CN115671297A - Intelligent drug carrier with pH sensitivity and active oxygen sensitivity and preparation method and application thereof - Google Patents
Intelligent drug carrier with pH sensitivity and active oxygen sensitivity and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of physical chemistry, and provides an intelligent drug carrier with pH sensitivity and active oxygen sensitivity, and a preparation method and application research thereof. The drug carrier takes mesoporous silicon dioxide as a carrier material, and takes pH-sensitive polymer PDPA and hydrophilic polymer PEG which are connected by an active oxygen-sensitive thioketal as a nanometer valve thereof to carry out controllable loading and release of drugs. The thioketal bond in the polymer nanometer valve can be oxidized and broken under the action of active oxygen, and the polymer PDPA can be swelled and extended under the condition that the pH value is less than 6.0. The drug carrier can realize targeted drug release at tumor tissue parts in the presence of acidic pH and active oxygen.
Description
Technical Field
The invention belongs to the field of physical chemistry, and particularly relates to a preparation method and application of an intelligent response type drug carrier with pH sensitivity and ROS sensitivity, which is applied to increase the solubility of an anti-cancer drug and the tumor microenvironment response release of the drug.
Background
Currently, cancer has become one of the major diseases threatening human life and health, and the cancer treatment situation is very severe. The development of novel intelligent drug delivery systems with high drug bioavailability and that are biologically friendly is an important direction for the current new methods of cancer treatment.
The tumor microenvironment is composed of cancer cells, the vascular system, stromal cells and extracellular matrix. The tumor microenvironment includes not only peripheral fibroblasts, stem cells, immune cells and the like, but also biological characteristics such as oxygen content, pH value, redox characteristics and the like in tumor tissues. The cellular components of the tumor stroma are important regulators of tumor cell proliferation, apoptosis, and metabolism, controlling the sensitivity of tumor cells to therapy. When the tumor tissue rapidly proliferates, the microenvironment of the tumor tissue changes, and the biological behavior is characterized by reduced tissue oxygen content, reduced pH value, increased ROS concentration and the like [1] 。
The mesoporous silica nano-particles have uniform and controllable mesoporous aperture, stable skeleton structure, large specific surface area and easily modified surface, and are widely applied to the field of drug carriers. The inner surface of a pore channel and the outer surface of the mesoporous silica nano particle are provided with a plurality of silicon hydroxyls which can be subjected to alkylation modification, and the silicon hydroxyls are subjected to functionalization modification, such as introduction of sulfydryl, amino, carboxyl and more complex organic functional groups, the functional groups can change the biochemical property of the mesoporous silica nano particle or can be connected with a macromolecular polymer, the polymer is wound and coated on the surface of the mesoporous silica to form a nano valve, and the early release of a loaded drug is reduced [2] 。
To achieve controlled release of the carrier at the tumor tissue site, polymers used for drug carriers often have stimuli-responsive properties, such as pH, temperature, ROS, GSH, ultrasound, and the like. Polymers such as polyacrylic acid, polymethacrylic acid, polyglutamic acid and the like show pH response characteristics, are protonated at acidic pH and are deprotonated at alkaline pH, so that hydrophilic-hydrophobic transition is generated, and the assembly and the disassembly of the drug carrier are controlled. The polymer can be used as a blocking material of MSN, and wraps and winds the surface of mesoporous silicon dioxide by utilizing the shrinkage state of the polymer when the polymer is hydrophobic, so that the drug is blocked in the pore canal. After entering tumor tissue, the polymer is protonated and stretched, and the medicine is released from the pore canal, so that the controlled release of the medicine in specific environment is realized. Reference documents:
[1]Rahmanian M.,Seyfoori A.,Ghasemi M.,et al.In-vitro tumor microenvironment models containing physical and biological barriers for modelling multidrug resistance mechanisms and multidrug delivery strategies[J].Journal of ControlledRelease,2021,334(10):164-77.
[2]Fenton O.S.,Olafson K.N.,Pillai P.S.,et al.Advances in Biomaterials for Drug Delivery[J].Adv Mater,2018,30(29):1705328.
disclosure of Invention
In order to solve the problems of low solubility, strong toxic and side effects and the like of part of chemotherapeutic drugs, the invention provides a mesoporous silica nano drug carrier with pH sensitivity and ROS sensitivity and a preparation method thereof, and also provides application of the drug carrier in increasing drug solubility and tumor microenvironment response release.
The technical scheme of the invention is as follows:
the nano-drug carrier provided by the invention is composed of PEG and PDPA-NH 2 And packaging the mesoporous silica to obtain the mesoporous silica. Preparing a polymer PDPA with pH sensitivity by a reversible addition-fragmentation chain transfer polymerization method, and then modifying TK bonds with ROS sensitivity at two ends to obtain PDPA-NH 2 . PEG and mesoporous silicon dioxide can be modified by carboxylation and can be reacted with PDPA-NH 2 The terminal amino group being linked by amidation, PDPA-NH 2 The polymer chain connected with PEG is wound and coated on the surface of the mesoporous silicon dioxide, thereby achieving the aim of encapsulating the drug. The nano-drug carrier isUnder the existence of acidic pH and ROS, TK bond is oxidized and broken, and a polymer chain falls off from the surface of the mesoporous silica, so that a large amount of drugs loaded in the mesoporous silica pore channel are promoted to be released.
PDPA-NH for encapsulating mesoporous silica in the invention 2 The block has ROS response and pH response characteristics, the middle part of the block is PDPA (poly (2-diisopropyl amino ethyl methacrylate)), the two ends of the block are modified with thioketal TK, PEG is polyethylene glycol, and PDPA-NH 2 Is connected with mesoporous silicon dioxide and PEG through TK group. The TK bond has a main structure of-S-C (CH) 3 ) -S-, and a symmetrical structure centered on a thioketal group, having ROS-responsive properties, and oxidatively cleavable under the action of ROS.
The average particle size of the drug carrier MSN-PDPA-PEG is 150-200nm, as shown in figure 2.
Further, in the presence of ROS, the polymer PDPA is converted from a hydrophobic state to a hydrophilic state, and polymer chains playing an encapsulation role stretch, so that the responsive release of the drug is realized.
Furthermore, in the nano-drug carrier, TK bond is oxidized and broken in the presence of ROS, and PDPA-NH with the surface having encapsulation effect 2 The block and the PEG block fall off, thereby realizing the responsive release of the drug.
ROS, i.e., reactive oxygen species, described herein include H 2 O 2 Singlet oxygen, and the like.
The invention also provides a preparation method of the intelligent drug carrier with pH sensitivity and active oxygen sensitivity, which comprises the following specific steps:
step 1: polymer PDPA-NH 2 Synthesis of (2)
Adding concentrated hydrochloric acid into beta-mercaptoethylamine, placing in an ice water bath, stirring until the solid is dissolved, and adding acetone and dichloromethane. And (4) carrying out suction filtration and washing on the product, and collecting an upper-layer filter cake. It was dissolved in methanol and precipitated in glacial ethyl ether. And adding a sodium hydroxide solution into the precipitated solid, and stirring, extracting and rotary evaporating to obtain the TK connector.
DPA, AIBN and bis (carboxymethyl) trithiocarbonate are dissolved in 1, 4-dioxane to remove water and oxygen. Stirring and reacting at 65 ℃, dialyzing the product with ethanol and ultrapure water, and freeze-drying to obtain the product PDPA.
PDPA was dissolved in THF and DCC and NHS were added. TK was dissolved in THF, added dropwise to the above system, and the product was dialyzed against ethanol and ultrapure water. Vacuum freeze drying to obtain product PDPA-NH 2 。
And 2, step: preparation of MSN and surface functionalization thereof
CTAB (cetyltrimethylammonium bromide) was dissolved in ultrapure water, and a NaOH solution was added dropwise, heated and stirred. TEOS (tetraethyl orthosilicate) is added, stirring is continued, and the product is centrifuged, washed and dried in vacuum. Calcining in a muffle furnace to obtain the product MSN.
Dispersing MSN in isopropanol by ultrasonic wave, adding APTES, and heating to 85 deg.C for reaction. Centrifuging, washing and vacuum drying to obtain MSN-NH 2 . Adding MSN-NH 2 Dispersing in DMF, and adding succinic anhydride dissolved in DMF. Centrifuging and vacuum drying to obtain the product MSN-COOH.
And 3, step 3: preparation of vector MSN-PDPA-PEG
Dispersing MSN-COOH in THF, adding DCC and NHS, and adding PDPA-NH 2 Dissolved in THF and added to the system. Centrifuging, washing and vacuum drying to obtain the MSN-PDPA.
PEG-COOH was dispersed in THF, DCC and NHS were added, MSN-PDPA was dispersed in THF, and added to the above system. Centrifuging, washing and vacuum drying to obtain MSN-PDPA-PEG.
Preferably, the volume ratio of dichloromethane to acetone in the step 1 is 1;
preferably, the molar ratio of AIBN, bis (carboxymethyl) trithiocarbonate to DPA in step 1 is 1;
preferably, the dialysis bags used in the dialysis process in step 1 have molecular weight cut-offs of 3500 and 5000;
preferably, the mass ratio of NHS to DCC in step 1 and step 3 is 1.5 to 2.5, preferably 1;
preferably, TK and PDPA-NH in the step 1 2 In a mass ratio of 1;
preferably, PDPA-NH in step 3 2 The mass ratio to MSN-COOH is 1.5-2.0, preferably 1.
The invention discloses a preparation method of a multiple-response type nano-drug carrier with ROS sensitivity and pH sensitivity, and PDPA-NH 2 The method comprises the steps of taking polymer chain PDPA as a main body, leading in micromolecules containing TK groups and having amino at the tail ends through chemical modification at two ends, and obtaining PDPA-NH 2 And the amino at the tail end, the carboxyl of the PEG chain and the carboxyl modified on the MSN are subjected to amide coupling reaction to obtain the target carrier.
The invention also provides application of the ROS-sensitive and pH-sensitive mesoporous silica nano-drug carrier in the fields of intelligent drug delivery, targeted release and the like.
The invention takes DOX/ICG as a template drug for co-loading, and researches H 2 O 2 The release of drug when co-acting with pH is shown in FIG. 7, H 2 O 2 The concentration was set at 1000 μ M, and release at different pH was investigated. The cumulative release rate gradually increases with decreasing pH, and can reach 53%,56% and 70%, respectively. pH 5.0 and H 2 O 2 The release rate of DOX at 1000. Mu.M co-action was higher than pH 5.0 (60%) only and H only 2 O 2 (53%) in the case of action. The drug release results show that pH/ROS cooperative response release, when the carrier enters cancer cells with low pH and excessive ROS expression, the cooperative effect can be exerted, and more drugs can be released for treatment. In addition, the carrier after ICG co-loading shows an NIR (808 nm) controlled burst release effect, and can realize timed, rapid and large-quantity drug release.
Compared with the prior art, the invention has the following beneficial effects:
(1) The mesoporous silica is used as a carrier for drug loading, compared with other carriers, the mesoporous silica has the advantages of rich and adjustable channels, good biocompatibility and the like, and the carrier is enriched at tumor tissue parts due to the influence of EPR effect by using the mesoporous silica as the drug carrier, so that the bioavailability of the drug is improved.
(2) The invention uses PDPA-NH 2 And PEG as a Nanoflive encapsulating mesoporous silica, PDPA-NH 2 The pH sensitive point of the carrier is 6.50, the carrier is taken as an encapsulation polymer, the stability of the carrier is improved, the early release of the carrier at a non-tumor part is reduced, and PDPA-NH is in an acid pH environment at a tumor part 2 The tertiary amine matriization of (a) results in polymer chain extension, facilitating drug release. PEG modified on the surface of the mesoporous silica has good biocompatibility, and can prevent the carrier from being captured and removed in the blood circulation process. As shown in figure 5, the particle size of the DOX-containing MSN-PDPA-PEG in both media was maintained at about 190nm, which was stable over the time tested (96 hours).
(3) The invention uses TK bond to connect MSN and PDPA-NH 2 And PEG, wherein the TK bond has ROS sensitive characteristics, and when the concentration of ROS is more than 50 mu M, the TK bond is subjected to oxidative breakage, so that a polymer chain is separated from the surface of the mesoporous silica, and the drug loaded by the carrier is released. The invention provides PDPA-NH 2 The block has ROS sensitivity and pH sensitivity, is an ideal polymer block with multi-response characteristic, and provides a feasible strategy for preparing stimulus-response intelligent drug carriers.
(4) The invention provides a nano mesoporous silicon dioxide drug carrier and PDPA-NH 2 And a PEG polymer. The drug carrier shows extremely high stability in a normal tissue environment, after entering a tumor tissue, the carrier is promoted to crack by low pH and high ROS concentration, and the drug is released rapidly. The intelligent drug delivery system provided by the invention has the characteristics of high drug loading, good stability, strong sensitivity and the like, and is a strategy capable of effectively improving the bioavailability of the drug and enhancing the treatment effect of cancer.
Drawings
FIG. 1 shows the polymer PDPA-NH of the present invention 2 The synthetic scheme of (1).
FIG. 2 shows MSN, MSN-NH 2 MSN-COOH, MSN-PDPA and MSN-PDPA-PEG particle size distribution plots.
FIG. 3 is a TEM image of MSN-PDPA-PEG.
FIG. 4 is an SEM image of MSN-PDPA-PEG.
FIG. 5 is a graph showing the change of particle size with time of MSN-PDPA-PEG @ DOX in DMEM containing 10% FBS and 1mM PBS.
FIG. 6 is a picture of the MSN-PDPA-PEG @ DOX/ICG solution before and after 10 minutes NIR irradiation.
FIG. 7 shows MSN-PDPA-PEG @ DOX at H 2 O 2 Concentrations were all 1000. Mu.M, and pH was 7.4,6.0 and 5.0, respectively, for cumulative release rates of DOX.
Detailed Description
In order to make the research background, the provided technical solutions and the beneficial effects of the present invention more intuitive, the following further describes the application of the present invention in the field of drug delivery with reference to specific implementation examples. The following examples are merely illustrative of the best mode of carrying out the invention and are not intended to limit the invention to any particular application in the field of intelligent drug carriers or the like.
Example 1PDPA-NH 2 Preparation of PEG-encapsulated dual-response type nano mesoporous silica drug carrier
(1) Preparation of MSN
Weighing 500mg CTAB dissolved in 240mL of ultrapure water, ultrasonic dissolution, then stirring and dropwise adding 1.75mL of 2M NaOH solution. The solution was heated to 80 ℃ and stirring was continued for 30 minutes, at a speed not too fast. And (3) increasing the rotating speed, slowly dripping 2.5mL TEOS by using a constant flow pump at a dripping speed of 167 mu L/min, and continuously stirring for 2 hours after the system is observed to be milky white. And cooling to room temperature, centrifuging to collect a product, alternately washing with ethanol and deionized water, and detecting the pH of the centrifuged supernatant by using a wide pH test paper, wherein the washing is finished when the pH is neutral. The product was dried in a vacuum oven at 60 ℃ for 24 hours under vacuum. Calcination was carried out for 6 hours at 550 ℃ using a muffle furnace to remove the template molecule CTAB. Finally obtaining the white product MSN.
(2) MSN surface amination
400mg of synthesized MSN is weighed, ultrasonically dispersed in 50mL of isopropanol, nitrogen is introduced to remove oxygen and remove water for 20 minutes, 80 mu L of (3-aminopropyl) -triethoxysilane coupling agent is dropwise added, and reflux reaction is carried out for 24 hours at 85 ℃. Centrifugally collectingThe product was washed with isopropyl alcohol to remove the unreacted silane coupling agent. Drying the product in a vacuum drying oven at normal temperature for 12 hours to obtain a white product MSN-NH 2 。
(3) Surface carboxylation of MSN
Weighing 300mg of MSN-NH 2 Ultrasonically dispersing in 40mL DMF solvent, stirring for 20 minutes, weighing 300mg succinic anhydride, dissolving in 5mL DMF, dropwise adding into the system, and continuously stirring for reaction for 24 hours. The product was collected by centrifugation, washed three times with DMF to remove unreacted succinic anhydride, washed three times with ethanol to remove DMF, and dried in a vacuum oven for 12 hours to give a white product MSN-COOH.
(4) Preparation of TK linker
Weighing 5.78g beta mercaptoethylamine, adding 4mL 12M concentrated hydrochloric acid dropwise, stirring in an ice water bath, adding a mixed solvent of 10mL acetone and 4mL dichloromethane, reacting for about 10 minutes, and observing that a large amount of white solid is separated out. The product was filtered off with suction and washed with a little dichloromethane, and the upper filter cake was collected. The filter cake was dissolved in 50mL of methanol, then concentrated to a small amount, precipitated in a suitable amount of glacial ethyl ether, and left to precipitate at low temperature for 4 hours, and the product was collected by centrifugation. The product was added to 10mL of 6M sodium hydroxide solution, and reacted for 12 hours. Adding a proper amount of dichloromethane, separating liquid, collecting a lower organic phase, washing with ultrapure water, separating liquid for three times, drying with anhydrous magnesium sulfate, removing water, and performing suction filtration. The product was obtained by rotary evaporation as a yellow-white transparent oil which was dried in a vacuum oven for 12 hours at 62% yield.
(5) Synthesis of Polymer PDPA
DPA, AIBN and bis (carboxymethyl) -trithiocarbonate 2g (9.38 mmol), 3mg (0.0188 mmol) and 43mg (0.188 mmol) were weighed into Schlenk bottles, respectively, and 20mL1, 4-dioxane was added to completely dissolve the solid. Introducing nitrogen for 15 minutes, freezing by liquid nitrogen, vacuumizing for 15 minutes, filling nitrogen for unfreezing for 15 minutes, circulating three times to remove water and oxygen, and heating to 65 ℃ to stir and react for 12 hours. The obtained product is yellow and viscous, and is placed in a dialysis bag (MW: 3500), dialyzed for 48 hours by using ethanol and ultrapure water, and freeze-dried to obtain a white solid product PDPA.
(6)PDPA-NH 2 Synthesis of (2)
300mg of PDPA-COOH was weighed and dissolved in 20mL of THF, stirred with nitrogen for 20 minutes, added with 38mg of DCC to activate for 15 minutes, then added with 19mg of NHS, and stirred to react for 3 hours. 120mg of TK was dissolved in 5mL of THF, and the solution was added dropwise to the above system, followed by further reaction for 24 hours. The resulting product was filtered to remove insoluble matter, then placed in a dialysis bag (MW = 5000) and dialyzed with ethanol and ultrapure water for 48 hours. The product is frozen and dried in vacuum to obtain yellow solid PDPA-NH 2 。
(7) Preparation of MSN-PDPA
350mg of MSN-COOH were weighed out, dispersed in THF, activated by adding 52mg of DCC, and after 15 minutes 26mg of NHS were added and the nitrogen was passed on for 3 hours. Weighing 200mg of PDPA-NH 2 Then, the reaction mixture was dissolved in an appropriate amount of THF, added dropwise to the above system, and the reaction was continued with stirring for 24 hours. The product was collected by centrifugation, washed three times with THF, and dried in a vacuum oven for 12 hours to give the product MSN-PDPA.
(8) Preparation of MSN-PDPA-PEG
PEG-COOH (MW = 2000) 98.6mg and DCC 46mg were weighed and dissolved in THF, activated by nitrogen for 15-20 minutes, and then 23mg NHS was added. After 3 hours, MSN-PDPA was dispersed in an appropriate amount of THF, added to the above system, and the reaction was continued at room temperature for 24 hours. And centrifuging to collect the product, washing the product with THF for three times, and drying in vacuum for 12 hours to obtain the multi-response nano-drug carrier MSN-PDPA-PEG.
Example 2 research on Loading and releasing DOX of multiple-response type nano mesoporous silica drug Carrier
(1) DOX Loading
100mg of carrier MSN-PDPA-PEG was weighed, ultrasonically dispersed in 30mL of 1mM PBS buffer solution with pH =7.4, the system pH was adjusted to 6.0, and stirred for 30 minutes. DOX solution with the concentration of 2mg/mL is prepared, 10mL is dripped into the system, and the mixture is stirred at room temperature in a dark place for 24 hours to be fully loaded. The system pH was adjusted to 7.4, stirred for 2 hours, and the DOX-loaded vehicle was collected by centrifugation, washed with PBS buffer solution, and the supernatant clarified. And determining the DOX content of the supernatant by using an ultraviolet visible spectrum, wherein the ultraviolet characteristic absorption wavelength of the DOX is 488nm. Vacuum freeze drying to obtain carrier MSN-PDPA-PEG @ DOX with red color.
(2) Controlled drug release
pH response release: an appropriate amount of MSN-PDPA-PEG @ DOX was weighed and placed in a 50mL centrifuge tube. 1mM PBS buffer solution at pH 7.4,6.0 and 5.0, respectively, was set as the release system. Placing the release system in a 37 ℃ constant-temperature oscillation box, sucking supernatant liquid at regular intervals, measuring the fluorescence intensity of the release system by a fluorescence spectrophotometer, wherein the excitation wavelength is 488nm, the emission wavelength is 550nm, and the slit width is 5nm, and then placing the release system back to the original system, wherein the release time is 96 hours.
H 2 O 2 And (4) responding to the release: weighing appropriate amount of MSN-PDPA-PEG @ DOX, placing in 50mL centrifuge tube, setting concentrations of H at 0 μ M,50 μ M,100 μ M and 1000 μ M respectively 2 O 2 As the releasing conditions, the solution was PBS buffer solution (1 mM) at pH 7.4, and the detection method was the same as above.
pH and H 2 O 2 Double response release: set pH at 7.4,6.0 and 5.0, respectively, containing 1000. Mu.MH 2 O 2 As release medium, PBS buffer solution. Other detection methods are the same as above.
Example 3 study on Loading and Release of DOX and ICG with Multi-responsive Nano-mesoporous silica drug Carrier
(1) Co-Loading of ICG and DOX
100mg of the carrier MSN-PDPA-PEG was weighed, dispersed in 20mL of 1% DMSO in PBS buffer, and the pH was adjusted to 6.0. DOX solution and ICG solution were prepared at a concentration of 2mg/mL, respectively, as 1% DMSO in PBS buffer, and 10mL of LDOX solution and 15mL of ICG solution were added dropwise to the above system. The system was stirred for 24 hours in the dark, pH was adjusted to 7.4 and stirring was continued for 2 hours, the product was collected by centrifugation, washed several times with PBS buffer solution, and unloaded DOX and ICG were removed. The content of the drug in the supernatant is detected by ultraviolet, and the detection wavelengths are 488nm (DOX) and 780nm (ICG) respectively. Vacuum freeze drying to obtain carrier MSN-PDPA-PEG @ DOX/ICG with dark green color.
(2) Controlled drug Release test
NIR stimulated release: an appropriate amount of MSN-PDPA-PEG @ DOX/ICG was weighed and placed in a 50mL centrifuge tube with the release medium being PBS buffer solution at pH 7.4 and 5.0. The release system was placed in a 37 ℃ thermostatted shaking box. Fluorescence intensities were measured at different times, NIR illumination was performed at specific times, and fluorescence intensities were measured to calculate cumulative release rates at different times.
Claims (10)
1. An intelligent drug carrier with pH sensitivity and active oxygen sensitivity is characterized in that the intelligent drug carrier is a multi-response type nano drug carrier MSN-PDPA-PEG with ROS sensitivity and pH sensitivity, and the carrier is composed of a polymer PDPA-NH 2 And PEG encapsulated mesoporous silica.
2. The intelligent pH-sensitive and active oxygen-sensitive drug carrier of claim 1 wherein the PDPA-NH used to encapsulate the mesoporous silica is PDPA-NH 2 The block has ROS response and pH response characteristics, the middle part of the block is PDPA (poly (2-diisopropyl amino ethyl methacrylate)), two ends of the block are modified with thioketal TK, PEG is polyethylene glycol, and PDPA-NH 2 Connected with mesoporous silicon dioxide and PEG through TK group.
3. The smart drug carrier with pH sensitivity and active oxygen sensitivity as claimed in claim 2, wherein the TK bond has a main structure of-S-C (CH) 3 ) -S-, and a symmetrical structure centered on the thioketal group, which has ROS-responsive properties and is oxidatively cleavable under the action of ROS.
4. The intelligent pH-sensitive and active oxygen-sensitive drug carrier of claim 1, wherein the average particle size of the MSN-PDPA-PEG is 150-200nm.
5. The intelligent pH-sensitive and active oxygen-sensitive drug carrier of claim 1, wherein the polymer PDPA is transformed from a hydrophobic state to a hydrophilic state in the presence of ROS, and the polymer chains for encapsulation are extended, thereby achieving the responsive release of the drug.
6. The intelligent pH-sensitive and active oxygen-sensitive drug carrier of claim 1, wherein the nano-drug carrier has PDPA-NH with TK bond being oxidized and cleaved in the presence of ROS, and surface encapsulation effect 2 The block and the PEG block fall off, thereby realizing the responsive release of the drug.
7. The intelligent pH-sensitive and reactive oxygen species-sensitive pharmaceutical carrier of claim 1, wherein said ROS comprise H 2 O 2 Singlet oxygen.
8. A method for preparing the intelligent pH-sensitive and active oxygen-sensitive pharmaceutical carrier according to claim 1, comprising the steps of:
1) Preparing a nano mesoporous silica material with uniform particle size by a sol-gel method by taking tetraethyl orthosilicate as a silicon source and cetyl trimethyl ammonium bromide as a template agent;
2) Adding acetone and dichloromethane into a hydrochloric acid solution of beta-mercaptoethylamine, adding a sodium hydroxide solution into the precipitated solid, and reacting to obtain a connector with a TK group;
3) DPA (2-diisopropyl amino ethyl methacrylate) is used as a monomer, azodiisobutyronitrile is used as an initiator, bis (carboxymethyl) -trithiocarbonate is used as a chain transfer agent, and a polymer PDPA with carboxyl groups at two ends is synthesized by an RAFT method;
4) Activating the product obtained in the step 3) in an organic solvent by using N, N' -Dicyclohexylcarbodiimide (DCC), adding N-hydroxy thiosuccinimide (NHS) and the product obtained in the step 2), and reacting to obtain PDPA-NH 2 ；
5) Dispersing the product obtained in the step 1) in an organic solvent, adding a (3-aminopropyl) -triethoxysilane coupling agent for reaction to obtain mesoporous silica MSN-NH with amino modified on the surface 2 ；
6) Dispersing the product obtained in the step 5) in an organic solvent, adding succinic anhydride to react to obtain carboxyl modified mesoporous silica MSN-COOH;
7) Dispersing the product obtained in the step 6) in an organic solvent, activating by N, N' -dicyclohexylcarbodiimide, adding N-hydroxy thiosuccinimide and the product obtained in the step 4), and amidating to obtain MSN-PDPA;
8) Dispersing PEG-COOH in an organic solvent, activating with N, N' -dicyclohexylcarbodiimide, adding N-hydroxy thiosuccinimide and the product obtained in the step 7), and amidating to obtain the multi-sensitive drug carrier MSN-PDPA-PEG.
9. Use of the intelligent pH-and active oxygen-sensitive pharmaceutical carrier according to any one of claims 1 to 7, wherein the pharmaceutical is doxorubicin hydrochloride and the photosensitizer indocyanine green.
10. The use of the intelligent pH-and reactive oxygen species-sensitive pharmaceutical carrier according to claim 9, wherein said pharmaceutical carrier comprises chemotherapeutic drugs and adjuvant drug delivery and tumor site release.
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