CN114507326B - pH response crosslinking bond-based hydrophilic side chain-adjustable triblock polymer and preparation and application thereof - Google Patents

pH response crosslinking bond-based hydrophilic side chain-adjustable triblock polymer and preparation and application thereof Download PDF

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CN114507326B
CN114507326B CN202210047325.XA CN202210047325A CN114507326B CN 114507326 B CN114507326 B CN 114507326B CN 202210047325 A CN202210047325 A CN 202210047325A CN 114507326 B CN114507326 B CN 114507326B
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triblock polymer
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章莉娟
黄柏浩
张富盛
裴公萃
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South China University of Technology SCUT
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Abstract

The invention discloses a pH response crosslinking bond-based hydrophilic side chain-adjustable triblock polymer, and preparation and application thereof. The polymer is poly (2-phenoxyethyl methacrylate) -b-poly (2-oxopropyl methacrylate) -b-poly (monomethoxy polyethylene glycol) methacrylate, and the hydrophilic side chain of the polymer is easy to regulate and control and can be self-assembled to form micelles with different stabilities. The pH response cross-linked micelle of the polymer can effectively load the water-insoluble drug. The micelle disclosed by the invention enhances the stability of the micelle in a physiological environment through hydrophilic side chain regulation and crosslinking strategies, has a better pH response performance, can quickly release a medicament in a tumor microenvironment, and improves the medicament delivery efficiency.

Description

pH response crosslinking bond-based hydrophilic side chain-adjustable triblock polymer and preparation and application thereof
Technical Field
The invention belongs to the technical field of biological high molecular polymer materials, and particularly relates to a pH response crosslinking bond-based triblock polymer with an adjustable hydrophilic side chain, and preparation and application thereof.
Background
In recent years, the harm of cancer to human health has received increasing attention. Among the many cancer treatment strategies, chemotherapy is one of the mainstreams of treatment. However, the traditional chemotherapeutic drugs have the defects of poor water solubility, strong toxic and side effects and the like. The use of drug carrier materials to deliver drugs can effectively remedy these deficiencies. In the drug-loaded materials developed at present, the polymer micelle is widely used for the entrapment and delivery of water-insoluble drugs due to the characteristics of excellent biocompatibility, easy chemical modification and the like.
The polymer micelle is a dynamic equilibrium aggregate formed by self-assembly of an amphiphilic block polymer in an aqueous medium. During in vivo drug delivery, micelles are often destabilized by adsorption of proteins, lipids, etc. in the blood, eventually leading to structural collapse. Meanwhile, foreign substances such as proteins adsorbed on the surfaces of the micelles may promote aggregation and sedimentation of the micelles through a bridging effect. In addition, there is a large amount of fluid in the blood circulation, and the micelle concentration is lowered below the Critical Micelle Concentration (CMC) by dilution, destabilizing the micelle, thereby seriously affecting the drug delivery effect. The method mainly aims at solving the problems by improving the structural stability and the colloidal stability. The adoption of chemical covalent bond crosslinking is one of effective strategies for improving the stability of the micelle structure. Zhang and the like prepare a shell reversible crosslinked micelle based on a four-arm star-shaped polymer, a crosslinked structure with reversible hydrazone bonds and disulfide bonds is formed on the shell, and the crosslinked micelle still maintains an integral structure after 1000 times of deionized water dilution, and has good anti-dilution capability and stability. For colloidal stability, modifying the properties of the hydrophilic block of the surface micelle (e.g., controlling its length, graft density, and chemical structure) can enhance its colloidal stability (Polymer 2017,114, 161-172). Shoichet et al investigated the effect of the grafting density of hydrophilic polyethylene glycol (PEG) on the stability of nanoparticles, with the stability of nanoparticles in physiological environments being enhanced as the PEG grafting density increases (chem. Mater.2014,26, 2847-2855).
In the drug delivery process, the polymer micelle needs to maintain higher physiological environment stability and realize accurate and rapid drug release at a tumor part. The reversible cross-linked bond structure responding to the fracture in the tumor microenvironment is selected, so that the combination of the reversible cross-linked bond structure and the reversible cross-linked bond structure can be realized, and the effect of drug delivery can be exerted to the maximum extent. Patent CN111978553B discloses a triple-stimulus responsive interfacial crosslinked polymer micelle, which is broken by disulfide crosslinking bonds under reducing conditions, so that the drug release amount is effectively improved. However, there has been no extensive systematic study on the regulation of stability by polymer structure, and the combination of stability and rapid drug release.
In conclusion, how to achieve the requirements of micelle stability and drug controlled release are the technical problems to be solved at present.
Disclosure of Invention
In order to overcome the defects of complex polymer structure, difficult regulation and control of stability, poor controlled release performance and the like in the prior art, the invention aims to provide the triblock polymer with the adjustable hydrophilic side chain based on the pH response crosslinking bond.
The structure of the polymer of the invention is: poly (2-phenoxyethyl methacrylate) -b-poly (2-oxopropyl methacrylate) -b-poly (monomethoxypolyethylene glycol) methacrylate (PPOEMA-b-POPMA-b-PPEGMA).
The preparation process of the polymer is simple and convenient, and the length of the hydrophilic side chain of the amphiphilic block polymer can be accurately and quickly regulated and controlled, so that the stability and the drug delivery performance of a micelle formed by the polymer are enhanced.
Another object of the present invention is to provide a method for preparing the above triblock polymer with adjustable hydrophilic side chains based on pH response crosslinking bonds. The process begins with the oxidation of 2-hydroxypropyl methacrylate (HPMA) to the keto-functional monomer 2-oxopropyl methacrylate (OPMA) with pyridinium chlorochromate; then, adopting an electron transfer activation regeneration atom transfer radical polymerization (ARGET ATRP) method, utilizing a small molecular initiator to sequentially polymerize hydrophobic monomer 2-phenoxyethyl methacrylate (POEMA), keto-functionalized monomer 2-oxopropyl methacrylate (OPMA) and hydrophilic monomer monomethoxypolyethylene glycol methacrylate (PEGMA), and finally obtaining triblock polymer PPOEMA-b-POPMA-b-PPEGMA. Wherein, by adding equimolar PEGMA with different relative molecular weights, triblock polymers with different hydrophilic side chains can be obtained in a controllable way.
The invention further aims to provide the application of the triblock polymer with the adjustable hydrophilic side chain based on the pH response cross-linking bond in loading a poorly water-soluble drug, in particular a poorly water-soluble anticancer drug (such as adriamycin). The triblock polymer is dissolved in a solvent and dialyzed to obtain a polymer micelle, wherein the core layer is a hydrophobic block, the middle layer contains a ketone group which can be used for reversible covalent bond crosslinking, and the shell layer is a hydrophilic block, and the polymer micelle reacts with a hydrazide bond in a crosslinking agent adipic dihydrazide under the environment of pH 6.5 and the action of a catalyst 2-amino-5-methoxybenzoic acid to generate an acylhydrazone bond crosslinking structure which can reversibly break the bond under an acidic condition. Under normal physiological environment, the adriamycin is stably loaded in the micelle core through the pi-pi accumulation effect of the benzene ring of the micelle core layer, and the loading stability is further enhanced due to the effects of a cross-linking structure and long hydrophilic side chains. When the micelle is in a tumor acidic microenvironment, acylhydrazone cross-linking bonds in the middle layer of the micelle are broken, so that the micelle structure is collapsed, and the adriamycin is released from the inner core of the micelle. Meanwhile, the protonation of the amino group of the adriamycin under the acidity improves the water solubility of the medicament, and further accelerates the release of the medicament.
The purpose of the invention is realized by the following technical scheme:
a pH response crosslinking bond based hydrophilic side chain adjustable triblock polymer has a structural formula shown as follows:
Figure BDA0003472577830000031
wherein x =15 to 35, y =5 to 20, z =15 to 35, and the number n of structural units of a side chain ethylene glycol group of the hydrophilic block monomer PEGMA is 5 to 20.
The triblock polymer with the adjustable hydrophilic side chains based on the pH response cross-linking bond is named as PPOEM-b-POPMA-b-PPEGMA.
The number average molecular weight of the triblock polymer with the hydrophilic side chains adjustable based on the pH response cross-linking bonds is 8499-43503 g/mol.
The preparation method of the triblock polymer with the adjustable hydrophilic side chain based on the pH response crosslinking bond comprises the following steps:
(1) Preparation of keto-functionalized monomer (OPMA): dissolving pyridinium chlorochromate (PCC) and silica gel powder in a solvent, adding 2-hydroxypropyl methacrylate (HPMA) under the ice bath condition, turning to room temperature for continuous reaction to obtain a keto-functionalized monomer 2-oxopropyl methacrylate (OPMA);
(2) Preparing an amphiphilic triblock polymer (PPOEM-b-POPMA-b-PPEGMA): dissolving a catalyst, a monomer 2-phenoxyethyl methacrylate (POEMA), a ligand 1,4,7, 10-Hexamethyltriethylenetetramine (HMTETA) in a solvent, adding a reducing agent after fully stirring, uniformly stirring, adding a small molecular initiator, heating for reaction, adding a ketone group functionalized monomer 2-oxopropyl methacrylate (OPMA) prepared in the step (1) after the monomer is completely converted for continuous reaction, and adding a monomer monomethoxypolyethylene glycol methacrylate (PEGMA) for continuous reaction after the monomer is completely converted to obtain the amphiphilic triblock polymer (PPOEM-b-POPMA-b-PPEGMA).
Preferably, the molar ratio of 2-hydroxypropyl methacrylate to pyridinium chlorochromate in step (1) is 1:1.2 to 2.
Preferably, the silica gel powder in step (1) is used in the same amount as the PCC in quality, so as to facilitate dispersion of reactants and increase reaction yield.
Preferably, the solvent of step (1) is dichloromethane; the molar volume ratio of the pyridinium chlorochromate to the solvent is 0.3-0.5 mmol/mL.
Preferably, the reaction time of the step (1) at room temperature is 12-18 h.
Preferably, the catalyst in step (2) is cupric bromide (CuBr) 2 ) And copper chloride; the reducing agent is stannous octoate (Sn (Oct) 2 ) And ascorbic acid; the small-molecular initiator is ethyl bromoisobutyrate (EBriB).
Preferably, the molar ratio of the catalyst, 2-phenoxyethyl methacrylate, 1,4,7, 10-hexamethyltriethylene tetramine, the reducing agent, the small molecule initiator, 2-oxopropyl methacrylate and monomethoxy polyethylene glycol methacrylate in the step (2) is 0.04-0.06: 15 to 35: 0.4-0.6: 0.4-0.6: 1:5 to 20:15 to 35.
Preferably, the solvent in the step (2) is at least one of anisole and N, N-Dimethylformamide (DMF); the molar volume ratio of the monomer methacrylic acid-2-phenoxyethyl ester to the solvent is 0.52-2.09 mmol/mL.
Preferably, the monomer 2-phenoxyethyl methacrylate in the step (2) is heated to react at the temperature of 40-50 ℃ for 4-10 h; the reaction temperature of the methacrylic acid-2-oxo propyl ester is 40 to 50 ℃ and the reaction time is 12 to 18 hours; the reaction temperature of the monomethoxy polyethylene glycol methacrylate is 60-70 ℃, and the reaction time is 36-72 h.
Preferably, after the reaction in step (1) is completed, the reaction product system is purified and concentrated to obtain a purified product. The purification includes adding the reaction solution into diatomite, vacuum filtering, rotary distilling to concentrate filtrate to obtain coarse product, chromatographic silica gel column to elute product, and rotary distilling to concentrate the eluted liquid to obtain purified product.
Preferably, after the monomer monomethoxy polyethylene glycol methacrylate in the step (2) is reacted, the reaction product system is cooled, purified and dried to obtain a purified product. And the purification refers to adding Tetrahydrofuran (THF) into a reaction product system after cooling to terminate the reaction, then removing the catalyst through a neutral alumina chromatographic column, dropwise adding the mixture to 10 times of ice hexane for precipitation after rotary evaporation and concentration, repeating the rotary evaporation and precipitation for three times, and drying in vacuum to obtain a purified product.
Preferably, the reactions in steps (1) to (2) are carried out under the protection of inert gas and under anhydrous conditions.
An application of a pH response cross-linking bond based triblock polymer with an adjustable hydrophilic side chain in loading of a poorly water-soluble drug.
Preferably, the application is: dissolving the triblock polymer with the adjustable hydrophilic side chain based on the pH response crosslinking bond and the water-insoluble drug in a solvent, uniformly mixing, dialyzing in phosphate buffer solution, adding a catalyst and a crosslinking agent, stirring for reaction at room temperature, and dialyzing with deionized water to obtain the pH response crosslinked micelle system loaded with the water-insoluble drug.
More preferably, the solvent is dimethyl sulfoxide (DMSO); the mass-volume ratio of the hydrophilic side chain adjustable triblock polymer based on the pH response crosslinking bond to the solvent is 1-5 mg/mL.
More preferably, the mass ratio of the pH-responsive crosslinking bond-based hydrophilic side chain-tunable triblock polymer to the poorly water-soluble drug is 2 to 10:1.
more preferably, the poorly water soluble drug is a poorly water soluble anticancer drug such as deacidified Doxorubicin (DOX) and paclitaxel; the water-insoluble drug refers to a drug having a solubility of 1g or less in 1L of water.
More preferably, the time for uniform mixing is 3 to 5 hours.
More preferably, the catalyst is 2-amino-5-methoxybenzoic acid; the cross-linking agent is adipic Acid Dihydrazide (ADH); the mole ratio of the pH response crosslinking bond-based hydrophilic side chain-adjustable triblock polymer to the crosslinking agent is 2:1; the concentration of the catalyst in the micellar solution obtained after dialysis in phosphate buffered saline solution is 8-12 mmol/L.
More preferably, the reaction time is 20-30 h under stirring at room temperature.
More preferably, the phosphate buffered saline solution has a pH =6.5; the dialysis time in phosphate buffer saline solution is 18-30 h, and the dialysis solution is replaced once every 2-6 h.
More preferably, the time of dialysis by deionized water is 10-24 h, and the dialysate is replaced every 2h.
The drug loaded in the pH response cross-linked micelle system loaded with the water-insoluble drug is slowly released in a normal physiological environment (pH 7.4), and the pH response cross-linked bond is broken in a tumor acid microenvironment (pH 5.0) to promote the rapid release of the drug.
The mechanism of the invention is as follows:
the invention uses oxidant pyridinium chlorochromate (PCC) to oxidize 2-hydroxypropyl methacrylate (HPMA) into ketone group functionalized monomer 2-oxopropyl methacrylate (OPMA), then sequentially polymerizes 2-phenoxyethyl methacrylate (POEMA), OPMA and monomethoxypolyethylene glycol methacrylate (PEGMA) by ARGET ATRP method to obtain triblock polymer, dissolves the triblock polymer in solvent, dialyzes, and carries out room temperature crosslinking reaction to obtain the crosslinked polymer micelle with hydrophobic PPOEM as a core, POPMA with acyl hydrazone bond crosslinking structure as a middle layer and PPEGMA as a shell. POEMA has a benzene ring, can efficiently load hydrophobic anticancer drug adriamycin (DOX) through pi-pi accumulation, ketone groups in OPMA can form a pH-responsive acylhydrazone bond cross-linked structure at room temperature and under mild conditions, PEGMA is good in hydrophilicity and biocompatibility, has excellent protein adsorption resistance, can well stabilize a micelle structure, and can accurately regulate and control the length of a hydrophilic side chain of the micelle through different PEGMA structural units added in ARGET ATRP, thereby enhancing the stability of the polymer micelle. The broad-spectrum anticancer drug DOX is loaded in the micelle core, can be stably encapsulated by the micelle at pH7.4 (normal physiological environment), and when the polymer micelle is delivered to a microenvironment (pH 5.0) in a tumor cell, the acid-sensitive acylhydrazone bond is broken to break the bond, so that the micelle structure is broken, and the aims of quick release and accurate delivery of the drug are fulfilled.
According to the pH response crosslinking bond-based hydrophilic side chain-adjustable triblock polymer and the micelle thereof, provided by the invention, the hydrophilic side chain is regulated and controlled to be combined with a crosslinking strategy, the colloid and the structural stability of the micelle are enhanced, the pH response bond breaking is realized in a tumor acidic microenvironment, the rapid release of a drug is promoted, and the pH response crosslinking bond-adjustable triblock polymer is a drug delivery material with application potential.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) The preparation process is simple in flow and mild in condition, can accurately regulate and control the block composition and the polymerization degree of the triblock polymer, changes the length of the hydrophilic side chain of the polymer by adding PEGMA monomers with different numbers of glycol structural units, and accurately regulates and controls the stability of the formed micelle.
(2) The invention simultaneously adopts the strategies of regulating and controlling the length of the hydrophilic side chain and reversible crosslinking, enhances the stability of the polymer micelle to the maximum extent and improves the drug delivery efficiency of the micelle.
(3) The cross-linked bond constructed by the invention is an acylhydrazone bond structure responding to pH, and after the drug-loaded micelle reaches tumor cells, the drug-loaded micelle can respond to the acidic environment in a microenvironment to break, so that the anticancer drug adriamycin is quickly released, and the treatment effect of the chemotherapeutic drug is realized.
Drawings
FIG. 1 shows the nuclear magnetic hydrogen spectrum of the keto-functional monomer OPMA of example 1.
FIG. 2 shows the nuclear magnetic hydrogen spectrum of the triblock polymer PPOEMA-b-POPMA-b-PPEGMA of example 2.
FIG. 3 is the GPC elution curve of the triblock polymer PPOEMA-b-POPMA-b-PPEGMA of example 2.
FIG. 4 is a DLS plot of pH-responsive crosslinked polymer micelles in example 5.
FIG. 5 is a graph showing the stability test of the crosslinked polymer micelle of example 6 in a physiological environment.
FIG. 6 is a TEM image of the drug-loaded cross-linked polymer micelle in example 7.
FIG. 7 is an in vitro release profile of the drug-loaded cross-linked micelle of example 8.
FIG. 8 is a graph of the cytotoxicity test of drug-loaded micelles and free doxorubicin of example 9.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.
Those who do not specify specific conditions in the examples of the present invention follow conventional conditions or conditions recommended by the manufacturer. The raw materials, reagents and the like which are not indicated for manufacturers are all conventional products which can be obtained by commercial purchase.
Example 1: keto-functional monomers (OPMA)
A stirrer, PCC (4.85g, 22.50mmol) and 4.85g of silica gel were put into a 50mL dry eggplant-shaped bottle, argon gas was introduced for 10min, then the bottle was sealed, 50mL of methylene chloride was injected into the bottle by a syringe, the bottle was placed in an ice bath, and a dichloroethane solution of HPMA (2.16mL, 15mmol) (HPMA was dissolved in 10mL of methylene chloride in advance) was added dropwise thereto, and the mixture was reacted at room temperature for 12 hours. To the reaction solution was added 50mL of diethyl ether, and celite was applied on a Buchner funnel, followed by filtration under reduced pressure and retention of the filtrate. The solvent was removed by rotary evaporation, and the resulting liquid was eluted by silica gel column chromatography (mobile phase: n-hexane: ethyl acetate 15. The synthetic reaction formula is shown in formula (1). By nuclear magnetic resonance hydrogen spectroscopy ( 1 H NMR) the structure of the product was characterized and analyzed, and the results are shown in fig. 1.
Figure BDA0003472577830000091
Example 2: preparation of triblock polymer (PPOEM-b-POPMA-b-PPEGMA) (x: y: z =35
Taking 50mL of dry eggplant-shaped bottle, adding a stirrer and a catalyst CuBr into the bottle 2 (5.01mg, 0.022mmol), sealing the reaction bottle, vacuumizing, introducing argon for 3 times, and sequentially adding anhydrous anisole (8 mL) as a solvent, POEMA (3 mL, 15.75mmol) as a monomer and a ligand by using a syringeHMTETA (0.06mL, 0.22mmol) was stirred well for 10min to allow the catalyst complex to form. Then, a reducing agent Sn (Oct) dissolved in advance in 2mL of anhydrous anisole was added 2 (0.07mL, 0.22mmol) and stirred for 10min, after adding the small molecule initiator EBRIB (0.06mL, 0.45mmol) with a micro-syringe, it was transferred to a 40 ℃ oil bath for reaction. After the POEMA reaction was complete, monomer OPMA (0.96g, 6.75mmol) was added and the reaction continued for 15h, monomer PEGMA (Mn =950g/mol,10.66g, 11.25mmol) pre-dissolved in 1mL anhydrous anisole was added and the temperature was adjusted to 60 ℃ and the reaction continued for 72h. After the reaction is completed, cooling the eggplant-shaped bottle to room temperature, adding THF to terminate the reaction, then passing through a neutral alumina column (THF is taken as an eluent), carrying out rotary evaporation and concentration, slowly dropwise adding into ten times of n-hexane for precipitation, and carrying out vacuum drying at 45 ℃ and 35mbar for 24 hours to obtain the product. The synthetic reaction formula is shown in formula (2). By using 1 H NMR, GPC analysis of the composition and structure of the product showed that FIG. 2 and FIG. 3 show that Mn =17.0kDa,
Figure BDA0003472577830000092
Figure BDA0003472577830000093
Figure BDA0003472577830000101
example 3: preparation of triblock polymer (PPOEMA-b-POPMA-b-PPEGMA) (x: y: z =35
Taking 50mL of dry eggplant-shaped bottle, adding a stirrer and a catalyst CuBr 2 (5.01mg, 0.022mmol), sealing the reaction bottle, vacuumizing, introducing argon for 3 times, sequentially adding anhydrous anisole (8 mL) serving as a solvent, POEMA (3 mL, 15.75mmol) serving as a monomer and HMTETA (0.06mL, 0.22mmol) serving as a ligand into the reaction bottle by using a syringe, and fully stirring the mixture for 10min to form a catalyst complex. Then, a reducing agent Sn (Oct) dissolved in advance in 2mL of anhydrous anisole was added 2 (0.07mL, 0.22mmol) and stirred for 10min, and after adding the small molecule initiator EBRIB (0.06mL, 0.45mmol) with a microsyringe, it was transferred to 40 ℃ oilReacting in a bath. After the POEMA reaction is completed, adding monomer OPMA (0.96g, 6.75mmol) and continuing the reaction for 15h, adding monomer PEGMA (Mn =475g/mol,5.33g, 11.25mmol), and adjusting the temperature to 60 ℃ to continue the reaction for 48h. After the reaction is completed, cooling the eggplant-shaped bottle to room temperature, adding THF to terminate the reaction, then passing through a neutral alumina column (THF is taken as an eluent), carrying out rotary evaporation and concentration, slowly dropwise adding into ten times of n-hexane for precipitation, and carrying out vacuum drying at 45 ℃ and 35mbar for 24 hours to obtain the product. The synthetic reaction formula is shown in formula (2). Mn =12.7kDa, and the total molecular weight of the zinc oxide,
Figure BDA0003472577830000102
example 4: preparation of triblock polymer (PPOEMA-b-POPMA-b-PPEGMA) n =5 (x: y: z =35
Taking 50mL of dry eggplant-shaped bottle, adding a stirrer and a catalyst CuBr into the bottle 2 (5.01mg, 0.022mmol), sealing the reaction bottle, vacuumizing, introducing argon for 3 times, adding solvent anhydrous anisole (8 mL), monomer POEMA (3 mL, 15.75mmol) and ligand HMTETA (0.06mL, 0.22mmol) in sequence by using a syringe, and fully stirring for 10min to form the catalyst complex. Then, a reducing agent Sn (Oct) dissolved in 2mL of anhydrous anisole in advance was added 2 (0.07mL, 0.22mmol) and stirred for 5min, and after adding the small molecule initiator EBRIB (0.06mL, 0.45mmol) with a micro syringe, it was transferred to a 40 ℃ oil bath for reaction. After the POEMA reaction was complete, monomer OPMA (0.96g, 6.75mmol) was added and the reaction continued for 15h, monomer PEGMA (Mn =300g/mol,3.37g, 11.25mmol) was added and the temperature was adjusted to 55 ℃ and the reaction continued for 48h. After the reaction is completed, cooling the eggplant-shaped bottle to room temperature, adding THF to terminate the reaction, then passing through a neutral alumina column (THF is taken as an eluent), carrying out rotary evaporation and concentration, slowly dropwise adding into ten times of n-hexane for precipitation, and carrying out vacuum drying at 45 ℃ and 35mbar for 24 hours to obtain the product. The synthetic reaction formula is shown in formula (2). Mn =11.1kDa, and the like,
Figure BDA0003472577830000111
example 5: preparation of pH-responsive crosslinked polymer micelles
The pH response cross-linked polymer micelle is prepared by a dialysis method: the polymer of example 2 (120 mg) was dissolved in 30mL DMSO and transferred into a dialysis bag (MWCO =3.5 kDa) and dialyzed against PBS solution (50 mmol/L, pH 6.5) for 24h. The dialysate was changed every two hours for the first 12h and then every 6h. Subsequently, the micelle solution was transferred to a flask, and 2-amino-5-methoxybenzoic acid (concentration in the micelle solution was 10 mmol/L) as a catalyst was added, and Adipic Dihydrazide (ADH), a crosslinking agent, was prepared as a solution having a concentration of 50mg/mL, and dropped into the flask until the molar ratio of the polymer to the ADH was 2/1. After one day of stirring reaction, the micellar solution was re-dialyzed against deionized water for 12h, with the dialysate replaced every two hours. Finally, the crosslinked micelle solution was filtered with a 0.45 μm aqueous phase microfiltration membrane and freeze-dried to obtain crosslinked polymer micelles.
The particle size and Polydispersity (PDI) of the crosslinked micelles were characterized by Dynamic Light Scattering (DLS). The hydrodynamic diameter (Dh) of the crosslinked micelle was 43.71nm and the PDI was 0.12 (FIG. 4).
Example 6: stability testing of crosslinked Polymer micelles in physiological Environment
The polymer of example 2 (120 mg), the fluorescent dye DiO (150 μ g) and DiI (150 μ g) were taken together and dissolved in 30mL DMSO and stirred for 4h, transferred to a dialysis bag (MWCO =3.5 kDa) and dialyzed against PBS solution (50 mmol/L, pH 6.5) for 24h. The dialysate was changed every two hours for the first 12h and then every 6h. Subsequently, the micelle solution was transferred to a flask, and the catalyst 2-amino-5-methoxybenzoic acid (concentration in the micelle solution was 10 mmol/L) was added to prepare a solution of the crosslinking agent ADH at a concentration of 50mg/mL, and the solution was dropped into the flask until the molar ratio of the polymer to the ADH was 2/1. After one day of stirring reaction, the micellar solution was re-dialyzed with deionized water for 12h, and the dialysate was changed every two hours. And finally, filtering the cross-linked micelle solution by using a 0.45-micron water-phase microporous filter membrane to obtain the cross-linked polymer micelle loaded with the two fluorescent dyes. Then, the filtered micelle solution was taken to prepare 1mL of micelle solution containing 10% Fetal Bovine Serum (FBS), and incubated at 37 ℃ with shaking. And (3) measuring the fluorescence emission intensity of the micellar solution containing 10% Fetal Bovine Serum (FBS) at 490-600 nm under different time by using a molecular fluorometer, and calculating the ratio of the sum of the intensity values at 505nm and 572nm to obtain the FRET efficiency.
As shown in FIG. 5, the FRET efficiency of the cross-linked polymer micelle has no obvious change in 72h of incubation with fetal calf serum, which indicates that the micelle can still maintain good structural stability for a long time under the action of physiological substances such as protein and the like, thereby stably encapsulating the fluorescent dye.
Example 7: preparation of cross-linked polymer micelle loaded with anticancer drug DOX
The drug-loaded cross-linked micelle is prepared by a dialysis method: dissolving 100mg DOX & HCl in 10mL borax buffer salt solution (pH 9.0), stirring at room temperature for 12h, centrifuging at 13000rpm for 15min, and freeze-drying the precipitate to obtain deacidified DOX. Deacidified DOX (36 mg) was then dissolved in 30mL DMSO together with polymer from example 2 (120 mg) and stirred for 4h, transferred to a dialysis bag (MWCO =3.5 kDa) and dialyzed against PBS solution (50 mmol/L, pH 6.5) for 24h. The dialysate was changed every two hours for the first 12h and then every 6h. Subsequently, the micelle solution was transferred to a flask, and the catalyst 2-amino-5-methoxybenzoic acid (concentration in the micelle solution was 10 mmol/L) was added to prepare a solution of the crosslinking agent ADH at a concentration of 50mg/mL, and the solution was dropped into the flask until the molar ratio of the polymer to the ADH was 2/1. After one day of stirring reaction, the micellar solution was re-dialyzed against deionized water for 12h, with the dialysate replaced every two hours. And finally, filtering the cross-linked micelle solution by using a 0.45-micron water-phase microporous filter membrane and carrying out cold drying to obtain the DOX-loaded cross-linked polymer micelle.
1mg of drug-loaded micelle is dissolved in 10mL of DMSO, an ultraviolet-visible spectrophotometer is used for measuring the absorption value of the micelle solution at the wavelength of 480nm, and the drug-Loaded Capacity (LC) and the Encapsulation Efficiency (EE) are calculated, wherein the LC is approximately equal to 11.32 percent, and the EE is approximately equal to 37.73 percent.
And (3) adopting a Transmission Electron Microscope (TEM) to represent the appearance and the particle size of the drug-loaded cross-linked micelle. The drug-loaded cross-linked micelle has a relatively uniform spherical morphology and a particle size of 61.11nm (FIG. 6).
Example 8: in vitro release of drug loaded cross-linked micelles
The drug-loaded cross-linked micelles (3 mg) in example 7 were taken, dispersed in 3mL of PBS solution (pH 7.4) and acetic acid buffer (pH 5.0), respectively, and then transferred to a dialysis bag (MWCO =3.5 kDa), immersed in the corresponding buffer solution (47 mL), and dialyzed at 37 ℃ under 100 rpm. The extra dialysate (4 mL) was taken at selected time points and supplemented with an equal amount of fresh corresponding buffer (4 mL). The in vitro release curves were plotted by measuring the absorbance at 480nm of the dialysate at different times using an ultraviolet-visible spectrophotometer, as shown in FIG. 7.
Example 9: cytotoxicity test
HepG2 cells were assayed at 37 ℃ and 5% CO 2 At the concentration, subculture was carried out using DMEM medium supplemented with 10% FBS, 1% penicillin and streptomycin (penicillin-streptomycin solution (100X), biyuntian C0222 as a raw material). Cells were then plated in 96-well plates at a density of 5000 cells per well and incubated for 24h. After the old media was aspirated and washed, 150 μ L of media containing 10 μ L drug-loaded micelles or free DOX, respectively, was added to the well plate and incubation continued for 24h. Then, the cells were aspirated and washed, 150. Mu.L of the medium containing 10. Mu.L of CCK-8 reagent was added thereto and allowed to act for 3 hours, and the UV absorbance of the well plate at a wavelength of 450nm was measured, and the cell viability at different material concentrations was calculated, as shown in FIG. 8.
Comparative example 1:
preparation of triblock polymer (PPOEMA-b-POPMA-b-PPEGMA) using toluene as a solvent (x: y: z =35
Taking 50mL of dry eggplant-shaped bottle, adding a stirrer and a catalyst CuBr into the bottle 2 (4.01mg, 0.018mmol), sealing the reaction bottle, vacuumizing, introducing argon for 3 times, sequentially adding solvent anhydrous toluene (8 mL), monomer POEMA (3 mL, 15.75mmol) and ligand HMTETA (0.05mL, 0.18mmol) by using an injector, and fully stirring for 10min to form the catalyst complex. Then, a reducing agent Sn (Oct) dissolved in 2mL of anhydrous toluene in advance was added 2 (0.06mL, 0.18mmol) and stirred for 10min, and after adding a small molecule initiator EBRIB (0.06mL, 0.45mmol) by a micro syringe, the mixture was transferred to an oil bath at 80 ℃ and reacted for 6h. Then monomer OPMA (0.96g, 6.75mmol) dissolved in 1mL of anhydrous toluene was added, the temperature was adjusted to 70 ℃ and reaction was continued for 12h, and monomer PEGMA (M) dissolved in 1mL of anhydrous toluene was added n =475g/mol,5.33g, 11.25mmol) continue the reaction for 48h. After the reaction is completed, cooling the eggplant-shaped bottle to room temperature, adding THF to terminate the reaction, then passing through a neutral alumina column (THF is used as an eluent), performing rotary evaporation and concentration, slowly dropwise adding into ten times of n-hexane for precipitation, performing vacuum drying at 45 ℃ under 35mbar for 24 hours,the product is obtained. Analysis of the product composition and Structure by GPC, M n ＝1.77kDa，
Figure BDA0003472577830000131
And the elution curve shows a tailing peak, indicating that the uniformity of the polymer is poor.
Comparative example 2: preparation of DOX-loaded cross-linked polymer micelle
45mg of DOX HCl was dissolved in 15mL of DMSO, and triethylamine (TEA, 1.08 mL) was added and stirred for 24h in the dark. The polymer from example 2 (120 mg) was then dissolved in 15mL DMSO, mixed with the DOX solution described above and stirred for 4h, transferred to a dialysis bag (MWCO =3.5 kDa) and dialyzed against PBS solution (50 mmol/L, pH 6.5) for 24h. The dialysate was changed every two hours for the first 12h and then every 6h. Subsequently, the micelle solution was transferred to a flask, and 2-amino-5-methoxybenzoic acid (concentration in the micelle solution: 10 mmol/L) as a catalyst was added to the solution, and the crosslinking agent ADH was prepared in a solution having a concentration of 50mg/mL, and dropped into the flask until the molar ratio of the polymer to the ADH was 2/1. After one day of stirring reaction, the micellar solution was re-dialyzed against deionized water for 12h, with the dialysate replaced every two hours. And finally, filtering the cross-linked micelle solution by using a 0.45-micron water-phase microporous filter membrane and carrying out cold drying to obtain the DOX-loaded cross-linked polymer micelle.
1mg of drug-loaded micelle is dissolved in 10mL of DMSO, and the absorption value of the micelle solution at the wavelength of 480nm is measured by an ultraviolet-visible spectrophotometer to calculate the drug-Loaded Capacity (LC) and the Encapsulation Efficiency (EE). LC ≈ 3.87%, EE ≈ 10.34%.
Comparative example 3:
preparation of triblock polymer (PPOEMA-b-POPMA-b-PPEGMA) using toluene as solvent (x: y: z =35
Taking 50mL of dry eggplant-shaped bottle, adding a stirrer and a catalyst CuBr into the bottle 2 (5.01mg, 0.022mmol), sealing the reaction bottle, vacuumizing, introducing argon for 3 times, adding solvent anhydrous toluene (8 mL), monomer POEMA (3 mL, 15.75mmol) and ligand HMTETA (0.06mL, 0.22mmol) in sequence by using a syringe, and fully stirring for 10min to form a catalyst complex. Then, a reducing agent Sn (Oct) dissolved in 2mL of anhydrous toluene in advance was added 2 (0.07mL, 0.22mmol) and stirred 1After 0min, a small molecule initiator EBRIB (0.06mL, 0.45mmol) was added by a micro-syringe and transferred to a 40 ℃ oil bath for reaction. Adding monomer OPMA (0.96g, 6.75mmol) after POEMA reaction is completed, continuing reaction for 15h, and adding monomer PEGMA (M) n =475g/mol,5.33g, 11.25mmol) continue the reaction for 48h. After the reaction is completed, the eggplant-shaped bottle is cooled to room temperature and added with THF to terminate the reaction, then the mixture is passed through a neutral alumina column (THF is used as an eluent), and is subjected to rotary evaporation and concentration, and then the mixture is slowly dripped into ten times of n-hexane for precipitation.
The apparent viscosity did not change significantly during the reaction, and no precipitate was formed after dropping into n-hexane, indicating that no polymer was formed. By using 1 H NMR characterizes the structure of the product, peaks at chemical shifts of 5-6 ppm, and shows that a large amount of monomers containing carbon-carbon double bonds still exist, and polymerization does not occur or the polymerization degree is low.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.

Claims (10)

1. A pH-responsive cross-linked bond-based hydrophilic side chain-tunable triblock polymer characterized by the following structural formula:
Figure FDA0003963456650000011
wherein x =15 to 35, y =5 to 20, z =15 to 35, and n is 5 to 20.
2. The method for preparing the triblock polymer with the adjustable hydrophilic side chains based on the pH response cross-linking bonds as claimed in claim 1, which is characterized by comprising the following steps of:
(1) Dissolving pyridinium chlorochromate and silica gel powder in a solvent, adding 2-hydroxypropyl methacrylate under an ice bath condition, and turning to room temperature for continuous reaction to obtain a keto-functionalized monomer 2-oxopropyl methacrylate;
(2) Dissolving a catalyst, 2-phenoxyethyl methacrylate monomer, 1,4,7, 10-hexamethyltriethylene tetramine ligand in a solvent, fully stirring, adding a reducing agent, uniformly stirring, adding a small molecular initiator, heating for reaction, adding the ketone group functionalized monomer 2-oxopropyl methacrylate prepared in the step (1) for continuous reaction after the monomer is completely converted, and adding monomethoxypolyethylene glycol methacrylate monomer for continuous reaction after the monomer is completely converted to obtain the amphiphilic triblock polymer.
3. The method for preparing a triblock polymer with a tunable hydrophilic side chain based on pH response cross-links as claimed in claim 2, wherein the solvent in step (2) is at least one of anisole and N, N-dimethylformamide; the molar volume ratio of the monomer methacrylic acid-2-phenoxyethyl ester to the solvent is 0.52-2.09 mmol/mL.
4. The method for preparing a triblock polymer with adjustable hydrophilic side chains based on pH response cross-linking bonds according to claim 2, wherein the molar ratio of 2-hydroxypropyl methacrylate to pyridinium chlorochromate in the step (1) is 1:1.2 to 2;
the molar ratio of the catalyst in the step (2), 2-phenoxyethyl methacrylate, 1,4,7, 10-hexamethyl triethylene tetramine, a reducing agent, a micromolecule initiator, 2-oxopropyl methacrylate and monomethoxy polyethylene glycol methacrylate is 0.04-0.06: 15 to 35:0.4 to 0.6:0.4 to 0.6:1:5 to 20:15 to 35.
5. The preparation method of the triblock polymer with the adjustable hydrophilic side chains based on the pH response cross-links as claimed in claim 2, wherein the reaction time of the step (1) at room temperature is 12-18 h;
the monomer 2-phenoxyethyl methacrylate in the step (2) is heated to react at the temperature of 40-50 ℃ for 4-10 h; the reaction temperature of the 2-oxo-propyl methacrylate is 40 to 50 ℃ and the reaction time is 12 to 18 hours; the temperature of the reaction of the monomethoxy polyethylene glycol methacrylate is 60-70 ℃, and the time is 36-72 hours.
6. The method for preparing a triblock polymer with tunable hydrophilic side chains based on pH response cross-linking bonds according to claim 2, wherein the solvent in the step (1) is dichloromethane; the molar volume ratio of the pyridinium chlorochromate to the solvent is 0.3-0.5 mmol/mL;
the mass ratio of the silica gel powder to the pyridinium chlorochromate in the step (1) is 1:1;
the catalyst in the step (2) is at least one of copper bromide and copper chloride; the reducing agent is at least one of stannous octoate and ascorbic acid; the small molecular initiator is ethyl bromoisobutyrate;
the reactions in the steps (1) to (2) are carried out under the protection of inert gas and under anhydrous conditions.
7. The application of the triblock polymer with the adjustable hydrophilic side chain based on the pH-responsive cross-linked bond and the pH-responsive cross-linked bond in the loaded poorly water-soluble drug is characterized in that the triblock polymer with the adjustable hydrophilic side chain based on the pH-responsive cross-linked bond and the poorly water-soluble drug in the claim 1 are dissolved in a solvent, are mixed uniformly, are dialyzed in a phosphate buffer solution, are added with a catalyst and a cross-linking agent, are stirred and react at room temperature, and are dialyzed with deionized water to obtain the pH-responsive cross-linked micelle system loaded with the poorly water-soluble drug.
8. The application of the pH-responsive crosslinking bond-based triblock polymer with adjustable hydrophilic side chains to loading of poorly water-soluble drugs according to claim 7, wherein the mass ratio of the pH-responsive crosslinking bond-based triblock polymer with adjustable hydrophilic side chains to the poorly water-soluble drugs is 2-10: 1;
the water-insoluble medicine is a water-insoluble anticancer medicine.
9. The application of the triblock polymer with the adjustable hydrophilic side chain based on the pH response cross-linked bond for loading the poorly water soluble drug is characterized in that the catalyst is 2-amino-5-methoxybenzoic acid; the cross-linking agent is adipic acid dihydrazide; the mole ratio of the pH response crosslinking bond-based hydrophilic side chain-adjustable triblock polymer to the crosslinking agent is 2:1; the concentration of the catalyst in a micelle solution obtained after dialysis in a phosphate buffer salt solution is 8-12 mmol/L;
the stirring reaction time at room temperature is 20-30 h;
the water-insoluble drug is at least one of deacidified adriamycin and paclitaxel.
10. The use of the triblock polymer with tunable hydrophilic side chains based on pH responsive crosslinks as claimed in claim 7 for loading poorly water soluble drugs, wherein the phosphate buffered saline solution has a pH =6.5; the dialysis time in phosphate buffer saline solution is 18-30 h, and the dialysate is replaced once every 2-6 h;
the time of dialysis with deionized water is 10-24 h, and the dialysate is replaced once every 2 h;
the solvent is dimethyl sulfoxide; the mass-to-volume ratio of the hydrophilic side chain adjustable triblock polymer based on pH response crosslinking bonds to the solvent is 4mg/mL.
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