Modified mesoporous silica material, preparation method thereof and application of modified mesoporous silica material as multifunctional nano-drug carrier material
By modifying the long and short chains of mesoporous silica nanoparticles in a synergistic manner, a pH-responsive nanodrug carrier was constructed, which solved the problems of low drug loading and burst release in traditional mesoporous materials. It achieved high drug loading, pH responsiveness and sustained release, adapting to complex physiological environments and ensuring efficient drug release and biosafety at the target site.
Patent Information
- Application Number
- CN202511546511.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-28
- Publication Date
- 2026-01-13
AI Technical Summary
Traditional mesoporous silica nanoparticles have low drug loading capacity, are prone to burst release, lack environmental responsiveness, cannot achieve targeted release at lesion sites, and are prone to structural collapse in physiological environments.
Mesoporous nano-silica was modified with the silane coupling agent 3-(2-aminoethylamino)propyltrimethoxysilane (AEPTMS), and pH-responsive nano-drug carrier materials were constructed through synergistic modification with triethanolamine and 1,3,5-benzenetripentol, forming a synergistic release mechanism of long and short chains.
It achieves high drug loading, pH-responsive release, and sustained release, adapts to complex physiological environments, and ensures efficient drug release and biosafety at the target site.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedical technology, specifically to a modified mesoporous silica material, its preparation method, and its application as a multifunctional nanomedicine carrier material. Background Technology
[0002] With the development of nanomedicine delivery systems, mesoporous silica nanoparticles have become a research hotspot for drug carriers due to their ordered pore structure, high specific surface area, and good biocompatibility. However, traditional mesoporous materials mainly load drugs through physical adsorption, with drug loading generally below 30%, and are prone to burst release. Studies have shown that unmodified mesoporous silica is particularly inefficient at loading hydrophobic drugs, mainly limited by its hydrophilic surface properties and limited pore volume. Conventional carriers lack environmental responsiveness and cannot achieve targeted release at lesion sites. The acidic microenvironment of tumors and other diseased tissues and inflammatory areas differs from that of normal tissues (pH 7.4), but existing carriers cannot utilize this difference to achieve intelligent release. Furthermore, directly functionalized carriers are prone to structural collapse in physiological environments, leading to premature drug release. Therefore, there is an urgent need to develop a novel multifunctional nanomedicine carrier material to achieve multi-dimensional optimization of carrier material performance. Summary of the Invention
[0003] In view of this, the purpose of this invention is to provide a modified mesoporous silica material and its preparation method, as well as its application as a multifunctional nanomedicine carrier material, and to provide a nanomedicine carrier material with high drug loading capacity, pH-responsive release, and sustained release.
[0004] Based on the above objectives, the present invention provides a novel multifunctional nanomedicine carrier material, wherein the carrier material is a modified silane coupling agent obtained by modifying 3-(2-aminoethylamino)propyltrimethoxysilane (AEPTMS) and grafting the modified silane coupling agent onto the surface of mesoporous nano silica. The modified silane coupling agent was prepared by reacting AEPTMMS, triethanolamine, and 1,3,5-benzenetripentol with sodium ethoxide.
[0005] The molar ratio of AEPTMMS, triethanolamine, and 1,3,5-benzenetripentol is 1:0.3-0.4:1.5-2; preferably 1:0.35-0.4:1.8-2; more preferably 1:0.35-0.37:1.9-1.95.
[0006] The sodium ethoxide is obtained by reacting anhydrous ethanol and sodium, wherein the mass-to-volume ratio of sodium to anhydrous ethanol is 0.1-0.2 g: 15-30 mL; the amount of sodium added is 0.9%-1.1% of the mass of AETMS, preferably 1%.
[0007] The mass ratio of the modified silane coupling agent to mesoporous nano silica is 4:1.
[0008] The mesoporous nano-silica has an outer diameter of 450-550 nm and a pore size of 2-4 nm.
[0009] The CAS number of the 1,3,5-benzenetripentol is 943552-46-3.
[0010] Furthermore, the present invention also provides a method for preparing a modified mesoporous silica material, comprising the following steps: (1) Mix ethanol and sodium and stir until sodium is completely dissolved. Then add silane coupling agent AEPTMS, triethanolamine and 1,3,5-benzenetripentol. Stir and reflux for 10-12 h, cool, distill under reduced pressure, and then stir the resulting solution at 100-110℃ for 8-10 h. Add anhydrous diethyl ether to precipitate the precipitate, filter, wash and dry to obtain the modified silane coupling agent. (2) Dissolve the modified silane coupling agent in deionized water, add mesoporous nano silica, react at 50°C for 1-2 hours, filter while hot, wash and dry to obtain modified mesoporous nano silica, which is the modified mesoporous silica material.
[0011] The purpose of vacuum distillation in step (1) is to remove anhydrous ethanol.
[0012] The washing process described in step (1) involves adding ether and acetone for cleaning.
[0013] The drying process described in step (2) involves drying in a 65°C forced-air drying oven for 24 hours.
[0014] Furthermore, the present invention also provides an application of the above-mentioned modified mesoporous nano-silica material as a nano-drug carrier material, wherein the modified mesoporous nano-silica material has pH responsiveness and can be used as a pH-responsive nano-drug carrier material.
[0015] This invention further provides a pH-responsive drug delivery system, wherein the modified mesoporous silica material is loaded with a drug in an organic solvent. In one embodiment of this invention, ibuprofen is used as a model drug, and the drug carrier of this invention has the characteristics of high drug loading capacity, pH-responsive release, and sustained release.
[0016] The technical principles and beneficial effects of this invention are as follows: This invention provides stable drug binding sites through a tightly cross-linked network formed by the short chains of triethanolamine, while the long chains of 1,3,5-benzenetripentol construct hydrophobic drug storage microregions within the mesopores, potentially generating a phased release kinetic: under acidic conditions, the preferential dissociation of the long-chain hydrophobic groups leads to an initial increase in carrier porosity, achieving initial sustained drug release; with continued environmental influence, the short-chain cross-linked network gradually dissociates, triggering a comprehensive expansion of the pore structure. This intelligent release mechanism, synergistic between long and short chains, enables the carrier system to automatically adjust its release behavior according to changes in the lesion microenvironment, providing a new technical solution for precision drug delivery.
[0017] This invention constructs an organic-inorganic hybrid interface structure with hierarchical response characteristics through an innovative multi-component synergistic modification strategy. It cleverly integrates the high specific surface area advantage of mesoporous materials with the intelligent response characteristics of organic functional groups, achieving a significant improvement in drug loading performance. By precisely controlling the types and spatial distribution of surface chemical groups, multi-level drug binding sites are formed, providing possibilities for loading different types of drug molecules.
[0018] The carrier material of this invention exhibits unique gradient release characteristics, wherein the modifying groups of different chain lengths generate staged responses to environmental stimuli, realizing precise temporal and tertiary control of drug release, enabling the carrier to adapt to the needs of complex physiological environments, and ensuring efficient drug release at the target site while maintaining a stable delivery process.
[0019] The carrier material of this invention also possesses excellent biocompatibility, solving the problem of balancing high drug loading capacity and high biocompatibility in traditional carrier materials. This invention combines high biocompatibility with high drug loading and intelligent response characteristics, enabling this carrier system to demonstrate significant application value in the field of precision drug delivery. Detailed Implementation
[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.
[0021] The properties or sources of the raw materials used in the embodiments and comparative examples of this invention are as follows: Mesoporous nano silica: Mesoporous nano silica has an outer diameter of 450-550 nm and a pore size of 2-4 nm.
[0022] Example 1: A modified mesoporous silica material, the specific preparation steps are as follows: (1) Mix 15 mL of anhydrous ethanol and 0.1 g of sodium and stir until the sodium is completely dissolved. Then add 10.3 g of silane coupling agent AEPTMS, 2.5 g of triethanolamine and 30 g of 1,3,5-benzenetripentol. Stir and reflux for 10 h, cool, remove anhydrous ethanol by vacuum distillation, stir the resulting solution at 100 °C for 8 h, add anhydrous diethyl ether to precipitate, filter, wash and dry to obtain modified silane coupling agent; (2) Dissolve 1.6g of modified silane coupling agent in 40mL of deionized water, add 0.4g of mesoporous nano silica, react at 50℃ for 1h, filter while hot, wash three times with deionized water, and place the obtained solid in a 65℃ forced-air drying oven to dry for 24h to obtain modified mesoporous nano silica, which is the modified mesoporous silica material.
[0023] Example 2: A modified mesoporous silica material, the specific preparation steps are as follows: (1) Mix 25 mL of anhydrous ethanol and 0.15 g of sodium and stir until the sodium is completely dissolved. Then add 15.4 g of silane coupling agent AEPTMS, 3.7 g of triethanolamine and 45 g of 1,3,5-benzenetripentol. Stir and reflux for 11 h, cool, remove anhydrous ethanol by vacuum distillation, stir the resulting solution at 105 °C for 9 h, add anhydrous diethyl ether to precipitate, filter, wash and dry to obtain modified silane coupling agent; (2) Dissolve 2.4g of modified silane coupling agent in 50mL of deionized water, add 0.6g of mesoporous nano silica, react at 50℃ for 2h, filter while hot, wash three times with deionized water, and place the obtained solid in a 65℃ forced-air drying oven to dry for 24h to obtain modified mesoporous nano silica, which is the modified mesoporous silica material.
[0024] Example 3: A modified mesoporous silica material, the specific preparation steps are as follows: (1) Mix 30 mL of anhydrous ethanol and 0.2 g of sodium and stir until the sodium is completely dissolved. Then add 20.6 g of silane coupling agent AEPTMS, 5 g of triethanolamine and 60 g of 1,3,5-benzenetripentol. Stir and reflux for 12 h, cool, remove anhydrous ethanol by vacuum distillation, stir the resulting solution at 110 °C for 10 h, add anhydrous diethyl ether to precipitate, filter, wash and dry to obtain modified silane coupling agent; (2) Dissolve 3.2g of modified silane coupling agent in 60mL of deionized water, add 0.8g of mesoporous nano silica, react at 50℃ for 2h, filter while hot, wash three times with deionized water, and place the obtained solid in a 65℃ forced-air drying oven to dry for 24h to obtain modified mesoporous nano silica, which is the modified mesoporous silica material.
[0025] Comparative Example 1: The difference from Example 2 is that triethanolamine is not added during the preparation of the modified silane coupling agent. The specific steps are as follows: (1) Mix 25 mL of anhydrous ethanol and 0.15 g of sodium and stir until the sodium is completely dissolved. Then add 15.4 g of silane coupling agent AEPTMS and 90 g of 1,3,5-benzenetripentol. Stir and reflux for 11 h, cool, remove anhydrous ethanol by vacuum distillation, stir the resulting solution at 105 °C for 9 h, add anhydrous diethyl ether to precipitate, filter, wash, and dry to obtain modified silane coupling agent; (2) Dissolve 2.4g of modified silane coupling agent in 50mL of deionized water, add 0.6g of mesoporous nano silica, react at 50℃ for 2h, filter while hot, wash three times with deionized water, and place the obtained solid in a 65℃ forced-air drying oven to dry for 24h to obtain modified mesoporous nano silica, which is the modified mesoporous silica material.
[0026] Comparative Example 2: The difference from Example 2 is that 1,3,5-benzenetripentol is not added during the preparation of the modified silane coupling agent. The specific steps are as follows: (1) Mix 25 mL of anhydrous ethanol and 0.15 g of sodium and stir until the sodium is completely dissolved. Then add 15.4 g of silane coupling agent AEPTMS and 7.4 g of triethanolamine. Stir and reflux for 11 h, cool, remove anhydrous ethanol by vacuum distillation, stir the resulting solution at 105 °C for 9 h, add anhydrous diethyl ether to precipitate, filter, wash, and dry to obtain modified silane coupling agent; (2) Dissolve 2.4g of modified silane coupling agent in 50mL of deionized water, add 0.6g of mesoporous nano silica, react at 50℃ for 2h, filter while hot, wash three times with deionized water, and place the obtained solid in a 65℃ forced-air drying oven to dry for 24h to obtain modified mesoporous nano silica, which is the modified mesoporous silica material.
[0027] Comparative Example 3: The difference from Example 2 is that a silane coupling agent was used to directly modify the mesoporous nano-silica. The specific steps are as follows: Dissolve 2.4g of silane coupling agent AEPTMMS in 50mL of deionized water, add 0.6g of mesoporous nano silica, react at 50℃ for 2h, filter while hot, wash three times with deionized water, and place the obtained solid in a 65℃ forced-air drying oven to dry for 24h to obtain modified mesoporous nano silica, which is the modified mesoporous silica material.
[0028] Comparative Example 4: Mesoporous nano-silica as a drug carrier material.
[0029] Performance testing
[0030] Using ibuprofen (IBU) as a model drug, the carrier materials obtained in the examples and comparative examples were used to load ibuprofen: 0.2 g of ibuprofen was dissolved in 50 mL of n-hexane, 0.3 g of modified mesoporous silica material was added, the mixture was stirred at 4000 rpm, filtered and the supernatant (filtrate) was collected for later use, and the filter residue was dried in a 50°C forced-air drying oven for 24 h to obtain IBU-modified mesoporous silica material. Loading capacity: Take 2 mL of filtrate and dilute it to 50 mL. Then use a UV-6100s ultraviolet spectrophotometer to measure the absorbance at a wavelength of 264 nm to obtain the concentration of ibuprofen in the filtrate and calculate the IBU loading capacity of the carrier. In vitro cytotoxicity assay: Human hepatocytes were selected as test cells, and the standard MTT assay was used to determine cell viability. The test results are shown in Table 1.
[0031] In vitro drug release assay: Preparation of phosphate buffer solution: Add 52.25g KH2PO4, 29.25g hydrated citric acid and 40.55g Na2HPO4 to 2500mL deionized water, adjust the pH to 4.5 to obtain a phosphate buffer solution with a pH of 4.5, and store it in a refrigerator at 4℃ for later use; Dissolve 20.25g KH2PO4 and 4.53g sodium hydroxide in 2500mL deionized water, store it in a refrigerator at 4℃ for later use, to obtain a phosphate buffer solution with a pH of 7.5.
[0032] In vitro drug release assay: 60 mg of IBU-loaded samples from both the example and comparative studies were placed in dialysis bags with molecular weights ranging from 8000 to 14000. 8 mL of phosphate buffer solutions at different pH values were added, followed by 250 mL of the corresponding pH phosphate buffer solution. The mixture was stirred at 37°C at 500 rpm. Immediately after stirring, 3 mL of the release solution was removed and 3 mL of fresh phosphate buffer solution was added. The absorbance was measured at 264 nm using a UV-6100s ultraviolet spectrophotometer. The result was plotted against the standard curve y = 0.0016x + 0.0006 (R²). 2 =0.998) Calculate the concentration of the released liquid at each time point and calculate the cumulative release rate of ibuprofen; the test results are shown in Tables 2 and 3.
[0033] Table 1 Performance Test Results
[0034] Table 2 Results of in vitro release (pH 4.5) test
[0035] Table 3 Results of in vitro release (pH 7.5) test
[0036] As can be seen from the data in Examples 1-3 in the table, the modified mesoporous silica material prepared by the present invention exhibits excellent drug loading performance and intelligent release characteristics: the cell survival rate results show that the preparation process effectively maintains the biocompatibility of the material, and at the same time, through precise control of the surface chemical group distribution, it achieves efficient loading and controllable release of drug molecules.
[0037] The differences in data between Example 2 and Comparative Examples 1 and 2 in the table show that this invention constructs a unique gradient release carrier system through the synergistic effect of triethanolamine and 1,3,5-benzenetripentol. The short-chain structure of triethanolamine and the tight cross-linked network formed by 1,3,5-benzenetripentol with the silane coupling agent during modification provide stable drug binding sites. This synergistic combination of long and short chains may generate staged release kinetics—the long-chain hydrophobic groups preferentially dissociate under acidic conditions, leading to an initial increase in carrier porosity and achieving initial sustained drug release; as the environmental pH continues to act, the short-chain cross-linked network gradually dissociates, triggering a comprehensive expansion of the pore structure, thereby triggering a later burst release of the drug. In contrast, Comparative Example 1, lacking triethanolamine, results in an incomplete short-chain cross-linked network, leading to decreased carrier structural stability and a lack of obvious burst release characteristics in the release curve; while Comparative Example 2, lacking long chains, causes the carrier to lose its hydrophobic micro-region regulation ability, resulting in premature drug release. This synergistic molecular design of long and short chains maintains the structural integrity of the carrier under physiological conditions and can achieve precise drug release regulation in response to the lesion microenvironment.
[0038] A comparison of the data from Example 2 with Comparative Examples 3 and 4 in the table shows that the mesoporous silica carrier constructed by the silane coupling agent modification process of the present invention exhibits significantly optimized drug loading and release characteristics, which may be due to the hierarchical functionalized structure formed on the mesoporous surface by multi-component synergistic modification: AEPTMS provides amino groups that form stable covalent bonds with hydroxyl groups on the mesoporous surface, constructing uniformly distributed drug anchoring sites. The short-chain structure of triethanolamine regulates the arrangement density of functional groups through steric hindrance, resulting in moderate drug binding strength. Meanwhile, the long chain of 1,3,5-benzenetripentol constructs drug reservoir microregions within the pores through hydrophobic interactions. This multi-scale modification allows the carrier to maintain a high specific surface area while achieving efficient loading of ibuprofen molecules through the synergistic effects of amino-carboxyl electrostatic interactions and hydrophobic interactions. During release, the acidic environment promotes amino protonation, triggering charge reversal on the carrier surface and simultaneously weakening hydrophobic interactions; this dual mechanism synergistically drives rapid drug release. In contrast, the directly modified sample in Comparative Example 3 lacks ordered multi-level structural regulation, leading to uneven distribution of drug loading sites; while the unmodified sample in Comparative Example 4 exhibits extremely low drug loading and release efficiency due to the absence of surface-active groups.
[0039] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.
Claims
1. A modified mesoporous silica material, characterized in that, The modified mesoporous silica material is obtained by grafting a modified silane coupling agent onto the surface of mesoporous nano-silica; the modified silane coupling agent is prepared by using silane coupling agent AEPTMMS, triethanolamine, and 1,3,5-benzenetripentol in the presence of sodium ethoxide.
2. The modified mesoporous silica material according to claim 1, characterized in that, The molar ratio of the silane coupling agent AEPTMMS, triethanolamine, and 1,3,5-benzenetripentol is 1:0.3-0.4:1.5-2.
3. The modified mesoporous silica material according to claim 1, characterized in that, The sodium ethoxide is obtained by reacting anhydrous ethanol and sodium, wherein the mass-to-volume ratio of sodium to anhydrous ethanol is 0.1-0.2 g: 15-30 mL; and the amount of sodium added is 0.9%-1.1% of the mass of AETMS.
4. The modified mesoporous silica material according to claim 1, characterized in that, The mass ratio of the modified silane coupling agent to mesoporous nano silica is 4:
1.
5. The modified mesoporous silica material according to claim 1, characterized in that, The mesoporous nano-silica has an outer diameter of 450-550 nm and a pore size of 2-4 nm.
6. A method for preparing a modified mesoporous silica material according to any one of claims 1-5, characterized in that, Includes the following steps: (1) Mix ethanol, sodium, silane coupling agent AEPTMMS, triethanolamine, and 1,3,5-benzenetripentol, stir and reflux for 10-12 h, cool, distill under reduced pressure, stir at 100-110℃ for 8-10 h, purify, and obtain modified silane coupling agent. (2) Mix the modified silane coupling agent, deionized water and mesoporous nano silica, react at 50°C for 1-2 hours, filter, wash and dry to obtain modified mesoporous nano silica, which is the nanomedicine carrier material.
7. An application of the modified mesoporous silica material according to any one of claims 1-5, characterized in that, As a nanomedicine carrier material.
8. The application according to claim 7, characterized in that, The modified mesoporous silica material serves as a pH-responsive nanomedicine carrier material.
9. A pH-responsive drug delivery system, characterized in that, Includes the modified mesoporous silica material as described in any one of claims 1-5 and the drug loaded on the modified mesoporous silica material.
10. The pH-responsive drug delivery system according to claim 9, characterized in that, The drug in question is ibuprofen.