ethanol to obtain HMCuS@CaCO3.

[0054] From Figure 3 It can be seen that the prepared HMCuS@CaCO3 has a particle size of about 268 nm, a PDI of 0.176, and good dispersibility.

[0055] From Figure 5 It can be clearly seen that CaCO3 with a particle size of about 50-80 nm is evenly adsorbed on HMCuS, and the structure is uniform.

[0056] From Figure 6 It can be seen that the Zeta potential of HMCuS after adsorbing CaCO3 changes from negative, which can also prove that CaCO3 is successfully loaded on HMCuS.

[0057] The preparation method of the hollow core-satellite structure nanoparticles is simple and feasible, and the morphology and particle size of the product are uniform, with good stability and dispersibility. The obtained pH-responsive hollow core-satellite structure nano drug delivery system consists of a bilayer structure. The inner layer is a hollow mesoporous copper sulfide core with a particle size of 150-300 nm, and the outer layer is multiple "satellite" calcium carbonate nanoparticles connected to the surface of the copper sulfide core, with a particle size of 50-80 nm. The hollow structure of the hollow mesoporous copper sulfide nanoparticles is expected to load small molecule chemotherapeutic drugs. Since the surface is wrapped by calcium carbonate nanoparticles, the small molecule chemotherapeutic drugs will not be released prematurely in the hollow structure. When the nano drug delivery reaches the tumor microenvironment, the calcium carbonate nanoparticles are slowly degraded by the acidic environment, achieving the slow release of the chemotherapeutic drugs, which has great potential application value in the field of biomedical tumor treatment.

[0058] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention also intends to include these changes and modifications.

Claims

1. A hollow core-satellite structured nanoparticle, characterized in that: It includes an inner layer and an outer layer. The inner layer is a hollow mesoporous copper sulfide core (HMCuS). The outer layer is composed of multiple "satellite" calcium carbonate nanoparticles (CaCO3) connected to the surface of the copper sulfide core, with a particle size of 50 - 80 nm. The copper sulfide core is HMCuS with a particle size of 150 - 300 nm prepared by the sacrificial template method. The outer layer uses the gas diffusion method to directly adsorb the generated CaCO3 on the surface of the copper sulfide core.

2. The preparation method of a hollow core-satellite structure nanoparticle according to claim 1, characterized in that: Specifically, it includes the following steps: Step 1: Add polyvinylpyrrolidone to deionized water and stir magnetically for 5 min until completely dissolved. Step 2: Add an aqueous solution of divalent copper salt to the mixed solution obtained in Step 1 and stir for 2 min until thoroughly blended. Step 3: Add an aqueous solution of sodium hydroxide to the mixed solution obtained in Step 2 and stir for 2 min. Step 4: Add a hydrazine hydrate solution to the mixed solution obtained in Step 3 and stir for 5 min. Step 5: Add a sulfur source to the mixed solution obtained in Step 4, stir at 60 °C for 2 h until the solution turns dark, wash with deionized water and ethanol respectively, and centrifuge to obtain HMCuS. Step 6: Add divalent calcium salt to ethanol and stir magnetically until completely dissolved. Step 7: Resuspend the HMCuS obtained in Step 5 in 3 ml of ethanol solution, and add the HMCuS ethanol solution to the mixed solution obtained in Step 6 under high-speed stirring, and stir for 5 min. Step 8: Place the mixed solution obtained in Step 7 in a desiccator containing ammonium bicarbonate, react fully in an oven at 40 °C for 12 h, wash with ethanol and deionized water, and centrifuge to obtain the hollow core-satellite structure nanoparticles HMCuS@CaCO3.

3. The preparation method of a hollow core-satellite structure nanoparticle according to claim 2, wherein: The molecular weight of the polyvinylpyrrolidone in Step 1 is 44000 - 54000; the mass of the polyvinylpyrrolidone in Step 1 is 0.48 g; the volume of deionized water in Step 1 is 50 ml.

4. The preparation method of a hollow core-satellite structure nanoparticle according to claim 2, wherein: The divalent copper salt in Step 2 is one or several of copper(II) chloride dihydrate and copper(II) sulfate pentahydrate; the molar concentration of the divalent copper salt in Step 2 is 0.5 M; the volume of the aqueous solution of divalent copper salt in Step 2 is 200 μl.

5. The preparation method of a hollow core-satellite structure nanoparticle according to claim 2, wherein: The pH value of the aqueous solution of sodium hydroxide in Step 3 is 9; the volume of the aqueous solution of sodium hydroxide in Step 3 is 50 ml.

6. The preparation method of a hollow core-satellite structure nanoparticle according to claim 2, characterized in that: The mass fraction of the hydrazine hydrate solution in Step 4 is 80 wt%; the volume of the hydrazine hydrate solution in Step 4 is 8 μl.

7. The preparation method of a hollow core-satellite structure nanoparticle according to claim 2, characterized in that: The sulfur source in Step 5 is sodium sulfide nonahydrate, the molar concentration of the sodium sulfide nonahydrate is 1.33 M; the volume of the sodium sulfide nonahydrate is 400 μl; the centrifugation speed in Step 5 is 11000 rpm, and the centrifugation time is 10 min.

8. The preparation method of a hollow core-satellite structure nanoparticle according to claim 2, characterized in that: The divalent calcium salt in Step 6 is calcium chloride dihydrate; the mass fraction of ethanol in Step 6 is 95 wt%; the volume of ethanol in Step 6 is 50 ml.

9. The preparation method of a hollow core-satellite structure nanoparticle according to claim 2, characterized in that: The centrifugation speed in Step 8 is 9000 rpm, and the centrifugation time is 8 min.

10. The preparation method of a hollow core-satellite structure nanoparticle according to claim 2, wherein: Application of the HMCuS@CaCO3 as a nano-drug delivery system in biomedical tumor treatment.

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