CuO2-metal organic framework composite nanomaterial, and preparation method and application thereof
By encapsulating CuO2 nanoparticles within the pores of ZIF-67, and combining them with photothermal agents and chemotherapy drugs, a quadruple synergistic treatment system was constructed, overcoming the limitations of traditional treatment methods and the poor stability of CuO2, thus achieving highly efficient breast cancer treatment.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- GUANGZHOU CHUANGSAI BIOLOGICAL MEDICAL MATERIALS CO LTD
- Filing Date
- 2026-06-24
- Publication Date
- 2026-08-04
AI Technical Summary
Existing methods for treating breast cancer have limitations such as strict requirements for tumor staging, high recurrence rates, significant toxic side effects, and limited immunotherapy. Traditional nanocatalysts exhibit slow Fenton-like reaction kinetics, and CuO2 nanoparticles are prone to aggregation and decomposition in physiological environments, resulting in poor stability and limiting the treatment efficiency of chemokinetic therapy.
By encapsulating CuO2 nanoparticles within ZIF-67 channels, the targeted and controllable release of copper ions is achieved by utilizing their proton disintegration properties in the acidic tumor microenvironment. A self-sufficient cascade catalytic mechanism is constructed, which, combined with photothermal agents and chemotherapeutic drugs, forms a four-fold synergistic therapeutic system of photothermal-chemotherapy-chemokinetics-immunoactivation.
It significantly enhances tumor-killing efficacy, achieving a transformation from local tumor killing to systemic anti-tumor immune activation, overcoming the limitations of insufficient endogenous H2O2 and low catalytic efficiency, and providing a simple and scalable preparation process.
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Figure CN122499323A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedicine, and in particular to a CuO2-metal-organic framework composite nanomaterial, its preparation method, and its application. Background Technology
[0002] According to global cancer statistics, a large number of women die from breast cancer each year. Breast cancer has an extremely high incidence rate and is the leading cause of cancer-related deaths among women worldwide. With the development of medical technology, the main strategies for treating cancer currently include surgical resection, image-guided ablation, radiotherapy, transarterial therapy (such as transarterial chemoembolization), chemotherapy, and immunotherapy. Among these, traditional treatments such as surgical resection, image-guided ablation, radiotherapy, transarterial chemoembolization, and chemotherapy have limitations such as stringent requirements for tumor staging, high recurrence rates, and significant toxic side effects. Furthermore, while immunotherapy has brought survival benefits to some patients, the overall objective response rate is limited, and it also presents problems such as immune-related adverse reactions and primary or acquired drug resistance. It is evident that existing treatment methods all face their own bottlenecks in clinical application, and there is an urgent need to explore new strategies that are more efficient, precise, and less toxic to break through the current predicament in breast cancer treatment.
[0003] Chemokinetic therapy (CDT), as an emerging cancer treatment strategy, primarily relies on nanomaterials to catalyze the conversion of endogenous hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (·OH) in the tumor microenvironment (TME), thereby inducing tumor cell apoptosis. However, the clinical translation of this therapy faces two major bottlenecks: first, the concentration of endogenous H2O2 in tumor tissue is extremely low (typically only 50-100 μM), making it difficult to continuously generate sufficient ·OH; second, the Fenton-like reaction kinetics of traditional nanocatalysts (such as iron-based materials) are slow, severely limiting treatment efficiency. Copper peroxide (CuO2) nanoparticles can autonomously decompose in an acidic TME, simultaneously releasing copper ions (CuO2). 2+ ) and H2O2, in which Cu 2+ CuO2 nanoparticles can further catalyze the generation of ·OH from H2O2, thus overcoming the limitation of insufficient endogenous H2O2 at its source. However, single CuO2 nanoparticles are prone to aggregation and premature decomposition in physiological environments, exhibiting poor stability and severely limiting their potential for in vivo application. Metal-organic frameworks (MOFs, such as ZIF-67 and UiO-66) have become highly promising drug delivery platforms due to their high specific surface area, tunable pore size, and excellent biodegradability. However, research on precisely encapsulating CuO2 nanoparticles within MOF channels and utilizing the unique confinement effect of MOFs to synergistically enhance CuO2 decomposition and subsequent Fenton-like reactions is still rarely reported in the field of anti-tumor therapy. This technological gap limits further breakthroughs in CDT (catheter arterial therapy) for precision tumor treatment. Summary of the Invention
[0004] To address the shortcomings of existing technologies, this invention provides an innovative systemic solution to two fundamental technical challenges in current copper-based chemokinetics: poor CuO2 stability and catalytic efficiency limited by the concentration of endogenous H2O2 in tumors. First, through a "encapsulation followed by activation" stability strategy, ZIF-67 is used as a protective nanoreactor to confine the CuO2 precursor within its pores, effectively preventing decomposition and inactivation during blood circulation. Simultaneously, the proton disintegration properties of this framework in the acidic tumor microenvironment enable targeted and controllable release of copper ions. Building upon this, this invention further constructs a "self-sufficient, cascade-scale" catalytic mechanism, creatively integrating the H2O2 supply source within the catalytic core. Through the controllable disproportionation of CuO2 under slightly acidic conditions, H2O2 is continuously generated in situ, providing sufficient substrate for subsequent catalytic reactions and fundamentally overcoming the limitation of insufficient endogenous H2O2. Crucially, this invention discovers that free Co after disintegration... 2+ With Cu 2+ It can form unexpected synergistic catalytic sites, and its efficiency and rate of catalytic production of ·OH far exceed that of single ions, resulting in an explosive increase in reactive oxygen species yield and achieving a catalytic effect of "dual ion synergy and efficiency enhancement". It is based on the cascade integration of the above three innovative mechanisms that this invention successfully constructs a quadruple synergistic therapeutic system integrating photothermal, chemotherapy, chemical kinetics and immune activation, significantly enhancing the induction of immunogenic cell death effects, and successfully expanding the therapeutic effect from local tumor killing to systemic anti-tumor immune activation, achieving a fundamental breakthrough in the therapeutic dimension.
[0005] The technical solution of the present invention is as follows: A CuO2-metal-organic framework composite nanomaterial, characterized in that it comprises a carrier (FA@CuO2@ZIF-67), a photothermal agent, and a drug, wherein the carrier comprises core-shell structured nanoparticles (CuO2@ZIF-67) and folic acid (FA). The core-shell structured nanoparticles include a core and a shell, wherein the core includes copper peroxide (CuO2), the shell includes a metal-organic framework, the metal-organic framework includes ZIF-67, and the core is encapsulated in the shell; The photothermal agent includes indocyanine green (ICG), the drug includes mitoxantrone (MTX), and the photothermal agent and the drug are loaded onto the carrier.
[0006] In one embodiment, the mass ratio of the carrier:the photothermal agent:the drug is (10~50):(5~20):(5~25).
[0007] A second aspect of the present invention also provides a method for preparing the above-mentioned CuO2-metal-organic framework composite nanomaterial, characterized by comprising the following steps: Preparation of core-shell structured nanoparticles: Dissolve copper chloride dihydrate (CuCl2·2H2O) in water, adjust the pH, add hydrogen peroxide (H2O2), stir, centrifuge and wash, and vacuum dry to obtain copper peroxide nanoparticles; disperse copper peroxide nanoparticles in 2-methylimidazole solution, add cobalt nitrate hexahydrate (Co(NO3)2·6H2O) solution, react, centrifuge and wash, and vacuum dry to obtain core-shell structured nanoparticles; Preparation of the carrier: Core-shell structured nanoparticles were dispersed in a mixed solution of ethanol and water. 3-Aminopropyltriethoxysilane (APTES) was added dropwise under nitrogen conditions. The mixture was refluxed, cooled, centrifuged to collect the product, washed, and vacuum dried to obtain the reactant. Folic acid was dissolved in buffer solution to obtain a folic acid solution. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide were dissolved in buffer solution, added to the folic acid solution, and mixed to activate the folic acid active ester intermediate. The reactant was dispersed in buffer solution, the folic acid active ester intermediate was added, and the mixture was reacted in the dark. The product was collected by centrifugation, washed, and freeze-dried to obtain the final product. Preparation of composite nanomaterials: The photothermal agent and the drug are dissolved in a buffer solution to obtain a mixed solution. The carrier is dispersed in the mixed solution, stirred in the dark, centrifuged and washed, and then freeze-dried to obtain the final product.
[0008] In one embodiment, in the preparation of core-shell structured nanoparticles, the ratio of copper chloride dihydrate to hydrogen peroxide is (0.2~1.0) mmol: (1~5) mL. The stirring and centrifugal washing process involves stirring for 20-60 minutes and centrifugation for 1-10 minutes.
[0009] In one embodiment, the hydrogen peroxide has a mass fraction of 30% in the preparation of the core-shell structured nanoparticles.
[0010] In one embodiment, in the preparation of core-shell structured nanoparticles, the mass ratio of copper peroxide nanoparticles: 2-methylimidazole: cobalt nitrate hexahydrate is (10~30) mg: (1~10) g: (0.5~10) g; The reaction takes 0.5 to 3 hours at a temperature of 25 to 50°C, followed by centrifugation and washing for 1 to 10 minutes.
[0011] In one embodiment, during the preparation of the carrier, the core-shell structured nanoparticles: 3-aminopropyltriethoxysilane: folic acid: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride: N-hydroxysuccinimide are in the following proportions: (50~300) mg: (0.5~2) mL: (20~50) mg: (20~40) mg: (10~20) mg.
[0012] In one embodiment, during the preparation of the carrier, the reflux reaction is carried out for 6-24 hours, followed by cooling, centrifugation for 1-10 minutes, and product collection. The reaction is carried out in the dark for 2-8 hours, followed by centrifugation for 1-10 minutes, and the product is collected.
[0013] In one embodiment, in the preparation of the composite nanomaterial, the carrier: the photothermal agent: the drug are in the following mass ratios: (10~50): (5~20): (5~25). The stirring time for light-protected stirring is 6-24 hours, and the centrifugation time for centrifugal washing is 1-10 minutes.
[0014] A third aspect of the present invention also provides the application of the above-described CuO2-metal-organic framework composite nanomaterial or the CuO2-metal-organic framework composite nanomaterial obtained by the above preparation method in the preparation of drugs for treating breast cancer.
[0015] In a fourth aspect, the present invention also provides a medicament for treating breast cancer, comprising the above-described CuO2-metal-organic framework composite nanomaterial or the CuO2-metal-organic framework composite nanomaterial prepared by the above-described preparation method.
[0016] Compared with the prior art, the present invention has the following beneficial effects: This invention employs a step-by-step method to achieve controllable encapsulation of CuO2 in ZIF-67: First, CuO2 nanoparticles are synthesized, and then, through in-situ encapsulation technology, ZIF-67 is uniformly self-assembled on the CuO2 surface to form a stable CuO2@ZIF-67 core-shell structure. Furthermore, utilizing the porous nature and coordination ability of ZIF-67, the photothermal agent ICG and the chemotherapeutic drug MTX are efficiently co-loaded through a synergistic effect of coordination and physical adsorption. This composite nanomaterial can successfully construct a four-fold synergistic therapeutic system integrating photothermal-chemotherapy-chemokinetics-immunoactivation through the synergistic integration of multiple functions, including self-enhanced CDT, photothermal-enhanced chemotherapy, triggering copper death, and activating anti-tumor immunity. Its innovative mechanism is reflected in: self-supplied substrate-enhanced chemokinetics: CuO2 autonomously decomposes in the acidic microenvironment of breast cancer to produce H2O2, providing sufficient substrate for Fenton-like reactions, overcoming the bottleneck of traditional CDT's dependence on insufficient endogenous H2O2; dual-effect synergistic weakening of tumor defense: Cu...2+ The Fenton-like reaction mediated by ZIF-67 efficiently consumes glutathione (GSH) while generating ·OH, synergistically weakening the antioxidant defense capacity of tumor cells; immunogenic death activates anti-tumor immunity: CuO2 decomposition and the photothermal effect of ICG synergistically induce immunogenic cell death (ICD), achieving a systemic anti-tumor effect from local killing to systemic immunity. Furthermore, the confinement effect of ZIF-67 allows the decomposition products of CuO2 (H2O2 and Cu) to react with the glutathione. 2+ The local enrichment of these nanomaterials within the nanopores significantly enhances reaction kinetics efficiency, achieving a synergistic enhancement effect of "1+1>2". Finally, regarding the preparation process, the provided composite nanomaterial preparation process is simple and operates under mild conditions, exhibiting good process repeatability and scalability, laying a solid foundation for subsequent industrial production and clinical translation. Attached Figure Description
[0017] Figure 1 The images show electron microscope (EM) images of CuO2 and CuO2@ZIF-67, with the left image being a transmission electron microscope (TEM) image of CuO2 and the right image being a scanning electron microscope (SEM) image of CuO2@ZIF-67. Figure 2 The UV spectra of different samples reacting with KMnO4; Figure 3 A represents the oxygen produced by CuO2@ZIF-67 in different media; Figure 3 B represents the change in pH; Figure 3 C is for the production of H2O2; Figure 4 This is a graph showing the cytotoxicity of different samples. Detailed Implementation
[0018] This invention first employs an in-situ encapsulation method to enable ZIF-67 to self-assemble on the surface of pre-synthesized CuO2 nanoparticles, forming a structurally stable CuO2@ZIF-67 core-shell structure. Then, through a synergistic mechanism of coordination and physical adsorption, it efficiently co-loads ICG and MTX, achieving precise spatial localization of multiple components at the nanoscale. Based on this, ZIF-67 is used as a biodegradable confined carrier, leveraging its physical barrier effect and pH-responsive degradation characteristics to achieve precise temporal and spatial control of copper ion release and safe in vivo clearance, effectively addressing the poor stability and metabolic toxicity issues of single CuO2. Simultaneously, this invention constructs a cascade catalytic reaction network independent of endogenous H2O2 supply—CuO2 autonomously decomposes to produce H2O2 in the acidic microenvironment of breast cancer, and the confinement effect of ZIF-67 channels significantly increases the local concentration of reactants, fundamentally overcoming the dual limitations of insufficient substrate and low reaction efficiency in traditional chemokinetic therapy (CDT). Furthermore, through Cu… 2+The Fenton-like reaction mediated by the system efficiently generates hydroxyl radicals (·OH) while synergistically consuming glutathione (GSH), and together with the photothermal effect of ICG, induces immunogenic cell death (ICD), ultimately constructing a four-fold synergistic therapeutic system of photothermal-chemotherapy-chemokinetics-immunoactivation. In addition, the entire preparation process adopts a step-by-step controllable strategy, with mild reaction conditions, simple operation, and good reproducibility, and has excellent scalability and clinical translation prospects.
[0019] To facilitate understanding of the present invention, a more complete description will be given below with reference to the accompanying drawings. Preferred embodiments of the invention are shown in the drawings. However, the invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the invention.
[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.
[0021] Unless otherwise specified, all reagents, materials, and equipment used in this embodiment are commercially available; unless otherwise specified, all test methods are conventional test methods in this field.
[0022] Example This invention provides a method for preparing CuO2@metal-organic framework composite nanomaterials, comprising the following steps: (1) Synthesis of CuO2 nanoparticles First, CuCl2·2H2O was dissolved in deionized water, and then NaOH was added to adjust the pH to 9.0 to form Cu(OH)2 precipitate. 30% H2O2 was added dropwise, stirred at room temperature, centrifuged and washed, and vacuum dried to obtain CuO2 nanoparticles.
[0023] (2) Synthesis of CuO2@ZIF-67 CuO2 nanoparticles were ultrasonically dispersed in a 2-methylimidazole solution, and Co(NO3)2·6H2O aqueous solution was added dropwise under vigorous stirring. The reaction was carried out at room temperature, followed by centrifugation, washing, and vacuum drying to obtain the CuO2@ZIF-67 composite material.
[0024] (3) Synthesis of FA@CuO2@ZIF-67 CuO2@ZIF-67 was dispersed in a mixed solution of anhydrous ethanol and deionized water, followed by the slow dropwise addition of 3-aminopropyltriethoxysilane (APTES) under nitrogen atmosphere. After the addition was complete, the mixture was refluxed overnight. After the reaction was complete, the mixture was cooled to room temperature, centrifuged to collect the product, and washed three times with anhydrous ethanol. Finally, the product was dried in a vacuum drying oven to obtain NH2-CuO2@ZIF-67. Next, folic acid was dissolved in 2-(N-morpholino)ethanesulfonic acid (MES) buffer (0.1 mol / L, 5 mL, pH=5.5). Separately, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide were added to the MES buffer and stirred at room temperature until completely dissolved. The folic acid solution was added to the above EDC / NHS mixture and activated at room temperature in the dark for 30 min to form a folic acid active ester intermediate. Then, NH2-CuO2@ZIF-67 was dispersed in MES buffer and added to the activated folic acid reaction solution. The reaction was carried out at room temperature in the dark. After the reaction was completed, the product was collected by centrifugation and washed successively with MES buffer, phosphate buffer, and deionized water to remove unreacted folic acid, EDC, and byproducts. Finally, the product was freeze-dried to obtain FA@CuO2@ZIF-67.
[0025] (4) Co-loaded indocyanine green (ICG) and mitoxantrone (MTX) FA@CuO2@ZIF-67 was dispersed in a PBS solution containing ICG and MTX and stirred overnight in the dark. The drug was loaded using the adsorption and coordination of ZIF-67 pores. The free drug was removed by centrifugation and washing, and then lyophilized to obtain FA@CuO2@ZIF-67 / ICG / MTX.
[0026] The present invention will now be described in more detail with reference to specific embodiments.
[0027] Example 1 Preparation of CuO2: First, CuCl2·2H2O (0.5 mmol, 85 mg) was dissolved in 50 mL of deionized water. Then, 0.1 M NaOH was added to adjust the pH to 9.0 to form Cu(OH)2 precipitate. 1 mL of 30% H2O2 was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The mixture was then centrifuged and washed three times (8000 rpm, 5 min), and vacuum dried to obtain CuO2 nanoparticles.
[0028] In this embodiment, the ratio of copper chloride dihydrate to hydrogen peroxide is 0.5 mmol: 1 mL.
[0029] like Figure 1 As shown in the transmission electron microscope, small-sized CuO2 nanoparticles were successfully synthesized.
[0030] Example 2 Preparation of CuO2@ZIF-67: 10 mg of CuO2 nanoparticles were ultrasonically dispersed in 2-methylimidazole solution (2.0 g / 10 mL, 10 mL), and Co(NO3)2·6H2O solution (0.5 g, 10 mL) was added dropwise under vigorous stirring. The mixture was reacted at room temperature for 60 minutes, centrifuged and washed three times (8000 rpm, 5 min), and dried to obtain CuO2@ZIF-67 composite material.
[0031] In this embodiment, the mass ratio of copper peroxide nanoparticles: 2-methylimidazole: cobalt nitrate hexahydrate is 10 mg: 2 g: 0.5 g.
[0032] like Figure 1 Scanning electron microscopy revealed the successful synthesis of CuO2@ZIF-67 composite nanomaterials with a polyhedral structure.
[0033] Example 3 Synthesis of FA@CuO2@ZIF-67: 200 mg CuO2@ZIF-67 was dispersed in a mixture of 40 mL anhydrous ethanol and 0.4 mL deionized water. Then, 1.0 mL of 3-aminopropyltriethoxysilane (APTES) was slowly added dropwise under nitrogen atmosphere. After the addition was complete, the mixture was refluxed at 78°C for 12 h. After the reaction was complete, the mixture was cooled to room temperature, centrifuged at 8000 rpm for 5 min to collect the product, and washed three times with anhydrous ethanol. Finally, the product was dried in a vacuum drying oven to obtain NH2-CuO2@ZIF-67. Next, 20 mg of folic acid was dissolved in 2-(N-morpholino)ethanesulfonic acid (MES) buffer (0.1 mol / L, 5 mL, pH=5.5). Separately, 15 mL of MES buffer was added sequentially with 25 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 15 mg of N-hydroxysuccinimide, and stirred at room temperature until completely dissolved. Folic acid solution was added to the above EDC / NHS mixture and activated at room temperature in the dark for 30 min to form a folic acid active ester intermediate. Then, NH2-CuO2@ZIF-67 (100 mg) was dispersed in 5 mL of MES buffer and added to the activated folic acid reaction solution. The reaction was carried out at room temperature in the dark for 4 h. After the reaction was completed, the product was collected by centrifugation at 8000 rpm for 5 min and washed successively with MES buffer, phosphate buffer, and deionized water to remove unreacted folic acid, EDC, and byproducts. Finally, the product was freeze-dried to obtain FA@CuO2@ZIF-67.
[0034] In this embodiment, the dosage ratio of core-shell structured nanoparticles: 3-aminopropyltriethoxysilane: folic acid: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride: N-hydroxysuccinimide is 200mg: 1mL: 20mg: 25mg: 15mg.
[0035] Example 4 Indocyanine green (ICG) and mitoxantrone (MTX) co-loaded: FA@CuO2@ZIF-67 (20 mg) was dispersed in a PBS solution containing ICG (5 mg) and MTX (10 mg) and stirred overnight in the dark. The drug was loaded using the adsorption and coordination of ZIF-67 pores. The free drug was removed by centrifugation and washing, and then lyophilized to obtain FA@CuO2@ZIF-67 / ICG / MTX.
[0036] In this embodiment, the mass ratio of carrier:photothermal agent:drug is 20:5:10.
[0037] Implementation effect evaluation 1. Detection of H2O2 To verify that CuO2@ZIF-67 degrades under acidic conditions, the presence of H2O2 after acid-induced decomposition of CuO2@ZIF-67 was verified by the potassium permanganate colorimetric method.
[0038] like Figure 2 As shown, due to the peroxide group, permanganate (MnO) 4- ) Reduced to colorless Mn 2+ Permanganate (MnO) in acidic solutions 4- The pink color of the sample faded after the addition of CuO2@ZIF-67 or H2O2. This indicates that CuO2 can produce H2O2 in acidic solutions.
[0039] 2. Catalase (CAT) activity The activity of catalase (CTA) was indirectly assessed by analyzing the rate at which hydrogen peroxide in nanomaterials is converted into dissolved oxygen. First, oxygen-deprived water was prepared by purging with nitrogen. Then, the dissolved oxygen concentration in the oxygen-deprived water containing the same concentration of nanomaterials and hydrogen peroxide was measured using a dissolved oxygen meter over a 10-minute period, with data recorded every 10 seconds.
[0040] The results are as follows Figure 3 As shown, the most oxygen is produced in a weakly acidic medium, indirectly verifying that the composite nanomaterial can generate oxygen in the tumor microenvironment, and also indicating that it can solve the hypoxic conditions in the tumor microenvironment. In addition, CuO2 reacts with water to form copper hydroxide, thus alkalizing the pH value to 10-12, indicating the potential to regulate the weakly acidic tumor microenvironment (TME).
[0041] 3. Cytotoxicity Using folate receptor-positive 4T1 breast cancer cells, such as Figure 4 As shown, in a simulated tumor microacidic environment (pH=6.5), FA@ZIF-67@CuO2 / ICG / MTX at a concentration of 50 μg / mL and under mild NIR irradiation achieved a tumor cell inhibition rate of 94.9%, while the inhibition rates of FA@ZIF-67 / MIX, FA@ZIF-67@CuO2, and FA@ZIF-67 / ICG+NIR were only 40.6%, 31.2%, and 35.2%, respectively. Notably, the inhibition rate of FA@ZIF-67@CuO2 / ICG+NIR was 79.2%, indicating that in the tumor microenvironment, the synergistic enhancement factor of the CDT+PTT (photothermal therapy) dual-mode reached 1.43, the synergistic enhancement factor of the three-mode full-platform reached 1.30, and the combination index CI value was less than 0.5, all demonstrating a strong synergistic effect. This cascade amplification effect of self-supplied H2O2 chemical kinetics, photothermal therapy, and chemotherapy within a nano-confined space can maximally inhibit tumor cell proliferation, thereby achieving the therapeutic goal.
[0042] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0043] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.
Claims
1. A CuO2-metal-organic framework composite nanomaterial, characterized in that, The components include a carrier, a photothermal agent, and a drug, wherein the carrier comprises core-shell structured nanoparticles and folic acid; The core-shell structured nanoparticles include a core and a shell, the core includes copper peroxide, the shell includes a metal-organic framework, the metal-organic framework includes ZIF-67, and the core is encapsulated in the shell; The photothermal agent includes indocyanine green, the drug includes mitoxantrone, and the photothermal agent and the drug are loaded onto the carrier.
2. The CuO2-metal-organic framework composite nanomaterial according to claim 1, characterized in that, According to the mass ratio, the carrier: the photothermal agent: the drug is (10~50):(5~20):(5~25).
3. The method for preparing CuO2-metal-organic framework composite nanomaterials according to any one of claims 1-2, characterized in that, Includes the following steps: Preparation of core-shell structured nanoparticles: Dissolve copper chloride dihydrate in water, adjust the pH, add hydrogen peroxide, stir, centrifuge and wash, and vacuum dry to obtain copper peroxide nanoparticles; disperse copper peroxide nanoparticles in 2-methylimidazole solution, add cobalt nitrate hexahydrate solution, react, centrifuge and wash, and vacuum dry to obtain core-shell structured nanoparticles. Preparation of the carrier: Core-shell structured nanoparticles were dispersed in a mixed solution of ethanol and water. 3-Aminopropyltriethoxysilane was added dropwise under nitrogen conditions. The mixture was refluxed, cooled, centrifuged to collect the product, washed, and vacuum dried to obtain the reactant. Folic acid was dissolved in buffer solution to obtain a folic acid solution. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide were dissolved in buffer solution, added to the folic acid solution, and mixed to activate the folic acid active ester intermediate. The reactant was dispersed in buffer solution, the folic acid active ester intermediate was added, and the mixture was reacted in the dark. The product was collected by centrifugation, washed, and freeze-dried to obtain the final product. Preparation of composite nanomaterials: The photothermal agent and the drug are dissolved in a buffer solution to obtain a mixed solution. The carrier is dispersed in the mixed solution, stirred in the dark, centrifuged and washed, and then freeze-dried to obtain the final product.
4. The preparation method according to claim 3, characterized in that, In the preparation of core-shell structured nanoparticles, the ratio of copper chloride dihydrate to hydrogen peroxide is (0.2~1.0) mmol: (1~5) mL, according to the dosage ratio. The stirring and centrifugal washing process involves stirring for 20-60 minutes and centrifugation for 1-10 minutes.
5. The preparation method according to claim 3, characterized in that, In the preparation of core-shell structured nanoparticles, the mass ratio of copper peroxide nanoparticles: 2-methylimidazole: cobalt nitrate hexahydrate is (10~30) mg: (1~10) g: (0.5~10) g; The reaction takes 0.5 to 3 hours at a temperature of 25 to 50°C, followed by centrifugation and washing for 1 to 10 minutes.
6. The preparation method according to claim 3, characterized in that, In the preparation of the carrier, the following dosage ratios are used: core-shell structured nanoparticles: 3-aminopropyltriethoxysilane: folic acid: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride: N-hydroxysuccinimide, which are (50~300) mg: (0.5~2) mL: (20~50) mg: (20~40) mg: (10~20) mg.
7. The preparation method according to claim 3, characterized in that, In the preparation of the support, the reflux reaction is carried out for 6-24 hours, followed by cooling, centrifugation for 1-10 minutes, and product collection. The reaction is carried out in the dark for 2-8 hours, followed by centrifugation for 1-10 minutes, and the product is collected.
8. The preparation method according to claim 3, characterized in that, In the preparation of composite nanomaterials, the mass ratio of the carrier: the photothermal agent: the drug is (10~50):(5~20):(5~25). The stirring time for light-protected stirring is 6-24 hours, and the centrifugation time for centrifugal washing is 1-10 minutes.
9. The use of the CuO2-metal-organic framework composite nanomaterial as described in any one of claims 1-2 or the CuO2-metal-organic framework composite nanomaterial obtained by the preparation method described in any one of claims 3-8 in the preparation of drugs for treating breast cancer.
10. A drug for treating breast cancer, characterized in that, Includes the CuO2-metal-organic framework composite nanomaterial according to any one of claims 1-2 or the CuO2-metal-organic framework composite nanomaterial obtained by the preparation method according to any one of claims 3-8.