CN114904017A - Novel double-drug-loading mesoporous silica nanoparticle system and application thereof in cancer treatment - Google Patents

Novel double-drug-loading mesoporous silica nanoparticle system and application thereof in cancer treatment Download PDF

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CN114904017A
CN114904017A CN202210485051.2A CN202210485051A CN114904017A CN 114904017 A CN114904017 A CN 114904017A CN 202210485051 A CN202210485051 A CN 202210485051A CN 114904017 A CN114904017 A CN 114904017A
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msn
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唐昭敏
金秋野
龙红雨
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Southwest Petroleum University
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Abstract

The invention discloses a novel double-drug-loading mesoporous silica nanoparticle system and application thereof in cancer treatment, and mainly solves the problems that the lower critical transition temperature LCST (lower temperature of 60 ℃ C.) which can be adjusted by F127 is lower due to the shorter hydrophobic PPO chain segment, and the MSN drug loading is reduced after polymer modification, so that the application of the MSN drug loading as a drug delivery system is limited in the prior art. The prepared temperature response polymer micelle is used as a switch after loading DOX, and is grafted on the surface of the DOX-loaded mesoporous silica nanoparticle through a disulfide bond to form a double drug-loaded nano system. By the scheme, the LCST temperature is increased, and the drug loading capacity and the outstanding stimulation response performance are achieved.

Description

Novel double-drug-loading mesoporous silica nanoparticle system and application thereof in cancer treatment
Technical Field
The invention relates to the technical field of nano drug-loaded materials, in particular to a novel double drug-loaded mesoporous silica nanoparticle system and application thereof in cancer treatment.
Background
Mesoporous silica nanoparticles (MSN for short) have received much attention in drug loading and transportation over the past few decades due to their ease of surface functionalization, high specific surface area, large pore volume, and adjustable pore size and shape. In addition, the good biocompatibility and high cellular uptake efficiency of mesoporous silica (MSN for short) make it a strong candidate for drug delivery systems.
MSNs with stimulus responsive "switches" have proven to be one of the advanced intelligent carriers due to their efficient drug loading capability and controlled drug release behavior. Many types of stimuli-responsive switches have been developed, such as inorganic nanoparticles, metal oxides, organic polymers, and small molecules. These switches can be opened by triggering from endogenous and exogenous stimuli, such as pH, reducing agents, enzymes, temperature, magnetic fields, light, and the like. In these stimuli, temperature is an important response. In one aspect, the tumor tissue has an abnormal temperature gradient; on the other hand, tumor tissue is more susceptible to temperature than normal tissue.
Poly (ethylene oxide) -poly (propylene oxide) -poly (ethylene oxide) triblock copolymer (Pluronic F127, PEO) 100 -PPO 65 -PEO 100 ) The copolymer is a temperature response copolymer widely applied to the field of biomedicine, but the lower critical transition temperature LCST (lower temperature of the fluid loss) of F127 adjustable is lower and is less than 37 ℃ due to the shorter hydrophobic PPO chain segment, and due to the steric hindrance of a long-chain polymer, the drug loading capacity of MSN coated by a block polymer is reduced, so that the application of the mesoporous silica MSN in a drug delivery system is limited.
Disclosure of Invention
The invention aims to provide a novel double-drug-loading mesoporous silica nanoparticle system and application thereof in cancer treatment, and aims to solve the problems that in the prior art, due to the fact that a hydrophobic PPO chain segment is short, the lower critical transition temperature (LCST) of F127 is low and is less than 37 ℃, and the MSN drug loading capacity is reduced after polymer modification, and the application of the MSN drug loading capacity as a drug delivery system is limited.
In order to solve the above problems, the present invention provides the following technical solutions:
a novel dual-drug-loading mesoporous silica nanoparticle system comprises a temperature response FPCL250 copolymer micelle, adriamycin DOX and mesoporous silica nanoparticles MSN; after the temperature response FPCL250 copolymer micelle is loaded with DOX, the micelle is used as a switch and grafted on the surface of DOX-loaded mesoporous silica nanoparticle MSN through a disulfide bond to form a double-drug-loading nano system DOX @ MSN-SS-FPCL @ DOX with pH/redox/temperature multiple responsiveness
The FPCL250 copolymer micelle in the double-drug-loading system has a Lower Critical Solution Temperature (LCST) of 39 ℃, and can keep the structural stability under physiological conditions and only release drugs at tumor tissues because the temperature (40 ℃) of the tumor tissues is slightly higher than the body temperature; the FPCL250 micelle is grafted to the surface of the medicament-carrying mesopore through a disulfide bond after being loaded with DOX, so that the medicament in the mesopore can be prevented from being leaked in advance; meanwhile, the double-drug-loading nano system DOX @ MSN-SS-FPCL @ DOX integrally improves the drug loading rate, so that the double-drug-loading nano system is more suitable for the application of a drug delivery system.
The preparation method of the novel double-drug-loading mesoporous silica nanoparticle system comprises the following steps:
s1, synthesizing aminated mesoporous silica MSN-NH 2 ；
S2, synthesizing drug-loaded mesoporous silica DOX @ MSN through the aminated mesoporous silica and the loaded chemotherapeutic drug DOX in the step S1;
s3, synthesizing disulfide bond-containing mesoporous silica DOX @ MSN-SS through the drug-loaded mesoporous silica DOX @ MSN of the step S2;
s4, synthesizing F127 activated by N, N' -carbonyldiimidazole, namely CDI-F127;
s5 Synthesis of amino terminated copolymer NH by Ring opening polymerization of ε -caprolactone and amino modification of N, N' -carbonyldiimidazole activated F127 step S4 2 -FPCL250；
S6, NH by step S5 2 -FPCL250 and chemotherapy drug loaded DOX are synthesized into drug loaded micelle NH 2 -FPCL@DOX；
S7, DOX @ MSN-SS by step S3 and NH by step S6 2 And synthesizing the-FPCL @ DOX to obtain a double-drug-loading system DOX @ MSN-SS-FPCL @ DOX.
Further, the specific process of step S1 is as follows:
s101, dissolving Cetyl Trimethyl Ammonium Bromide (CTAB) in distilled water containing ammonia water and ethanol;
s102, stirring the mixed solution obtained in the step S101, and then dropwise adding tetraethyl orthosilicate TEOS and 3-aminopropyltriethoxysilane APTES to obtain a mixed solution;
s103, stirring the mixed solution obtained in the step S102 for reaction, centrifuging to collect a product, and washing with water for multiple times to obtain aminated silicon dioxide;
s104, re-dispersing the aminated silica obtained in the step S103 in a solution containing ethanol and HCl, removing the template after condensation and reflux, and drying in vacuum to obtain aminated mesoporous silica MSN-NH 2 。
Further, the specific process of step S2 is as follows:
s201, dissolving doxorubicin DOX in dimethyl sulfoxide DMSO;
s202, mixing MSN-NH 2 Dissolving in the mixed solution of S201, stirring overnight in the dark, and removing unloaded free adriamycin by centrifugation to obtain a product;
and S203, centrifuging and washing the product obtained in the step S202 for a plurality of times, and freeze-drying to obtain DOX @ MSN.
Further, the specific process of step S3 is as follows:
s301, dissolving 3, 3-dithiodipropionic acid DTDP, 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride EDC & HCl and N-hydroxysuccinimide NHS in dimethyl sulfoxide DMSO to obtain a mixture;
s302, stirring and activating the mixture obtained in the step S301, and adding DOX @ MSN to obtain a mixed solution;
and S303, stirring the mixed solution obtained in the step S302, reacting, centrifuging, collecting a product, transferring the product into a dialysis bag, dialyzing to remove DMSO, and freeze-drying to obtain DOX @ MSN-SS.
Further, the specific process of step S4 is as follows:
s401, dissolving Pluronic F127 and N, N' -carbonyl diimidazole CDI in dried dichloromethane DCM to obtain a mixed solution;
s402, reacting the mixed solution of the S401 for 6 hours at room temperature in a nitrogen atmosphere;
s403, removing excessive dichloromethane DCM from the mixture obtained in the step S402 through rotary evaporation to obtain a mixture;
s404, precipitating the mixture obtained in the step S403 in glacial ethyl ether to remove unreacted substances, performing suction filtration to collect a product, and performing vacuum drying to obtain N, N' -carbonyldiimidazole activated F127, namely CDI-F127.
Further, the specific process of step S5 is as follows:
s501, F127 ring-opening polymerization epsilon-caprolactone activated by N, N' -carbonyldiimidazole is added with stannous chloride SnCl 2 As a catalyst, obtaining a product by high-temperature reaction after vacuumizing;
s502, after the product obtained in the step S501 is cooled and solidified, dichloromethane DCM is added to dissolve the product;
and S503, sequentially carrying out rotary evaporation, glacial ethyl ether sedimentation and suction filtration on the mixture dissolved in the step S502, and then carrying out vacuum drying to obtain the FPCL 250.
S504, dissolving FPCL in dry dichloromethane DCM to obtain a solution;
s505, adding Ethylenediamine (EDA) into the solution obtained in the step S504 in a nitrogen atmosphere at room temperature, and stirring to obtain a mixture;
s506, removing the unreacted ethylenediamine EDA and the excessive dichloromethane DCM in the step S505 by rotary evaporation to obtain a product;
s507, the product of the step S506 is settled by cold ether, and the amino-terminated copolymer NH is obtained after vacuum drying after suction filtration 2 -FPCL250。
Further, the specific process of step S6 is as follows:
s601, dissolving doxorubicin DOX in tetrahydrofuran THF to obtain a mixed solution;
s602, adding NH into the mixed solution in the step S601 2 -FPCL250, added dropwise to distilled water under high speed rotation, added dropwiseStirring at low speed to obtain a mixed solution;
s603, after the organic solvent is volatilized in the step S602, dialyzing the solution to remove the free DOX which is not loaded in the micelle to obtain a drug-loaded micelle solution NH 2 -FPCL@DOX。
Further, the specific process of step S7 is as follows:
s701, reacting DOX @ MSN-SS with 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC & HCl and N-hydroxysuccinimide NHS to obtain a mixed solution;
s702, adding a drug-loaded micelle solution NH into the mixed solution in the step S701 2 -FPCL @ DOX reaction to obtain a solution;
s703, centrifuging the solution obtained in the step S702 to remove non-grafted NH 2 -FPCL @ DOX, washing with water for several times, and freeze-drying to obtain the target product DOX @ MSN-SS-FPCL @ DOX.
An application of a novel dual drug-loading mesoporous silica nanoparticle system for cancer treatment in cancer treatment drugs.
Compared with the prior art, the invention has the following beneficial effects:
(1) the prepared polymer micelle with multiple stimulus responsiveness is used as a switch after being loaded with DOX, and is grafted on the surface of mesoporous silica nanoparticle MSN loaded with DOX through a disulfide bond, so that a double-drug-loading nano system DOX @ MSN-SS-FPCL @ DOX with pH/redox/temperature multiple responsiveness is formed, and the polymer micelle with multiple stimulus responsiveness has high drug loading capacity and outstanding stimulus responsiveness.
(2) According to the invention, FPCL250 micelles are selected to be grafted on the surface of MSN through disulfide bonds to form a double-drug-loading nano system (DOX @ MSN-SS-FPCL @ DOX), and when the double-drug-loading nano system is under physiological conditions (pH 7.4,37 ℃, 10mM glutathione GSH is not contained), the FPCL250 micelles on the MSN block drug release. When in the intratumoral environment (pH5.0,40 ℃ C., containing 10mM glutathione GSH), FPCL250 micelles are shed and a burst occurs to release DOX. In addition, as the pH decreased, more DOX also escaped from the MSN.
(3) The DOX @ MSN-SS-FPCL @ DOX can be effectively internalized by cells after being enriched at a tumor part by enhancing the permeability and retention Effect (EPR) of a solid tumor. Under the stimulation of high glutathione GSH concentration in cells, disulfide bonds in DOX @ MSN-SS-FPCL @ DOX are broken, and the FPCL250 micelle switch is separated from the MSN surface. Subsequently, the simultaneous release of FPCL250 micelles and the drug in MSN was triggered under the conditions of high tumor self-height and low pH. Finally, the drug intercalates the DNA double strand by free diffusion into the nucleus, inhibiting the activity of topoisomerase II, ultimately interfering with DNA replication and transcription to kill cancer cells.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art descriptions will be briefly described below, it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without inventive efforts, wherein:
figure 1 is a schematic of a novel dual drug-loaded system for cancer treatment.
FIG. 2 is a synthetic route to DOX @ MSN-SS.
FIG. 3 is NH 2 -synthetic route of FPCL250 copolymer.
FIG. 4 shows MSN-NH 2 Particle size diagram (transmission electron microscope picture in the upper right corner).
FIG. 5 is a graph of the particle size of MSN-SS-FPCL250 (transmission electron microscopy image thereof in the upper right corner).
FIG. 6 shows MSN-NH 2 And N of MSN-SS-FPCL250 2 Adsorption and desorption isotherms (pore size distribution in the upper left corner).
FIG. 7 is NH 2 -particle size and absorbance change of FPCL250 at different temperatures.
FIG. 8 is an in vitro drug release profile of DOX @ MSN-SS-FPCL @ DOX.
FIG. 9 is the biological transmission electron microscope image of HeLa cells cultured with MSN-SS-FPCL 250. Black arrows indicate the position of the material.
FIG. 10 is a graph showing the cell viability of HeLa cells after incubation with free DOX and DOX @ MSN-SS-FPCL @ DOX at 37 ℃ or 40 ℃ for 1 hour followed by further incubation at 37 ℃ for 23 hours.
FIG. 11 is an apoptosis image of HeLa cells cultured at (A)37 ℃ and (B)40 ℃ for 1 hour with PBS, DOX and DOX @ MSN-SS-FPCL @ DOX, respectively, and then further cultured at 37 ℃ for 23 hours.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to fig. 1 to 11, the described embodiments should not be construed as limiting the present invention, and all other embodiments obtained by a person of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.
Example 1
As shown in fig. 1, a novel dual drug-loaded mesoporous silica nanoparticle system comprises a temperature-responsive FPCL250 copolymer micelle, doxorubicin DOX, and a mesoporous silica nanoparticle MSN; after the temperature response FPCL250 copolymer micelle is loaded with DOX, the temperature response FPCL250 copolymer micelle is used as a switch to be grafted on the surface of the mesoporous silica nanoparticle MSN loaded with DOX through a disulfide bond, so that a double-drug-loading nano system DOX @ MSN-SS-FPCL @ DOX with pH/redox/temperature multiple responsiveness is formed.
The invention combines organic polymer and inorganic nano particles, designs an intelligent nano carrier for effectively transferring the anticancer drug to tumor cells for treatment; the temperature response FPCL250 copolymer micelle is used as a switch, and finally a double-drug-loading nano system DOX @ MSN-SS-FPCL @ DOX with pH/redox/temperature multiple responsiveness is formed, and the double-drug-loading nano system DOX @ MSN-SS-FPCL @ DOX has high drug loading capacity and outstanding stimulation response performance.
Example 2
As shown in fig. 1, the preparation method of the novel dual drug-loaded mesoporous silica nanoparticle system comprises the following steps:
s1, synthesizing aminated mesoporous silica MSN-NH 2 ；
S2, synthesizing drug-loaded mesoporous silica DOX @ MSN through the aminated mesoporous silica and the loaded chemotherapeutic drug DOX in the step S1;
s3, synthesizing disulfide bond-containing mesoporous silica DOX @ MSN-SS through the drug-loaded mesoporous silica DOX @ MSN of the step S2;
s4, synthesizing F127 activated by N, N' -carbonyldiimidazole, namely CDI-F127;
s5 Synthesis of amino terminated copolymer NH by Ring opening polymerization of ε -caprolactone and amino modification of N, N' -carbonyldiimidazole activated F127 step S4 2 -FPCL250；
S6, NH by step S5 2 -FPCL250 and chemotherapy drug loaded DOX are synthesized into drug loaded micelle NH 2 -FPCL@DOX；
S7, DOX @ MSN-SS by step S3 and NH by step S6 2 And synthesizing the-FPCL @ DOX to obtain a double-drug-loading system DOX @ MSN-SS-FPCL @ DOX.
The materials required for preparing the novel dual drug-loaded mesoporous silica nanoparticle system for cancer treatment are as follows: pluronic F127, epsilon-caprolactone (. epsilon. -CL), Glutathione (GSH), Doxorubicin (DOX) and Fluorescein Isothiocyanate (FITC) (Shanghai Allantin Biotech Co., Ltd.); cetyl trimethylammonium bromide (CTAB), tetraethyl orthosilicate (TEOS), Dimethylformamide (DMF), Dichloromethane (DCM), glutaraldehyde, triethylamine (Et) 3 N), Ether (Et) 2 O), Ethylenediamine (EDA), Dimethylsulfoxide (DMSO), ammonia, Tetrahydrofuran (THF), and 5,5' -dithiobis (2-nitrobenzoic acid) (DTNB) (guycoron chemicals, ltd); 3-Aminopropyltriethoxysilane (APTES) and stannous chloride (SnCl) 2 ) (Shanghai Tantake Technique, Inc.); n, N '-Carbonyldiimidazole (CDI), 3' -dithiodipropionic acid (DTDP), 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride (EDC. HCl) and N-hydroxysuccinimide (NHS) (Meglan Biochemical technologies, Inc., Shanghai); (3- (4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyltetrazolium bromide) (MTT), Calcein (Calcein AM) and 4', 6-diamidino-2-phenylindole (DAPI) (Biyunnan Biotech Ltd.); pyridine (PI) iodide (Shanghai assist san Biotech, Inc.); apoptosis kits (Unico Biotechnology Co., Ltd.).
Example 3
Synthesis of aminated mesoporous silica (MSN-NH) 2 )
First, 1g CTABDissolved in distilled water containing 3g of ammonia water; subsequently, 3g TEOS and 250. mu.L APTES were added dropwise to the above mixture and reacted at 85 ℃ for 8 hours; the product was collected by centrifugation and washed several times with water. In order to obtain a mesoporous structure, the nano particles obtained in the previous step are re-dispersed in a mixed solution containing ethanol and HCl, the template is removed by condensation and reflux for 10 hours at high temperature, and finally white powder MSN-NH is obtained by vacuum drying 2 。
Example 4
Synthesis of drug-loaded mesoporous silica (DOX @ MSN)
40mg of Dox was dissolved in DMSO, and 100mg of MSN-NH was added 2 After stirring overnight in the dark, the unloaded free doxorubicin DOX was removed by centrifugation and washed several times with water to give the product DOX @ MSN.
Example 5
Synthesis of disulfide bond-containing mesoporous silica (DOX @ MSN-SS) as shown in FIG. 2
2g DTDP, 2g EDC. HCl and 1.092g NHS were dissolved in DMSO, activated with stirring for 12 hours, and 1.48g DOX @ MSN was added and the reaction was continued for 24 hours. And centrifuging to collect the product, transferring the product into a dialysis bag, dialyzing to remove DMSO, and freeze-drying to obtain DOX @ MSN-SS.
Example 6
Synthesis of N, N' -Carbonyldiimidazole (CDI) activated F127 (CDI-F127)
10g of purified Pluronic F127 and 0.129g of CDI were dissolved in dry DCM. Then, reacting for 6 hours at room temperature under the nitrogen atmosphere; subsequently, excess DCM was removed by rotary evaporation. And precipitating the product in glacial ethyl ether for 3 times to remove unreacted CDI, performing suction filtration to collect the product, and performing vacuum drying to obtain the product.
Example 7
Synthesis of amino terminated FPCL250 copolymer (NH) as shown in FIG. 3 2 -FPCL250)
A50 mL single neck flask was charged with 2g of CDI-F127, 4.24mL of ε -caprolactone and SnCl 2 (1 wt%) after evacuation, the reaction was carried out in an oven at a high temperature for 6 hours. Dissolving in dichloromethane, rotary evaporating, settling, vacuum filtering, and vacuum concentratingDrying to obtain the FPCL250 copolymer.
2g of the FPCL250 copolymer was dissolved in 20mL of dry methylene chloride, 1.47g of Ethylenediamine (EDA) was added under a nitrogen atmosphere, and the reaction was stirred at room temperature for 24 hours. Removing unreacted EDA and excess dichloromethane by rotary evaporation; the product is settled by a large amount of cold ether, and is dried in vacuum after being filtered to obtain a product NH 2 -FPCL250。
Example 8
Drug loaded micelle NH 2 Synthesis of-FPCL @ DOX
Dissolving 2mg of Doxorubicin DOX in 10mL of tetrahydrofuran THF, and adding 10mg of FPCL-NH 2 Dripping distilled water dropwise under high-speed rotation, dialyzing the solution to remove DOX not loaded in micelle after the organic solvent is volatilized, and obtaining drug-loaded micelle solution NH 2 -FPCL@DOX。
Example 9
Synthesis of double-drug-loading system DOX @ MSN-SS-FPCL @ DOX
Reacting DOX @ MSN-SS with EDC, HCl and NHS to obtain a mixed solution, and adding a drug-loaded micelle solution NH 2 -FPCL @ DOX reaction was continued at room temperature for 24 hours and finally centrifuged to remove ungrafted NH 2 -FPCL @ DOX, washing with water for several times, and freeze-drying to obtain the target product DOX @ MSN-SS-FPCL @ DOX.
Characterization of
The particle size distribution was determined using dynamic light scattering (DLS, Malvern Zetasizer Nano ZS90, British). The samples were analyzed for particle size, morphology and dispersion by transmission electron microscopy (TEM, HF-3300, Japan). N of MSN 2 The adsorption/desorption isotherms were determined using a Belsorp Max II detector, Japan.
Drug Loading (LC) and drug loading efficiency (EE) were determined by UV-Vis spectrophotometer (UV-2600, Shimadzu, Japan). The amount of DOX in the nanoparticles was determined by measuring the absorbance at 480 nm. LC and EE are calculated by the following formulas respectively,
Figure BDA0003628868920000111
Figure BDA0003628868920000112
investigation of temperature sensitivity
NH studies by DLS and UV-vis 2 -thermal response behavior of FPCL250 micelles, temperature range set at 25 to 55 ℃. The particle size of the micellar solution and the absorbance at λ 500nm were recorded at 5 ℃ intervals. During heating, the micellar solution was equilibrated at each temperature for 15 minutes to achieve stability.
In vitro drug delivery
The drug release behavior of DOX @ MSN-SS-FPCL @ DOX under different circumstances (phosphate buffer PBS: pH7.4+37 ℃ + 10. mu.M GSH; acetate buffer ABS: pH5.0 +40 ℃ +10mM GSH) was examined. The prepared nanoparticles DOX @ MSN-SS-FPCL @ DOX are respectively weighed and dispersed in solutions with different pH values, the solutions are transferred into a dialysis bag (MWCO 1000kDa) and immersed in a centrifugal tube filled with 30mL of corresponding buffer solution. In vitro release was simulated in a water bath thermostated shaker at 37 ℃ or 40 ℃ at a rate of 100 rpm/min. At different time intervals 2mL of buffer solution was aspirated for detection. At the same time, 2mL of fresh buffer was added. Finally, the drug release behavior was measured by uv-vis spectrophotometer.
In vitro cellular uptake
Cellular uptake was confirmed using Bio-TEM (JEM-1400FLASH, Japan). HeLa cells at 1X 10 5 Cell density seeding per well was incubated in 6-well plates for 24 hours. Then, MSN-SS-FPCL250 was added for incubation. Cells were washed with PBS, trypsinized, collected by centrifugation and fixed with glutaraldehyde. Intracellular uptake of MSN-SS-FPCL was directly observed by Bio-TEM.
Effect of temperature on cytotoxicity
HeLa cells were seeded in 96-well plates and incubated for 1 hour at 37 ℃ or 40 ℃ with free DOX or DOX @ MSN-SS-FPCL @ DOX nanoparticles. Then, the cells were further incubated at 37 ℃ for 23 hours, and finally, cytotoxicity was evaluated by the MTT method. The absorbance value (OD) at 490nm was measured with a microplate reader (Thermo, Japan) to determine the relative cell viability. Cell viability was calculated using the following formula:
Figure BDA0003628868920000121
apoptosis of cells
To quantify the effect of different temperatures on apoptosis, HeLa cells were plated at 1X 10 5 The density of individual cells/well was seeded on 6-well plates. Then, incubation at 37 ℃ was continued after addition of free DOX and DOX @ MSN-SS-FPCL @ DOX at 37 ℃ or 40 ℃. Cells were detached by trypsinization without EDTA and collected by centrifugation, and then stained with Annexin V-APC and 7-AAD at room temperature. Finally, the cells were tested and analyzed by flow cytometry (CytoFLEX).
Results and discussion
Preparation and characterization of nanocomposites
The mesoporous silica nano-particles with uniform size and ordered pore channels are synthesized by adopting a sol-gel method. The hydrodynamic diameters of the mesopores (fig. 4) and the target product after micelle modification of the mesopores (fig. 5) were measured by Dynamic Light Scattering (DLS). MSN-NH 2 And MSN-SS-FPCL250 has diameters of 123.9nm and 202.2nm, respectively. TEM image of TEM (FIG. 4, top right corner), MSN-NH 2 Has a particle size of about 90nm, and has a uniform monodisperse spherical shape and an ordered mesoporous structure. With MSN-NH 2 In contrast, the surface of MSN-SS-FPCL250 (upper right corner of FIG. 5) is obviously changed, which indicates that FPCL250 micelles are successfully modified on mesopores. The hydrodynamic diameter is slightly larger than the transmission electron microscope results due to fluid interaction. BET analysis showed MSN-NH 2 N of (A) 2 The adsorption-desorption isothermal curve (figure 6) shows a typical IV-type curve of the mesoporous silica, and the specific surface area is calculated to be about 578.05m 2 ·g -1 The pore size distribution was around 2.7nm (upper left corner of FIG. 6), indicating MSN-NH 2 Has uniform pore size distribution and can effectively load chemotherapeutic drugs DOX. With MSN-NH 2 Compared with the MSN-SS-FPCL250, the specific surface area is obviously and greatly reduced to 84.08m 2 ·g -1 And the pore diameter becomes unmeasurable, which indicates that the micelle is successfully grafted to the mesoporous surface to seal the mesoporous pore channel.
Investigation of temperature sensitivity
In order to screen out the optimal temperature response copolymer, the temperature-sensitive behavior of the micelle is examined by measuring the particle size of the micelle solution and the change of solution absorbance with temperature in different proportions (as shown in FIG. 7). NH when the temperature is increased from 25 ℃ to 55 ℃ 2 The particle size of the FPCL250 micelles decreases with increasing absorbance with a Lower Critical Solution Temperature (LCST) of 39 ℃. NH due to the temperature of the tumor tissue (40 ℃) being slightly above body temperature 2 The FPCL250 micelle can keep structural stability under physiological conditions, and the medicament can be released only at tumor tissues, so that the temperature response characteristic is good.
Drug delivery
Drug release plays a key role in drug delivery, and therefore it is necessary to evaluate drug loading and drug release performance by uv-vis spectrophotometry. First, the UV-visible absorption peak of DOX at 480nm is used to determine the standard curve of free DOX in buffers with different pH values, and the drug loading rate and the encapsulation efficiency are calculated. MSN-NH 2 Has high drug loading capacity (21.3 percent of drug loading capacity). When the copolymer self-assembles into micelle loaded with DOX, the drug loading rate is 4.4%, so that the drug loading rate of the composite double drug-loaded system is the sum of the two (25.7%). The drug release profile of DOX @ MSN-SS-FPCL @ DOX is shown in FIG. 8. Under physiological conditions (pH 7.4+37 ℃ + 10. mu.M GSH), the cumulative release of DOX over 48 hours was negligible, indicating that the micelle acts as a pore-blocking switch, avoiding premature release of the drug. When the tumor is in a microenvironment (pH5.0 +40 ℃ plus 10mM GSH), due to the breakage of disulfide bonds between micelles and mesopores, DOX in the mesopores is released in a low pH environment, and simultaneously, temperature-sensitive micelles are suddenly contracted to pump out the DOX along with the temperature rise to 40 ℃, so that the release of the drugs in the DOX @ MSN-SS-FPCL @ DOX is rapidly increased. These results indicate that DOX @ MSN-SS-FPCL @ DOX has highly sensitive pH/redox/temperature responsive drug release behavior.
In vitro cellular uptake
An important factor in determining the therapeutic efficacy of a drug delivery system is cellular internalization. Therefore, intracellular localization of MSN-SS-FPCL250 was observed by biological transmission electron microscopy (Bio-TEM). As shown in FIG. 9, the gray spherical dots in HeLa cells are represented as MSN-SS-FPCL250 nanoparticles. It can be directly observed that the nanoparticles successfully phagocytosed by HeLa cells enter the interior of the cells, and the black arrows indicate the location of the material.
Effect of temperature on cytotoxicity
The cytotoxicity results of free DOX and DOX @ MSN-SS-FPCL @ DOX incubated with HeLa cells at 37 ℃ and 40 ℃ are shown in FIG. 10. The MTT results show that both free DOX and DOX @ MSN-SS-FPCL @ DOX inhibit cell growth and cell viability decreases with increasing drug concentration, regardless of whether treatment at 40 ℃ is performed. Free DOX significantly enhanced cytotoxicity due to rapid diffusion into HeLa cells. However, under the low-temperature thermotherapy (40 ℃), the activity of each group of cells is reduced along with the increase of DOX concentration, and the cytotoxicity of the temperature-sensitive DOX @ MSN-SS-FPCL @ DOX is more obvious than that of free DOX, because the temperature-sensitive micelle shrinks and extrudes the medicine at the same time.
Apoptosis of cells
Apoptosis HeLa cells were stained by flow cytometry using Annexin V-APC and 7-AAD apoptosis detection kits at different temperatures after 24 hours incubation with free DOX and DOX @ MSN-SS-FPCL @ DOX (see FIG. 11). Cells treated with PBS at 40 ℃ had almost the same viability compared to 37 ℃, indicating that hyperthermia at low temperature (40 ℃) did not kill cells in a short time. However, after incubation with DOX @ MSN-SS-FPCL @ DOX at 40 ℃, apoptosis increased from 46.6% to 91.2% due to the disruption of the disulfide bond between the mesopores and micelles, the shedding of the micelle switch, and the simultaneous release of drug from both the mesopores and micelles. The apoptotic cells in the DOX group also increased with increasing temperature, but the apoptotic cells in the DOX group were only 1.6 times as much as 37 ℃ and the DOX @ MSN-SS-FPCL @ DOX group was 1.96 times. The percentage of apoptotic cells in the DOX group at 37 ℃ was higher than DOX @ MSN-SS-FPCL @ DOX due to the rapid diffusion of DOX into HeLa cells. These results indicate that the double drug delivery system DOX @ MSN-SS-FPCL @ DOX can obviously enhance the cytotoxicity to tumor cells at low temperature (40 ℃).
Conclusion
In summary, we developed a polymer drug-loaded micelle FPCL250 as a pore-blocking switch, grafted on the surface of drug-loaded MSN through disulfide bonds. This dual drug-loaded drug delivery system with multiple stimulation responses (DOX @ M SN-SS-FPCL @ DOX) showed potent apoptosis in HeLa cells. DOX @ MSN-SS-FPCL @ DO X has high drug loading capacity, and keeps structural stability under physiological conditions, so that premature release of the drug is avoided. Under the stimulation of high-concentration GSH, the micelle switch FPCL250 falls off, and the drug is released from MSN and FPCL250 micelles under the tumor microenvironment. DOX @ MSN-SS-FPCL @ DOX showed high cellular uptake and enhanced pro-apoptotic capacity in HeLa cells. Therefore, this effective multi-stimulus responsive dual drug delivery system may provide a promising strategy for cancer treatment.
The invention is well implemented in accordance with the above-described embodiments. It should be noted that, based on the above structural design, in order to solve the same technical problems, even if some insubstantial modifications or colorings are made on the present invention, the adopted technical solution is still the same as the present invention, and therefore, the technical solution should be within the protection scope of the present invention.

Claims (10)

1. A novel double-drug-loading mesoporous silica nanoparticle system is characterized by comprising a temperature response FPCL250 copolymer micelle, adriamycin DOX and mesoporous silica nanoparticles MSN; after the temperature response FPCL250 copolymer micelle is loaded with DOX, the temperature response FPCL250 copolymer micelle is used as a switch to be grafted on the surface of the mesoporous silica nanoparticle MSN loaded with DOX through a disulfide bond to form a double-drug-loading nano system DOX @ MSN-SS-FPCL @ DOX with pH/redox/temperature multiple responsiveness.
2. The preparation method of the novel double-drug-loaded mesoporous silica nanoparticle system of claim 1, which is characterized by comprising the following steps:
s1, synthesizing aminated mesoporous silica MSN-NH 2 ；
S2, synthesizing drug-loaded mesoporous silica DOX @ MSN through the aminated mesoporous silica and the loaded chemotherapeutic drug DOX in the step S1;
s3, synthesizing disulfide bond-containing mesoporous silica DOX @ MSN-SS through the drug-loaded mesoporous silica DOX @ MSN of the step S2;
s4, synthesizing F127 activated by N, N' -carbonyldiimidazole, namely CDI-F127;
s5 Synthesis of amino terminated copolymer NH by Ring opening polymerization of ε -caprolactone and amino modification of N, N' -carbonyldiimidazole activated F127 step S4 2 -FPCL250；
S6, NH by step S5 2 -FPCL250 and chemotherapy drug loaded DOX are synthesized into drug loaded micelle NH 2 -FPCL@DOX；
S7, DOX @ MSN-SS by step S3 and NH by step S6 2 And synthesizing the-FPCL @ DOX to obtain a double-drug-loading system DOX @ MSN-SS-FPCL @ DOX.
3. The method according to claim 2, wherein the step S1 is as follows:
s101, dissolving Cetyl Trimethyl Ammonium Bromide (CTAB) in distilled water containing ammonia water and ethanol;
s102, stirring the mixed solution obtained in the step S101, and then dropwise adding tetraethyl orthosilicate TEOS and 3-aminopropyltriethoxysilane APTES to obtain a mixed solution;
s103, stirring the mixed solution obtained in the step S102 for reaction, centrifuging to collect a product, and washing with water for multiple times to obtain aminated silicon dioxide;
s104, re-dispersing the aminated silica obtained in the step S103 in a solution containing ethanol and HCl, removing the template after condensation and reflux, and drying in vacuum to obtain aminated mesoporous silica MSN-NH 2 。
4. The method according to claim 2, wherein the step S2 is as follows:
s201, dissolving doxorubicin DOX in dimethyl sulfoxide DMSO;
s202, mixing MSN-NH 2 Dissolving in the mixed solution of S201, stirring overnight in the dark, and removing unloaded free adriamycin by centrifugation to obtain a product;
and S203, centrifuging and washing the product obtained in the step S202 for a plurality of times, and freeze-drying to obtain DOX @ MSN.
5. The method according to claim 2, wherein the step S3 is as follows:
s301, dissolving 3, 3-dithiodipropionic acid DTDP, 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride EDC & HCl and N-hydroxysuccinimide NHS in dimethyl sulfoxide DMSO to obtain a mixture;
s302, stirring and activating the mixture obtained in the step S301, and adding DOX @ MSN to obtain a mixed solution;
and S303, stirring the mixed solution obtained in the step S302, reacting, centrifuging, collecting a product, transferring the product into a dialysis bag, dialyzing to remove DMSO, and freeze-drying to obtain DOX @ MSN-SS.
6. The method according to claim 2, wherein the step S4 is as follows:
s401, dissolving Pluronic F127 and N, N' -carbonyl diimidazole CDI in dried dichloromethane DCM to obtain a mixed solution;
s402, reacting the mixed solution of the S401 for 6 hours at room temperature in a nitrogen atmosphere;
s403, removing excessive dichloromethane DCM from the mixture obtained in the step S402 through rotary evaporation to obtain a mixture;
s404, precipitating the mixture obtained in the step S403 in glacial ethyl ether to remove unreacted substances, performing suction filtration to collect a product, and performing vacuum drying to obtain N, N' -carbonyldiimidazole activated F127, namely CDI-F127.
7. The method according to claim 2, wherein the step S5 is as follows:
s501, F127 ring-opening polymerization epsilon-caprolactone activated by N, N' -carbonyldiimidazole is added with stannous chloride SnCl 2 As a catalyst, obtaining a product by high-temperature reaction after vacuumizing;
s502, after the product obtained in the step S501 is cooled and solidified, dichloromethane DCM is added to dissolve the product;
and S503, sequentially carrying out rotary evaporation, glacial ethyl ether sedimentation and suction filtration on the mixture dissolved in the step S502, and carrying out vacuum drying to obtain the FPCL 250.
S504, dissolving FPCL250 in dry dichloromethane DCM to obtain a solution;
s505, adding Ethylenediamine (EDA) into the solution obtained in the step S504 in a nitrogen atmosphere at room temperature, and stirring to obtain a mixture;
s506, removing the unreacted ethylenediamine EDA and the excessive dichloromethane DCM in the step S505 by rotary evaporation to obtain a product;
s507, the product of the step S506 is settled by cold ether, and the amino-terminated copolymer NH is obtained after vacuum drying after suction filtration 2 -FPCL250。
8. The method according to claim 2, wherein the step S6 is as follows:
s601, dissolving doxorubicin DOX in tetrahydrofuran THF to obtain a mixed solution;
s602, adding NH into the mixed solution in the step S601 2 -FPCL250, which is dripped into distilled water under high-speed rotation, and then stirred at low speed to obtain a mixed solution;
s603, after the organic solvent is volatilized in the step S602, dialyzing the solution to remove the free DOX which is not loaded in the micelle to obtain a drug-loaded micelle solution NH 2 -FPCL@DOX。
9. The method according to claim 2, wherein the step S7 is as follows:
s701, reacting DOX @ MSN-SS with 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC & HCl and N-hydroxysuccinimide NHS to obtain a mixed solution;
s702, adding a drug-loaded micelle solution NH into the mixed solution in the step S701 2 -FPCL @ DOX reaction to obtain a solution;
s703, centrifuging the solution obtained in the step S702 to remove non-grafted NH 2 -FPCL @ DOX, washing with water for several times, and freeze-drying to obtain the target product DOX @ MSN-SS-FPCL @ DOX.
10. The application of the novel double-drug-loaded mesoporous silica nanoparticle system in cancer treatment is characterized in that any one of claims 1 to 9 is applied to a cancer treatment drug.
CN202210485051.2A 2022-05-06 2022-05-06 Novel double-drug-loading mesoporous silica nanoparticle system and application thereof in cancer treatment Pending CN114904017A (en)

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