CN113371722A - Preparation method of degradable small-size hollow mesoporous silica nanoparticles - Google Patents
Preparation method of degradable small-size hollow mesoporous silica nanoparticles Download PDFInfo
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 239000000377 silicon dioxide Substances 0.000 title claims abstract description 44
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 208000006411 Hereditary Sensory and Motor Neuropathy Diseases 0.000 claims abstract description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 208000021995 hereditary motor and sensory neuropathy Diseases 0.000 claims abstract description 24
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910052681 coesite Inorganic materials 0.000 claims abstract description 19
- 229910052906 cristobalite Inorganic materials 0.000 claims abstract description 19
- 229910052682 stishovite Inorganic materials 0.000 claims abstract description 19
- 229910052905 tridymite Inorganic materials 0.000 claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 238000010992 reflux Methods 0.000 claims abstract description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000009833 condensation Methods 0.000 claims abstract description 3
- 230000005494 condensation Effects 0.000 claims abstract description 3
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 3
- -1 triethoxysilyl Chemical group 0.000 claims abstract description 3
- 239000002245 particle Substances 0.000 claims description 10
- 239000010703 silicon Substances 0.000 claims description 10
- 229910052710 silicon Inorganic materials 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 239000006185 dispersion Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- FBBATURSCRIBHN-UHFFFAOYSA-N triethoxy-[3-(3-triethoxysilylpropyldisulfanyl)propyl]silane Chemical compound CCO[Si](OCC)(OCC)CCCSSCCC[Si](OCC)(OCC)OCC FBBATURSCRIBHN-UHFFFAOYSA-N 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 abstract description 9
- 229910021641 deionized water Inorganic materials 0.000 abstract description 9
- 239000003513 alkali Substances 0.000 abstract 1
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Chemical compound [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 8
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 238000003917 TEM image Methods 0.000 description 4
- 239000005543 nano-size silicon particle Substances 0.000 description 4
- 108010024636 Glutathione Proteins 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960003180 glutathione Drugs 0.000 description 3
- 239000002086 nanomaterial Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IWXAZSAGYJHXPX-BCEWYCLDSA-N Bisbentiamine Chemical compound C=1C=CC=CC=1C(=O)OCC/C(SS\C(CCOC(=O)C=1C=CC=CC=1)=C(/C)N(CC=1C(=NC(C)=NC=1)N)C=O)=C(/C)N(C=O)CC1=CN=C(C)N=C1N IWXAZSAGYJHXPX-BCEWYCLDSA-N 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000004833 X-ray photoelectron spectroscopy Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
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- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/18—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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Abstract
The invention discloses a preparation method of degradable small-size hollow mesoporous silica nanoparticles, which mainly comprises the following steps: mixing a template agent of hexadecyl trimethyl ammonium chloride aqueous solution and a triethanolamine aqueous solution, adjusting the pH value to a weak alkali environment, heating to 90-98 ℃, adding tetraethyl orthosilicate, and stirring to form a silicon core; step two, TEOS and bis- [3- (triethoxysilyl) propyl ] are added]Uniformly mixing disulfide, adding the mixture into the solution obtained in the step one, and stirring the mixture to react to obtain SiO2@ DS-HMSN-CTAC; step three, SiO2@ DS-HMSN-CTAC is dispersed in absolute methanol, hydrochloric acid is added for condensation and reflux to obtain SiO2@ DS-HMSN nanoParticles; step four, SiO2The @ DS-HMSN nano-particles are dispersed in deionized water, anhydrous sodium carbonate is added to react to remove silicon cores, and the degradable small-size hollow mesoporous silica nano-particles DS-HMSN are obtained.
Description
Technical Field
The invention belongs to the field of nano materials, and particularly relates to a preparation method of degradable small-size hollow mesoporous silica nanoparticles.
Background
The Hollow Mesoporous Silica Nanoparticle (HMSN) material has an internal large cavity and a shell layer mesoporous pore channel, a stable skeleton structure and a very high specific surface area, so that excellent material transmission capacity, high dispersion and encapsulation of various components and light reflection performance are shown, and a wide potential application prospect is shown in the fields of medicine, catalysis, optics and the like.
The existing HMSN material preparation technology is not exhaustive, and generally comprises a hard core template method, a liquid interface assembly method, an interface recombination and conversion method and the like. Wherein, the hollow inner cavity is constructed by taking rigid particles (hard template) as the core, and the hollow mesoporous silicon oxide nano-particles are prepared by the synergistic action of the rigid particles and the mesoporous guiding agent
The method comprises coating the outer surface of CTAB and tetraethyl orthosilicate (TEOS) by self-assembly to form SiO2@ HMSN-CTAB core-shell nanoparticles sequentially passing through Na2CO3Solution etching to remove hard core (SiO)2) And extracting the alcohol acid mixed solution to remove a mesoporous structure directing agent CTAB, and preparing HMSN with an inner cavity of about 90nm and a particle size of about 150 nm.
Although the HMSN material has various excellent performances, the shape and the size are always important factors for limiting the stable expression of the performances. For example, in the construction of carriers for anticancer drugs, the size of the carrier is the primary factor affecting the degree of dispersion within the tumor. However, the hundred-nanometer hollow mesoporous silica carrier realized by the prior art can not go deep into the tumor and can not meet the treatment requirement. In the fields of catalysis, optics and the like, the size of the nano material is also one of important influence factors for limiting the reaction speed and the characterization of the nano material. In addition, the difficulty of removing the template agent limits the HMSN capacity, and the self-structure stability causes the difficulty of releasing the internal carrier, so that the HMSN is difficult to be used as an efficient substance transmission carrier.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of degradable small-size hollow mesoporous silica nanoparticles aiming at the defects in the prior art, wherein the obtained product has smaller size, larger mesoporous capacity, easier degradation and the like.
The technical scheme adopted by the invention for solving the problems is as follows:
a preparation method of degradable small-size hollow mesoporous silica nanoparticles mainly comprises the following steps:
mixing a template agent Cetyl Trimethyl Ammonium Chloride (CTAC) aqueous solution and a Triethanolamine (TEA) aqueous solution, adjusting the pH to 8.0-10.0, heating to 90-98 ℃ after ultrasonic dissolution and dispersion, adding tetraethyl orthosilicate (TEOS), and stirring for 30-60 min to form silicon cores;
step two, TEOS and bis- [3- (triethoxysilyl) propyl ] are added]Uniformly mixing disulfide (BTDS), dropwise adding the mixture into the solution obtained in the step one, and stirring and reacting for 4-8 hours to obtain the degradable small-size hollow mesoporous silica nanoparticle SiO containing the template agent and the silicon core2@DS-HMSN-CTAC；
Step three, SiO2Dispersing @ DS-HMSN-CTAC in absolute methanol, adding hydrochloric acid, performing condensation reflux for 8-12 h at 75-80 ℃, repeating for three times to remove the CTAC as far as possible, and obtaining the degradable small-size hollow mesoporous silica nanoparticle SiO containing silicon core2@ DS-HMSN nanoparticles;
step four, SiO2@ DS-HMSN nano-particles are dispersed in deionized water, and anhydrous sodium carbonate (Na) is added2CO3) And reacting for 8-12 h at 50-60 ℃ to remove silicon nuclei, thereby obtaining the degradable small-size hollow mesoporous silica nanoparticle DS-HMSN.
According to the scheme, in the first step, the concentration of a CTAC aqueous solution is 10-15 mg/ml, and the concentration of a TEA solution is 0.3-0.8 mg/ml; the mass ratio of CTAC to TEA is 20-25: 1; the mass ratio of CTAC to TEOS is 2.0-2.2: 1.
According to the scheme, in the second step, the mass ratio of tetraethyl orthosilicate to bis- [3- (triethoxysilyl) propyl ] -disulfide is 1.50-1.8: 1; the mass ratio of the tetraethyl orthosilicate in the second step to the tetraethyl orthosilicate in the first step is 0.5-1: 1.
According to the scheme, SiO2The particle size of @ DS-HMSN-CTAC is in the range of 50-70 nm.
According to the scheme, in the third step, the adding concentration of SiO2@ DS-HMSN-CTAC in anhydrous methanol is 4-8 mg/mL, and the volume ratio of the anhydrous methanol to hydrochloric acid is 8-12: 1; wherein the hydrochloric acid concentration is 37%.
According to the scheme, in the fourth step, SiO2The adding concentration of @ HMSN in deionized water is 2-4 mg/mL; the adding concentration of the anhydrous sodium carbonate in the deionized water is 10-15 mg/mL.
Compared with the prior art, the invention improves the method of the hard core template
The size of the prepared degradable small-size hollow mesoporous silica nano particles is reduced from hundred nanometers to 50-70 nm; the specific surface area and the mesoporous capacity of the HMSN material are ensured by selecting a template agent which is easier to extract; and the disulfide bond is introduced, so that the HMSN material shows more excellent controllable degradation capability under the reducing condition.
Drawings
FIG. 1 is a diagram of degradable small-sized hollow mesoporous silica nanoparticles SiO containing a template and a silicon core in an example2TEM image of @ DS-HMSN-CTAC;
FIG. 2 is the degradable small-sized hollow mesoporous silica nanoparticle SiO containing silicon core in the example2TEM image of @ DS-HMSN;
FIG. 3 is a TEM image of DS-HMSN of degradable small-sized hollow mesoporous silica nanoparticles in the example;
FIG. 4 is a PCS particle size diagram of DS-HMSN of the degradable small-sized hollow mesoporous silica nanoparticles in the examples;
FIG. 5 is an XPS plot of the characterization sulfur element of the degradable small-sized hollow mesoporous silica nanoparticles DS-HMSN in the examples;
FIG. 6 is a schematic diagram of the degradable small-sized hollow mesoporous silica nanoparticle DS-HMSN in the embodiment after carrying a drug and then releasing the drug by cracking under the action of reductive glutathione.
Detailed Description
In order to better understand the present invention, the following examples are further provided to illustrate the content of the present invention, but the present invention is not limited to the following examples.
Examples
A preparation method of small-size hollow mesoporous silica nanoparticles specifically comprises the following steps:
(1) degradable small-size hollow mesoporous silica nanoparticle SiO containing template agent and silicon core2@DS-HMSN-CTAC
Mixing CTAC solution (1 wt% of 2g CTAC and 200g deionized water), TEA solution (1 wt% of 0.08g TEA and 8g deionized water), adding 1ml TEOS at 95 deg.C, reacting for 45min, adding mixed silicon source (1ml TEOS and 0.6ml BTDS), reacting for 6h, centrifuging, washing, and drying to obtain SiO2@DS-HMSN-CTAC；
(2) Removing template
Dispersing 200mg of prepared SiO2@ DS-HMSN-CTAC in 50ml of methanol, adding 5ml of 37% hydrochloric acid, condensing and refluxing for 12h at 78 ℃, repeating for three times, and centrifugally washing and drying to prepare SiO2@ DS-HMSN;
(3) kernel removal
200mg of the prepared SiO2@ HMSN were dispersed in 100ml of deionized water, and 1g of Na was added2CO3Reacting for 12h at 50 ℃, centrifuging, washing and drying to obtain the DS-HMSN.
The obtained degradable small-size hollow mesoporous silicon dioxide nano-particles SiO containing the template agent and the silicon core2@ DS-HMSN-CTAC was diluted with deionized water by a certain factor and observed for morphology by transmission electron microscopy, as shown in FIG. 1, SiO2The particle size of @ DS-HMSN-CTAC is about 50-60 nm; FIG. 2 is a TEM image of degradable small-sized hollow mesoporous silica nanoparticles (DS-HMSN); as can be seen from FIG. 3, SiO2The nucleus is successfully removed, the hollow structural characteristics can be found through image observation, and the hollow cavity inside the sphere can be clearly distinguished from the thin sphere wall.
Diluting the obtained degradable small-sized hollow mesoporous silicon nanoparticles (DS-HMSN) by a certain multiple with deionized water, and testing the size of the particles by using a particle size and potential tester, as can be seen from FIG. 4, the degradable small-sized hollow mesoporous silicon dioxide nanoparticles SiO containing a template agent and a silicon core2The particle size of @ DS-HMSN-CTAC is about 50 to 70 nm.
The obtained degradable small-size hollow mesoporous silicon nano-particles (DS-HMSN) are analyzed by X-ray photoelectron spectroscopy, and the existence of sulfur elements can be represented. As shown in FIG. 5 in combination with the use of bis- [3- (triethoxysilyl) propyl ] -disulfide in the synthesis process, the sulfur element in the degradable small-sized hollow mesoporous silicon nanoparticles exists in the form of disulfide bond.
And loading the obtained degradable small-size hollow mesoporous silicon nanoparticles (DS-HMSN) into adriamycin (DOX) for drug loading in a dark place by a physical stirring means, plugging the pore channel by chitosan, and performing cracking drug release under the action of reductive glutathione. As can be seen from fig. 6, in the environment at PH 7.4, as the concentration of reduced Glutathione (GSH) increases, the disulfide bond in DS-HMSN is cleaved in the same time, the degree of degradation of nanoparticles increases, and the cumulative amount of released drug DOX increases. It is known that DS-HMSN shows remarkable degradability in a reducing physicochemical environment.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, many modifications and changes can be made without departing from the inventive concept of the present invention, and these modifications and changes are within the protection scope of the present invention.
Claims (8)
1. A preparation method of degradable small-size hollow mesoporous silica nanoparticles is characterized by mainly comprising the following steps:
mixing a template agent of hexadecyl trimethyl ammonium chloride aqueous solution and a triethanolamine aqueous solution, adjusting the pH value to 8.0-10.0, heating to 90-98 ℃ after ultrasonic dissolution and dispersion, adding tetraethyl orthosilicate, and stirring for 30-60 min to form silicon nuclei;
step two, TEOS and bis- [3- (triethoxysilyl) propyl ] are added]Uniformly mixing disulfide, dropwise adding the mixture into the solution obtained in the step one, and stirring and reacting for 4-8 hours to obtain the degradable small-size hollow mesoporous silica nanoparticle SiO containing the template agent and the silicon core2@DS-HMSN-CTAC；
Step three, SiO2Dispersing the @ DS-HMSN-CTAC in methanol, adding hydrochloric acid, and performing condensation reflux at 75-80 ℃ for 8-12 h to obtain the degradable small-size hollow mesoporous silica nanoparticle SiO containing silicon core2@ DS-HMSN nanoparticles;
step four, SiO2And (2) dispersing the @ DS-HMSN nano-particles in water, adding sodium carbonate, and reacting at 50-60 ℃ for 8-12 h to remove silicon cores to obtain the degradable small-size hollow mesoporous silica nano-particles DS-HMSN.
2. The preparation method of the degradable small-sized hollow mesoporous silica nanoparticle as claimed in claim 1, wherein in the first step, the concentration of the aqueous solution of cetyltrimethylammonium chloride is 10-15 mg/ml, and the concentration of the aqueous solution of triethanolamine is 0.3-0.8 mg/ml.
3. The preparation method of the degradable small-size hollow mesoporous silica nanoparticle as claimed in claim 1, wherein in the first step, the mass ratio of cetyltrimethylammonium chloride to triethanolamine is 20-25: 1; the mass ratio of the hexadecyl trimethyl ammonium chloride to the TEOS is 2.0-2.2: 1.
4. The preparation method of the degradable small-sized hollow mesoporous silica nanoparticle as claimed in claim 1, wherein in the second step, the mass ratio of tetraethyl orthosilicate to bis- [3- (triethoxysilyl) propyl ] -disulfide is 1.50-1.8: 1; the mass ratio of the tetraethyl orthosilicate in the second step to the tetraethyl orthosilicate in the first step is 0.5-1: 1.
5. The method for preparing degradable small-sized hollow mesoporous silica nanoparticles according to claim 1, wherein SiO is2The particle size of @ DS-HMSN-CTAC is within the range of 50-70 nm.
6. The preparation method of the degradable small-size hollow mesoporous silica nanoparticle as claimed in claim 1, wherein in the third step, the adding concentration of SiO2@ DS-HMSN-CTAC in methanol is 4-8 mg/mL, and the volume ratio of methanol to hydrochloric acid is 8-12: 1; wherein the concentration of the hydrochloric acid is 30-40%.
7. The method for preparing degradable small-sized hollow mesoporous silica nanoparticles according to claim 1, wherein in the fourth step, SiO is added2The adding concentration of the @ DS-HMSN in water is 2-4 mg/mL.
8. The preparation method of the degradable small-sized hollow mesoporous silica nanoparticle according to claim 1, wherein in the fourth step, the adding concentration of sodium carbonate in water is 10-15 mg/mL.
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