CN110922543B - Six-arm star-shaped amphiphilic polymer, preparation method thereof and prepared nano hydrogel drug-loading system - Google Patents
Six-arm star-shaped amphiphilic polymer, preparation method thereof and prepared nano hydrogel drug-loading system Download PDFInfo
- Publication number
- CN110922543B CN110922543B CN201911053359.4A CN201911053359A CN110922543B CN 110922543 B CN110922543 B CN 110922543B CN 201911053359 A CN201911053359 A CN 201911053359A CN 110922543 B CN110922543 B CN 110922543B
- Authority
- CN
- China
- Prior art keywords
- reaction
- pcl
- arm star
- amphiphilic polymer
- polymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/12—Hydrolysis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2438/00—Living radical polymerisation
- C08F2438/01—Atom Transfer Radical Polymerization [ATRP] or reverse ATRP
Abstract
The invention belongs to the technical field of biomedical high-molecular polymer materials, and discloses a six-arm star-shaped amphiphilic polymer, a preparation method thereof and a nano hydrogel drug-loading system based on the six-arm star-shaped amphiphilic polymer. The six-arm star-shaped amphiphilic polymer has a structure shown in the following formula (I), wherein x is 5-15, y is 50-70, and z is 4-10. The polymer is easy to regulate and control the proportion of each block, and can prepare polymer micelle solution with stable structure and small particle size. The invention also provides the nano drug-loaded hydrogel with the uniform structure prepared based on the polymer micelle solution, and the nano drug-loaded hydrogel with the uniform structure prepared is expected to be applied to a delivery system loaded with hydrophobic anti-tumor drugs.
R4 is:
Description
Technical Field
The invention belongs to the technical field of biomedical high-molecular polymer materials, and particularly relates to a six-arm star-shaped amphiphilic polymer, a preparation method thereof, and a nano hydrogel drug-loading system based on the six-arm star-shaped amphiphilic polymer.
Background
The hydrogel is a material with a three-dimensional cross-linked hydrophilic network prepared by water or a hydrophilic solvent, can entrap various guest molecules with different physicochemical properties by utilizing the structural characteristics of the hydrogel and release the guest molecules in modes of swelling, diffusion, degradation and the like. In the past decades, hydrogels have been extensively studied and developed for wide applications in drug release, perfume release, controlled release of pesticides, and the like. Among the various methods for preparing hydrogels, hydrogels containing polymer nanoparticles, dendrimers, and polymer micelles have unique advantages in many fields because they can entrap both hydrophilic and hydrophobic molecules. When the responsive hydrogel is used for drug loading, the stimulation of the environment such as temperature, pH, reducibility, magnetic field, illumination and the like can cause the change of the aperture, volume and microstructure of the gel, change the internal circulation time of chemotherapeutic drugs, prolong the treatment time and reduce the toxic and side effects, thereby receiving wide attention.
One of the research focuses today on stimulus-responsive hydrogels is the development of dual or multiple stimulus responses, as they can combine two or more stimuli (simultaneously or stepwise), thereby expanding the range of applications. The controllable release of the release behavior of the anti-tumor drug is carried out by combining the change of the pH stimulation signal of the tumor environment and other stimulation responses, and the method is one of the hot spots in the research of an anti-tumor drug delivery system. Patent application CN106237336A discloses the application of pH/temperature dual-responsive nano hydrogel drug-loaded system in breast cancer treatment. Patent CN109864967A application discloses a preparation method of a drug-loaded hydrogel drug-loaded system with pH/temperature dual responsiveness.
And based on polymer micelle crosslinked hydrogel, the hydrogel can show sol-gel transformation under specific conditions, so that the hydrogel can be applied to delivery systems loaded with hydrophobic antitumor drugs. The polymer micelle formed by the star-shaped polymer in the carrier has lower viscosity and more compact molecular topological structure in aqueous solution due to smaller hydrodynamic volume and radius of gyration, and is favorable for forming hydrogel with a three-dimensional network structure. Patent application CN109431971A discloses a drug-loaded hydrogel for local injection, including but not limited to the treatment of solid tumors such as intratumoral injection and paratumoral injection, but no further investigation on its responsiveness is made.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention mainly aims to provide a six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA; the polymer is 6-AS-PCL-PAA-PPEGMA which is a six-arm star-shaped amphiphilic polymer obtained by sequentially polymerizing dipentaerythritol, epsilon-CL, tBA and PEGMA and hydrolyzing.
The invention also aims to provide a preparation method of the six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA. Firstly, initiating caprolactone to generate ring-opening polymerization by hydroxyl of pentaerythritol to synthesize a segment of PCL segmented copolymer to obtain 6-AS-PCL, then reacting the 6-AS-PCL with 2-bromoisobutyryl bromide to functionalize the tail end of the PCL segmented copolymer to obtain 6-AS-PCL-Br, then sequentially carrying out electron transfer activation regeneration atom transfer radical polymerization reaction (ARGET ATRP) polymerization with a monomer (tBA) and a macromonomer monomethoxy polyethylene glycol methacrylate (PEGMA) to obtain 6-AS-PCL-PtBA-PPEGMA, and then adding TFA to hydrolyze the tail end of the BA Ptblock on the basis to obtain a product, namely 6-AS-PCL-PAA-PPEGMA.
The invention also aims to provide a micellar solution based on the six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA; the six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA is dissolved in a solvent to prepare the six-arm star-shaped amphiphilic polymer micelle solution.
The invention further aims to provide a nano hydrogel drug-loading system based on the micelle solution of the polymer. In the six-arm star-shaped amphiphilic polymer micelle, carboxyl in the block PAA can perform a complexing reaction with chelated ferric ions, and finally a nano hydrogel drug-loading system with a uniform structure is formed.
The invention further aims to provide application of the nano hydrogel drug-loading system with the uniform structure in a delivery system for loading a hydrophobic anti-tumor drug.
The purpose of the invention is realized by the following scheme:
a six-arm star-shaped amphiphilic polymer has a structure shown as the following formula (I):
R4comprises the following steps:
wherein x is 5-15, y is 50-70, and z is 4-10.
The preparation method of the six-arm star-shaped amphiphilic polymer comprises the following specific steps:
(1) preparation of 6-AS-PCL: putting dipentaerythritol into a reaction container, sealing, vacuumizing and introducing argon for three times; in an inert gas environment, adding a monomer epsilon-caprolactone (epsilon-CL), performing three times of freezing-air extraction-temperature rise circulation through liquid nitrogen, and reacting in an oil bath to obtain a product 6-AS-PCL;
(2) preparing an initiator 6-AS-PCL-Br: dissolving the 6-AS-PCL prepared in the step (1) in a solvent, introducing argon, sealing, injecting triethylamine, and cooling in an ice water bath; adding 2-bromine isobutyryl bromide, reacting in an ice bath, and reacting at room temperature to obtain an initiator 6-AS-PCL-Br;
(3) preparation of six-arm Star-shaped Polymer 6-AS-PCL-PtBA-PPEGMA: putting the initiator 6-AS-PCL-Br and the catalyst prepared in the step (2) into a reaction vessel, sealing, vacuumizing, introducing argon, sequentially adding a solvent, monomer tert-butyl acrylate (tBA) and part of ligand hexamethyl triethylene tetramine (HMTETA), fully stirring, adding part of reducing agent, stirring, carrying out oil bath reaction, adding monomer monomethoxy polyethylene glycol methacrylate (PEGMA), the rest of ligand hexamethyl triethylene tetramine (HMTETA) and the rest of mixed solution of reducing agent, and continuing to react; after the reaction is finished, performing column chromatography, rotary evaporation, precipitation and vacuum drying to obtain a six-arm star-shaped polymer 6-AS-PCL-PtBA-PPEGMA; the addition amount of the partial ligand hexamethyl triethylene tetramine is 47-75% of the total molar amount of hexamethyl triethylene tetramine, and the addition amount of the residual ligand hexamethyl triethylene tetramine is 25-53% of the total molar amount of hexamethyl triethylene tetramine; the adding amount of the partial reducing agent is 47-75% of the total molar amount of the reducing agent, and the adding amount of the residual reducing agent is 25-53% of the total molar amount of the reducing agent;
(4) preparing a six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA: and (3) adding the six-arm star-shaped polymer prepared in the step (3) into a solvent, stirring until the polymer is dissolved, carrying out ice-water bath, adding trifluoroacetic acid (TFA), carrying out ice-bath reaction, continuing room-temperature reaction, and carrying out rotary evaporation, precipitation and vacuum drying after the reaction is finished to obtain the six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA.
The formula of the reactants in the step (1) in parts by mole is as follows:
1 part of dipentaerythritol
30-90 parts of epsilon-caprolactone;
the formula of the reactants in the step (2) in parts by mole is as follows:
6-AS-PCL 1 part
6-10 parts of triethylamine
6-10 parts of 2-bromoisobutyryl bromide;
the formula of the reactants in the step (3) in parts by mole is as follows:
the formula of the reactants in the step (4) in parts by mole is as follows:
six-arm star polymer 1 part
300-420 parts of trifluoroacetic acid.
The reaction in the oil bath in the step (1) is heating to 130-150 ℃ for 24-48 h.
The ice-bath reaction in the step (2) is reaction for 4-6 hours, and the room-temperature reaction is reaction for 24-48 hours;
the oil bath reaction in the step (3) is heating to 50-80 ℃ for 24-48 h;
the ice-bath reaction in the step (4) is a reaction for 2-5 hours, and the continuous room-temperature reaction is a reaction for 22-24 hours.
The solvent described in step (3) is used to provide a solution reaction environment, and may be an organic solvent commonly used in the art, such as toluene.
The catalyst in the step (3) is a divalent copper catalyst commonly used in the field, such as CuBr2The dosage of the catalyst is catalytic amount.
The reducing agent in the step (3) is a reducing agent commonly used in the field, such as Sn (Oct)2Or ascorbic acid in an amount consistent with the amount of the ligand.
The solvent described in steps (2) and (4) is used to provide a solution reaction environment, and may be an organic solvent commonly used in the art, such as tetrahydrofuran or dichloromethane.
After the reaction in step (1) is completed, the reaction system is preferably purified and dried to obtain a purified product. The purification preferably refers to distilling toluene by adopting a reduced pressure distillation method, dissolving the toluene in tetrahydrofuran, performing rotary evaporation concentration, and adding 10 times of methanol with the volume at 0 ℃ for precipitation.
After the reaction in step (2) is completed, the reaction system is preferably purified and dried to obtain a purified product. The purification preferably refers to removing quaternary ammonium salt by using neutral alumina column, finally performing rotary evaporation concentration, and adding 10 times of volume of 0 ℃ methanol for precipitation.
After the reaction in step (3) is completed, the reaction system is preferably cooled, purified and dried to obtain a purified product. The purification preferably means that the product is dissolved in tetrahydrofuran, then the catalyst is removed through a neutral alumina chromatographic column, and finally the product is concentrated by rotary evaporation and precipitated by adding 10 times of volume of 0 ℃ n-hexane.
After the reaction in step (4) is completed, the reaction system is preferably cooled, purified and dried to obtain a purified product. The purification preferably means that the product is concentrated by rotary evaporation, then dissolved in tetrahydrofuran, and finally precipitated by adding 10 times of volume of 0 ℃ n-hexane.
Preferably, the above reaction is carried out under the protection of inert gas and under anhydrous condition.
A micellar solution based on the six-arm star-shaped amphiphilic polymer is prepared by dissolving the six-arm star-shaped amphiphilic polymer in a solvent.
The nano hydrogel drug-loading system is prepared by respectively dissolving the six-arm star-shaped amphiphilic polymer and water-soluble ferric salt in the same solvent, adding the water-soluble ferric salt solution into the micelle solution of the six-arm star-shaped amphiphilic polymer, and mixing and stirring.
The water-soluble gold salt can be ferric chloride hexahydrate and the like. The solvent is preferably water.
The application of the nano hydrogel drug-loading system of the six-arm star-shaped amphiphilic polymer micellar solution in a delivery system for loading a hydrophobic anti-tumor drug is disclosed. The hydrophobic anti-tumor drug can be added into the polymer micelle solution before mixing and stirring, and then the nano hydrogel drug-loaded product can be obtained after mixing and stirring.
The principle of the invention is as follows:
the invention utilizes pentaerythritol AS initiator to prepare ring-opening polymerization (ROP) and ARGET ATRP to obtain six-arm star-shaped block copolymer 6-AS-PCL-PtBA-PPEGMA with suitable molecular weight, removes tert-butyl on the end of PtBA block by hydrolysis to obtain product 6-AS-PCL-PAA-PPEGMA, and utilizes polyacrylic acid (PAA) block and ferric ion (Fe) in polymer micelle3+) The coordination interaction between the iron ions and the iron ions (Fe) is introduced in the presence of citric acid3+) And, finally,the polymer hydrogel is prepared, the hydrogel is based on 6-AS-PCL-PAA-PPEGMA micelle crosslinking of a six-arm star-shaped amphiphilic polymer, can show sol-gel transformation under specific conditions, the segmented PCL has biodegradability and good drug permeability and nontoxicity, the segmented PEGMA has nontoxicity, nonimmunity and antigenicity, and the polymer is expected to be applied to a delivery system loaded with hydrophobic antitumor drugs.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the preparation method has mild reaction conditions, simple operation, easy regulation of the polymerization degree of each block of the star polymer and adjustable molecular weight in a wider range.
(2) The block PCL and PEGMA contained in the six-arm star-shaped amphiphilic polymer prepared by the invention have no toxicity.
(3) The nano drug-loaded hydrogel prepared by the invention is degradable, has pH responsiveness, and provides a valuable preparation technology for a delivery system loaded with a hydrophobic anti-tumor drug.
Drawings
FIG. 1 shows the nuclear magnetic hydrogen spectra of 6-AS-PCL, 6-AS-PCL-Br, 6-AS-PCL-PtBA-PPEGMA, and 6-AS-PCL-PAA-PPEGMA in example 1, wherein A is 6-AS-PCL, B is 6-AS-PCL-Br, C is 6-AS-PCL-PtBA-PPEGMA, and D is 6-AS-PCL-PAA-PPEGMA.
FIG. 2 is a GPC chart of 6-AS-PCL, 6-AS-PCL-Br, 6-AS-PCL-PtBA-PPEGMA, and 6-AS-PCL-PAA-PPEGMA in example 1.
FIG. 3 is a DLS diagram of a six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA micelle in example 4.
FIG. 4 shows the addition of Fe in example 53+Drug-loaded gel diagram of before, after and blank of/citrate, wherein A is adding Fe3+Before/citrate, B is Fe3+After/citrate, C is blank.
FIG. 5 is a graph of the cumulative drug release profile of the DOX gel of example 6 under five different conditions, pH 7.4, pH 5.0+ VC, pH 7.4+ UV irradiation and pH 5.0+ VC + UV irradiation.
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.
The sources of reagents used in the following examples are all commercially available.
Example 1: preparation of six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA
(1) Preparing a macroinitiator 6-AS-PCL: a100 mL dry reaction flask was taken, baked for 10 minutes with an alcohol burner and then cooled, and a stirrer and an initiator dipentaerythritol (1.27g, 5mmol) were added to the reaction flask and sealed with a rubber stopper. Vacuumizing, introducing argon for 3 times, adding monomer epsilon-caprolactone (34.22g, 300mmol) under the protection of argon, performing three freezing-air extraction-temperature rise cycles by using liquid nitrogen, placing in an oil bath at 150 ℃ under the protection of argon, heating for 20 minutes, and then adding Sn (Oct)2(0.1 wt% of ε -CL,0.03g), followed by reaction for 24h, heating was stopped, the eggplant-shaped bottle was cooled, 30mL of anhydrous THF was added to dissolve the white viscous solid, the solution was precipitated in 300mL of cold methanol/water (1:1, v/v) and filtered to remove unreacted monomer and catalyst, and the product was dried under vacuum to give a white powdery solid (or the product was dried under vacuum at 40 ℃ C. and 35mb for 24 h). The synthetic reaction formula is shown in formula (1). The molecular structure and composition were analyzed by nuclear magnetism, and the results are shown in FIG. 1; the synthesis of polymer 6-AS-PCL was analyzed by GPC and the results are shown in FIG. 2.
R1Comprises the following steps:
(2) preparation of 6-AS-PCL-Br: a250 mL three-neck flask is taken, a stirrer is added, the prepared 6AS-PCL (13.09g, 2mmol) is weighed and added into a reaction bottle, THF (100mL) is added AS a solvent, argon is introduced for 10min, TEA (5.56mL, 40mmol) is injected into the flask after the flask is sealed, the temperature is cooled to 0 ℃ by using an ice water bath, then 2-bromoisobutyryl bromide (4.94mL, 40mmol) is dropwise added into the flask by using a syringe, and the mixture reacts at 0 ℃ for 5h and then at room temperature for 36 h. The resulting reaction solution was filtered through a neutral alumina column to remove the quaternary ammonium salt, then the excess solvent was removed by rotary evaporation, followed by precipitation with cold methanol/water (1:1, v/v) and vacuum drying. The synthesis reaction is shown in formula (2). The molecular structure and composition were analyzed by nuclear magnetism, and the results are shown in FIG. 1; the synthesis of polymer 6-AS-PCL-Br was analyzed by GPC, and the results are shown in FIG. 2.
R1Comprises the following steps:
R2comprises the following steps:
(3) preparing a six-arm star polymer 6-AS-PCL-PtBA-PPEGMA: 100mL of dry eggplant-shaped bottle is put into a stirrer, and the prepared initiator 6-AS-PCL-Br (2.98g, 0.4mmol) and CuBr are weighed2(0.018g, 0.08mmol) was placed in an eggplant-shaped bottle and then sealed with a rubber stopper on the back, and vacuum-evacuated and argon-purged three times. Anhydrous toluene (20mL), monomer tBA (18.45g,144mmol) and ligand HMTETA (0.42mL, 1.56mmol) pre-dissolved in 2mL of anhydrous toluene were added to the flask in sequence by syringe and stirred for 15min to form the catalyst complex Cu/HMTETA. Then reducing agent Sn (Oct)2(0.51mL,1.56mmol) is dissolved in toluene (1mL) and added into a reaction bottle, stirred for 5min and then transferred into an oil bath at 70 ℃ to be stirred for reaction for a certain time. After 80% conversion had been achieved, monomer PEGMA (5.7g,12mmol) and ligand HMTETA (0.195mL, 0.72mmol) pre-dissolved in 2mL of anhydrous toluene and reducing agent Sn (Oct) were added2The mixture (0.24mL, 0.72mmol) was reacted for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, 50mL of THF was added and the reaction mixture was dissolved with stirring, and then the catalyst was removed by filtration through a neutral alumina column (using THF as an eluent). Removing excessive solvent by rotary evaporation, slowly adding the obtained concentrated solution into 300mL cold n-hexane for precipitation to remove impurities such as small molecular monomerAnd (4) quality. The product was dried under vacuum at 45 ℃ and 35mb for 24 hours. The synthetic reaction formula is shown in formula (3). The molecular structure and composition were analyzed by nuclear magnetism, and the results are shown in FIG. 1; the synthesis of polymer 6-AS-PCL-PtBA-PPEGMA was analyzed by GPC and the results are shown in FIG. 2.
R2Comprises the following steps:
R3comprises the following steps:
(4) preparing a six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA: 6-AS-PCL-PtBA-PPEGMA (3.14g,0.05mmol) was added to a 100mL flask, a stirrer was added, anhydrous dichloromethane (20mL) was added to dissolve the polymer, the mixture was cooled to 0 ℃ with an ice water bath (sodium chloride was added to retard freezing time), TFA (5.74mL,75mmol) was added dropwise slowly with rapid stirring, and after 3h reaction at 0 ℃ the mixture was reacted at room temperature for 23 h. And removing the solvent from the obtained reaction solution by rotary evaporation, dissolving with THF, precipitating with cold n-hexane, and finally vacuum drying at 40 ℃ and 35mb for 24h to obtain the final target polymer. The synthetic reaction formula is shown in formula (4). The molecular structure and composition were analyzed by nuclear magnetism, and the results are shown in FIG. 1; the synthesis of polymer 6-AS-PCL-PAA-PPEGMA was analyzed by GPC, and the results are shown in FIG. 2.
R3Comprises the following steps:
R4comprises the following steps:
wherein x is 10, y is 60, and z is 5.
Example 2: preparation of six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA
(1) Preparing a macroinitiator 6-AS-PCL: a100 mL dry reaction flask was taken, baked for 10 minutes with an alcohol burner and then cooled, and a stirrer and an initiator dipentaerythritol (1.27g, 5mmol) were added to the reaction flask and sealed with a rubber stopper. Vacuumizing, introducing argon for 3 times, adding monomer epsilon-caprolactone (17.11g, 150mmol) under the protection of argon, performing three freezing-air extraction-temperature rise cycles by using liquid nitrogen, placing in an oil bath at 130 ℃ under the protection of argon, heating for 20 minutes, and then adding Sn (Oct)2(0.1 wt% of ε -CL,0.03g), followed by reaction for 24h, heating was stopped, the eggplant-shaped bottle was cooled, 30mL of anhydrous THF was added to dissolve the white viscous solid, the solution was precipitated in 300mL of cold methanol/water (1:1, v/v) and filtered to remove unreacted monomer and catalyst, and the product was dried under vacuum to give a white powdery solid (or the product was dried under vacuum at 40 ℃ C. and 35mb for 24 h). The synthetic reaction formula is shown in formula (1).
(2) Preparation of 6-AS-PCL-Br: a250 mL three-neck flask is taken, a stirrer is added, the prepared 6AS-PCL (13.09g, 2mmol) is weighed and added into a reaction bottle, THF (100mL) is added AS a solvent, argon is introduced for 10min, TEA (5.56mL, 40mmol) is injected into the flask after the flask is sealed, the temperature is cooled to 0 ℃ by using an ice water bath, then 2-bromoisobutyryl bromide (4.94mL, 40mmol) is dropwise added into the flask by using a syringe, and the mixture reacts at 0 ℃ for 4h and then at room temperature for 24 h. The resulting reaction solution was filtered through a neutral alumina column to remove the quaternary ammonium salt, then the excess solvent was removed by rotary evaporation, followed by precipitation with cold methanol/water (1:1, v/v) and vacuum drying. The synthesis reaction is shown in formula (2).
(3) Preparing a six-arm star polymer 6-AS-PCL-PtBA-PPEGMA: 100mL of dry eggplant-shaped bottle is put into a stirrer, and the prepared initiator 6-AS-PCL-Br (2.98g, 0.4mmol) and CuBr are weighed2(0.018g, 0.08mmol) was placed in an eggplant-shaped bottle and then sealed with a rubber stopper on the back, and vacuum-evacuated and argon-purged three times. Anhydrous toluene (20mL), monomer tBA (21.53g,168mmol) and a formulation predissolved in 2mL of anhydrous toluene were combined in sequence by syringeBulk HMTETA (0.50mL, 1.84mmol) was added to the flask and stirred for 15min to form the catalyst complex Cu/HMTETA. Then reducing agent Sn (Oct)2(0.060mL,1.84mmol) is dissolved in toluene (1mL) and added into a reaction bottle, stirred for 5min and then transferred into an oil bath at 80 ℃ to be stirred and reacted for a certain time. After 80% conversion had been reached, monomer PEGMA (11.4g,24mmol) and ligand HMTETA (0.39mL, 1.44mmol) pre-dissolved in 2mL of anhydrous toluene and reducing agent Sn (Oct) were added2The mixture (0.47mL, 1.44mmol) was reacted for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, 50mL of THF was added and the reaction mixture was dissolved with stirring, and then the catalyst was removed by filtration through a neutral alumina column (using THF as an eluent). After removing excessive solvent by rotary evaporation, the obtained concentrated solution is slowly added into 300mL of cold n-hexane for precipitation so as to remove impurities such as small molecular monomers. The product was dried under vacuum at 45 ℃ and 35mb for 24 hours. The synthetic reaction formula is shown in formula (3).
(4) Preparing a six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA: 6-AS-PCL-PtBA-PPEGMA (3.14g,0.05mmol) was added to a 100mL flask, a stirrer was added, anhydrous dichloromethane (20mL) was added to dissolve the polymer, the mixture was cooled to 0 ℃ with an ice water bath (sodium chloride was added to retard freezing time), TFA (5.74mL,75mmol) was added dropwise slowly with rapid stirring, and after 5h reaction at 0 ℃ the mixture was allowed to react at room temperature for 24 h. And removing the solvent from the obtained reaction solution by rotary evaporation, dissolving with THF, precipitating with cold n-hexane, and finally vacuum drying at 40 ℃ and 35mb for 24h to obtain the final target polymer. The synthesis reaction formula is shown in formula (4), wherein x is 5, y is 70, and z is 10.
Example 3: preparation of six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA
(1) Preparing a macroinitiator 6-AS-PCL: a100 mL dry reaction flask was taken, baked for 10 minutes with an alcohol burner and then cooled, and a stirrer and an initiator dipentaerythritol (1.27g, 5mmol) were added to the reaction flask and sealed with a rubber stopper. Vacuumizing, introducing argon for 3 times, adding a monomer epsilon-caprolactone (51.33g, 450mmol) under the protection of argon, performing three freezing-air extraction-temperature rise cycles by using liquid nitrogen, placing the mixture in an oil bath at 130 ℃ under the protection of argon, heating for 20 minutes, adding Sn (Oct)2(0.1 wt% of epsilon-CL, 0.03g), stopping heating after reacting for 48 hours, cooling the eggplant-shaped bottle, adding 30mL of anhydrous THF to dissolve a white viscous solid, precipitating in 300mL of cold methanol/water (1:1, v/v), filtering to remove unreacted monomers and a catalyst, and performing vacuum drying to obtain a white powdery solid (or performing vacuum drying on the product at 40 ℃ and 35mb for 24 hours). The synthetic reaction formula is shown in formula (1).
(2) Preparation of 6-AS-PCL-Br: a250 mL three-neck flask is taken, a stirrer is added, the prepared 6AS-PCL (13.09g, 2mmol) is weighed and added into a reaction bottle, THF (100mL) is added AS a solvent, argon is introduced for 10min, TEA (5.56mL, 40mmol) is injected into the flask after the flask is sealed, the temperature is cooled to 0 ℃ by using an ice water bath, then 2-bromoisobutyryl bromide (4.94mL, 40mmol) is dropwise added into the flask by using a syringe, and the mixture reacts at 0 ℃ for 6h and then at room temperature for 48 h. The resulting reaction solution was filtered through a neutral alumina column to remove the quaternary ammonium salt, then the excess solvent was removed by rotary evaporation, followed by precipitation with cold methanol/water (1:1, v/v) and vacuum drying. The synthesis reaction is shown in formula (2).
(3) Preparing a six-arm star polymer 6-AS-PCL-PtBA-PPEGMA: 100mL of dry eggplant-shaped bottle is put into a stirrer, and the prepared initiator 6-AS-PCL-Br (2.98g, 0.4mmol) and CuBr are weighed2(0.018g, 0.08mmol) was placed in an eggplant-shaped bottle and then sealed with a rubber stopper on the back, and vacuum-evacuated and argon-purged three times. Anhydrous toluene (20mL), monomer tBA (15.38g,120mmol) and ligand HMTETA (0.36mL, 1.32mmol) pre-dissolved in 2mL of anhydrous toluene were added to the flask in sequence with a syringe and stirred for 15min to form the catalyst complex Cu/HMTETA. Then reducing agent Sn (Oct)2(0.43mL,1.32mmol) is dissolved in toluene (1mL) and added into a reaction bottle, stirred for 5min and then transferred into an oil bath at 50 ℃ to be stirred for reaction for a certain time. After 80% conversion had been reached, monomer PEGMA (4.56g,9.6mmol) and ligand HMTETA (0.16mL, 0.6mmol) pre-dissolved in 2mL of anhydrous toluene and reducing agent Sn (Oct) were added2The mixture (0.20mL, 0.6mmol) was reacted for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, 50mL of THF was added and the reaction mixture was dissolved with stirring, and then the catalyst was removed by filtration through a neutral alumina column (using THF as an eluent). After removing excessive solvent by rotary evaporation, the obtained concentrated solution is slowly added into 300mL of cold n-hexane for precipitation so as to remove impurities such as small molecular monomers. The product is in 4Vacuum drying at 5 deg.C and 35mb for 24 hr.
(4) Preparing a six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA: 6-AS-PCL-PtBA-PPEGMA (3.14g,0.05mmol) was added to a 100mL flask, a stir bar was added, anhydrous dichloromethane (20mL) was added to dissolve the polymer, the mixture was cooled to 0 ℃ with ice water bath (sodium chloride was added to delay freezing time), TFA (5.74mL,75mmol) was added dropwise slowly with rapid stirring, and after 2h reaction at 0 ℃ the mixture was allowed to react at room temperature for 22 h. And removing the solvent from the obtained reaction solution by rotary evaporation, dissolving with THF, precipitating with cold n-hexane, and finally vacuum drying at 40 ℃ and 35mb for 24h to obtain the final target polymer. The synthesis reaction formula is shown in formula (4), wherein x is 15, y is 50, and z is 4.
Example 4: preparation of amphiphilic star polymer 6-AS-PCL-PAA-PPEGMA micellar solution
Weighing the prepared amphiphilic star polymer 6-AS-PCL-PAA-PPEGMA (687.7mg,0.015mmol), dissolving in 30mL of anhydrous dichloromethane, adding 10mL of deionized water, stirring for 24h, and volatilizing dichloromethane to form a polymer micelle solution.
Testing the particle size and the potential of the star polymer 6-AS-PCL-PAA-PPEGMA in the aqueous solution by using Dynamic Light Scattering (DLS), diluting 0.5mL of polymer micelle solution into 1mg/mL, stabilizing for 24h, and testing the particle size and the potential of the star polymer in the aqueous solution by using the DLS at room temperature; the particle size was found to be 175nm (see FIG. 3), PDI was found to be 0.145, and the potential was found to be-30.19 mV, which is a suitable nanopolymer for antitumor drug carriers.
Example 5: preparation of blank and DOX loaded nanogels
5mL of the polymer micelle solution was taken, and 0.5mL of ferric chloride hexahydrate (FeCl) previously used was added thereto under rapid stirring3·6H20) Ferric citrate solution (Fe) prepared by mixing citric acid monohydrate3+＝0.02mol/L，Fe3+Molar ratio to Citrate is l: 2, rapidly stirring the solution with pH 4), gradually increasing the solution viscosity after a few minutes, standing the solution and converting the solution into gel, namely obtaining blank nanogel; doxorubicin (50mg) was added to 5mL of the polymer micelle solution, and 0.5mL of ferric chloride hexahydrate (FeCl) previously added under rapid stirring3·6H20) Ferric citrate solution (Fe) prepared by mixing citric acid monohydrate3+＝0.02mol/L，Fe3+Molar ratio to Citrate is l: 2, solution pH 4), stirring rapidly, solution viscosity gradually increased after a few minutes, and was converted to DOX loaded nanogel after standing, results are shown in fig. 4.
Example 6: in vitro Release assay
Dispersing 25mg DOX loaded nanogel into 10mL PBS buffer solution, and then dividing into five equal parts;
(1) two gel liquid samples are taken and firstly irradiated by ultraviolet light with the irradiation power of 300mW/cm2The irradiation time was 15min, and then the cells were transferred into dialysis bags, which were placed in 48mL PBS phosphate buffer (pH 7.4) and acetate buffer (pH 5.0+1mg/mL of Vitamin C) respectively and then placed in a shaker, and the in vitro release was carried out at 37 ℃ and 100rpm, and 2mL samples were periodically taken, and its absorbance at 480nm was measured in an UV-visible spectrophotometer, and 2mL of fresh buffer was added to keep the total volume of the solution constant.
(2) Taking other three gel liquid samples, transferring into a dialysis bag, respectively putting the dialysis bag into 48mL of phosphate buffer solution (pH 7.4), acetic acid buffer solution (pH 5.0) and acetic acid buffer solution (pH 5.0+1mg/mL of Vitamin C), placing into a shaking table, carrying out in-vitro release at 37 ℃ and 100rpm, periodically sampling 2mL, measuring the absorbance at 480nm on an ultraviolet-visible spectrophotometer, and supplementing 2mL of fresh buffer solution in order to keep the total volume of the solution unchanged. The cumulative released amount Er of DOX was calculated by the following formula.
In the formula, Er: cumulative amount of released DOX,%; ve: displacement volume of buffer, 4.0m L; v0: volume of release medium, 100m L; ci: the concentration of DOX in the release solution is g/mL in the ith replacement sampling; m isDOX: mass of DOX in drug loaded micelle for release, g; n: n is the number of times the buffer was replaced. In order to evaluate the drug release performance of nanogel 6-AS-PCL-PAA-PPEGMA, the carrier was studiedThe DOX gel showed drug release behavior under five different conditions of pH 7.4, pH 5.0, pH 5.0+ VC, pH 7.4+ UV irradiation and pH 5.0+ VC + UV irradiation, and the results are shown in FIG. 5.
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 changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. A six-arm star-shaped amphiphilic polymer is characterized by having a structure shown as the following formula (I):
R4comprises the following steps:
wherein x is 5-15, y is 50-70, and z is 4-10.
2. The preparation method of the six-arm star-shaped amphiphilic polymer according to claim 1, which is characterized by comprising the following specific steps of:
(1) preparation of 6-AS-PCL: putting dipentaerythritol into a reaction container, sealing, vacuumizing and introducing argon for three times; in an inert gas environment, adding a monomer epsilon-caprolactone, performing three times of freezing-air extraction-temperature rise circulation through liquid nitrogen, and reacting in an oil bath to obtain a product 6-AS-PCL;
(2) preparing an initiator 6-AS-PCL-Br: dissolving the 6-AS-PCL prepared in the step (1) in a solvent, introducing argon, sealing, injecting triethylamine, and cooling in an ice water bath; adding 2-bromine isobutyryl bromide, reacting in an ice bath, and reacting at room temperature to obtain an initiator 6-AS-PCL-Br;
(3) preparation of six-arm Star-shaped Polymer 6-AS-PCL-PtBA-PPEGMA: putting the initiator 6-AS-PCL-Br and the catalyst prepared in the step (2) into a reaction vessel, sealing, vacuumizing, introducing argon, sequentially adding a solvent, monomer tert-butyl acrylate and part of ligand hexamethyl triethylene tetramine, fully stirring, adding part of reducing agent, stirring, carrying out oil bath reaction, adding a mixed solution of monomer monomethoxy polyethylene glycol methacrylate, the rest of ligand hexamethyl triethylene tetramine and the rest of reducing agent, and continuing to react; after the reaction is finished, performing column chromatography, rotary evaporation, precipitation and vacuum drying to obtain a six-arm star-shaped polymer 6-AS-PCL-PtBA-PPEGMA; the addition amount of the partial ligand hexamethyl triethylene tetramine is 47-75% of the total molar amount of hexamethyl triethylene tetramine, and the addition amount of the residual ligand hexamethyl triethylene tetramine is 25-53% of the total molar amount of hexamethyl triethylene tetramine; the adding amount of the partial reducing agent is 47-75% of the total molar amount of the reducing agent, and the adding amount of the residual reducing agent is 25-53% of the total molar amount of the reducing agent;
(4) preparing a six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA: and (3) adding the six-arm star-shaped polymer prepared in the step (3) into a solvent, stirring until the polymer is dissolved, carrying out ice-water bath, adding trifluoroacetic acid, carrying out ice-bath reaction, continuing room-temperature reaction, and carrying out rotary evaporation, precipitation and vacuum drying after the reaction is finished to obtain the six-arm star-shaped amphiphilic polymer 6-AS-PCL-PAA-PPEGMA.
3. The method of preparing the six-armed star-shaped amphiphilic polymer of claim 2, wherein:
the formula of the reactants in the step (1) in parts by mole is as follows:
1 part of dipentaerythritol
30-90 parts of epsilon-caprolactone;
the formula of the reactants in the step (2) in parts by mole is as follows:
6-AS-PCL 1 part
6-10 parts of triethylamine
6-10 parts of 2-bromoisobutyryl bromide;
the formula of the reactants in the step (3) in parts by mole is as follows:
the formula of the reactants in the step (4) in parts by mole is as follows:
1 part of six-arm star-shaped polymer
300-420 parts of trifluoroacetic acid.
4. The method of preparing the six-armed star-shaped amphiphilic polymer of claim 2, wherein: the dosage of the reducing agent in the step (3) is the same as that of the ligand hexamethyltriethylenetetramine.
5. The method of preparing the six-armed star-shaped amphiphilic polymer of claim 2, wherein: the reaction in the oil bath in the step (1) is heating to 130-150 ℃ for 24-48 h.
6. The method of preparing the six-armed star-shaped amphiphilic polymer of claim 2, wherein: the ice-bath reaction in the step (2) is reaction for 4-6 hours, and the room-temperature reaction is reaction for 24-48 hours; the oil bath reaction in the step (3) is heating to 50-80 ℃ for 24-48 h; the ice-bath reaction in the step (4) is a reaction for 2-5 hours, and the continuous room-temperature reaction is a reaction for 22-24 hours.
7. A micellar solution based on the six-arm star-shaped amphiphilic polymer according to claim 1, characterized in that it is prepared by dissolving the six-arm star-shaped amphiphilic polymer in a solvent.
8. The six-arm star-shaped amphiphilic polymer micelle solution nano hydrogel drug-loading system is characterized in that the nano hydrogel drug-loading system is obtained by respectively dissolving the six-arm star-shaped amphiphilic polymer and water-soluble ferric salt in the same solvent, adding the water-soluble ferric salt solution into the six-arm star-shaped amphiphilic polymer micelle solution, mixing and stirring.
9. The application of the nano hydrogel drug-loaded system of the micellar solution of the six-arm star-shaped amphiphilic polymer according to claim 8 in a delivery system loaded with a hydrophobic anti-tumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911053359.4A CN110922543B (en) | 2019-10-31 | 2019-10-31 | Six-arm star-shaped amphiphilic polymer, preparation method thereof and prepared nano hydrogel drug-loading system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911053359.4A CN110922543B (en) | 2019-10-31 | 2019-10-31 | Six-arm star-shaped amphiphilic polymer, preparation method thereof and prepared nano hydrogel drug-loading system |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110922543A CN110922543A (en) | 2020-03-27 |
| CN110922543B true CN110922543B (en) | 2022-03-25 |
Family
ID=69850082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911053359.4A Active CN110922543B (en) | 2019-10-31 | 2019-10-31 | Six-arm star-shaped amphiphilic polymer, preparation method thereof and prepared nano hydrogel drug-loading system |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110922543B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117645698A (en) * | 2024-01-29 | 2024-03-05 | 广东工业大学 | Amphiphilic 21-arm photosensitizer-prodrug star polymer and preparation method and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102633959A (en) * | 2012-03-27 | 2012-08-15 | 华南理工大学 | PH-responsive comb-like copolymer and preparation and application thereof |
| CN102702453A (en) * | 2012-06-11 | 2012-10-03 | 华南理工大学 | pH-responsive 6-arm star block copolymer and preparation method and application thereof |
| CN106237336A (en) * | 2016-07-29 | 2016-12-21 | 金陵科技学院 | A kind of breast carcinoma combined chemotherapy nano combined Graphene aquogel system and preparation method thereof |
| CN107141488A (en) * | 2017-07-03 | 2017-09-08 | 陕西师范大学 | Multiple stimulation response shell-crosslinked polymeric micelles and preparation method thereof |
| CN109431971A (en) * | 2018-10-19 | 2019-03-08 | 广州医科大学 | A kind of injectable carries liquid medicine gel and preparation method thereof |
| CN109864967A (en) * | 2019-03-04 | 2019-06-11 | 金陵科技学院 | A kind of temperature/pH responsiveness carboxylated nano-hydrogel and preparation method thereof |
-
2019
- 2019-10-31 CN CN201911053359.4A patent/CN110922543B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102633959A (en) * | 2012-03-27 | 2012-08-15 | 华南理工大学 | PH-responsive comb-like copolymer and preparation and application thereof |
| CN102702453A (en) * | 2012-06-11 | 2012-10-03 | 华南理工大学 | pH-responsive 6-arm star block copolymer and preparation method and application thereof |
| CN106237336A (en) * | 2016-07-29 | 2016-12-21 | 金陵科技学院 | A kind of breast carcinoma combined chemotherapy nano combined Graphene aquogel system and preparation method thereof |
| CN107141488A (en) * | 2017-07-03 | 2017-09-08 | 陕西师范大学 | Multiple stimulation response shell-crosslinked polymeric micelles and preparation method thereof |
| CN109431971A (en) * | 2018-10-19 | 2019-03-08 | 广州医科大学 | A kind of injectable carries liquid medicine gel and preparation method thereof |
| CN109864967A (en) * | 2019-03-04 | 2019-06-11 | 金陵科技学院 | A kind of temperature/pH responsiveness carboxylated nano-hydrogel and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| Redox-Responsive Gel-Sol/Sol-Gel Transition in Poly(acrylic acid) Aqueous Solution Containing Fe(III) Ions Switched by Light;Fei Peng, et al.;《Journal of the American Chemical Society》;20081110;第130卷(第48期);第16166-16167页 * |
| Star-Shaped Drug Carriers for Doxorubicin with POEGMA and POEtOxMA Brush-like Shells: A Structural, Physical, and Biological Comparison;Katrin Knop, et al.;《Biomacromolecules》;20130621;第14卷;第2536-2548页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110922543A (en) | 2020-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tan et al. | An insight into aqueous photoinitiated polymerization-induced self-assembly (photo-PISA) for the preparation of diblock copolymer nano-objects | |
| CN104758247B (en) | A kind of pH responsive polymers mixed micelle and its application | |
| Yuan et al. | Light-and pH-dually responsive dendrimer-star copolymer containing spiropyran groups: synthesis, self-assembly and controlled drug release | |
| Yuan et al. | Amphiphilic block copolymer terminated with pyrene group: from switchable CO 2-temperature dual responses to tunable fluorescence | |
| Wang et al. | Synthesis and pH/sugar/salt-sensitivity study of boronate crosslinked glycopolymer nanoparticles | |
| CN111991563A (en) | PH response type nano-drug delivery system and preparation method thereof | |
| Bian et al. | Thermoresponsive biotinylated star amphiphilic block copolymer: Synthesis, self-assembly, and specific target recognition | |
| Hu et al. | Preparation of hyperstar polymers with encapsulated Au 25 (SR) 18 clusters as recyclable catalysts for nitrophenol reduction | |
| CN110922543B (en) | Six-arm star-shaped amphiphilic polymer, preparation method thereof and prepared nano hydrogel drug-loading system | |
| Jiang et al. | Covalently stabilized temperature and pH responsive four-layer nanoparticles fabricated from surface ‘clickable’shell cross-linked micelles | |
| Yuan et al. | A star-shaped amphiphilic block copolymer with dual responses: synthesis, crystallization, self-assembly, redox and LCST–UCST thermoresponsive transition | |
| Liu et al. | A one-pot synthesis of oleic acid end-capped temperature-and pH-sensitive amphiphilic polymers | |
| Yan et al. | Construction of polymer–paclitaxel conjugate linked via a disulfide bond | |
| Li et al. | Synthesis and self-assembly behavior of pH-responsive star-shaped POSS-(PCL-P (DMAEMA-co-PEGMA)) 16 inorganic/organic hybrid block copolymer for the controlled intracellular delivery of doxorubicin | |
| Tapdiqov | A drug-loaded gel based on graft radical co-polymerization of n-vinylpyrrolidone and 4-vinylpyridine with chitosan | |
| CN114507326B (en) | pH response crosslinking bond-based hydrophilic side chain-adjustable triblock polymer and preparation and application thereof | |
| CN109134870B (en) | pH response polymer carrier, micelle prepared from pH response polymer carrier, preparation method and application | |
| Soleimani et al. | Photodegradable poly (ester amide) s for indirect light-triggered release of paclitaxel | |
| CN111154084A (en) | Preparation of PVA reversible crosslinked drug-loaded micelle with triple response | |
| He et al. | Sodium Bis (acyl) phosphane oxide (SBAPO): An efficient photoinitiator for blue light initiated aqueous RAFT dispersion polymerization | |
| Zhang et al. | Preparation of core cross-linked PCL-PEG-PCL micelles for doxorubicin delivery in vitro | |
| Chen et al. | Synthesis and characterization of a pentaerythritol-based amphiphilic star block copolymer and its application in controlled drug release | |
| Weiss-Maurin et al. | Direct one-pot synthesis of poly (ionic liquid) nanogels by cobalt-mediated radical cross-linking copolymerization in organic or aqueous media | |
| Luo et al. | Mediating physicochemical properties and paclitaxel release of pH-responsive H-type multiblock copolymer self-assembly nanomicelles through epoxidation | |
| Chen et al. | Amphiphilic block copolymer micelles with fluorescence as nano-carriers for doxorubicin delivery |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |