Nano drug delivery platform as well as preparation method and application thereof

Abstract

The invention discloses a nano drug delivery platform and a preparation method and application thereof. The nano drug delivery platform is obtained by modifying the surfaces of carboxylated mesoporous silica nanoparticles (MSN) with polyethyleneimine to obtain MCP nanoparticles, then loading drugs on the MCP nanoparticles and finally depositing acrylic resin on the material surface. Through the synergistic effect of multiple materials, integration of multiple functions of colon-targeted drug treatment, inflammatory factor removal and the like is achieved, and a remarkable treatment effect is achieved on an animal model.

Description

Technical Field

[0001] The present invention belongs to the field of nanomedicine technology, and specifically relates to a nano drug delivery platform and its preparation method and application, and more particularly to a preparation method and application of a nano drug delivery platform that can target the colon and simultaneously release drugs and clear inflammatory factors. Background Art

[0002] Inflammatory bowel disease (IBD) is a group of chronic inflammatory intestinal diseases encompassing two major forms: ulcerative colitis (UC) and Crohn's disease (CD). Although a range of genetic, immune, and environmental factors are known to play a role in the development of IBD, the causes of IBD remain incompletely understood. Currently, there is no cure for IBD, and management strategies primarily focus on inducing and maintaining remission. IBD management typically includes the use of aminosalicylates, antibiotics, corticosteroids, immunomodulators, and biologics. The main delivery methods for IBD drugs include oral and rectal administration. Direct rectal administration provides localized treatment for IBD in the distal colon. However, rectal administration is associated with poor patient compliance and is ineffective for disease in the more proximal colon and small intestine. Given that most IBD patients require lifelong disease management, oral administration offers the highest patient compliance and adherence. However, oral administration presents multiple challenges for the treatment of IBD, including the inability of the drug to target the diseased tissue, a high risk of systemic drug exposure, and increased excretion of the therapeutic drug due to accelerated intestinal transit. These challenges continue to limit the development of better IBD management. Therefore, new oral colon-targeted drug delivery technologies are urgently needed.

[0003] Nanotechnology offers new hope for colon-targeted drug delivery. Studies have shown that nanoparticles (less than 500 nm) can pass through the mucus layer, and due to the epithelial enhanced permeability and retention effect (eEPR), the delivery and permeability of drugs into colitis tissues are increased, and the drug residence time in the colon of the inflamed intestinal area is prolonged. Further modification of the nanoparticle surface with positive charges, its cationic properties can enhance adhesion to the inflamed tissue of the colon and subsequent absorption by inflammatory cells. However, the nonspecific electrostatic binding of surface positively charged nanoparticles to the upper gastrointestinal mucosa, especially the small intestinal mucosa, may undermine the advantage of cationic nanoparticles in selective delivery to the inflamed colon. Therefore, the cationic surface charge of nanoparticles needs to be shielded before they reach the colon tissue, and then removed in the colon, which can be used to overcome the challenges encountered by cationic surfaces in oral colon-targeted delivery. Therefore, the nano-colonic drug delivery platform that can flip the charge on demand is a very promising drug delivery system.

[0004] In recent years, mesoporous silica nanoparticles (MSNs) have proven to be a valuable platform for constructing a variety of multifunctional smart drug and / or gene delivery systems due to their attractive properties, including good biocompatibility, large surface area and pore volume, tunable pore and particle size, and ease of surface modification. Previous studies have shown that modifying inorganic MSNs with organic molecules can impart enhanced functionality to nanocarriers. Among the numerous functional organic molecules, polyethyleneimine (PEI) has attracted considerable research attention. Its naturally positive charge facilitates the loading of negatively charged drugs, such as nucleic acids and proteins. Importantly, PEI can clear cfDNA. cfDNA can lead to aberrant activation of Toll-like receptors (TLRs) on effector immune cells, resulting in excessive production of inflammatory mediators and promoting IBD. However, direct oral administration of PEI carriers may result in premature release of the cargo, and nonspecific electrostatic binding to the upper gastrointestinal mucosa may compromise the nanocarrier's advantage of selective delivery to the inflamed colon. Compared to the positively charged PEI, the pH-sensitive acrylic resin Eudragit S100 (ES) is a negatively charged organic molecule. Its dissociation pH is higher than 7, and it can dissolve in the colonic fluid. Therefore, wrapping nanoparticles with ES can shield the nonspecific binding of positively charged nanoparticles to the upper gastrointestinal tract, which is beneficial for colon targeting. Although MSN has been widely reported as a sustained-release drug carrier, it is difficult to integrate multiple functions such as colon targeting, responsive release of therapeutic drugs, and clearance of inflammatory factors as a multifunctional nano-drug delivery platform for the treatment of IBD. Oral administration provides the highest compliance for IBD patients, but faces the risk of failure to target diseased tissues, high risk of systemic drug exposure, and accelerated intestinal transit in patients, leading to increased excretion of therapeutic drugs. In addition, in terms of achieving a therapeutic strategy of targeted delivery of drug therapy and clearance of inflammatory factors to relieve inflammation, there is a lack of a platform tool that integrates multiple functions such as colon targeting, responsive release of therapeutic drugs, and clearance of inflammatory factors.

[0005] In previous studies, it was found that simple enteric coating can achieve colonic release of therapeutic drugs, but they cannot reside in the colon for a long time for continuous treatment. In addition, in terms of treatment strategy, the use of drug treatment or clearance of inflammatory factors alone cannot integrate the advantages of both treatment strategies. Therefore, a nano drug delivery platform was invented that can achieve higher distribution and longer residence time in the colon, and release small molecule anti-inflammatory drugs on PEI while eliminating inflammatory factor cfDNA. This nano drug delivery platform has important theoretical and application prospects for the management of inflammatory bowel disease. Summary of the Invention

[0006] Purpose of the invention: The technical problem to be solved by the present invention is to provide a multifunctional nanoplatform that can not only deliver therapeutic drugs in a targeted manner but also eliminate inflammatory factors by means of a charge reversal mechanism, so as to achieve a dual-strategy treatment of drug therapy and inflammatory factor elimination.

[0007] Technical solution: In order to solve the above technical problems, the present invention provides a nano drug delivery platform, which is obtained by modifying the surface of carboxylated MSN with polyethyleneimine to obtain MCP nanoparticles, then loading drugs on the MCP nanoparticles and finally depositing acrylic resin on the surface of the material.

[0008] The carboxylated MSN is prepared by adding succinic anhydride and triethylamine to aminated MSN.

[0009] Wherein, the acrylic resin is pH-sensitive acrylic resin Eudragit S100.

[0010] The molecular weight of the polyethyleneimine modified on the surface of the MSN is 0.3 kDa to 250 kDa, preferably 0.8 kDa to 25 kDa.

[0011] Wherein, the mass ratio of the MCP nanoparticles to the acrylic resin is 2:1.

[0012] The present invention also includes a method for preparing the nano drug delivery platform, comprising the following steps:

[0013] (1) Preparation of MCP: Polyethyleneimine was modified on the surface of carboxylated MSN to obtain MCP nanoparticles;

[0014] (2) Preparation of drug-loaded nanoparticles: MCP nanoparticles are dispersed in a drug solution to obtain drug-loaded nanoparticles;

[0015] (3) Preparation of drug-loaded MCP@ES nanoparticles: The aqueous solution of drug-loaded nanoparticles was added to the ES solution.

[0016] The preparation steps of the MCP nanoparticles described in step (1) are as follows: the MSN-COOH nanoparticles are ultrasonically treated and dispersed in a DMSO solution, EDC and NHS are added, the suspension is stirred to activate the carboxyl groups, the PEI solution is added, the suspension is continued to be stirred, and the MCP nanoparticles are obtained by centrifugation.

[0017] The preparation steps of the MSN-COOH nanoparticles are as follows: MSN-NH2 is dispersed in a DMSO solution and stirred, and then succinic anhydride and triethylamine are added in sequence, and the mixture is centrifuged to obtain MSN-COOH.

[0018] Wherein, the concentration of the drug solution in step (2) is 0.25-10 mg / mL, preferably 10 mg / mL, and preferably, the drug is olsalazine.

[0019] Wherein, the mass ratio of the drug-loaded nanoparticles to ES in step (3) is 2:1.

[0020] The present invention also includes the use of the nano drug delivery platform in the preparation of drugs for treating inflammatory bowel disease. Preferably, the inflammatory bowel disease includes ulcerative colitis.

[0021] Mechanism of the Invention: This invention integrates inorganic nanomaterials, organic cationic polymers, and enteric anionic coating materials to create a nanoplatform. The nanomaterials' eEPR effect and charge reversal enable colonic targeting and retention. The synergistic effects of the organic cationic and anionic polymers increase drug loading, enabling pH-responsive release of therapeutic drugs while simultaneously clearing inflammatory cytokines (cfDNA).

[0022] Beneficial effects: Compared with the existing technology, the present invention has the following advantages: the present invention integrates multiple functions such as colon-targeted drug therapy and inflammatory factor clearance through the synergistic effect of multiple materials, and has achieved significant therapeutic effects in animal models. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 (a)-(c) are representative TEM images of MSN-NH2, MCOOH, and MCP, respectively;

[0024] Figure 2 (a) Drug adsorption capacity of different types of PEI-modified nanoparticles at an OLZ concentration of 0.1 mg / mL; Figure 2 (b) Drug adsorption capacity of MCP at OLZ concentrations of 0.25, 0.5, 1.0, 2.5, 5.0, and 10.0 mg / ml;

[0025] Figure 3 Drug release profiles for OLZ-loaded MCP@ES. The nanoparticles were first placed in SGF, then transferred to SIF, and finally to SCF. The two vertical lines between the three colors represent the two time points of buffer exchange: 2 h and 5 h. All release experiments were performed at 37°C.

[0026] Figure 4 (a) In vitro near-infrared fluorescence images of the gastrointestinal tract of mice 2, 6, 12, and 24 h after oral administration of Cy7-labeled MSN-NH2, MSN-NH2@ES, and MCP@ES. Figure 4 (b) Figure 4 (a) Fluorescence intensity analysis of colon tissue at different time points; Figure 4 (c) Figure 4 (a) Ratio of the fluorescence intensity of the mid-colon tissue to the fluorescence intensity of the entire gastrointestinal tract tissue;

[0027] Figure 5 (a) Daily changes in mouse body weight during the 14 experimental days; Figure 5 (b) DAI scores of mice during the 14 experimental days;

[0028] Figure 6 These are digital photos of the isolated colon and spleen of mice in each group on the 14th experimental day;

[0029] Figure 7 (a) Binding efficiency of different nanoparticles (MSN, MSN-NH2, MCP) with DNA at 37°C in vitro experiments; Figure 7 (b) The cfDNA levels in the serum of mice in different groups (DSS, OLZ, NanoA) on the 14th day of the experiment in the in vivo experiment. DETAILED DESCRIPTION

[0030] Example 1 Preparation and morphology characterization of nano drug delivery platform

[0031] 1. Synthesis of aminated MSN (MSN-NH2):

[0032] 1g of solid hexadecyltrimethylammonium chloride (CTAC) and 40mg of triethanolamine (TEOA) were added to 40mL of deionized water and stirred at 95°C for 1h. 2.78g of tetraethyl orthosilicate (TEOS) was then added dropwise to the solution, and stirring continued at the same temperature for 0.5h. The resulting MSN cores formed a reaction suspension containing MSNs. Next, a mixture containing 28mg of TEOS and 32mg of aminopropyltriethoxysiloxane (APTES) was added to the MSN suspension, grafting aminopropyl groups onto the surface of the mesoporous silica nanoparticles (MSNs) through co-condensation. Stirring was continued for 1h, and the nanoparticles were collected by centrifugation at 12,000 rpm for 10min. The template was then extracted with ethanol containing 10mg / mL of ammonium nitrate under reflux to yield MSN-NH2.

[0033] 2. Synthesis of carboxylated MSN (MSN-COOH):

[0034] 200 mg of the MSN-NH2 obtained above was dispersed in 10 mL of DMSO and stirred, and then 60 mg of succinic anhydride and 60 mg of triethylamine were added in sequence. After reacting at 40°C for 48 h, the MSN-COOH was obtained by centrifugation and washed with ethanol three times.

[0035] 3. Synthesis of surface grafted MSN (MCP):

[0036] 200mg nanoparticles MSN-COOH were collected from an ethanol suspension by centrifugation. Then, the nanoparticles MSN-COOH were ultrasonically treated and dispersed in 4mL DMSO. After adding 106mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and 63mg of N-hydroxysuccinimide (NHS), the suspension was stirred for 0.5h to activate the carboxyl group. Next, 66.7mg of polyethyleneimine (PEI, molecular weight 0.8kDa or 25kDa) solution (100mg / mL, ethanol) was added and the suspension was stirred for 5h. Finally, the nanoparticles were centrifuged and repeatedly washed with deionized water and ethanol to remove unreacted reagents. The resulting sample was stored in ethanol.

[0037] The morphology, size and structure of various nanoparticles were observed using a transmission electron microscope (JEOL, JEM-1010, JP). Figure 1 show, Figure 1 (a) is the electron microscope image of MSN-NH2, which shows that it is a uniform sphere with clear mesopores. Figure 1 As shown in (b), since the attached small molecular groups do not affect electron transmission, their shape and structure do not change significantly. On the contrary, after modifying the macromolecular PEI, the obtained MCP is as follows Figure 1 As shown in (c), the contrast between the matrix and the mesopores is reduced. Compared with MSN-NH2 and MSN-COOH, MCP has an additional film on the surface of the nanoparticles, indicating that the macromolecules have been successfully grafted onto the nanoparticles.

[0038] Example 2 Characterization of drug loading, release effect and charge reversal ability of the nano drug delivery platform

[0039] 1. Determination of drug adsorption and drug loading

[0040] The UV-visible spectrum of olsalazine sodium OLZ in deionized water was recorded by UV-visible spectrophotometer (UV-2450, Shimadzu, JP). A standard concentration curve A = 0.04132C + 0.13, R was constructed at a wavelength of 361 nm. 2=0.98092 (A is absorbance, C is OLZ concentration: 5-25 μg / mL) to determine the OLZ concentration in the solution. MCP (1 mg) was ultrasonically treated and dispersed in 0.2 mL of OLZ solution. The sample was shaken on a reciprocating shaker for 5 hours. After centrifugation at 12000 rpm for 10 minutes, the drug-loaded nanoparticles were collected, and the OLZ concentration in the supernatant was tested using the above-mentioned standard curve to calculate the drug loading. In order to study the effect of PEI type on nanoplatform drug delivery, PEI with molecular weights of 0.8 kDa and 25 kDa were used to modify the nanoplatform, respectively, and then incubated in 0.1 mg / mL of OLZ solution. The results showed that the nanoplatform modified with PEI material with a larger molecular weight can adsorb more OLZ, so 25 kDa PEI is preferably used as the modified material ( Figure 2 a). In order to study the effect of drug concentration on drug loading, MCP (1 mg) was incubated with OLZ solutions of different concentrations (0.25, 0.5, 1.0, 2.5, 5.0, and 10 mg / mL). The experiment found that when the incubation concentration increased to above 5 mg / mL, the maximum adsorption amount reached a platform of approximately 126 μg / mg ( Figure 2 b) In order to achieve the largest possible adsorption capacity, we used an incubation concentration of 10 mg / mL to obtain drug-loaded nanoparticles.

[0041] 2. Drug encapsulation

[0042] 250 mg of OLZ-adsorbed MCP was dispersed in 5 mL of deionized water. Then, 125 mg of the pH-sensitive acrylic resin Eudragit S100 (ES) was dissolved in 5 mL of methanol by sonication. The drug-loaded nanoparticle dispersion was added dropwise to the methanol solution under stirring at 500 rpm to form a mixture. To deposit ES on the MCP, the mixture was transferred to a round flask and the organic solvent was removed using a rotary evaporator at 100 rpm and 43°C for 1 hour. The resulting nanoparticles were centrifuged at 12,000 rpm for 10 minutes, washed with deionized water, and finally dispersed in water to form a suspension of OLZ-loaded MCP@ES.

[0043] 3. Drug release

[0044] In order to predict the release curve of OLZ from MCP@ES in the gastrointestinal tract, 0.5 mL of OLZ-loaded MCP@ES suspension (containing approximately 500 μg OLZ) was transferred to a dialysis bag, immersed in different release media in turn, and stirred at 500 rpm. The different release media were simulated gastric fluid (SGF, pH 1.2, 2h), simulated small intestinal fluid (SIF, pH 6.8, 3h), and simulated colonic fluid (SCF, pH 7.4, 43h). The preparation methods of simulated gastric fluid, simulated small intestinal fluid, and simulated colonic fluid can be found in the literature Int. J. Pharm. 2022, 616, 121531. 200 μL samples were extracted at the set time points, the OLZ concentration was detected, and the release rate was calculated. The results are shown in Figure 2. Figure 3 As shown, the nanoplatform did not release OLZ in simulated gastric and small intestinal digestive fluids, but achieved pH-responsive release in simulated colonic fluid, demonstrating its potential for colon-targeted delivery.

[0045] 4. Characterization of Nanoplatform Charge Flipping Capability

[0046] To give the nanoplatform charge reversal capability, ES was coated on the MCP surface by rotary evaporation. As shown in Table 1, the particle size of the original MPC was 155.8 nm with a positive charge of +37.2 mV. After encapsulation of ES, the particle size increased to 225.3 nm and the charge was reversed to -35 mV. This potential of MCP@ES is the same as that of pure ES nanoparticles prepared by dispersing a methanol solution of ES in water, while the size of pure ES nanoparticles in water is only 40.8 nm, much smaller than the size of MCP@ES. These data demonstrate that ES is coated on MCP. Next, MCP@ES was washed with simulated colonic fluid (SCF, pH 7.4), and the resulting particles were redispersed in water. After washing, the particle size was measured to be reduced from 225.3 nm to 171.8 nm, and the zeta potential also returned to a positive charge of +31.5 mV. The SCF-treated MCP@ES was very similar to the original MCP in terms of size and zeta potential, indicating that the nanoplatform can achieve a surface charge reversal from negative to positive in the colon due to the dissolution of ES in SCF. These results demonstrate that this nanoplatform has the potential to achieve colon targeting through charge reversal and the eEPR effect.

[0047] Table 1. Dynamic light scattering analysis and comparison of different types of nanoparticles. Mean ± SD, n = 3.

[0048]

[0049] Example 3 Application of Nanoplatform

[0050] 1. Distribution in the digestive tract of mice

[0051] Nanoplatform labeling: 10 mg of nanoparticles (MSN-NH2 or MCP) and 1 mg of triethylamine (TEA) were dispersed in 0.8 mL of DMF. 10 μg of Cy7-NHS (Aladdin, C171360-1 mg) in 0.2 mL of DMF was then mixed with the suspension. The mixture was shaken overnight on a reciprocating shaker. Cy7-labeled nanoparticles were obtained by centrifugation and repeatedly washed with DMF and deionized water to remove unreacted dye molecules. ES was deposited on the labeled nanoparticles using the drug encapsulation method described in Example 2.

[0052] Digestive Tract Distribution: Cy7-labeled MSN-NH2, MSN-NH2@ES, and MCP@ES were orally administered to mice via gavage. Mice in each group were sacrificed 2, 6, 12, and 24 hours after oral administration, and major organs (heart, liver, spleen, lung, kidney, small intestine, and colon) were harvested. Fluorescence intensity of each organ was recorded and analyzed using a small animal imaging system (IVIS Spectrum, Perkin Elmer, USA) using the Cy7 filter channel.

[0053] From 0 to 6 h after oral administration, the accumulation of these nanoparticles in the colon gradually increased, and the retention in the colon decreased after 6 h ( Figure 4 Of the three nanoparticles, MSN-NH2 exhibited the lowest fluorescence intensity and the shortest retention time in the colon. This is likely because bare MSN-NH2 readily binds to various negatively charged electrolytes and digestive enzymes in the upper gastrointestinal tract, neutralizing the surface positive charge and allowing rapid passage through the colon. Compared to MSN-NH2, MSN-NH2@ES exhibited stronger fluorescence intensity in the colon, reaching a maximum after 6 hours and gradually decreasing to a level similar to that of MSN-NH2. This enhanced fluorescence is attributed to the wrapping effect of the ES around the MSN-NH2, which prevents external negatively charged substances in the upper gastrointestinal tract from prematurely interacting with the positively charged core particle. When the MSN-NH2@ES reaches the colon and the ES dissolves, the exposed positively charged core attracts the negatively charged colonic mucosa, thereby enhancing the nanoparticle's retention in the colon. At 2, 6, and 12 hours after oral administration, the fluorescence intensity of MCP@ES in the colon was significantly stronger than that of MSN-NH2 and MSN-NH2@ES. This is attributed not only to the protective effect of ES in the upper gastrointestinal tract but also to the higher density of amino groups modified on MCP@ES.

[0054] 2. Therapeutic Effects in Model Mice

[0055] Dextran sodium sulfate (DSS)-induced ulcerative colitis model in mice: Male C57 / BL6 mice (6-8 weeks old, 18-22 g) were acclimated for one week. They were given free access to DSS-supplemented water (3%, w / v) for 7 consecutive days to induce ulcerative colitis. The model mice were then fed normal drinking water for the following days. Seven days after colitis induction, the model mice were given a nanoparticle suspension (100 mg OLZ / kg, 200 μL) of normal saline (DSS group), OLZ solution (OLZ group), OLZ-loaded MCP@ES (NanoA group), OLZ-loaded MSN-NH2@ES (NanoB group), and OLZ-loaded MSN-NH2 (NanoC group) via oral gavage daily for 7 consecutive days. In addition, mice in the healthy control group were fed normal drinking water throughout the experiment (CK group).

[0056] Mouse Weight and DAI Score Measurements: During the experiment, the weight of all mice was recorded daily. Stool characteristics and fecal occult blood were continuously monitored from the time of colitis induction. Fecal occult blood was detected using fecal occult blood test strips, and the Disease Activity Index (DAI) was calculated.

[0057] Organ harvesting and histological analysis: After 7 days of treatment, mice were euthanized and the colon and spleen were harvested to investigate the therapeutic effect. The colon and spleen were photographed and their length and mass were measured, respectively.

[0058] The results showed that the NanoA group had the most significant protective effect against colitis-induced weight loss ( Figure 5 a). At 14 days, the weight of mice in the NanoA group recovered close to that of the CK group, while the weight of mice in the DSS group was much lower than that of the NanoA group at the same time point. Among all model groups, the DAI of the NanoA group was lower, and this index first returned to normal levels at 12 days. In contrast, the DAI of the DSS group was still significantly higher than that of the CK group at 14 days ( Figure 5 b). In addition, compared with the other model groups, the mice in the NanoA group had longer colon length and smaller spleen volume ( Figure 6 This indicates that the mice were effectively protected, with DSS-induced colitis significantly alleviated. Compared to the DSS group, mice in the NanoB and NanoC groups also showed some improvement in their condition. Their body weight, DAI, spleen mass, and colon length were similar to those of the OLZ group, but inferior to those of the NanoA group. Compared to the other groups, the advantage of the nanoplatform used in the NanoA group may lie in its improved colon targeting and retention capabilities. This was also well demonstrated in digestive tract distribution experiments.

[0059] 3. Nanoplatform’s ability to clear cfDNA

[0060] In vitro binding assays for MCP, MSN-NH2, and MSN to ct-DNA: 0.25 μg (10 μg / ml) of Calfthymus DNA (MCE, catalog number: HY-109517) was mixed with MCP, MSN-NH2, and MSN at mass ratios of 1:0.1, 1:1, 1:10, and 1:100, respectively, to prepare the test solution. An equal volume of PicoGreen dsDNA detection reagent (Yeasen, catalog number: 12641ES01) was added, and the mixture was incubated at room temperature in the dark for 5 min. Fluorescence intensity (Ex = 480 nm, Em = 520 nm) was measured using a microplate reader (Biotek Synergy H1).

[0061] Determination of the nanoplatform's ability to clear cfDNA in mouse serum: Peripheral blood samples were collected from mice in different experimental groups to measure cfDNA concentrations. Serum cfDNA concentrations were measured using the Quant-iT PicoGreen dsDNA Assay Kit (Thermo Fisher Scientific, Catalog No. P11496).

[0062] The present invention investigates the ability of the nanoplatform to clear cfDNA. Figure 7 a shows that MCP has the strongest binding ability with DNA, while the binding ability of MSN-NH2 is much weaker than that of MCP. In contrast, MSN hardly binds to DNA under experimental conditions. This is attributed to the fact that MCP has a higher surface positive charge density, MSN-NH2 has a lower surface positive charge density, and MSN has a negative charge on the surface. The different surface positive charge densities of nanoparticles lead to different electrostatic binding abilities with negatively charged macromolecular DNA. Therefore, it is reasonable to assume that MCP@ES with MCP as the core may have the strongest ability to eliminate cfDNA. Next, the cfDNA levels in the serum of mice in the DSS, OLZ or NanoA groups on day 14 were studied in an in vivo experiment ( Figure 7 b). As expected, in the colitis model mice, the DSS group had the highest serum cfDNA levels (average 207.3 ng / mL). Olsalazine (OLZ) exerted an anti-inflammatory effect, reducing the cfDNA content in mouse serum (OLZ group), with an average cfDNA content of 79.5 ng / mL. MCP@ES (NanoA group) not only reduced intestinal inflammation by releasing olsalazine in the colon, but also further reduced the cfDNA content in mouse serum (average as low as 6.6 ng / mL) through its ability to adsorb and clear cfDNA. Compared with mice in the OLZ and DSS groups, the NanoA group had the lowest serum cfDNA levels on day 14 of the experiment. As shown in the above experiments, drug-loaded MCP@ES has a stronger ability to clear cfDNA, thereby achieving a better therapeutic effect on colitis.

Claims

1. A nano drug delivery platform, characterized in that: The nano drug delivery platform is obtained by modifying the surface of carboxylated MSN with polyethyleneimine to obtain MCP nanoparticles, then loading drugs on the MCP nanoparticles, and finally depositing acrylic resin on the surface of the material.

2. The nano drug delivery platform according to claim 1, characterized in that The carboxylated MSN is prepared by adding succinic anhydride and triethylamine to aminated MSN.

3. The nano drug delivery platform according to claim 1, characterized in that The molecular weight of the polyethyleneimine modified on the surface of the MSN is 0.3 kDa to 250 kDa, preferably 0.8 kDa to 25 kDa.

4. The nano drug delivery platform according to claim 1, characterized in that The mass ratio of the MCP nanoparticles to the acrylic resin is 2:

1.

5. The method for preparing the nano drug delivery platform according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) Preparation of MCP: Polyethyleneimine was modified on the surface of carboxylated MSN to obtain MCP nanoparticles; (2) Preparation of drug-loaded nanoparticles: MCP nanoparticles are dispersed in a drug solution to obtain drug-loaded nanoparticles; (3) Preparation of drug-loaded MCP@ES nanoparticles: Add the aqueous solution of drug-loaded nanoparticles into the ES solution.

6. The method for preparing the nano drug delivery platform according to claim 5, characterized in that: The preparation steps of the MCP nanoparticles described in step (1) are as follows: the MSN-COOH nanoparticles are ultrasonically treated and dispersed in a DMSO solution, EDC and NHS are added, the suspension is stirred to activate the carboxyl groups, PEI solution is added, the suspension is continued to be stirred, and the MCP nanoparticles are obtained by centrifugation.

7. The method for preparing the nano drug delivery platform according to claim 6, characterized in that: The preparation steps of the MSN-COOH nanoparticles are as follows: MSN-NH2 is dispersed in a DMSO solution and stirred, and then succinic anhydride and triethylamine are added in sequence, and the mixture is centrifuged to obtain MSN-COOH.

8. The method for preparing the nano drug delivery platform according to claim 5, characterized in that: The concentration of the drug solution in step (2) is 0.25-10 mg / mL, preferably 10 mg / mL. Preferably, the drug is olsalazine.

9. The method for preparing the nano drug delivery platform according to claim 5, characterized in that: The mass ratio of the drug-loaded nanoparticles to ES in step (3) is 2:

1.

10. Use of the nano drug delivery platform according to any one of claims 1 to 4 in the preparation of a drug for treating inflammatory bowel disease, preferably, the inflammatory bowel disease includes ulcerative colitis.

Images