CN114522248A - Ultraviolet/active oxygen dual-response targeted nano-drug carrier for gating hepatoma cells and preparation method thereof - Google Patents
Ultraviolet/active oxygen dual-response targeted nano-drug carrier for gating hepatoma cells and preparation method thereof Download PDFInfo
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 31
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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 relates to an ultraviolet/active oxygen dual-response targeted nano-drug carrier for gating liver cancer cells and a preparation method thereof. A preparation method of an ultraviolet/active oxygen dual-response targeted nano-drug carrier for liver cancer cells comprises the following steps: (1) preparing mesoporous silicon dioxide; (2) carrying out amination modification on the mesoporous silica; (3) performing thioketal modification; (4) loading an anticancer drug; (5) performing cyclodextrin modification; (6) and then connecting the ultraviolet light-responsive targeting polymer chain with the cyclodextrin to obtain the ultraviolet/active oxygen dual-response gated liver cancer cell targeting nano-drug carrier. According to the ultraviolet/active oxygen dual-response gated liver cancer cell targeted nano-drug carrier and the preparation method thereof, the defects of low utilization rate and strong toxic and side effects of the traditional drugs are overcome by using a layer-by-layer structural design, the problem of targeting and response release of the liver cancer of the nano-material is solved, and the purpose of efficiently treating cancer is achieved.
Description
Technical Field
The invention belongs to the field of nano-drug carrier materials, and particularly relates to an ultraviolet/active oxygen dual-response gated liver cancer cell targeted nano-drug carrier and a preparation method thereof.
Background
Cancer is the result of canceration of normal cells of the body caused by various carcinogens and carcinogenic factors, such as environmental pollution, chemical pollution, ionizing radiation, free radical toxins, microorganisms and their metabolic toxins, genetic characteristics, endocrine imbalance, immune dysfunction, etc.
The high morbidity and mortality rate in recent years makes HCC (liver cancer) one of the serious health-threatening diseases. The toxic side effects of chemotherapy result in limited treatment of HCC. Therefore, improved drug enrichment and response to release chemotherapy methods are an urgent need for HCC treatment. The nano drug-carrying system modified by functionalization can improve the in-vivo distribution of the chemotherapeutic drug, improve the treatment selectivity of the chemotherapeutic drug and the like. The multiple stimulation combined strategy can improve the controllability of drug release and avoid the problem of early drug release in a complex in-vivo environment.
ASGPR is a glycoprotein receptor which is over-expressed on the cell surface of a liver cancer cell, and has stronger affinity with molecules such as Gal and galactosamine, and researches show that multivalent recognition of the ASGPR and the Gal molecules can show stronger binding effect and can more easily mediate endocytosis of nanoparticles. Therefore, increasing the density of Gal groups on the surface of the nanoparticle is a feasible way to promote the nanoparticle uptake by HCC cells.
The target response nano-carrier is a hotspot of research in recent years, and the efficient nano-carrier is designed, so that the requirement of target, local chemotherapy and biological safety synergy is met, the efficiency is improved, and the side effect is reduced, which has important significance on tumor treatment. Therefore, the invention provides the ultraviolet/active oxygen double-response gated liver cancer cell targeted nano-drug carrier and the preparation method thereof, and the drug carrier has high biocompatibility, response release and targeting characteristics and is an effective way for improving the tumor treatment effect.
Disclosure of Invention
The invention aims to provide a preparation method of an ultraviolet/active oxygen dual-response gated liver cancer cell targeted nano-drug carrier, which utilizes a layer-by-layer structural design to obtain the ultraviolet/active oxygen dual-response gated liver cancer cell targeted nano-drug carrier, makes up the defects of low utilization rate and strong toxic and side effects of the traditional drugs, solves the problems of targeting and response release of liver cancer of nano-materials, and achieves the purpose of efficiently treating cancer.
In order to realize the purpose, the adopted technical scheme is as follows:
a preparation method of an ultraviolet/active oxygen dual-response gated liver cancer cell targeted nano-drug carrier comprises the following steps:
(1) preparing mesoporous silicon dioxide;
(2) carrying out amination modification on the mesoporous silica;
(3) performing thioketal modification on the aminated and modified mesoporous silica obtained in the step (2);
(4) the sulfur ketal modified mesoporous silica obtained in the step (3) loads anticancer drugs;
(5) carrying out cyclodextrin modification on the mesoporous silica loaded with the anticancer drug obtained in the step (4);
(6) and then connecting the ultraviolet light-responsive targeting polymer chain with the cyclodextrin to obtain the ultraviolet/active oxygen dual-response gated liver cancer cell targeting nano-drug carrier.
Further, in the step (1), the preparation method of the mesoporous silica comprises:
mixing CTAC, ultrapure water and triethanolamine, stirring for 1h at 60 ℃, after stirring uniformly, dropwise adding 20 v/v% TEOS/cyclohexane solution, reacting for 12h, then washing by using a centrifuge, stirring for 12h at 60 ℃ by using 6g/L ammonium nitrate/ethanol solution, washing by using a centrifuge, and drying in vacuum to obtain the mesoporous silica nano-particles.
Further, the step of thioketal modification in the step (3) is as follows: dissolving the aminated and modified mesoporous silica in DMF, adding DIC and NHS, and adding N2Reacting for 24 hours after protection, washing with DMF and water in sequence, and drying in vacuum;
in the step (4), the mass-to-volume ratio of the thioketal-modified mesoporous silica to the anticancer drug is 20 mg: 3 mL.
Further, in the step (3), the mass ratio of the aminated and modified mesoporous silica to DIC and NHS is 1: 3-4: 3-4;
in the step (4), the anticancer drug is anticancer drug DOX.
Still further, in the step (3), the mass ratio of the aminated and modified mesoporous silica to DIC and NHS is 1:4: 4;
in the step (4), the concentration of the anticancer drug DOX is 1000 mug/mL.
Further, the coupling step in the step (5) is as follows:
dispersing the mesoporous silica loaded with the anticancer drug in MES buffer solution, adding EDC and NHS, uniformly mixing, preheating to 37 ℃, reacting for 15min, centrifuging, dispersing in PBS buffer solution containing aminated cyclodextrin, and stirring for reacting for 12 h.
Further, in the step (5), the mass ratio of the mesoporous silica loaded with the anticancer drug to the EDC, the NHS and the aminated cyclodextrin is 1:4:6: 1;
the mass-to-volume ratio of the mesoporous silica loaded with the anticancer drug to the MES buffer solution and the PBS buffer solution is 2 g: 2 ml: 1 ml.
Further, the step (6) comprises the following steps: adding the target polymer chain into the reaction obtained after the stirring reaction for 12 hours in the step (5), uniformly mixing, and stirring for reaction for 12 hours.
Further, in the step (6), the mass ratio of the targeting polymer chain to the anticancer drug-loaded mesoporous silica obtained in the step (4) is 2: 1.
The invention also aims to provide an ultraviolet/active oxygen double-response gated liver cancer cell targeted nano-drug carrier, which is prepared by adopting the preparation method and is an ultraviolet/active oxygen-response targeted nano-drug carrier for treating tumors, and the synthesized nano-particles can have the characteristic of targeting liver cancer cells by modifying the surface of gal, so that the high-efficiency accumulation of the nano-particles in the tumors can be realized by targeting; the biocompatibility and controllable release property of the drug carrier are improved.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the ultraviolet/active oxygen double-response gated liver cancer cell targeted nano-drug carrier has the following advantages:
(1) the improved coupling method of amino modified cyclodextrin and thioketal is more effective and can be carried out in one pot with subsequent modification targeting.
(2) Has the characteristic of ultraviolet active oxygen double response.
(3) The modification of the targeting galactose enables the drug carrier to carry out active targeting, and further improves the aggregation of the drug carrier at the tumor part. The invention shows that the biocompatibility of the carrier is improved, the controllable release and the aggregation at the tumor part are controlled, and the invention can be used for the delivery of the drugs at the tumor part.
(4) The internal stimulation of the tumor microenvironment is combined with the external stimulation with controllable time and space, so that the intracellular accurate release of tumor cells is realized, the treatment efficiency of chemotherapeutic drugs is improved, and meanwhile, the toxic and side effects on normal tissues are reduced.
Drawings
FIG. 1 is transmission electron micrographs of nanoparticles modified with macromolecules in steps (1) and (6) of example 1, the scale of the transmission electron micrograph being 200 nm;
FIG. 2 is a graph showing the surface potential change during the modification in example 2;
FIG. 3 is a chart of the mid-infrared spectrum of example 3;
FIG. 4 is a graph showing the particle size distribution of nanoparticles in example 4;
FIG. 5 shows the release of the drug in example 6;
FIG. 6 is an XPS analysis of nanoparticles in step (3) of example 1.
Detailed Description
In order to further illustrate the ultraviolet/active oxygen dual-response gated liver cancer cell targeted nano-drug carrier and the preparation method thereof of the present invention, and achieve the intended purpose of the invention, the following detailed description is provided with reference to the preferred embodiments of the ultraviolet/active oxygen dual-response gated liver cancer cell targeted nano-drug carrier and the preparation method thereof according to the present invention, and the specific implementation manner, structure, characteristics and efficacy thereof are described in detail. In the following description, different "one embodiment" or "an embodiment" refers to not necessarily the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
The ultraviolet/active oxygen double-response gated liver cancer cell targeted nano-drug carrier and the preparation method thereof of the invention are further described in detail by combining the specific embodiments as follows:
the invention connects active oxygen responsive thioketal and functional amino beta-CD on the surface of a mesoporous silicon sphere as a basis, and wraps the synthesized polymer host-object effect containing Azo and Gal on the surface of the silicon sphere to prepare the nano system MSN-TK-CD/GAP with liver cancer targeting property and ultraviolet/active oxygen dual response, the high-density Gal provided by the polymer GAP on the surface of the nano particles can improve the uptake of HepG2 cells to the nano particles, and the drug is controlled to release under dual stimulation, thereby further improving the treatment effect on liver cancer.
The tumor environment is in an oxygen-enriched environment, the active oxygen content is 10-100 times of that in a normal environment of a human body, and the invention utilizes the characteristics of the microenvironment to access a response substance and then combines a targeting substance to achieve the purpose of active targeting.
The technical scheme of the invention is as follows:
a preparation method of an ultraviolet/active oxygen dual-response gated liver cancer cell targeted nano-drug carrier comprises the following steps:
(1) preparing mesoporous silicon dioxide;
(2) carrying out amination modification on the mesoporous silica;
(3) performing thioketal modification on the aminated and modified mesoporous silica obtained in the step (2);
(4) the sulfur ketal modified mesoporous silica obtained in the step (3) loads anticancer drugs;
(5) carrying out cyclodextrin modification on the mesoporous silica loaded with the anticancer drug obtained in the step (4);
(6) and then connecting the ultraviolet light-responsive targeting polymer chain with the cyclodextrin under the action of a host and an object to obtain the ultraviolet/active oxygen dual-response gated liver cancer cell targeting nano-drug carrier.
The preparation method comprises the following steps: firstly, mesoporous silica is prepared, amination modification is carried out on the surface of the mesoporous silica, amino on the surface of the modified mesoporous silica is coupled with one carboxyl group in thioketal (the thioketal contains double-end carboxyl groups, namely two carboxyl groups), the other carboxyl group of the thioketal is coupled with cyclodextrin, and finally, a targeting polymer chain is connected with the cyclodextrin through the action of a host and an object.
Preferably, in the step (1), the preparation method of the mesoporous silica comprises:
mixing CTAC, ultrapure water and triethanolamine, stirring for 1h at 60 ℃, after stirring uniformly, dropwise adding 20 v/v% TEOS/cyclohexane solution, reacting for 12h, then washing by using a centrifuge, stirring for 12h at 60 ℃ by using 6g/L ammonium nitrate/ethanol solution, washing by using a centrifuge, and drying in vacuum to obtain the mesoporous silica nano-particles.
The TEOS must be GC purity, CTAC purity must be 99%, and the TEOS must be thick and gel-like after dissolution.
The reaction temperature must be 60 ℃. + -. 1.
All the purity of the drugs and the reaction temperature in the step (1) are strictly observed. The magneton speed must be 150rpm when TEOS/cyclohexane is added dropwise.
Preferably, the amination process in the step (2) needs to control the water content in the system, and the reagent needs to remove water.
Preferably, the step of thioketal modification in step (3) is: dissolving the aminated and modified mesoporous silica in DMF, adding DIC and NHS, and adding N2Reacting for 24 hours after protection, washing with DMF and water in sequence, and drying in vacuum;
in the step (4), the mass-to-volume ratio of the thioketal-modified mesoporous silica to the anticancer drug is 20 mg: 3 mL.
More preferably, in the step (3), the mass ratio of the aminated and modified mesoporous silica to DIC and NHS is 1: 3-4: 3-4;
in the step (4), the anticancer drug is anticancer drug DOX.
More preferably, in the step (3), the mass ratio of the aminated and modified mesoporous silica to DIC and NHS is 1:4: 4;
in the step (4), the concentration of the anti-cancer drug DOX is 1000 mug/mL.
Preferably, the coupling step in step (5) is:
dispersing the mesoporous silica loaded with the anticancer drug in MES buffer solution, adding EDC and NHS, uniformly mixing, preheating to 37 ℃, reacting for 15min, centrifuging, dispersing in PBS buffer solution containing aminated cyclodextrin, and stirring for reacting for 12 h.
Preferably, in the step (5), the mass ratio of the mesoporous silica loaded with the anticancer drug to the EDC, the NHS and the aminated cyclodextrin is 1:4:6: 1;
the mass-to-volume ratio of the mesoporous silica loaded with the anticancer drug to the MES buffer solution and the PBS buffer solution is 2 g: 2 ml: 1 ml.
The acylation reaction design of the steps (3) and (5) of the invention can enable the organic matter to be more effectively and rapidly connected on the surface of the inorganic carrier.
Preferably, the step (6) comprises the following steps: adding the target polymer chain into the reaction obtained after the stirring reaction for 12 hours in the step (5), uniformly mixing, and stirring for reaction for 12 hours.
Further preferably, in the step (6), the mass ratio of the targeting polymer chain to the anticancer drug loaded mesoporous silica obtained in the step (4) is 2: 1.
The reagent in the invention specification is as follows:
DIC is N, N' -diisopropylcarbodiimide; EDC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride); NHS for N-hydroxy succinimide.
Example 1.
The specific operation steps are as follows:
(1) preparation of Polydopamine doped mesoporous silica (PDA/MSN):
mixing 8mL of 25 wt% CTAC (with purity of 99%), 12mL of ultrapure water and 48 mu L of triethanolamine, stirring for 1h at 60 ℃, after stirring uniformly, dropwise adding 20 v/v% TEOS/cyclohexane solution (TEOS purity GC) by using a constant-pressure funnel, reacting for 12h at 60 ℃, then washing by using a centrifuge, stirring for 12h at 60 ℃ by using 6g/L ammonium nitrate/ethanol solution to wash away CTAC, finally washing by a centrifuge, and drying in vacuum to obtain the mesoporous silica.
(2) Aminated mesoporous silica (MSN-NH)2)：
Adjusting pH of anhydrous ethanol to 5 with acetic acid, dispersing 150mg mesoporous silica in 40mL ethanol acetic acid solution, adding 1g APTES, stirring at 60 deg.C for 24 hr, centrifuging, and washing to obtain aminated modified mesoporous silica (MSN-NH)2)。
(3) Thioketal-modified mesoporous silica (MSN-TK):
adding MSN-NH2Dispersing in DMF, adding DIC and NHS, N2And reacting for 24h after protection, washing with DMF for three times, washing with water for 5 times, and drying in vacuum to obtain the thioketal modified mesoporous silicon dioxide (MSN-TK).
(4) Preparing mesoporous silicon dioxide (DOX/MSN-TK) loaded with anticancer drug DOX:
adding the thioketal modified mesoporous silica nanoparticles and the anticancer drug DOX into water (the mass ratio of the nanoparticles to the DOX to the water is 1: 1.5: 1.5), and stirring for 24h to obtain the anticancer drug loaded mesoporous silica (DOX @ MSN-TK).
The amount of adsorption of the loaded DOX on the nanoparticles was further quantified by measuring the absorbance of the supernatant.
(5) Cyclodextrin coupling (MSN-TK-CD):
the preparation method of the carboxyl coupling of the macromolecular cyclodextrin and the thioketal on the silicon sphere comprises the following steps:
0.1M MES buffer and 0.1M PBS buffer were prepared.
Dispersing the mesoporous silica loaded with the anticancer drug in the step (4) in MES buffer solution, adding EDC and NHS, performing ultrasonic treatment for 30s, preheating a shaking table to 37 ℃, placing the reaction solution in the shaking table, vibrating for 15min, then performing rapid centrifugation, dispersing in PBS containing aminated cyclodextrin, and continuing stirring for 12 h.
The mass ratio of the mesoporous silica loaded with the anticancer drug to EDC, NHS and the aminated cyclodextrin is 1:4:6: 1.
(6) Targeting ligand coupling (DOX @ MSN-TK-CD/GAP)
Adding the target polymer chain into the reaction obtained after the stirring reaction for 12 hours in the step (5), performing ultrasonic treatment for 3min, and performing stirring reaction for 12 hours.
The mass ratio of the targeting polymer chain to the mesoporous silica loaded with the anticancer drug obtained in the step (4) is 2: 1.
In order to improve the shelf life of the product, the product is stored at 4 ℃.
The prepared nanoparticle suspension is dropped on a silicon wafer and dried. The surface of the nano particle before modification has a plurality of holes, and the surface of the nano particle after modification is covered by the polymer, thereby proving the successful synthesis of the nano particle.
And (3) carrying out scanning electron microscope observation on the mesoporous silica obtained in the step (1) and the DOX @ MSN-TK-CD/GAP obtained in the step (6). The result is shown in FIG. 1, the left image is an MSN scanning electron microscope, and the size range is 200 nm; the right picture is a DOX @ MSN-TK-CD/GAP scanning electron microscope with a size range of 200 nm.
As can be seen from fig. 1, comparing the left and right images, the gaps on the surface of the nanoparticles on the right image are significantly less and disappear after finishing the modification of the macromolecules and the targeting polymer, which indicates the successful synthesis of the nanoparticles.
Example 2.
Using the procedures of steps (1) to (6) in example 1,
and (3) characterizing the surface charge change of the nano particles in the preparation process.
The results are shown in fig. 2, and further demonstrate that the Zeta potential changes continuously in the preparation process of the nanoparticles through the characterization of the Zeta potential, which proves the successful modification of each substance.
Example 3.
The IR spectra were measured separately for each part of the preparation of example 1 and are shown in FIG. 3.
As can be seen from FIG. 3, the comparison revealed a significant change in the spectrum of the cyclodextrin after modification.
Example 4: the particle size distribution of the nanoparticles was determined.
The nanoparticles prepared in example 1 were dispersed in PBS for 24 hours and then subjected to a particle size distribution test, and the results are shown in fig. 4.
As can be seen from fig. 4, the particle size distribution is normal, most of the nanoparticles are within 200nm, the particle size of the nanoparticles is in accordance with efficient utilization, and the nanoparticles can be stably distributed in a body fluid state.
Example 5: and (4) measuring the drug release effect of the nanoparticles.
The experimental test of the drug release of DOX @ MSN-TK-CD/GAP in PBS solutions in different environments is shown in figure 5.
As shown in FIG. 5, DOX has a responsive drug release effect in different environments such as ultraviolet light, active oxygen, etc.
Example 6: XPS analysis of MSN-TK
XPS analysis was performed using MSN-TK prepared in step (3) of example 1, and the results are shown in FIG. 6.
As can be seen from FIG. 6, after thioketal coupling, the characteristic peak of S appears on the surface of the nanoparticle, thus proving successful coupling of TK (thioketal).
In the invention, the key point of the invention is the grafting of the thioketal on the surface of the silicon dioxide and the covalent coupling of the cyclodextrin and the thioketal, and the invention researches the coupling effect of different acylation modes on the two reactions.
After EDC and NHS are used for connecting mesoporous silica and thioketal for modification, the nano particles cannot stably exist in PBS and ultrapure water and rapidly aggregate, which indicates that the nano particles contain a large amount of amino positive charges on the surface to cause rapid aggregation in a buffer solution, so that coupling is unsuccessful. After DIC and NHS are connected with mesoporous silica and thioketal, the nanoparticles can be stabilized for a period of time in PBS and ultrapure water without immediate aggregation, and successful coupling is proved.
Different solvents were tried in the research of EDC, NHS coupled silica with thioketal and cyclodextrin, and coupling was carried out by acylation reaction in DMF, deoxygenated ultrapure water, buffer solution. After DMF and deoxygenated ultrapure water are used for reaction, the dispersion effect in PBS after host-object modification is obviously inferior to that of the coupling reaction in buffer solution. Therefore, the coupling mode of the acylation reaction adopts MES buffer and PBS buffer as reaction media.
The invention modifies the thioketal through effective amidation reaction, then modifies the functional cyclodextrin efficiently and quickly, can effectively plug the hydrophobic anticancer drug in the pore canal to be tightly combined with the carrier, and generates the effect of responding to drug release under the irradiation of ultraviolet light or in the environment with the existence of hyperactive oxygen, which is beneficial to effectively releasing the drug in the oxidation environment of tumor, and simultaneously can realize the ultraviolet/active oxygen double-control drug release treatment of cancer tissues by ultraviolet light control, reduce the leakage condition of the drug-carrying carrier and improve the biological safety of the drug in vivo. Through the modification of the outer-layer azobenzene coupled liver cancer targeting polymer, after the nanoparticles enter cells, azobenzene is isomerized under the condition of ultraviolet illumination to dissociate and release part of drug molecules from cyclodextrin. The active targeting is carried out by copolymerizing azobenzene monomers and galactose monomers and then modifying the monomers on the surface of the nano particles, so that the aggregation of the medicament at a tumor site is further improved.
The invention is based on biosafety, and greatly improves the biocompatibility of the drug carrier and the leakage problem in human body. The nano particles are not leaked after being wrapped with the medicine, have the effects of biological safety and liver targeting, and provide a new scheme for the fixed-point release of the nano particle medicine in a tumor oxidation environment.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiments according to the technical spirit of the present invention are within the scope of the technical solution of the present invention.
Claims (10)
1. A preparation method of an ultraviolet/active oxygen dual-response targeted nano drug carrier for liver cancer cells is characterized by comprising the following steps:
(1) preparing mesoporous silicon dioxide;
(2) carrying out amination modification on the mesoporous silica;
(3) performing thioketal modification on the aminated and modified mesoporous silica obtained in the step (2);
(4) the sulfur ketal modified mesoporous silica obtained in the step (3) loads anticancer drugs;
(5) carrying out cyclodextrin modification on the mesoporous silica loaded with the anticancer drug obtained in the step (4);
(6) and then connecting the ultraviolet light-responsive targeting polymer chain with the cyclodextrin to obtain the ultraviolet/active oxygen dual-response gated liver cancer cell targeting nano-drug carrier.
2. The production method according to claim 1,
in the step (1), the preparation method of the mesoporous silica comprises the following steps:
mixing CTAC, ultrapure water and triethanolamine, stirring for 1h at 60 ℃, after stirring uniformly, dropwise adding 20 v/v% TEOS/cyclohexane solution, reacting for 12h, then washing by centrifugation, stirring for 12h at 60 ℃ by 6g/L ammonium nitrate/ethanol solution, washing by centrifugation, and drying in vacuum to obtain the mesoporous silica nano-particles.
3. The production method according to claim 1,
the step of thioketal modification in the step (3) is as follows: dissolving the aminated and modified mesoporous silica in DMF, adding DIC and NHS, and adding N2Reacting for 24 hours after protection, washing with DMF and water in sequence, and drying in vacuum;
in the step (4), the mass-to-volume ratio of the thioketal-modified mesoporous silica to the anticancer drug is 20 mg: 3 mL.
4. The production method according to claim 3,
in the step (3), the mass ratio of the aminated and modified mesoporous silica to DIC and NHS is 1: 3-4: 3-4;
in the step (4), the anticancer drug is anticancer drug DOX.
5. The production method according to claim 4,
in the step (3), the mass ratio of the aminated and modified mesoporous silica to DIC and NHS is 1:4: 4;
in the step (4), the concentration of the anticancer drug DOX is 1000 mug/mL.
6. The production method according to claim 1,
the coupling step in the step (5) is as follows:
dispersing the mesoporous silica loaded with the anticancer drug in MES buffer solution, adding EDC and NHS, uniformly mixing, preheating to 37 ℃, reacting for 15min, centrifuging, dispersing in PBS buffer solution containing aminated cyclodextrin, and stirring for reacting for 12 h.
7. The production method according to claim 6,
in the step (5), the mass ratio of the mesoporous silica loaded with the anticancer drug to EDC, NHS and aminated cyclodextrin is 1:4:6: 1;
the mass-to-volume ratio of the mesoporous silica loaded with the anticancer drug to the MES buffer solution and the PBS buffer solution is 2 g: 2 ml: 1 ml.
8. The production method according to claim 1,
the step (6) comprises the following steps: adding the target polymer chain into the reaction obtained after the stirring reaction for 12 hours in the step (5), uniformly mixing, and stirring for reaction for 12 hours.
9. The method according to claim 8,
in the step (6), the mass ratio of the targeting polymer chain to the mesoporous silica loaded with the anticancer drug obtained in the step (4) is 2: 1.
10. An ultraviolet/active oxygen dual-response gated hepatoma cell targeted nano-drug carrier, characterized by being prepared by the preparation method of any one of claims 1 to 9.
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