A kind of magnetic response mesoporous silica composite nanoparticles, composite nano drug-loaded complex and its preparation method and application

Abstract

The application discloses a kind of magnetic response mesoporous silica composite nanoparticles, composite nano drug-loaded complex and its preparation method and application, it is related to nanobiomaterial and drug delivery technical field.The magnetic response mesoporous silica composite nanoparticles can effectively avoid the problem of channel blockage caused by the continuous filling of magnetic nanoparticles along the full length of mesoporous channel, so that the composite material still retains larger effective pore volume and specific surface area while maintaining good magnetic response performance, for loading drug.The obtained composite nano drug-loaded complex can produce magnetic heat effect under the action of external alternating magnetic field, thereby triggering the controlled release of drug molecules in the channel, realizing the magnetic response regulated drug delivery.Compared with existing mesoporous materials, the magnetic response mesoporous silica composite nanoparticles of the application show obvious advantages in drug loading capacity, structural stability and magnetic field response efficiency, and can be applied to magnetic field targeted drug transport, magnetic heat synergistic therapy and tumor treatment.

Description

Technical Field

[0001] This invention relates to the field of nanobiomaterials and drug delivery technology, and more specifically, to a magnetically responsive mesoporous silica composite nanoparticle, a composite nano-drug-carrying complex, its preparation method, and its application. Background Technology

[0002] In recent years, with the development of nanomaterials science and biomedical engineering, drug delivery systems based on nanocarriers have gradually become an important research direction in biomedical fields such as tumor therapy. Nanocarrier materials can achieve efficient drug loading, targeted delivery, and controlled release through structural design and surface regulation, thereby improving drug utilization efficiency and reducing toxic side effects on normal tissues.

[0003] Among numerous nanomaterial carriers, mesoporous silica has attracted widespread attention in the field of drug delivery due to its high specific surface area, regularly tunable pore structure, and good chemical stability and biocompatibility. Typical ordered mesoporous silica materials include MCM-41 and SBA-15, among which MCM-41 possesses a two-dimensional hexagonal ordered pore structure (space group: p6mm Its pore size is typically in the range of 2-10 nm, with a large pore volume and high specific surface area, making it very suitable as a carrier for drug storage and release.

[0004] However, mesoporous silica materials alone still have certain limitations in practical applications. For example, in the in vivo environment, these materials typically lack active targeting capabilities, and drug release mainly relies on a concentration gradient-driven diffusion process, making it difficult to achieve precise delivery and controlled release to specific lesion sites. Therefore, in recent years, researchers have attempted to introduce magnetic nanoparticles into mesoporous silica systems to endow the materials with magnetic responsive properties.

[0005] Magnetic nanoparticles exhibit significant magnetic response behavior under an applied magnetic field, enabling magnetic field-assisted targeted transport. Simultaneously, some magnetic materials can generate a magnetocaloric effect under an alternating magnetic field, raising the local temperature and promoting drug release. Therefore, constructing magnetically responsive drug carriers by combining magnetic nanoparticles with mesoporous silica holds broad application prospects in tumor-targeted therapy, magnetocaloric therapy, and related biomedical fields.

[0006] Currently, the main methods for combining magnetic nanoparticles with mesoporous silica materials include the following: The first type is the core-shell structure. This structure typically uses magnetic nanoparticles as the core, covered by a silica shell, and further constructs a mesoporous structure. Although this method can stably encapsulate the magnetic components inside the material, the magnetic core is usually isolated by a relatively thick silica shell, which reduces the magnetic response efficiency of the material to some extent.

[0007] The second type is the surface-loaded structure. This involves depositing or adsorbing magnetic nanoparticles onto the outer surface of mesoporous silica particles. While this method is relatively simple, the magnetic nanoparticles are prone to agglomeration on the material surface and may desorb during use, thus affecting the structural stability of the composite material.

[0008] The third type is the pore-confined loading structure. This involves magnetic nanoparticles located inside or distributed along the pores of a mesoporous material. This type of structure can utilize the confinement effect of mesoporous materials to regulate the dispersion state of magnetic components. However, when the size of the magnetic particles is close to the pore size, they tend to occupy too much pore space, thereby reducing the specific surface area and effective pore volume of the material, and affecting the diffusion and release behavior of drug molecules.

[0009] In summary, the existing technology still has the following shortcomings: (1) the magnetic nanoparticles are not stable enough and are easy to fall off or agglomerate; (2) the magnetic particles may block the pores and reduce the specific surface area of ​​the material; (3) the pore structure is damaged, affecting the drug loading and release performance; (4) it is difficult to optimize the magnetic response performance and drug release performance at the same time.

[0010] Therefore, how to introduce magnetic response units while avoiding excessive impact on the effective pore volume and drug loading space of mesoporous materials, thus balancing magnetic response performance, composite stability, and drug loading / release capacity, remains a technical problem to be solved in this field. It is necessary to develop a novel structural design that enables magnetic nanoparticles to exist stably within the structure of mesoporous materials while maintaining the integrity of the pore structure, thereby improving the overall performance of the material in drug delivery systems.

[0011] In view of this, the present invention is proposed. Summary of the Invention

[0012] The purpose of this invention is to provide magnetically responsive mesoporous silica composite nanoparticles, composite nano-drug-carrying complexes, their preparation methods, and applications to solve at least one of the above-mentioned problems.

[0013] This invention is implemented as follows: In a first aspect, the present invention provides a magnetically responsive mesoporous silica composite nanoparticle, comprising: a mesoporous silica carrier and magnetic nanoparticles mainly distributed in at least one of the following regions of the mesoporous silica carrier: the outer surface of the mesoporous silica carrier, the pore opening of the mesoporous silica carrier, and the near-surface pore region near the pore opening. The magnetic nanoparticles are bonded to the mesoporous silica support through interfacial interactions. The mesoporous silica support is selected from MCM-41 or SBA-15. The magnetic nanoparticles have a particle size of 5-50 nm, while the average pore size of the mesoporous silica support is 2-10 nm. The particle size of the magnetic nanoparticles is larger than the average pore size of the mesoporous silica support.

[0014] Secondly, the present invention provides a method for preparing magnetically responsive mesoporous silica composite nanoparticles, comprising the following steps: (1) Magnetic nanoparticles and mesoporous silica carriers are prepared separately. The preparation method of magnetic nanoparticles includes: dissolving a first metal salt and an iron salt precursor in a solvent, preparing a superparamagnetic iron oxide precursor by co-precipitation reaction, and obtaining magnetic nanoparticles by washing, drying and calcining; the first metal salt is selected from copper salt, nickel salt, manganese salt or cobalt salt. The preparation method of mesoporous silica support includes: preparing MCM-41 or SBA-15 mesoporous silica support by template guiding method, and performing drying or dehydration pretreatment; (2) Magnetic nanoparticles are dispersed in a solvent to form a dispersion, and then a mesoporous silica carrier is added for mixing, so that the magnetic nanoparticles are mainly distributed in at least one of the following regions of the mesoporous silica carrier through interfacial interaction: the outer surface of the mesoporous silica carrier, the pore opening of the mesoporous silica carrier, and the near-surface pore region near the pore opening.

[0015] Thirdly, the present invention also provides a composite nanoparticle drug-carrying complex, which includes the above-mentioned magnetically responsive mesoporous silica composite nanoparticles and a drug.

[0016] Fourthly, the present invention also provides the application of magnetically responsive mesoporous silica composite nanoparticles or the above-mentioned composite nano-drug-carrying complexes in the preparation of drugs for tumor treatment.

[0017] The present invention has the following beneficial effects: This invention utilizes the interfacial interaction between the abundant silanol groups on the surface of a mesoporous silica support and magnetic nanoparticles to fix magnetic nanoparticles onto the outer surface of the mesoporous silica support, the pore openings of the support, and the near-surface pore region close to the pore openings. The particle size of the magnetic nanoparticles is controlled to be larger than the average pore size of the mesoporous silica support. The larger particle size prevents the magnetic nanoparticles from continuously filling the entire length of the mesoporous silica support pores, effectively avoiding excessive occupation of the mesoporous channels. The abundant silanol groups on the surface of the mesoporous silica support, such as isolated hydroxyl groups, associated hydroxyl groups, and hydroxyl groups, can bind the magnetic nanoparticles through interfacial interactions such as hydrogen bonding, coordination bonding, electrostatic attraction, and van der Waals forces. This maintains the large specific surface area and effective pore volume of the MCM-41 material, and the magnetically responsive mesoporous silica composite nanoparticles retain unoccupied mesoporous channels, enabling them to still be used for efficient loading and storage of drug molecules.

[0018] Compared to schemes that continuously fill the deep pores with magnetic particles, this invention emphasizes preserving the remaining effective pore volume while introducing magnetic response units. Compared to surface-loaded structures (i.e., magnetic nanoparticles deposited or adsorbed on the outer surface of mesoporous silica particles), the distribution characteristics of magnetic nanoparticles at the pore openings and near-surface pore regions of the mesoporous silica carrier in this invention are beneficial for improving composite stability and provide conditions for the synergistic design of magnetic response and drug loading.

[0019] This invention also provides the application of the composite nanoparticle drug-carrying complex in magnetic field-assisted targeted drug delivery and magnetic response-regulated drug release, so that the obtained composite nanoparticle drug-carrying complex has both drug loading capacity and magnetic field response capability, which can realize magnetic field-assisted targeted enrichment and magnetic response-controlled release, thereby helping to increase the drug concentration at the lesion site and reduce systemic toxic side effects to a certain extent. Attached Figure Description

[0020] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 A schematic diagram of the preparation method of the composite nano-drug-carrying complex provided in the examples; Figure 2 TEM image of MCM-41 mesoporous silica; Figure 3This is a schematic diagram of the structure of the composite nanoparticle drug delivery complex and a schematic diagram of its targeted transport and drug release process under the action of a magnetic field; Figure 4 Nitrogen adsorption-desorption isotherms of CuFe2O4 / MCM-41 magnetically responsive mesoporous silica composite nanoparticles and MCM-41 mesoporous silica support prepared in Example 1. Figure 5 The pore size distribution diagrams are shown for the prepared CuFe2O4 magnetic nanoparticles and MCM-41 mesoporous silica support. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0023] Definitions: The pore openings of a mesoporous silica carrier refer to the openings of the mesopores on both sides of the carrier. Specifically, they refer to the two ends of the pores in a two-dimensional hexagonal ordered pore structure.

[0024] The near-surface pore area near the pore opening refers to the area of ​​the pore that is close to the pore opening.

[0025] In a first aspect, the present invention provides a magnetically responsive mesoporous silica composite nanoparticle, comprising: a mesoporous silica carrier and magnetic nanoparticles mainly distributed in at least one of the following regions of the mesoporous silica carrier: the outer surface of the mesoporous silica carrier, the pore opening of the mesoporous silica carrier, and the near-surface pore region near the pore opening. The magnetic nanoparticles are bonded to the mesoporous silica support through interfacial interactions. The mesoporous silica support is selected from MCM-41 or SBA-15. The magnetic nanoparticles have a particle size of 5-50 nm, while the average pore size of the mesoporous silica support is 2-10 nm. The particle size of the magnetic nanoparticles is larger than the average pore size of the mesoporous silica support.

[0026] Magnetic nanoparticles are fixed to the outer surface, pore openings, and near-surface pore regions of the mesoporous silica support through interfacial interactions between the abundant silanol groups on the surface of the support and the magnetic nanoparticles. This process controls the particle size of the magnetic nanoparticles to be larger than the average pore size of the silica support. The larger particle size prevents the magnetic nanoparticles from continuously filling the entire length of the pores, effectively avoiding excessive occupation of the mesoporous channels. The abundant silanol groups on the surface of the mesoporous silica support, such as isolated hydroxyl groups, associated hydroxyl groups, and hydroxyl groups, can bind the magnetic nanoparticles through interfacial interactions such as hydrogen bonds, coordination bonds, electrostatic attraction, and van der Waals forces. This maintains the large specific surface area and effective pore volume of the MCM-41 material, and the magnetically responsive mesoporous silica composite nanoparticles retain unoccupied mesoporous channels, enabling them to remain highly efficient for loading and storing drug molecules.

[0027] It should be noted that magnetic nanoparticles do not completely occupy the pores of the mesoporous silica carrier. In practice, only surfaces rich in active groups such as silanol groups can bind magnetic nanoparticles. As long as there are remaining pores, the remaining effective pore volume can be achieved, thus facilitating subsequent drug loading.

[0028] The magnetic nanoparticles have particle sizes of 5, 6, 7, 8, 9, 10, 12, 15, 18, 20, 25, 30, 35, 40, 45, or 50 nm. The average pore size of the mesoporous silica support is 2, 3, 4, 5, 6, 7, 8, 9, or 10 nm. Furthermore, the particle size of the magnetic nanoparticles is larger than the average pore size of the mesoporous silica support.

[0029] If the particle size of the magnetic nanoparticles is smaller than the average pore size of the mesoporous silica carrier, the magnetic nanoparticles may block the entire length of the mesoporous silica channels, affecting drug loading.

[0030] In a preferred embodiment of the present invention, the magnetic nanoparticles are selected from superparamagnetic iron oxide-based nanoparticles. The superparamagnetic iron oxide-based nanoparticles are selected from CuFe2O4, NiFe2O4, MnFe2O4, CoFe2O4 or γ-Fe2O3.

[0031] In a preferred embodiment of the present invention, the content of magnetic nanoparticles in the magnetically responsive mesoporous silica composite nanoparticles is 5-40 wt%. Within this content range, it exhibits high magnetic field response capability. The content of magnetic nanoparticles in the magnetically responsive mesoporous silica composite nanoparticles is 5 wt%, 6 wt%, 8 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 28 wt%, 30 wt%, 35 wt%, 36 wt%, or 40 wt%.

[0032] In a preferred embodiment of the present invention, the specific surface area of ​​the magnetically responsive mesoporous silica composite nanoparticles is 300-900 m². 2 / g.

[0033] Compared to mesoporous silica supports, the pore size of the magnetically responsive mesoporous silica composite nanoparticles per unit mass did not change significantly, but their nitrogen adsorption capacity decreased. In other words, after combining magnetic nanoparticles with the mesoporous silica support, the pore size of the mesopores remained unchanged, but the specific surface area decreased significantly. This means that the magnetically responsive mesoporous silica composite nanoparticles still possess a large specific surface area and effective pore volume, enabling them to remain suitable for efficient loading of anticancer drugs.

[0034] In a preferred embodiment of the present invention, the magnetic nanoparticles are partially embedded in the pores of the mesoporous silica support, and partially exposed outside the pores, so that the mesoporous silica support and the magnetic nanoparticles form an embedded structure with pore openings. Through this structural design, while introducing magnetic response functionality, excessive occupation of the mesoporous channels by the magnetic particles can be effectively avoided, thereby maintaining a large specific surface area and effective pore volume of the magnetically responsive mesoporous silica composite nanoparticle material, enabling it to still be used for efficient loading of anticancer drugs.

[0035] In a preferred embodiment of the present invention, the interfacial interaction is selected from at least one of hydrogen bonding, coordination bonding, electrostatic attraction, and van der Waals forces, but is not limited thereto.

[0036] Secondly, the present invention provides a method for preparing magnetically responsive mesoporous silica composite nanoparticles, comprising the following steps: (1) Magnetic nanoparticles and mesoporous silica carriers are prepared separately. The preparation method of magnetic nanoparticles includes: dissolving a first metal salt and an iron salt precursor in a solvent, preparing a superparamagnetic iron oxide precursor by co-precipitation reaction, and obtaining magnetic nanoparticles by washing, drying and calcining; the first metal salt is selected from copper salt, nickel salt, manganese salt or cobalt salt. The preparation method of mesoporous silica support includes: preparing MCM-41 or SBA-15 mesoporous silica support by template guiding method, and performing drying or dehydration pretreatment; (2) Magnetic nanoparticles are dispersed in a solvent to form a dispersion, and then a mesoporous silica carrier is added for mixing, so that the magnetic nanoparticles are mainly distributed in at least one of the following regions of the mesoporous silica carrier through interfacial interaction: the outer surface of the mesoporous silica carrier, the pore opening of the mesoporous silica carrier, and the near-surface pore region near the pore opening.

[0037] Copper salts, nickel salts, manganese salts, or cobalt salts include, but are not limited to, nitrates.

[0038] In a preferred embodiment of the present invention, the solvent is an alcohol solvent, which is selected from at least one of methanol, ethanol and isopropanol.

[0039] In a preferred embodiment of the present invention, the magnetic nanoparticles are ultrasonically dispersed before mixing in step (2). In a preferred embodiment of the present invention, after mixing, the mixture is magnetically stirred at room temperature for 0.5-24 hours.

[0040] Thirdly, the present invention also provides a composite nanoparticle drug-carrying complex, which includes the above-mentioned magnetically responsive mesoporous silica composite nanoparticles and a drug. In a preferred embodiment of the present invention, the drug is an anticancer drug; In a preferred embodiment of the present invention, the anticancer drug is curcumin or a chemotherapy drug; Chemotherapy drugs include one or more of the following: paclitaxel, cytotoxic antitumor drugs, epigenetic modifying enzyme inhibitors, PARP1 / 2 inhibitors, ubiquitin-proteasome inhibitors, cyclin-dependent kinase inhibitors, immune checkpoint inhibitors, anti-apoptotic protein inhibitors, metabolic pathway inhibitors, anti-angiogenic drugs, tyrosine kinase inhibitors, and other kinase inhibitors.

[0041] Tyrosine kinase inhibitors include one or more of EGFR inhibitors, ALK inhibitors, BCR-ABL inhibitors, BTK inhibitors, ErB2 / HER2 inhibitors, vascular endothelial growth factor receptor inhibitors, and multi-target inhibitors. In one embodiment, the tyrosine kinase inhibitor includes at least one of imatinib, dasatinib, nilotinib, sunitinib, bosutinib, lapatinib, regorafenib, pazopanib, and ponatinib.

[0042] Other kinase inhibitors include one or more of the following: PI3K, AKT / mTOR pathway inhibitors, and MAPK signaling pathway inhibitors.

[0043] Cytotoxic antitumor drugs include at least one of the following: drugs that affect DNA structure and function, drugs that affect nucleic acid biosynthesis, drugs that interfere with transcription and prevent RNA synthesis, and drugs that inhibit protein synthesis and function.

[0044] Drugs that affect DNA structure and function include at least one of the following: cyclophosphamide, cisplatin, carboplatin, camptothecin derivatives, irinotecan, topotecan, podophyllotoxin derivatives, and anthracycline antitumor antibiotics. Anthracycline antitumor antibiotics are selected from doxorubicin.

[0045] Drugs that affect nucleic acid biosynthesis include at least one of methotrexate, 5-FU, and capecitabine.

[0046] Drugs that interfere with transcription and inhibit RNA synthesis include at least one of doxorubicin, epirubicin, pirarubicin, arubicin, idarubicin, daunorubicin, and mitoxantrone.

[0047] In a preferred embodiment of the present invention, the drug loading in the composite nanoparticle drug-loaded complex is 20-300 mg / g, exhibiting a high drug loading level, which is attributed to the large pore volume and channel size of the mesoporous material. The drug loading is 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 260, 280, or 300 mg / g.

[0048] The obtained magnetically responsive mesoporous silica composite nanoparticles were contacted with a solution containing anticancer drugs, allowing drug molecules to enter the mesoporous channels of the magnetically responsive mesoporous silica composite nanoparticles or be adsorbed onto their surface. After separation and drying, a magnetically responsive composite drug-carrying nanocomposite was obtained.

[0049] Fourthly, the present invention also provides the application of magnetically responsive mesoporous silica composite nanoparticles or the above-mentioned composite nano-drug-carrying complexes in the preparation of drugs for tumor treatment.

[0050] The tumor can be a solid tumor or a hematologic tumor. For example, the tumor type can be one or more of the following: digestive system tumor, respiratory system tumor, reproductive system tumor, musculoskeletal system tumor, nervous system tumor, endocrine system tumor, circulatory system tumor, urinary system tumor, and reproductive system tumor.

[0051] In a preferred embodiment of the present invention, the tumor is an epithelial tumor, including but not limited to papilloma, gastrointestinal cancer, uterine cancer, ovarian cancer, cervical cancer, lung cancer, adenocarcinoma, breast cancer, adenoma, or squamous cell carcinoma.

[0052] In a preferred embodiment of the present invention, the drug can achieve targeted enrichment or magnetic response release under the action of an external magnetic field. In a preferred embodiment of the present invention, the applied magnetic field is a constant magnetic field or an alternating magnetic field, and the magnetic field strength is 0.01-1 T.

[0053] This invention also provides a method for applying the above-mentioned magnetically responsive mesoporous silica composite nanoparticle drug-carrying composition in cancer treatment, comprising: (1) Applying the drug-loaded composition to the body; (2) Apply an external magnetic field to the target lesion area to cause the drug-loaded composition to accumulate under the action of the magnetic field; (3) Promote drug release through magnetic response effect.

[0054] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0055] Example 1 This embodiment provides a method for preparing magnetically responsive mesoporous silica composite nanoparticles, the preparation flowchart of which is shown below. Figure 1 As shown: (1) Preparation of CuFe2O4 magnetic nanoparticles: 2.42 g of Cu(NO3)2·3H2O and 6.06 g of Fe(NO3)3·9H2O were weighed and dissolved in 100 mL of deionized water. The mixture was magnetically stirred at room temperature until a homogeneous solution was formed. Then, 1 mol / L NaOH solution was slowly added dropwise to adjust the pH of the reaction system to 9-10, so that a precipitation reaction occurred and a brown precipitate was formed.

[0056] The resulting precipitate was separated by centrifugation and repeatedly washed with deionized water until the washing solution was nearly neutral; then dried at 80 °C for 12 h. The dried precursor was placed in air and calcined at 500 °C for 3 h, followed by natural cooling to obtain CuFe₂O₄ magnetic nanoparticles. The obtained CuFe₂O₄ magnetic nanoparticles can be further used to construct magnetic porous silicon composite supports.

[0057] The specific surface area of ​​the obtained material is approximately 650 m². 2 / g, with an average pore size of approximately 8 nm.

[0058] (2) Preparation of MCM-41 mesoporous silica support: 0.8 g of hexadecyltrimethylammonium bromide (CTAB) was dissolved in 38 g of deionized water and 4.0 g of 2.0 mol / L NaOH solution, and stirred to obtain a homogeneous solution. Then, 3.8 g of tetraethyl orthosilicate (TEOS) was added, and the mixture was stirred for 1 hour. The resulting white precipitate was transferred to a hydrothermal reactor and placed in a 100 °C oven for hydrothermal treatment for 3 days. After cooling, the mixture was filtered and washed to obtain a white powder. After drying, the powder was calcined in a muffle furnace at 550 °C for 6 hours to remove the CTAB template. MCM-41 mesoporous silica material was obtained. TEM images of MCM-41 mesoporous silica are shown below. Figure 2 .

[0059] Pretreatment of MCM-41 mesoporous silica carrier: Weigh 1.00g of MCM-41 mesoporous silica material, place it in a vacuum drying oven, and dry it at 120 ℃ for 6 h to remove adsorbed moisture and residual impurities from the material. After cooling to room temperature, it is ready for use.

[0060] (3) Preparation of magnetically responsive mesoporous silica composite nanoparticles: Weigh 0.30 g of CuFe2O4 magnetic nanoparticles obtained in step (1), add them to 50 mL of anhydrous ethanol, and disperse them under ultrasonic conditions for 30 min; then add 1.00 g of MCM-41 mesoporous silica material treated in step (2), and stir magnetically at room temperature for 12 h to allow the CuFe2O4 magnetic nanoparticles to fully contact the MCM-41 mesoporous silica carrier and form a composite system.

[0061] After the reaction was completed, the particles were separated by centrifugation and washed three times each with ethanol and deionized water, and then dried at 60 °C for 8 h to obtain magnetically responsive mesoporous silica composite nanoparticles.

[0062] Example 2 This embodiment provides a composite nanoparticle drug-carrying complex, the preparation method of which is as follows: Weigh 50 mg of curcumin and dissolve it in 50 mL of anhydrous ethanol to obtain a homogeneous curcumin solution. 0.50 g of the magnetically responsive mesoporous silica composite nanoparticles prepared in Example 1 were added to the solution and magnetically stirred for 24 h under light-protected conditions to allow curcumin to enter the pores of the porous silica support and / or adsorb onto its surface.

[0063] After loading was completed, the mixture was centrifuged and washed with ethanol to remove unloaded curcumin. Then, it was vacuum dried at 40 °C to obtain a magnetic composite nano-drug-loaded complex.

[0064] A schematic diagram of the structure of the magnetic porous silicon-based drug-loaded composition and a schematic diagram of its targeted transport and drug release process under the influence of a magnetic field are shown below. Figure 3 As shown.

[0065] Example 3 This embodiment describes the preparation of NiFe2O4 / MCM-41 magnetically responsive mesoporous silica composite nanoparticles. The specific preparation method includes the following steps: 2.91 g of Ni(NO3)2·6H2O and 8.08 g of Fe(NO3)3·9H2O were weighed and dissolved in 100 mL of deionized water. The solution was magnetically stirred at room temperature to form a homogeneous solution. Then, 1 mol / L NaOH solution was slowly added dropwise to adjust the pH of the reaction system to 9–10, inducing a precipitation reaction. The resulting precipitate was separated by centrifugation and repeatedly washed with deionized water until neutral, then dried at 80 °C for 12 h. The obtained precursor was calcined in air at 500 °C for 3 h, and after cooling, NiFe2O4 magnetic nanoparticles were obtained.

[0066] 1.00 g of pretreated MCM-41 mesoporous silica support was weighed, and 0.30 g of NiFe2O4 magnetic nanoparticles were separately weighed and dispersed in 50 mL of anhydrous ethanol. After sonication for 30 min, the MCM-41 support was added, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, the mixture was centrifuged and washed three times each with ethanol and deionized water, and dried at 60 °C for 8 h to obtain NiFe2O4 / MCM-41 magnetically responsive mesoporous silica composite nanoparticles.

[0067] The results of this embodiment demonstrate that when the metal in the magnetic nanoparticles is replaced by Ni instead of Cu, the interface anchoring composite method of the present invention can still be used to construct a magnetic porous silicon composite carrier.

[0068] Example 4 This embodiment describes the preparation of CuFe2O4 / SBA-15 magnetically responsive mesoporous silica composite nanoparticles. The specific preparation method includes the following steps: Weigh 2.42 g of Cu(NO3)2·3H2O and 8.08 g of Fe(NO3)3·9H2O, dissolve them in 100 mL of deionized water, and stir magnetically at room temperature until homogeneous. Slowly add 1 mol / L NaOH solution to adjust the pH to 9–10, inducing a precipitation reaction. The resulting precipitate was centrifuged, repeatedly washed until neutral, dried at 80 °C for 12 h, and calcined in air at 500 °C for 3 h to obtain CuFe2O4 magnetic nanoparticles.

[0069] 1.00 g of pretreated SBA-15 mesoporous silica support was weighed, and 0.30 g of CuFe2O4 magnetic nanoparticles were dispersed in 50 mL of anhydrous ethanol. After sonication for 30 min, the support was added, and the mixture was magnetically stirred at room temperature for 12 h. After centrifugation, washing with ethanol and deionized water, and drying at 60 °C for 8 h, CuFe2O4 / SBA-15 magnetic porous silica composite support was obtained.

[0070] The results of this embodiment show that, while keeping the CuFe2O4 magnetic nanoparticles unchanged, a magnetic porous silicon composite carrier can still be obtained when the mesoporous silica carrier is replaced by SBA-15 instead of MCM-41.

[0071] Example 5 This embodiment demonstrates magnetic field-induced drug release: the composite nanoparticle drug-carrying complex prepared in Example 2 is dispersed in a buffer solution, and a release experiment is conducted under the action of an alternating magnetic field.

[0072] The composite drug-carrying nanocomposite (10 mg) prepared in Example 2 was dispersed in 10 mL of PBS buffer solution (pH = 7.4) and pre-equilibrated in a constant temperature shaker (37 °C, 100 rpm) for 2 h. Subsequently, a release experiment was conducted under the action of an alternating magnetic field.

[0073] The alternating magnetic field parameters are set as follows: Magnetic field strength: 0.08-0.15 T; Frequency: 100-300 kHz; Mode of action: intermittent (10 min ON / 10 min OFF cycle).

[0074] The concentration of curcumin in the solution at different time points was determined using a UV-Vis spectrophotometer (λ = 425 nm), and the cumulative release rate was calculated.

[0075] Experimental results: 1. Temperature rise behavior (magnetocaloric effect): Under conditions of 0.12 T and 200 kHz, the system temperature increased from 37 ℃ to approximately 43.5 ℃ within 10 min, and then tended to stabilize, indicating that CuFe2O4 nanoparticles have good magnetocaloric conversion capabilities.

[0076] 2. Release kinetics Table 1. Kinetics of curcumin release from magnetic mesoporous silica-loaded curcumin in an alternating magnetic field

[0077] 3. On / Off Magnetic Response Behavior During the "on" phase of the magnetic field, the release rate increases significantly (approximately 1.8-2.3 times that under no magnetic field conditions); during the "off" phase, the release rate decreases rapidly, demonstrating good controllability.

[0078] In summary, the drug release rate was significantly increased under the influence of a magnetic field, indicating that the magnetocaloric effect generated by the CuFe2O4 nanoparticles raises the local temperature, thereby promoting the diffusion and release of drug molecules. This result demonstrates that the composite nanoparticle drug-carrying complex provided by this invention can achieve magnetically responsive controlled release.

[0079] Experimental Example 1 A tumor cell model was selected as the research subject, specifically the human breast cancer cell line MCF-7. Cells were seeded in 96-well plates (1 × 10⁶ cells per well). 4 The cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS) at 37 °C and 5% CO2 for 24 h before the experiment was conducted.

[0080] The cells were randomly divided into a control group and an experimental group, as detailed below: Control group: No treatment was given; Experimental group: The magnetic porous silicon-based drug-loaded composition (CuFe2O4 / MCM-41 loaded with curcumin) prepared in Example 3 was added. The experimental group was further divided into two groups: one without a magnetic field and one with an external magnetic field.

[0081] (1) Drug administration and magnetic field conditions: Nanomaterial concentration: 100 μg / mL; Drug concentration (curcumin): 10 μg / mL (equivalent concentration); Administration method: Directly add to the culture medium for incubation; Magnetic field type: constant magnetic field; Magnetic field strength: 0.12 T; Magnetic field application method: A permanent magnet was placed locally at the bottom of the culture plate and applied for 4 hours, followed by continued culture for a total incubation time of 24 hours.

[0082] (2) Cell viability detection Cell viability in each group was assessed using the CCK-8 assay, with the control group representing 100%. The results are as follows: Table 2. Survival assay of human breast cancer cell line MCF-7

[0083] (3) Characterization of magnetic properties The hysteresis loop of the sample was measured using a vibrating sample magnetometer (VSM) at room temperature (300 K), and the results are shown in Table 3: Table 3. Magnetic property parameters of magnetically responsive mesoporous silica composite nanoparticles

[0084] (4) Results Analysis Experimental results show that: Compared with the control group, the cell survival rate of the drug-loaded group was significantly reduced, indicating that the composite nano-drug delivery system has good anti-tumor activity; Under the influence of an external magnetic field, the cell survival rate further decreased from 56.3% to 30.4%, a decrease of approximately 46.0%, indicating that the magnetic field can significantly enhance the anti-tumor effect. The VSM results show that the material has good magnetic response performance and can be effectively enriched under a low magnetic field strength (0.12 T), thereby increasing the local drug concentration. Meanwhile, the magnetic response process may be accompanied by a certain magnetocaloric effect, which further promotes drug release and cell killing.

[0085] Experiment Example 2 The nitrogen adsorption-desorption isotherms of the magnetically responsive mesoporous silica composite nanoparticles CuFe2O4 / MCM-41 and MCM-41 mesoporous silica supports prepared in Example 1 are shown in the figure. Figure 4 As shown, the pore size diagrams of the prepared CuFe2O4 magnetic nanoparticles and MCM-41 mesoporous silica support are referenced. Figure 5 As shown in the figure, the results indicate that compared to the mesoporous silica support, the pore size of the magnetically responsive mesoporous silica composite nanoparticles per unit mass remained unchanged, but their nitrogen adsorption capacity decreased. In other words, after the mesoporous silica support is combined with magnetic nanoparticles, the pore size of the mesopores does not change, but the specific surface area decreases significantly. This means that the magnetically responsive mesoporous silica composite nanoparticles still possess a large specific surface area and effective pore volume, enabling them to remain suitable for efficient loading of anticancer drugs.

[0086] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A magnetically responsive mesoporous silica composite nanoparticle, characterized in that, It includes: mesoporous silica The carrier and the magnetic nanoparticles mainly distributed in at least one of the following regions of the mesoporous silica carrier: the outer surface of the mesoporous silica carrier, the pore openings of the mesoporous silica carrier, and the near-surface pore region near the pore openings. The magnetic nanoparticles are bonded to the mesoporous silica support through interfacial interaction, and the mesoporous silica support is selected from MCM-41 or SBA-15. The magnetic nanoparticles have a particle size of 5-50 nm, and the average pore size of the mesoporous silica support is 2-10 nm. The particle size of the magnetic nanoparticles is larger than the average pore size of the mesoporous silica support.

2. The magnetically responsive mesoporous silica composite nanoparticles according to claim 1, characterized in that, The magnetic nanoparticles are selected from superparamagnetic iron oxide-based nanoparticles; The superparamagnetic iron oxide-based nanoparticles are selected from CuFe2O4, NiFe2O4, MnFe2O4, CoFe2O4, or γ-Fe2O3.

3. The magnetically responsive mesoporous silica composite nanoparticles according to claim 2, characterized in that, The magnetic nanoparticles constitute 5-40 wt% of the magnetically responsive mesoporous silica composite nanoparticles. Preferably, the specific surface area of ​​the magnetically responsive mesoporous silica composite nanoparticles is 300-900 m². 2 / g.

4. The magnetically responsive mesoporous silica composite nanoparticles according to claim 1, characterized in that, The magnetic nanoparticles are partially embedded in the pores of the mesoporous silica carrier and partially exposed outside the pores, so that the mesoporous silica carrier and the magnetic nanoparticles form an embedded structure with pores.

5. The magnetically responsive mesoporous silica composite nanoparticles according to claim 1, characterized in that, The interfacial interaction is selected from at least one of hydrogen bonding, coordination bonding, electrostatic attraction, and van der Waals forces.

6. A method for preparing magnetically responsive mesoporous silica composite nanoparticles as described in any one of claims 1-5, characterized in that, It includes the following steps: (1) Magnetic nanoparticles and mesoporous silica carriers are prepared separately, wherein the preparation method of magnetic nanoparticles includes: dissolving a first metal salt and an iron salt precursor in a solvent, preparing a superparamagnetic iron oxide precursor by co-precipitation reaction, and obtaining magnetic nanoparticles by washing, drying and calcining; the first metal salt is selected from copper salt, nickel salt, manganese salt or cobalt salt. The method for preparing the mesoporous silica support includes: preparing MCM-41 or SBA-15 mesoporous silica support using a template-guided method, and performing drying or dehydration pretreatment; (2) Magnetic nanoparticles are dispersed in a solvent to form a dispersion, and then the mesoporous silica carrier is added and mixed so that the magnetic nanoparticles are mainly distributed in at least one of the following regions of the mesoporous silica carrier through interfacial interaction: the outer surface of the mesoporous silica carrier, the pore opening of the mesoporous silica carrier, and the near-surface pore region near the pore opening.

7. The method for preparing magnetically responsive mesoporous silica composite nanoparticles according to claim 6, characterized in that, The solvent is an alcohol solvent, and the alcohol solvent is selected from at least one of methanol, ethanol and isopropanol.

8. The method for preparing magnetically responsive mesoporous silica composite nanoparticles according to claim 6, characterized in that, The magnetic nanoparticles described in step (2) are ultrasonically dispersed before mixing; Preferably, after mixing, the mixture is magnetically stirred at room temperature for 0.5-24 hours.

9. A composite nanoparticle drug delivery complex, characterized in that, It includes the magnetically responsive mesoporous silica composite nanoparticles and the drug as described in any one of claims 1-5; Preferably, the drug is an anticancer drug; Preferably, the anticancer drug is curcumin or a chemotherapy drug; the chemotherapy drug includes one or more of the following: paclitaxel, cytotoxic antitumor drugs, epigenetic modifying enzyme inhibitors, PARP1 / 2 inhibitors, ubiquitin-proteasome inhibitors, cyclin-dependent kinase inhibitors, immune checkpoint inhibitors, anti-apoptotic protein inhibitors, metabolic pathway inhibitors, anti-angiogenic drugs, tyrosine kinase inhibitors, and other kinase inhibitors. Preferably, the drug loading in the composite nanoparticle drug-carrying complex is 20-300 mg / g.

10. The use of the magnetically responsive mesoporous silica composite nanoparticles as described in any one of claims 1-5 or the composite nano-drug-carrying complex as described in claim 9 in the preparation of drugs for tumor treatment; Preferably, the drug can achieve targeted enrichment or magnetic response release under the action of an external magnetic field; Preferably, the applied magnetic field is a constant magnetic field or an alternating magnetic field, with a magnetic field strength of 0.01-1 T.

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