Composite nano material as well as preparation method and application thereof

Abstract

The invention relates to the technical field of nano materials, and discloses a composite nano material as well as a preparation method and application thereof. The composite nano material is of a core-shell structure and comprises BiVO4 nano particles as a core; the MnO2 layer is coated on the surfaces of the BiVO4 nano particles; and the alendronate is used for modifying the outer part of the MnO2 layer. The composite nanomaterial can obviously inhibit the growth of bone tumors, has a good analgesic effect on mechanical pain and cold and heat pain, and has no obvious side effect after treatment. The pharmaceutical preparation provided by the invention has the advantages that the raw materials are easy to obtain, and the pharmaceutical preparation has a good application prospect in preparation of drugs with dual effects of resisting tumors and relieving pain.

Description

Technical Field

[0001] This application relates to the field of nanomaterials technology, and more specifically, to a composite nanomaterial, its preparation method, and its application. Background Technology

[0002] Currently, opioids and non-opioid analgesics are mainly used for pain management in clinical practice, and the demand for their use is constantly expanding. Opioids are commonly used analgesics in the management of moderate to severe acute or cancer pain; however, more than half of patients receiving anticancer treatment experience pain, and one-third of these patients still experience pain even after completing treatment. However, opioids are highly addictive, and their clinical use carries a high risk of respiratory depression, requiring monitoring of the effects of respiratory depression. Therefore, their use needs strict management and restriction.

[0003] Solid tumors, which account for over 90% of malignant tumors, still lack effective treatments. Long-term use can lead to drug resistance, requiring frequent regimen changes and impacting efficacy. Traditional anti-tumor drugs have poor targeting effects, resulting in unsatisfactory treatment outcomes. Chemotherapy drugs can easily cause systemic reactions such as nausea, hair loss, and bone marrow suppression; or produce rashes, hypertension, and damage to specific organs. Currently, preclinical novel targeted drugs or immunotherapies are expensive, placing an unbearable financial burden on most cancer patients.

[0004] Ultrasound-mediated sonodynamic therapy (SDT) has become a promising anti-tumor treatment due to its advantages such as non-invasiveness, deep tissue penetration, and high spatiotemporal accuracy. SDT overcomes the limitation of poor light penetration depth in traditional photodynamic therapy (PDT), precisely activating sonosensitizers accumulated deep within tumors to generate cytotoxic reactive oxygen species (ROS), effectively killing tumor cells. Traditional organic sonosensitizers suffer from poor water solubility and insufficient targeting ability, while inorganic sonosensitizers have low ROS yields and poor biocompatibility. These shortcomings hinder the clinical translation and application of SDT. Therefore, designing highly efficient nano-sonic sensitizers with high ROS yield, good water solubility, strong targeting, and good biocompatibility is the current direction of SDT development. Bismuth vanadate (BiVO4) has become a safe and efficient sonosensitizer due to its small band gap, good biocompatibility, and stability. BiVO4 can induce electron-hole pair separation under ultrasound irradiation. The released energy, electrons, and holes can react with surrounding oxygen or water to produce cytotoxic reactive oxygen species, leading to cell death.

[0005] Alendronate alleviates or treats osteoporosis through mechanisms such as inhibiting osteoclasts, maintaining bone structure, and improving mineralization. Due to its excellent bone-targeting capabilities, alendronate is also used in carrier functionalization for the treatment of bone-related diseases. Compared to its bone repair and bone-targeting functions, its analgesic effect in clinical practice is often overlooked. Traditionally, it was believed that alendronate could reduce osteoclast activity, leading to a decrease in afferent acid-induced activation of primary nociceptors.

[0006] The cGAS-STING signaling pathway has been a research hotspot in recent years, and it has been proven to be a key innate immune pathway that can promote various immune effector responses, thereby inhibiting tumor growth. STING agonists directly activate dendritic cells (DCs), inducing specific immune responses and promoting T cell migration and infiltration in tumor tissues, thereby fighting tumors. However, most STING agonists require intratumoral injection, which is not suitable for tumors that have already metastasized. Intravenous or intraperitoneal administration of STING agonists may trigger a cytokine storm and may exhibit severe inflammatory side effects.

[0007] Therefore, if a composite nanomaterial that can target and synergistically treat tumors and manage pain, and can modulate the cGAS-STING signaling pathway can be developed, it will be expected to provide new strategies and methods for the comprehensive treatment of tumors. Summary of the Invention

[0008] The purpose of this invention is to develop a composite nanomaterial for targeted and synergistic tumor treatment and pain management for the treatment and pain management of bone cancer patients.

[0009] To achieve the above-mentioned objectives, this application adopts the following technical solution: In a first aspect, this application provides a composite nanomaterial, the composite nanomaterial having a core-shell structure, comprising: BiVO4 nanoparticles serve as the core; The MnO2 layer coating the surface of the BiVO4 nanoparticles; and alendronate is modified on the exterior of the MnO2 layer.

[0010] Furthermore, the surface of the BiVO4 nanoparticles is modified with polyethyleneimine.

[0011] Furthermore, the alendronate is coupled to the MnO2 surface via polyallylamine hydrochloride.

[0012] Secondly, this application provides a method for preparing the aforementioned composite nanomaterial, comprising the following steps: Preparation of S1,BiVO4 nanoparticles; Bi(NO3)3·5H2O and VO(acac)2 were dissolved separately, the solutions were mixed, PVP was added, and the mixture was stirred and refluxed at 80°C. After centrifugation, BiVO4 nanoparticles were obtained. Preparation of S2,BiVO4@MnO2 nanoparticles; BiVO4 nanoparticles were dissolved, and polyethyleneimine was added for surface modification. The mixture was ultrasonically mixed, centrifuged, and dissolved again. KMnO4 solution was added and mixed thoroughly. The mixed solution was then added to ddH2O and centrifuged to obtain BiVO4@MnO2 nanoparticles. Preparation of S3,BiVO4@MnO2@Ale nanoparticles; After dissolving BiVO4@MnO2 nanoparticles, polyallylamine hydrochloride was added and stirred thoroughly. After centrifugation, ddH2O was added and dissolved thoroughly. Then, sodium alendronate trihydrate was added, stirred at room temperature, and centrifuged. The precipitate obtained by centrifugation was dried to finally obtain BiVO4@MnO2@Ale nanoparticles.

[0013] Furthermore, the specific steps of step 1 are as follows: 1 mmol of bismuth nitrate pentahydrate Bi(NO3)3·5H2O was dissolved in 10 mL of acetic acid, and 1 mmol of VO(acac)2 was dissolved in 40 mL of ethanol. After mixing the two solutions, 10 g of polyvinylpyrrolidone was added to the mixture. The solution was transferred to a 100 mL round-bottom flask and refluxed at 80°C with magnetic stirring for 2 hours. The mixture was then centrifuged twice at 13000 rpm for 5 minutes at room temperature to obtain BiVO4 nanoparticles.

[0014] Furthermore, the specific steps of step 2 are as follows: After dissolving the BiVO4 nanoparticles in 10 mL of ddH2O, 3 mg of polyethyleneimine was added for surface modification. The mixture was thoroughly mixed with ultrasound, shaken for 5 minutes, and centrifuged twice at 13000 rpm for 5 minutes each time. After dissolving the mixture in 5 mL of ddH2O, 5 mL of 5 mg / mL KMnO4 solution was added, and the mixture was shaken for 2 minutes to ensure thorough mixing. The mixture was then stirred at room temperature for 2 hours. The resulting solution was then added to 10 mL of ddH2O and centrifuged twice at 13000 rpm for 5 minutes each time at room temperature to obtain BiVO4@MnO2 nanoparticles.

[0015] Furthermore, the specific steps of step 3 are as follows: The BiVO4@MnO2 nanoparticles were dissolved in 10 mL of ddH2O, and then 50 mg of polyallylamine hydrochloride was added and stirred thoroughly for 2 hours. The mixture was centrifuged twice at 13000 rpm for 5 minutes at room temperature. After dissolving the mixture in 10 mL of ddH2O, 5 mg of alendronate sodium trihydrate was added and stirred at room temperature for 2 hours. The mixture was then centrifuged twice at 13000 rpm for 5 minutes at room temperature. The precipitate obtained by centrifugation was dried in a vacuum oven at 20°C for 24 hours to finally obtain BiVO4@MnO2@Ale nanoparticles.

[0016] Thirdly, this application provides a pharmaceutical composition comprising a therapeutically effective amount of composite nanomaterial and a pharmaceutically acceptable carrier.

[0017] Fourthly, this application provides the use of the aforementioned composite nanomaterial or the aforementioned pharmaceutical composition in the preparation of a medicament for treating tumors.

[0018] Furthermore, the tumor is a bone tumor.

[0019] In summary, this application has the following beneficial effects: This composite nanomaterial formulation exhibits bone-targeting characteristics. Compared to traditional drug formulations, its sodium alendronate component can effectively bind to hydroxyapatite in bone. This drug formulation can be administered directly via intravenous injection, meeting patients' needs for tumor treatment and pain relief. It decomposes rapidly in vivo, exhibits good biocompatibility, and does not cause adverse reactions in major organs (heart, liver, spleen, lungs, and kidneys) after injection. This drug formulation can be prepared in one step without further processing, and the raw materials are simple, readily available, and low-cost, making it a highly promising multifunctional nanomedicine. Attached Figure Description

[0020] Figure 1 Characterization of composite nanomaterial formulations; Figure 2 Evaluation results of the bone targeting properties of composite nanomaterial formulations; Figure 3 Evaluation results of the antitumor effects of composite nanomaterial formulations; Figure 4 Evaluation results of the analgesic effect of composite nanomaterial formulations; Figure 5 Results of biosafety evaluation of composite nanomaterial formulations. Detailed Implementation

[0021] The technical solutions and effects of this application will be further described in detail below with reference to the embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are merely for explaining the invention and are not intended to limit the invention.

[0022] The raw materials and equipment used in the composite nanomaterial formulation of this invention can all be obtained directly by purchasing commercially available products.

[0023] Example 1: Preparation and Characterization of Composite Nanomaterials 1 mmol of bismuth nitrate pentahydrate Bi(NO3)3·5H2O was dissolved in 10 mL of acetic acid, and 1 mmol of VO(acac)2 was dissolved in 40 mL of ethanol. After mixing, 10 g of polyvinylpyrrolidone (PVP) was added to the mixture, and the solution was transferred to a 100 mL round-bottom flask and refluxed at 80°C with magnetic stirring for 2 hours. The mixture was centrifuged twice at 13000 rpm for 5 minutes at room temperature to obtain BiVO4 nanoparticles. The BiVO4 nanoparticles were dissolved completely in 10 mL of ddH2O, and then 3 mg of polyethyleneimine (PEI) was added for surface modification. The mixture was thoroughly mixed with ultrasound, shaken for 5 minutes, and centrifuged twice at 13000 rpm for 5 minutes. After dissolving completely in 5 mL of ddH2O, 5 mL of 5 mg / mL KMnO4 solution was added, and the mixture was shaken for 2 minutes to ensure thorough mixing. The mixture was stirred at room temperature for 2 hours, and the final mixture was added to 10 mL of ddH2O. BiVO4@MnO2 nanoparticles were obtained by centrifugation twice at 13000 rpm for 5 minutes at room temperature. The BiVO4@MnO2 nanoparticles were then dissolved in 10 mL of ddH2O, followed by the addition of 50 mg of polyallylamine hydrochloride (PAH). The mixture was stirred thoroughly for 2 hours and centrifuged twice at 13000 rpm for 5 minutes at room temperature. After further dissolution in 10 mL of ddH2O, 5 mg of alendronate sodium trihydrate was added. The mixture was stirred at room temperature for 2 hours and centrifuged twice at 13000 rpm for 5 minutes at room temperature. The resulting precipitate was dried in a vacuum oven at 20°C for 24 hours to obtain BiVO4@MnO2@Ale nanoparticles. TEM images of the intermediate product BiVO4, BiVO4@MnO2 nanoparticles, and the final material BiVO4@MnO2@Ale confirmed the formation of the composite nanomaterial formulation BiVO4@MnO2@Ale. Figure 1 AC). Figure 1 D represents the elemental mapping results, which prove the presence of Bi, V, Mn, and P elements in BiVO4@MnO2@Ale, demonstrating the successful synthesis of the composite nanomaterial formulation BiVO4@MnO2@Ale.

[0024] Example 2: Evaluation of bone targeting properties of composite nanomaterial formulations BiVO4@MnO2@Ale was conjugated with Cy5.5 and injected into mice via the tail vein. The femurs of mice were removed at 2, 4, 6, 12, 24, 48, and 72 hours later, and the fluorescence intensity of Cy5.5 was observed using fluorescence imaging. This demonstrated that 24 hours after tail vein injection of BiVO4@MnO2@Ale, the strongest enrichment effect was observed in the mouse femur. Figure 2 ).

[0025] Example 3: Evaluation of the antitumor effect of composite nanomaterial formulations Six- to eight-week-old C5 mice were randomly divided into six groups (n=5 per group): Control group, US group, BiVO4@MnO2 group, BiVO4@MnO2+US group, BiVO4@MnO2@Ale group, and BiVO4@MnO2@Ale+US group. All drugs were administered via tail vein injection (100 μL), followed by ultrasound therapy (1 W / cm²) 24 hours post-injection. 2 (50% duty, 2 min), in vivo fluorescence imaging was performed on day 4, day 7, day 11 and day 14 respectively. Figure 3 A shows the in vivo fluorescence imaging results of mice in different treatment groups on day 14. Figure 3 B shows the tumor growth curves for each mouse in different treatment groups.

[0026] Combination Figure 3 It can be seen that the growth of bone tumors in mice in the BiVO4@MnO2@Ale+US group was significantly inhibited, showing the strongest anti-tumor growth effect compared with other groups.

[0027] Example 4: Evaluation of the analgesic effect of composite nanomaterial formulations Six- to eight-week-old C5 mice were randomly divided into six groups (n=5 per group): Control group, US group, BiVO4@MnO2 group, BiVO4@MnO2+US group, BiVO4@MnO2@Ale group, and BiVO4@MnO2@Ale+US group. All drugs were administered via tail vein injection (100 μL), followed by ultrasound therapy (1 W / cm²) 24 h post-injection. 2 (50% duty, 2 min) to evaluate the analgesic effects related to mechanical pain, cold pain and heat pain respectively.

[0028] Combination Figure 4 It can be seen that the BiVO4@MnO2@Ale+US group exhibited the strongest analgesic effect among mechanical pain, cold pain, and heat pain, and can be used to prepare drugs for clinical bone cancer analgesia.

[0029] Example 5: Biosafety Evaluation of Composite Nanomaterial Formulations On day 14 after injection of the composite nanomaterial formulation, mice were euthanized with an overdose of sevoflurane, and their hearts were perfused with 20 mL of 0.9% saline. Hearts, livers, spleens, lungs, and kidneys were collected, fixed in 4% paraformaldehyde, embedded in paraffin, sectioned, and stained with H&E.

[0030] Combination Figure 5 It can be seen that muscles and nerves remained intact after injection treatment, and the drug formulation did not induce local tissue toxicity. Furthermore, almost no inflammation or other pathological changes were observed in the heart, liver, spleen, lungs, and kidneys in any group, indicating that the composite material has satisfactory biocompatibility and safety.

[0031] In summary, this invention provides a novel composite nanomaterial formulation and its application in the treatment of bone tumors and pain management. Experimental results show that this composite nanomaterial formulation can significantly inhibit the growth of bone tumors and has good analgesic effects on both mechanical pain and pain caused by cold and heat, with no significant side effects after treatment. The pharmaceutical formulation provided by this invention uses readily available raw materials and has promising applications in the preparation of drugs with both anti-tumor and analgesic effects.

[0032] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A composite nanomaterial, characterized in that, The composite nanomaterial has a core-shell structure and includes: BiVO4 nanoparticles serve as the core; The MnO2 layer coating the surface of the BiVO4 nanoparticles; and alendronate is modified on the exterior of the MnO2 layer.

2. The composite nanomaterial according to claim 1, characterized in that, The surface of the BiVO4 nanoparticles is modified with polyethyleneimine.

3. The composite nanomaterial according to claim 1, characterized in that, The alendronate is coupled to the MnO2 surface via polyallylamine hydrochloride.

4. The method for preparing the composite nanomaterial according to any one of claims 1-3, characterized in that, Includes the following steps: Preparation of S1,BiVO4 nanoparticles; Bi(NO3)3·5H2O and VO(acac)2 were dissolved separately, the solutions were mixed, PVP was added, and the mixture was stirred and refluxed at 80°C. After centrifugation, BiVO4 nanoparticles were obtained. Preparation of S2,BiVO4@MnO2 nanoparticles; BiVO4 nanoparticles were dissolved, and polyethyleneimine was added for surface modification. The mixture was ultrasonically mixed, centrifuged, and dissolved again. KMnO4 solution was added and mixed thoroughly. The mixed solution was then added to ddH2O and centrifuged to obtain BiVO4@MnO2 nanoparticles. Preparation of S3,BiVO4@MnO2@Ale nanoparticles; After dissolving BiVO4@MnO2 nanoparticles, polyallylamine hydrochloride was added and stirred thoroughly. After centrifugation, ddH2O was added and dissolved thoroughly. Then, sodium alendronate trihydrate was added, stirred at room temperature, and centrifuged. The precipitate obtained by centrifugation was dried to finally obtain BiVO4@MnO2@Ale nanoparticles.

5. The preparation method according to claim 4, characterized in that, The specific steps of step 1 are as follows: 1 mmol of bismuth nitrate pentahydrate Bi(NO3)3·5H2O was dissolved in 10 mL of acetic acid, and 1 mmol of VO(acac)2 was dissolved in 40 mL of ethanol. After mixing the two solutions, 10 g of polyvinylpyrrolidone was added to the mixture. The solution was transferred to a 100 mL round-bottom flask and refluxed at 80°C with magnetic stirring for 2 hours. The mixture was then centrifuged twice at 13000 rpm for 5 minutes at room temperature to obtain BiVO4 nanoparticles.

6. The preparation method according to claim 4, characterized in that, The specific steps of step 2 are as follows: After dissolving the BiVO4 nanoparticles in 10 mL of ddH2O, 3 mg of polyethyleneimine was added for surface modification. The mixture was thoroughly mixed with ultrasound, shaken for 5 minutes, and centrifuged twice at 13000 rpm for 5 minutes each time. After dissolving the mixture in 5 mL of ddH2O, 5 mL of 5 mg / mL KMnO4 solution was added, and the mixture was shaken for 2 minutes to ensure thorough mixing. The mixture was then stirred at room temperature for 2 hours. The resulting solution was then added to 10 mL of ddH2O and centrifuged twice at 13000 rpm for 5 minutes each time at room temperature to obtain BiVO4@MnO2 nanoparticles.

7. The preparation method according to claim 4, characterized in that, The specific steps of step 3 are as follows: The BiVO4@MnO2 nanoparticles were dissolved in 10 mL of ddH2O, and then 50 mg of polyallylamine hydrochloride was added and stirred thoroughly for 2 hours. The mixture was centrifuged twice at 13000 rpm for 5 minutes at room temperature. After dissolving the mixture in 10 mL of ddH2O, 5 mg of alendronate sodium trihydrate was added and stirred at room temperature for 2 hours. The mixture was then centrifuged twice at 13000 rpm for 5 minutes at room temperature. The precipitate obtained by centrifugation was dried in a vacuum oven at 20°C for 24 hours to finally obtain BiVO4@MnO2@Ale nanoparticles.

8. A pharmaceutical composition, characterized in that, The composite nanomaterial comprising a therapeutically effective amount of any one of claims 1-3 and a pharmaceutically acceptable carrier.

9. The use of the composite nanomaterial of any one of claims 1-3 or the pharmaceutical composition of claim 8 in the preparation of a medicament for treating tumors.

10. The application according to claim 9, characterized in that, The tumor is a bone tumor.

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