CN108743951B - Preparation method of pH-responsive degradable hollow mesoporous organic silicon nanoparticles - Google Patents
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
The invention discloses a preparation method of pH-responsive degradable hollow mesoporous organic silicon nanoparticles, which comprises the following steps of firstly preparing pH-sensitive micromolecules containing acetal groups; then the small molecule is introduced into a shell skeleton of the hollow mesoporous organic silicon nano particle to obtain the pH response degradable hollow mesoporous organic silicon nano particle. The hollow mesoporous structure ensures that the organic silicon nano particles have higher drug loading capacity when being used as an anti-tumor drug carrier; under the weak acidic condition, the organic silicon nano particles can be degraded, so that the loaded drug can be efficiently released, the self degradation ensures the safe metabolism of the carrier, the toxicity enrichment is avoided, and more selectivity is provided for the preparation of the anti-tumor drug carrier.
Description
Technical Field
The invention belongs to the technical field of nano composite materials, and particularly relates to a preparation method of pH-responsive degradable hollow mesoporous organic silicon nanoparticles.
Background
At present, chemotherapy is one of the main means for clinically treating cancer, but the antitumor drugs have great side effects, can cause irreversible damage to normal tissues of a human body in the treatment process, reduce the immunocompetence of the human body, and cause the reduction of the utilization rate of the drugs so as to delay treatment. The reason for this is mainly caused by the wide distribution of the antitumor drugs in human body due to their non-selectivity. Therefore, designing and preparing safe and efficient drug carriers to improve the utilization efficiency of antitumor drugs and reduce the side effects thereof is a research hotspot.
The mesoporous silica nanoparticle MSN as a drug carrier has unique structure and performance advantages: large specific surface area and dielectric pore volume, regular and adjustable pore channel structure, good biocompatibility, easy surface modification and the like. In 2001, MSN was first reported for drug delivery vehicles, and in the next decade, research into MSN-based nano-drug carriers has been greatly advanced. Although MSN has been shown to have some biocompatibility as well as degradability. However, in practical application, it is still difficult to ensure complete metabolism of the nano material, and the nano material may be rapidly enriched in the reticuloendothelial system, such as liver and spleen, thereby causing problems of long-term toxicity and the like, and severely limiting clinical transition application of the MSN-based drug carrier. Therefore, the prepared biodegradable organic-inorganic hybrid nano particles have the mesoporous structure and performance of an inorganic matrix and the biodegradability of an organic part, improve the efficiency and the safe metabolism of the drug carrier, and become the key point of the research in the field of the drug carrier.
The discovery and preparation of the periodic mesoporous organosilicon nanoparticles open a new door for solving the problems. The periodic mesoporous organosilicon is a novel organic-inorganic hybrid nano mesoporous material, has an ordered mesoporous structure between 2 and 30nm and a pore wall structure, and organic functional groups pass through two or more SiO1.5Bridging groups, e.g. (EtO)3Si-R-Si(OEt)3，R＝CH2-CH2，C6H4As building units, are uniformly distributed in the mesoporous framework of the material. The surface properties of the material can be changed by adjusting the organic functional bridging group in the framework, and then the overall properties of the material can be changed. Therefore, researchers take an alkoxy silane precursor containing an organic bridging group which can be cleaved under the stimulation of an external environment as a silicon source to prepare a series of stimulation-response type self-degradable organic silicon nanoparticles for drug or gene transportation so as to ensure the drug transportation efficiency and the safe metabolism of a carrier. At present, self-degradable organic silicon nano particles with redox and enzyme response are prepared by using alkoxy silane precursors containing disulfide bonds, but the types of the stimulus response type degradable organic silicon nano particles are few, so that the application of the stimulus response type degradable organic silicon nano particles as anti-tumor drug carriers is limited to a certain extent.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the defects in the prior art, the invention aims to provide a preparation method of pH-responsive degradable hollow mesoporous organic silicon nanoparticles which can be applied to antitumor drug carriers.
The technical scheme is as follows: the invention relates to a preparation method of pH-responsive degradable hollow mesoporous organic silicon nanoparticles, which comprises the following steps:
a. adding terephthalaldehyde and dibromo neopentyl glycol into an organic solvent A containing p-toluenesulfonic acid, and reacting at 100-120 ℃ for 9-16 h to obtain a pH-response micromolecule containing an acetal group, wherein the structural formula is as follows:
the organic solvent A is toluene or benzene;
b. adding triethylamine, a silane coupling agent and a pH-response micromolecule into an organic solvent B, reacting for 5-8 h at 50-80 ℃, adding n-hexane after the reaction is finished, removing ammonium salt through a neutral alumina column, and performing rotary evaporation drying to obtain a bridged alkoxy silane precursor containing a pH-response group, wherein the structural formula is as follows:
the organic solvent B is tetrahydrofuran or dimethyl sulfoxide;
c. dissolving cetyl trimethyl ammonium bromide in water, adding triethylamine and tetraethyl orthosilicate, reacting for 0.5-1.5 h at 80-100 ℃, adding a mixed silicon source, continuing to react for 4-6 h, centrifuging, washing with ethanol to obtain a white solid, re-dispersing the white solid into water, adding 2-5 ml of ammonia water, reacting for 4-6 h at 80-100 ℃, centrifuging, washing with water, and drying to obtain the pH-responsive degradable hollow mesoporous organosilicon nanoparticles.
In the step a, the mass ratio of the terephthalaldehyde to the dibromoneopentyl glycol to the p-toluenesulfonic acid is 10-30: 35-45: 1-3.
In the step b, the silane coupling agent is 3-aminopropyltriethoxysilane or 3-isocyanatopropyl trimethoxysilane, and the mass ratio of triethylamine to the silane coupling agent to the pH-responsive micromolecules is 2-4: 3-5: 1 to 3.
In the step c, the mass ratio of the hexadecyl trimethyl ammonium bromide to the triethylamine to the tetraethyl orthosilicate is 2-5: 1-3: 2-5: 4-7, the mixed silicon source is the tetraethyl orthosilicate and the pH-responsive bridged alkoxy silane precursor, and the mass ratio of the tetraethyl orthosilicate to the pH-responsive bridged alkoxy silane precursor is 1-2: 1-5.
The pH response degradable hollow mesoporous organic silicon nano particle is used as a carrier of an anti-tumor medicament.
Has the advantages that: compared with the prior art, the invention has the following remarkable characteristics: the invention synthesizes acetal group-based pH-responsive degradable hollow mesoporous organic silicon nanoparticles for the first time, can realize self-degradation under the stimulation of a weak acid environment, and provides new selectivity for preparing the stimulation-responsive organic silicon nanoparticles; the pH-responsive degradable hollow mesoporous organosilicon nanoparticles have hollow cavities which are used as containers for loading drugs, so that the drug loading capacity can be greatly improved, and mesoporous channels provide a way for loading and releasing the drugs; the pH-responsive degradable hollow mesoporous organic silicon nanoparticle obtained by the invention is used for conveying antitumor drugs, can realize safe metabolism of a carrier, avoids toxic and side effects caused by in vivo enrichment, and has a certain clinical application value.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of a pH-responsive small molecule containing an acetal group prepared in example four;
FIG. 2 is a transmission electron microscope image of pH-responsive degradable hollow mesoporous organosilicon nanoparticles prepared in example four;
FIG. 3 is a transmission electron microscope image of different degradation times of pH-responsive degradable hollow mesoporous organosilicon nanoparticles;
figure 4 is the killing effect of drug-loaded nanoparticles on KB cells.
Detailed Description
Example one
(1) Dissolving 20.0g of terephthalaldehyde, 80.0g of dibromoneopentyl glycol and 0.5g of p-toluenesulfonic acid into 300ml of toluene, carrying out reflux reaction at 100 ℃ for 9 hours, cooling to room temperature, and filtering to obtain white powder, namely the pH-responsive micromolecule of the acetal group.
(2) Adding 1.0g of triethylamine, 1.5g of 3-aminopropyltriethoxysilane coupling agent and 0.5g of pH-responsive micromolecule into 20ml of tetrahydrofuran, reacting for 5 hours at 50 ℃, adding 30ml of n-hexane after the reaction is finished, removing ammonium salt through a neutral alumina column, and performing rotary evaporation drying to obtain the bridged alkoxysilane precursor containing the pH-responsive group.
(3) Dissolving 2.0g of hexadecyl trimethyl ammonium bromide in 20ml of water, then adding 1.0g of triethylamine and 2.0g of tetraethyl orthosilicate, and reacting for 1h at 80 ℃ to obtain a silicon dioxide template; and then adding 4.0g of a mixed silicon source, wherein the mixed silicon source consists of 2.0g of tetraethyl orthosilicate and 2.0g of a pH-responsive bridged alkoxysilane precursor, continuing to react for 4 hours, centrifuging and washing with ethanol to obtain a white solid, re-dispersing the white solid into water, adding 2ml of ammonia water, reacting for 4 hours at 80 ℃ to remove template silicon dioxide, centrifuging, washing with water and drying to obtain the pH-responsive degradable hollow mesoporous organosilicon nanoparticles.
Example two
(1) Dissolving 25.0g of terephthalaldehyde, 90.0g of dibromoneopentyl glycol and 1.5g of p-toluenesulfonic acid into 1000ml of benzene, carrying out reflux reaction at 120 ℃ for 16h, cooling to room temperature, and filtering to obtain white powder, namely the pH-responsive micromolecule of the acetal group.
(2) Adding 2.0g of triethylamine, 2.5g of 3-isocyanatopropyl trimethoxy silane coupling agent and 1.5g of pH-responsive micromolecule into 20ml of tetrahydrofuran, reacting at 80 ℃ for 8h, adding 60ml of n-hexane after the reaction is finished, removing ammonium salt through a neutral alumina column, and performing rotary evaporation drying to obtain the bridged alkoxy silane precursor containing the pH-responsive group.
(3) Dissolving 5.0g of hexadecyl trimethyl ammonium bromide in 50ml of water, then adding 3.0g of triethylamine and 5.0g of tetraethyl orthosilicate, and reacting for 1.5h at 100 ℃ to obtain a silicon dioxide template; and then adding 7.0g of a mixed silicon source, wherein the mixed silicon source consists of 2.0g of tetraethyl orthosilicate and 5.0g of a pH-responsive bridged alkoxysilane precursor, continuing to react for 6 hours, centrifuging and washing with ethanol to obtain a white solid, re-dispersing the white solid into water, adding 5ml of ammonia water, reacting for 6 hours at 100 ℃ to remove template silicon dioxide, centrifuging, washing with water and drying to obtain the pH-responsive degradable hollow mesoporous organosilicon nanoparticles.
EXAMPLE III
(1) 45.0g of terephthalaldehyde, 170.0g of dibromoneopentyl glycol and 2.0g of p-toluenesulfonic acid are dissolved in 1200ml of toluene, reflux reaction is carried out at 110 ℃ for 12.5h, and white powder, namely the pH-responsive micromolecule of the acetal group, is obtained by cooling to room temperature and filtering.
(2) Adding 1.5g of triethylamine, 2.0g of 3-aminopropyltriethoxysilane coupling agent and 1.0g of pH-responsive micromolecule into 10ml of dimethyl sulfoxide, reacting at 65 ℃ for 6.5h, adding 30ml of n-hexane after the reaction is finished, removing ammonium salt through a neutral alumina column, and performing rotary evaporation drying to obtain the bridged alkoxysilane precursor containing the pH-responsive group.
(3) Dissolving 3.5g of hexadecyl trimethyl ammonium bromide in 35ml of water, then adding 2.0g of triethylamine and 3.5g of tetraethyl orthosilicate, and reacting for 1h at 90 ℃ to obtain a silicon dioxide template; and then adding 5.0g of a mixed silicon source, wherein the mixed silicon source consists of 1.5g of tetraethyl orthosilicate and 3.5g of a pH-responsive bridged alkoxysilane precursor, continuing to react for 5 hours, centrifuging and washing with ethanol to obtain a white solid, re-dispersing the white solid into water, adding 3.5ml of ammonia water, reacting at 90 ℃ for 5 hours to remove template silicon dioxide, centrifuging, washing with water and drying to obtain the pH-responsive degradable hollow mesoporous organosilicon nanoparticles.
Example four
(1) Dissolving 13.0g of terephthalaldehyde, 52.0g of dibromoneopentyl glycol and 0.3g of p-toluenesulfonic acid into 200ml of toluene, carrying out reflux reaction at 120 ℃ for 14h, cooling to room temperature, and filtering to obtain white powder, namely the pH-responsive micromolecule of the acetal group. FIG. 1 is a nuclear magnetic spectrum of a pH-responsive small molecule containing an acetal group prepared in example four, and it is apparent from the figure that the pH-responsive small molecule containing an acetal group has been successfully synthesized.
(2) Adding 1.5g of triethylamine, 3.3g of 3-aminopropyltriethoxysilane, 1.0g of pH-responsive micromolecule into 10ml of tetrahydrofuran, reacting at 50 ℃ for 6h, adding 30ml of n-hexane after the reaction is finished, removing ammonium salt through a neutral alumina column, and performing rotary evaporation drying to obtain the bridged alkoxy silane precursor containing the pH-responsive group.
(3) Dissolving 2.0g of hexadecyl trimethyl ammonium bromide in 20ml of water, then adding 0.8g of triethylamine and 0.9g of tetraethyl orthosilicate, and reacting for 1h at the temperature of 95 ℃ to obtain a silicon dioxide template; and then adding 2.0g of a mixed silicon source, wherein the mixed silicon source consists of 1.0g of tetraethyl orthosilicate and 1.0g of a pH-responsive bridged alkoxysilane precursor, continuing to react for 4 hours, centrifuging and washing with ethanol to obtain a white solid, re-dispersing the white solid into water, adding 2ml of ammonia water, reacting for 4 hours at 95 ℃ to remove template silicon dioxide, centrifuging, washing with water and drying to obtain the pH-responsive degradable hollow mesoporous organosilicon nanoparticles. Fig. 2 is a transmission electron microscope image of the pH-responsive degradable hollow mesoporous organosilicon nanoparticles prepared in example four, from which it can be seen that the pH-responsive degradable hollow mesoporous organosilicon nanoparticles having a hollow mesoporous structure have a particle size of about 100 nm.
EXAMPLE five
(1) Dissolving 47.0g of terephthalaldehyde, 162.0g of dibromoneopentyl glycol and 2.5g of p-toluenesulfonic acid into 1600ml of toluene, carrying out reflux reaction at 115 ℃ for 15h, cooling to room temperature, and filtering to obtain white powder, namely the pH-responsive micromolecule of the acetal group.
(2) Adding 1.7g of triethylamine, 4.5g of 3-aminopropyltriethoxysilane, 2.7g of pH-responsive micromolecules into 30ml of tetrahydrofuran, reacting at 75 ℃ for 7.5h, adding 60ml of n-hexane after the reaction is finished, removing ammonium salt through a neutral alumina column, and performing rotary evaporation drying to obtain a bridged alkoxy silane precursor containing pH-responsive groups.
(3) Dissolving 4.5g of hexadecyl trimethyl ammonium bromide in 45ml of water, then adding 2.7g of triethylamine and 4.6g of tetraethyl orthosilicate, reacting for 1.4h at 95 ℃ to obtain a silicon dioxide template, then adding 6.0g of a mixed silicon source, wherein the mixed silicon source consists of 1.7g of tetraethyl orthosilicate and 4.3g of a pH-responsive bridged alkoxysilane precursor, and continuing to react for 5.4 h; centrifuging and washing with ethanol to obtain a white solid, re-dispersing the white solid into water, adding 2ml of ammonia water, reacting at 98 ℃ for 4.2h to remove template silicon dioxide, centrifuging, washing with water and drying to obtain the pH-responsive degradable hollow mesoporous organosilicon nanoparticles.
Effect testing
Degradation behavior of nanoparticles in weakly acidic environment
Dispersing 5mg of the pH-responsive degradable hollow mesoporous organosilicon nanoparticles prepared in example four into 50ml of PBS solution (pH 5), stirring, sampling at different times, and performing transmission electron microscope testing to determine the degradation behavior of the nanoparticles in a weakly acidic environment. FIG. 3 is a transmission electron microscope image of pH-responsive degradable hollow mesoporous organosilicon nanoparticles at different times, and it is obvious from the image that the pH-responsive degradable hollow mesoporous organosilicon nanoparticles synthesized by the invention can be degraded in a weakly acidic environment.
Second, drug Loading Properties
Doxorubicin was used as a mock drug to study the drug loading performance of the vehicle. Adding 0.5ml of adriamycin solution into 10ml of aqueous solution containing 1mg of pH-responsive degradable hollow mesoporous organic silicon nanoparticles prepared in the fourth embodiment, stirring for 24 hours, centrifuging to obtain a nano composite drug carrier, testing the concentration of adriamycin in supernatant, and calculating to obtain the drug loading efficiency and the drug loading capacity of the nanoparticles to be 86.4 percent and 162.9ug mg of the nanoparticles respectively-1。
Third, cell survival rate
The prepared nano composite medicine carrier is loaded into human oral epithelial cancer cells (KB cells), and the survival rate of the cells under different conditions is researched. Fig. 4 shows the cell survival rate of KB cells after co-culturing with drug-loaded hollow mesoporous silica nanoparticles, pH-responsive degradable hollow mesoporous organosilicon nanoparticles, and pure doxorubicin for a period of time, respectively. MTT results show that after the drug carrier enters cells, the drug carrier loaded with adriamycin (DOX) has better inhibition effect on tumor cells due to pH response self-degradation.
Claims (7)
1. A preparation method of pH-responsive degradable hollow mesoporous organic silicon nanoparticles is characterized by comprising the following steps:
(a) adding terephthalaldehyde and dibromo neopentyl glycol into an organic solvent A containing p-toluenesulfonic acid, and reacting at 100-120 ℃ for 9-16 h to obtain a pH-response micromolecule containing an acetal group, wherein the structural formula is as follows:
the organic solvent A is toluene or benzene;
(b) adding triethylamine, a silane coupling agent and a pH-response micromolecule into an organic solvent B, reacting for 5-8 h at 50-80 ℃, adding n-hexane after the reaction is finished, removing ammonium salt through a neutral alumina column, and performing rotary evaporation drying to obtain a bridged alkoxy silane precursor containing a pH-response group, wherein the structural formula is as follows:
the organic solvent B is tetrahydrofuran or dimethyl sulfoxide;
(c) dissolving hexadecyl trimethyl ammonium bromide in water, adding triethylamine and tetraethyl orthosilicate, reacting for 0.5-1.5 h at 80-100 ℃, adding a mixed silicon source which is tetraethyl orthosilicate and a pH-response bridged alkoxy silane precursor, continuing to react for 4-6 h, centrifuging, washing with ethanol to obtain a white solid, re-dispersing the white solid into water, adding 2-5 ml of ammonia water, reacting for 4-6 h at 80-100 ℃, centrifuging, washing with water, and drying to obtain the pH-response degradable hollow mesoporous organosilicon nanoparticles.
2. The preparation method of the pH-responsive degradable hollow mesoporous organosilicon nanoparticle according to claim 1, wherein the preparation method comprises the following steps: in the step (a), the mass ratio of the terephthalaldehyde to the dibromoneopentyl glycol to the p-toluenesulfonic acid is 40-50: 160-180: 1-3.
3. The preparation method of the pH-responsive degradable hollow mesoporous organosilicon nanoparticle according to claim 1, wherein the preparation method comprises the following steps: the silane coupling agent in the step (b) is 3-aminopropyltriethoxysilane.
4. The preparation method of the pH-responsive degradable hollow mesoporous organosilicon nanoparticle according to claim 1, wherein the preparation method comprises the following steps: the mass ratio of the triethylamine, the silane coupling agent and the pH-response micromolecules in the step (b) is 2-4: 3-5: 1-3.
5. The preparation method of the pH-responsive degradable hollow mesoporous organosilicon nanoparticle according to claim 1, wherein the preparation method comprises the following steps: in the step (c), the mass ratio of the hexadecyl trimethyl ammonium bromide to the triethylamine to the tetraethyl orthosilicate is 2-5: 1-3: 2-5: 4-7.
6. The preparation method of the pH-responsive degradable hollow mesoporous organosilicon nanoparticle according to claim 1, wherein the preparation method comprises the following steps: the mass ratio of the tetraethyl orthosilicate to the pH-responsive bridged alkoxy silane precursor is 1-2: 1-5.
7. The pH-responsive degradable hollow mesoporous organosilicon nanoparticle prepared by the preparation method of claim 1, wherein: the pH response degradable hollow mesoporous organic silicon nano particle is used as a carrier of an anti-tumor drug.
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