CN114605600B - Esterase-response amphiphilic linear polymer and preparation method and application thereof - Google Patents

Esterase-response amphiphilic linear polymer and preparation method and application thereof Download PDF

Info

Publication number
CN114605600B
CN114605600B CN202210052436.XA CN202210052436A CN114605600B CN 114605600 B CN114605600 B CN 114605600B CN 202210052436 A CN202210052436 A CN 202210052436A CN 114605600 B CN114605600 B CN 114605600B
Authority
CN
China
Prior art keywords
esterase
solvent
linear polymer
micelle
catalyst
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
Application number
CN202210052436.XA
Other languages
Chinese (zh)
Other versions
CN114605600A (en
Inventor
章莉娟
裴公萃
张富盛
黄柏浩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
South China University of Technology SCUT
Original Assignee
South China University of Technology SCUT
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by South China University of Technology SCUT filed Critical South China University of Technology SCUT
Priority to CN202210052436.XA priority Critical patent/CN114605600B/en
Publication of CN114605600A publication Critical patent/CN114605600A/en
Application granted granted Critical
Publication of CN114605600B publication Critical patent/CN114605600B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
    • Y02W30/00—Technologies for solid waste management
    • Y02W30/50—Reuse, recycling or recovery technologies
    • Y02W30/62—Plastics recycling; Rubber recycling

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Inorganic Chemistry (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

The invention discloses an esterase-responsive amphiphilic linear polymer and a preparation method and application thereof. The polymer is poly (3- (methacryloyloxy) -2-oxypropylbenzoate) -b-poly (2-hydroxybutyl methacrylate-co-monomethoxypolyethylene glycol methacrylate), PPEGMA and PHBMA are used as hydrophilic outer layers, the hydrophilicity of the surface of the micelle is enhanced, the protein adsorption resistance is improved, so that the circulation time of the micelle in vivo is prolonged, PBOOPMA is used as a hydrophobic inner core of the micelle for solubilizing insoluble anticancer drugs, a ketone functional group on the PBOOPMA can react with a cross-linking agent, the stability of the micelle is effectively improved, ester bonds can be broken in response to higher enzyme concentration in a tumor microenvironment, the hydrophobic property of the inner core of the micelle is changed into the hydrophilic property, and the release property of the drugs can be greatly improved.

Description

Esterase-response amphiphilic linear polymer and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biomedical high-molecular polymer materials, and particularly relates to an esterase-responsive amphiphilic linear polymer and a preparation method and application thereof.
Background
Cancer is a disease seriously threatening the health of human beings, free chemotherapeutic drugs have poor stability and lack targeting property, can cause serious toxic and side effects due to nonspecific distribution of the drugs while obtaining the treatment effect by systemic administration, can cause drug resistance of tumor cells after long-term use, and can seriously damage normal cells and tissues.
In recent years, the polymer micelle has shown obvious advantages as a nano-drug carrier of hydrophobic anticancer drugs. The polymer micelle has the advantages of low side effect, high biocompatibility, passive accumulation of the medicine in tumor tissues, prolonged circulation time and the like, and can improve water solubility, increase medicine-loading rate, reduce protein adsorption, improve bioavailability and the like. However, the traditional micelle system has the defects of poor stability in body fluid circulation, easy leakage of the medicine in the delivery process, slow or incomplete release of the medicine in the tumor and the like.
The construction of a cross-linked structure in a polymer to form a cross-linked micelle is an effective way to improve the stability of a system. However, the irreversible crosslinked micelle is too stable in the formed crosslinked structure, and thus cannot control the release of the drug at a specific site, resulting in poor therapeutic effect. The cross-linked structure based on the reversible covalent bond can respond to the change of environmental factors to break or recombine the cross-linked bond, and is used for responding to the intelligent controlled release by environmental stimulation. The reversible cross-linked micelle not only has better stability, but also can respond to the stimulation of a tumor microenvironment to realize the control of drug release at a specific part. The stimulation reaction sites are introduced into the cross-linked micelles to form a stimulation responsive drug delivery system, so that the toxicity of the system can be reduced to the maximum extent, the interaction between the drug and blood plasma can be reduced, and when the nano-carrier is stimulated, the structure of the nano-carrier is changed, so that the loaded drug is released in a specific environment, and the high-efficiency treatment effect is achieved.
In order to enhance the intelligence of the polymer micelle system and improve the application performance of the polymer micelle system, researchers design various stimulus response systems to realize the controllable release of the drugs. Based on the over-expression of specific enzyme in pathological tissue, the esterase concentration in tumor cells is far higher than that in normal tissue, and ester bonds are introduced into the main chain or side group of the nano material, so that the nano material has esterase responsiveness and good application prospect.
Disclosure of Invention
In order to overcome the defects of poor stability, poor drug delivery and release targeting property, slow release or incomplete release and the like of the traditional polymer micelle, the invention aims to provide an esterase-responsive amphiphilic linear polymer, which is specifically poly (3- (methacryloyloxy) -2-oxypropylbenzoate) -b-poly (2-hydroxybutyl methacrylate-co-monomethoxypolyethylene glycol methacrylate).
The invention also aims to provide a preparation method of the esterase-responsive amphiphilic linear polymer. The invention synthesizes monomer 2-hydroxy-3- (methacryloxy) propyl Benzoate (BOHPMA) by a ring opening reaction method, and then prepares monomer 3- (methacryloxy) -2-oxopropyl Benzoate (BOOPMA) with esterase response through pyridinium chlorochromate (PCC) oxidation. By an electron transfer activation regeneration atom transfer radical polymerization (ARGET ATRP), an esterase response monomer 3- (methacryloxy) -2-oxypropyl Benzoate (BOOPMA), 2-hydroxybutyl methacrylate (HBMA) and monomethoxypolyethylene glycol methacrylate (PEGMA) are sequentially initiated to carry out radical polymerization by taking ethyl 2-bromoisobutyrate (EBRIB) as a small molecular initiator, and then poly (3- (methacryloxy) -2-oxypropyl benzoate) -b-poly (2-hydroxybutyl methacrylate-co-monomethoxypolyethylene glycol methacrylate) [ PBOOPMA-b-P (HBMA-co-PEGMA) ].
The invention further aims to provide application of the esterase-response amphiphilic linear polymer in drug loading. The polymer is self-assembled to form micelles, the core layer provides a hydrophilic shell for hydrophobic block BOOPMA, and the shell layers PEGMA and HBMA, so that the stability and the protein adsorption resistance of the micelles are enhanced; meanwhile, a cross-linking agent Adipic Dihydrazide (ADH) or 1, 2-bis (2-aminoethoxy) ethane (EDE) and a ketone functional group of BOOPMA form an acylhydrazone bond under the catalysis effect to obtain the core layer reversible cross-linked micelle, thereby realizing drug loading. The preparation method of the drug-loaded micelle is simple and rapid, has good biocompatibility, and ester bonds on the inner core block can respond to higher enzyme concentration in a tumor microenvironment, so that a new candidate system is provided for development of a nano carrier, and the drug-loaded micelle has good application prospect.
The purpose of the invention is realized by the following technical scheme:
an esterase-responsive amphiphilic linear polymer chemically designated as: poly (3- (methacryloyloxy) -2-oxopropylbenzoate) -b-poly (2-hydroxybutyl methacrylate-co-monomethoxypolyethylene glycol methacrylate) having the following structural formula:
Figure BDA0003474815560000031
wherein: x =15 to 25; y =8 to 10; z =9 to 13.
The number average molecular weight of the polymer is 10000-14000 g/mol.
The preparation method of the esterase-responsive amphiphilic linear polymer comprises the following steps:
(1) Preparation of the monomer 2-hydroxy-3- (methacryloyloxy) propylbenzoate (BOHPMA): dissolving glycidyl methacrylate in a solvent, adding benzoic acid and a catalyst, and carrying out reflux reaction at the temperature of 80-85 ℃ for 16-24 h to obtain a monomer 2-hydroxy-3- (methacryloyloxy) propyl Benzoate (BOHPMA);
(2) Preparation of the monomer 3- (methacryloyloxy) -2-oxopropyl Benzoate (BOOPMA): pyridinium chlorochromate (PCC) and 100-200-mesh silica gel are added into a solvent, 2-hydroxy-3- (methacryloyloxy) propyl benzoate is added under the ice bath condition, and the mixture is oxidized at room temperature to obtain a monomer 3- (methacryloyloxy) -2-oxypropyl benzoate BOOPMA;
(3) Preparing an amphiphilic esterase response block polymer PBOOPMA-b-P (HBMA-co-PEGMA): dissolving an initiator and a catalyst in a solvent, adding the monomer 3- (methacryloyloxy) -2-oxypropyl benzoate obtained in the step (2) and the ligand 1,4,7, 10-hexamethyltriethylenetetramine, uniformly mixing, adding a reducing agent, and carrying out heating reaction; after the monomer is completely converted, adding monomer 2-hydroxybutyl methacrylate and monomer monomethoxy polyethylene glycol methacrylate to continue reacting to obtain polymer PBOOPMA-b-P (HBMA-co-PEGMA).
Preferably, the molar ratio of the glycidyl methacrylate, the benzoic acid and the catalyst in the step (1) is 1: 1.2-1.5: 0.03 to 0.06.
Preferably, the catalyst of step (1) is tetrabutylammonium bromide (TBAB).
Preferably, the solvent in step (1) is at least one of acetonitrile and dichloromethane, and the molar volume ratio of the glycidyl methacrylate to the solvent is 0.2-0.4 mmol/mL.
Preferably, the molar ratio of the 2-hydroxy-3- (methacryloyloxy) propylbenzoate to pyridinium chlorochromate in the step (2) is 1:1.2 to 1.5.
Preferably, the mass ratio of the pyridinium chlorochromate to the silica gel in the step (2) is 0.8-1: 1.
preferably, the solvent of step (2) is dichloromethane; the molar volume ratio of the 2-hydroxy-3- (methacryloyloxy) propyl benzoate to the solvent is 0.25-0.375 mmol/mL.
Preferably, the time of the oxidation reaction in the step (2) is 12 to 16 hours.
Preferably, the initiator of step (3) is ethyl 2-bromoisobutyrate (EBriB); the catalyst is copper bromide; the reducing agent is stannous isooctanoate (Sn (Oct) 2 )。
Preferably, the molar ratio of the initiator, the catalyst, the ligand 1,4,7, 10-hexamethyltriethylenetetramine, the reducing agent, 3- (methacryloyloxy) -2-oxopropyl benzoate, 2-hydroxybutyl methacrylate and monomethoxypolyethylene glycol methacrylate in step (3) is 1: 0.04-0.06: 0.4-0.6: 0.4-0.6: 15 to 25: 8-10: 9 to 13.
Preferably, the solvent in the step (3) is anisole, and the mass-to-volume ratio of the 3- (methacryloyloxy) -2-oxopropyl benzoate to the solvent is 0.2 to 0.25g/mL.
When the monomers of 2-hydroxybutyl methacrylate (HBMA) and monomethoxypolyethylene glycol methacrylate (PEGMA) are added in the step (3) for continuous reaction, the HMTETA and the reducing agent are insufficient, and the HMTETA and the reducing agent can be properly and continuously added to ensure complete reaction.
Preferably, the heating reaction temperature in the step (3) is 65-70 ℃, and the reaction time of the monomer 3- (methacryloyloxy) -2-oxypropylbenzoate is 10-12 h; adding monomer 2-hydroxybutyl methacrylate and monomer monomethoxypolyethylene glycol methacrylate, and continuing to react at 65-70 ℃ for 2-3 days.
The preparation reaction formula of the esterase-responsive amphiphilic linear polymer is shown as follows:
Figure BDA0003474815560000051
the esterase-responsive amphiphilic linear polymer nano micelle is prepared by the following method:
dissolving the esterase-responsive amphiphilic linear polymer in a solvent, uniformly mixing, dialyzing in phosphate buffer solution to obtain a micelle solution, adding a small-molecular cross-linking agent Adipic Dihydrazide (ADH) and a catalyst or only adding a small-molecular cross-linking agent 1, 2-bis (2-aminoethoxy) ethane (EDE), stirring at room temperature for reaction, dialyzing with deionized water, filtering, and drying to obtain the esterase-responsive amphiphilic linear polymer reversible covalent bond crosslinked nano micelle.
Preferably, the solvent is dimethyl sulfoxide (DMSO); the mass-volume ratio of the esterase-responsive amphiphilic linear polymer to the solvent is 0.5-1 mg/mL.
Preferably, when the crosslinking agent is adipic acid dihydrazide, the phosphate buffered saline solution has a pH =6.5 to 6.8; when the crosslinker is 1, 2-bis (2-aminoethoxy) ethane, the phosphate buffered saline solution has a pH =8.5 to 9.
Preferably, the dialysis in phosphate buffered saline refers to transferring the uniformly mixed solution into a dialysis bag with cut-off molecular weight MWCO =3500, and then dialyzing in phosphate buffered saline for 24-36 h, wherein the dialysate is replaced every 2h for the first 12h and every 6h after 12h during the dialysis process.
Preferably, the molar ratio of ketone groups in the esterase-responsive amphiphilic linear polymer to small molecule crosslinker Adipic Dihydrazide (ADH) or 1, 2-bis (2-aminoethoxy) ethane (EDE) is 1-2: 1; the concentration of the catalyst in the micellar solution is 8-12 mmol/L; the catalyst is 2-amino-5-methoxybenzoic acid.
Preferably, the reaction time is 24-36 h under stirring at room temperature.
Preferably, the dialysis with deionized water means that the reaction product is transferred into a dialysis bag with MWCO =3500, and then is dialyzed in deionized water for 12-24 h, and water is changed every 2h in the dialysis process.
Preferably, the filtration refers to filtration with a 0.45 μm filter membrane; the drying is freeze drying.
The application of the esterase-response amphiphilic linear polymer in loading of poorly water-soluble drugs.
Preferably, the poorly water soluble drug is camptothecin.
Preferably, the application is: dissolving the esterase-responsive amphiphilic linear polymer and the water-insoluble drug in a solvent, uniformly mixing, dialyzing in phosphate buffer solution to obtain micelle solution, adding a small-molecule cross-linking agent Adipic Dihydrazide (ADH) and a catalyst or only adding a small-molecule cross-linking agent 1, 2-bis (2-aminoethoxy) ethane (EDE), stirring for reaction at room temperature, dialyzing with deionized water, filtering, and drying to obtain the esterase-responsive amphiphilic linear polymer reversible covalent bond crosslinked nano-micelle.
More preferably, the mass ratio of the esterase-responsive amphiphilic linear polymer to the poorly water-soluble drug is 3-6: 1.
more preferably, the solvent is dimethyl sulfoxide (DMSO); the mass-volume ratio of the esterase response amphiphilic linear polymer to the solvent is 0.5-1 mg/mL.
More preferably, when the crosslinking agent is adipic acid dihydrazide, the phosphate buffered saline solution has a pH =6.5 to 6.8; when the crosslinker is 1, 2-bis (2-aminoethoxy) ethane, the phosphate buffered saline solution has a pH =8.5 to 9.
More preferably, the dialysis in phosphate buffered saline refers to transferring the uniformly mixed solution into a dialysis bag with cut-off molecular weight MWCO =3500, and then dialyzing in phosphate buffered saline for 24-36 h, wherein the dialysate is replaced every 2h for the first 12h and every 6h after 12h during the dialysis process.
More preferably, the molar ratio of ketone groups in the esterase-responsive amphiphilic linear polymer to the small molecule crosslinker Adipic Dihydrazide (ADH) or 1, 2-bis (2-aminoethoxy) ethane (EDE) is 1 to 2:1; the concentration of the catalyst in the micellar solution is 8-12 mmol/L; the catalyst is 2-amino-5-methoxybenzoic acid.
More preferably, the reaction time is 24-36 h under room temperature stirring.
More preferably, the dialysis with deionized water means transferring the reaction product into a dialysis bag with MWCO =3500, and then dialyzing in deionized water for 12-24 h, wherein the water is changed every 2h during the dialysis.
The amphiphilic block polymer disclosed by the invention is a drug-loaded material with excellent performance and esterase sensitivity. The PPEGMA and the PHBMA are used as hydrophilic outer layers, so that the hydrophilicity of the surface of the micelle is enhanced, the protein adsorption resistance is improved, and the circulation time of the micelle in vivo is prolonged. The poly 3- (methacryloyloxy) -2-oxypropyl benzoate (PBOOPMA) is used as a hydrophobic core of the micelle and is used for solubilizing the insoluble anticancer drug, a ketone group functional group on the poly 3- (methacryloyloxy) -2-oxypropyl benzoate can react with a cross-linking agent Adipic Dihydrazide (ADH) or 1, 2-bis (2-aminoethoxy) ethane (EDE), the stability of the micelle is effectively improved, ester bonds can be broken in response to higher enzyme concentration in a tumor microenvironment, the micelle core is changed from hydrophobicity to hydrophilicity, and therefore the release property of the drug can be greatly improved.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the preparation method of the amphiphilic block polymer is simple, the operation is easy, the reaction condition is mild, and the molecular weight is adjustable in a wider range.
2. The amphiphilic linear block polymer prepared by the invention can form a core-shell micelle in a self-assembly manner in an aqueous solution, wherein a hydrophobic monomer can form a hydrophobic core of the micelle, a certain volume of drug loading space is provided, pi-pi conjugation effect can be formed with a hydrophobic drug, and a hydrophilic monomer extends out to form a shell layer of the micelle.
3. The nano micelle prepared by the method has small particle size, low polymer critical micelle concentration and better stability and dispersibility in aqueous solution, and the preparation process of the micelle can be realized by the simplest dialysis method.
4. The reversible covalent bond cross-linked micelle based on the amphiphilic esterase response block polymer has good stability, can enhance the anti-dilution property of the micelle, and ester bonds on the inner core block can respond to higher esterase concentration in tumors to break, so that a great amount of medicaments are quickly released.
Drawings
FIG. 1 is the monomer 2-hydroxy-3- (methacryloyloxy) propylbenzoate prepared in example 1Nuclear magnetic hydrogen spectrum (solvent is CDCl) 3 )。
FIG. 2 is a nuclear magnetic hydrogen spectrum of 3- (methacryloyloxy) -2-oxopropyl benzoate monomer prepared in example 1 (solvent CDCl) 3 )。
FIG. 3 is a nuclear magnetic hydrogen spectrum of the amphiphilic block polymer prepared in example 1 (the solvent is CDCl) 3 )。
FIG. 4 is a test curve of the critical micelle concentration of the polymer in example 3.
Fig. 5 is a DLS graph of the blank non-crosslinked polymer micelle in example 4.
FIG. 6 is a DLS diagram of a micelle crosslinked with a reversible acylhydrazone bond core in example 4.
FIG. 7 is a TEM image of core-crosslinked micelles of reversible acylhydrazone bonds in example 4.
FIG. 8 is a DLS map of reversibly imine-bonded core-crosslinked micelles in example 5.
FIG. 9 is a TEM image of the reversible imine bond core-crosslinked micelle in example 5.
FIG. 10 is the response of the core-crosslinked micelle of reversible acylhydrazone bonds in esterase solution in example 6.
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
(1) Synthesis of monomer 2-hydroxy-3- (methacryloyloxy) propylbenzoate (BOHPMA)
To a solution of glycidyl methacrylate (2.85g, 0.02mol) in anhydrous acetonitrile (80 mL) were added benzoic acid (3.0 g, 0.024mol) and tetrabutylammonium bromide (0.2g, 0.62mmol), and the solution was refluxed at 85 ℃ for 24 hours. Evaporating the solvent and suspending the crude mixture in 5% 2 CO 3 Solution (50 mL) to remove unreacted benzoic acid. CH for organic phase 2 Cl 2 (2X 50 mL) extractTaking and mixing in anhydrous Na 2 SO 4 After drying, the mixture was filtered, the solvent was removed by rotary evaporation, and the obtained crude product was passed through a silica gel column (mobile phase n-hexane-ethyl acetate 7, rf value 0.4), and finally the solvent was removed by rotary evaporation to obtain a colorless oily liquid. The structure and composition were analyzed by nuclear magnetism and the results are shown in FIG. 1.
(2) Synthesis of monomer 3- (methacryloyloxy) -2-oxopropyl Benzoate (BOOPMA)
A stirrer, 4.85g of PCC (22.5 mmol) and 4.85g of silica gel (80-100 mesh) were put into a dry eggplant-shaped bottle, followed by vacuum inflation and injection of 50mL of a methylene chloride solvent. The eggplant-shaped bottle was placed in an ice bath, and a dichloromethane solution of 2-hydroxy-3- (methacryloyloxy) propylbenzoate (3.96g, 15mmol, dissolved in 10mL of dichloromethane) was slowly added dropwise and reacted at room temperature for 15 hours. Adding 50mL of diethyl ether, adding diatomaceous earth, filtering under reduced pressure with a funnel, collecting the filtrate, steaming the filtrate under reduced pressure to remove dichloromethane and diethyl ether (t) b =39.75and 34.6 ℃). Silica gel column with n-hexane: the ethyl acetate mixture (10 by volume. Solvent removal by rotoevaporation (t) b =70and 77 ℃) to give a white solid. The structure and composition were analyzed by nuclear magnetism and the results are shown in FIG. 2.
(3) Synthetic polymer PBOOPMA-b-P (HBMA-co-PEGMA), x: y: z =20:10:13.
adding a stirrer and a catalyst CuBr into a 50mL dry eggplant-shaped bottle 2 (5.11 mg), then a reverse rubber stopper is sleeved on and sealed by a sealing film, vacuum is slowly pumped and argon is introduced for 3 times, the solvent anisole (6 mL), monomer 3- (methacryloxy) -2-oxypropylbenzoate (BOOPMA) (3 g) and ligand HMTETA (62.23 μ L) are added by a syringe, and the mixture is fully stirred for 10min to form a catalyst complex. The reducing agent Sn (Oct) was dissolved in 4mL of anisole 2 (74.08 μ L) and then injected into an eggplant-shaped bottle, stirred for 5min, and then a small molecular initiator EBRIB (82.55 μ L) is added dropwise by a micro syringe and then transferred to an oil bath at 70 ℃ for reaction. After complete monomer conversion, the solvent anisole (2 mL), monomer HBMA (0.91 g), PEGMA (3.53 g), ligand HMTETA (8 μ L) and reducing agent Sn (Oct) were added 2 (10. Mu.L) the reaction was continued at 65 ℃ for 72h. After the reaction was completed, the eggplant-shaped bottle was cooled to room temperature. AddingAdding a large amount of cold n-hexane to precipitate the polymer, repeating the process for 3 times, dissolving with tetrahydrofuran, passing through a neutral alumina column (THF as eluent) to remove copper salt, performing rotary evaporation and concentration, slowly dropping to ten times of n-hexane for precipitation, repeating the dissolving and precipitation for three times, and vacuum drying at 45 ℃ and 35mbar for 24h to obtain a light yellow solid with a nuclear magnetic resonance hydrogen spectrum shown in FIG. 3.
Example 2
(1) Synthesis of monomer 2-hydroxy-3- (methacryloyloxy) propylbenzoate (BOHPMA)
To a solution of glycidyl methacrylate (2.85g, 0.02mol) in anhydrous acetonitrile (80 mL) were added benzoic acid (3.0 g, 0.024mol) and tetrabutylammonium bromide (0.35g, 1.085 mmol), and the solution was refluxed at 85 ℃ for 22 hours. Evaporating the solvent and suspending the crude mixture in 5% 2 CO 3 Solution (50 mL) to remove unreacted benzoic acid. CH for organic phase 2 Cl 2 (2X 50 mL) and extracted over anhydrous Na 2 SO 4 After drying, the mixture was filtered, the solvent was removed by rotary evaporation, and the obtained crude product was passed through a silica gel column (mobile phase n-hexane-ethyl acetate 7, rf value 0.4), and finally the solvent was removed by rotary evaporation to obtain a colorless oily liquid.
(2) Synthesis of monomer 3- (methacryloyloxy) -2-oxopropyl Benzoate (BOOPMA)
A stirrer, 4.85g of PCC (22.5 mmol) and 4.85g of silica gel (80-100 mesh) were put into a dry eggplant-shaped bottle, followed by vacuum inflation and injection of 50mL of a methylene chloride solvent. The eggplant-shaped bottle was placed in an ice bath, and a solution of 2-hydroxy-3- (methacryloyloxy) propylbenzoate in methylene chloride (4.75g, 18mmol, dissolved in 10mL of methylene chloride) was slowly added dropwise and reacted at room temperature for 16 hours. Adding 50mL of diethyl ether, adding diatomaceous earth, filtering under reduced pressure with a funnel, collecting filtrate, rotary evaporating the filtrate under reduced pressure to remove dichloromethane and diethyl ether (t) b =39.75and 34.6 ℃). Silica gel column with n-hexane: the ethyl acetate mixture (10 by volume. The solvent is removed by rotary evaporation again (t) b =70and 77 ℃) gave a white solid.
(3) Synthetic polymer PBOOPMA-b-P (HBMA-co-PEGMA), x: y: z =15:10:9.
to 50mL dry eggplant-shaped bottleAdding a stirrer and a catalyst CuBr 2 (4.54 mg), then a reverse rubber stopper is sleeved on and sealed by a sealing film, vacuum is slowly pumped and argon is introduced for 3 times, the solvent anisole (6 mL), monomer 3- (methacryloxy) -2-oxypropylbenzoate (BOOPMA) (2 g) and ligand HMTETA (55.31 μ L) are added by a syringe, and the mixture is fully stirred for 10min to form a catalyst complex. Dissolving reducing agent Sn (Oct) by using 4mL of anisole 2 (65.85 mu L) and then injected into an eggplant-shaped bottle, stirred for 5min, and then a micromolecular initiator EBRIB (73.4 mu L) is added dropwise by a micro syringe and then transferred to an oil bath at 70 ℃ for reaction. After complete monomer conversion, the solvent anisole (2 mL), monomer HBMA (0.804 g), PEGMA (2.17 g), ligand HMTETA (7 μ L) and reducing agent Sn (Oct) were added 2 The reaction (8. Mu.L) was continued at 70 ℃ for 72h. After the reaction was completed, the eggplant-shaped bottle was cooled to room temperature. Adding a large amount of cold n-hexane to precipitate the polymer, repeating the process for 3 times, dissolving with tetrahydrofuran, removing copper salt by passing through a neutral alumina column (THF is used as an eluent), performing rotary evaporation and concentration, slowly dropping until ten times of n-hexane is precipitated, repeating the dissolving and precipitation for three times, and performing vacuum drying at 45 ℃ and 35mbar for 24 hours to obtain a yellow solid.
Example 3: critical micelle concentration CMC value of amphiphilic esterase response block polymer
The critical micelle concentration of the amphiphilic esterase response block polymer PBOOPMA-b-P (HBMA-co-PEGMA) prepared in example 1 was tested by a fluorescence probe method.
(1) Preparing a pyrene-acetone solution: accurately weighing 121.356mg of pyrene, dissolving in 10mL of acetone, transferring to a 50mL volumetric flask, diluting to constant volume with acetone to prepare the solution with the concentration of 12 multiplied by 10 -3 And (5) preparing a pyrene solution in mol/L for later use. Then, 1mL of 12X 10 was taken -3 Adding 200mL of acetone into the pyrene solution of mol/L to dilute the solution to be 6 x 10 -5 And (4) preparing a pyrene solution at mol/L for later use.
(2) Preparing a sample solution: 10mg of amphiphilic block polymer (example 1 product PBOOPMA-b-P (HBMA-co-PEGMA)) is weighed and dissolved in 5mL of acetone, 100mL of deionized water is added accurately under stirring, the mixture is stirred overnight to volatilize the acetone to obtain 0.1mg/mL of polymer mother liquor, and the polymer mother liquor is diluted into a series of solutions of 0.0001-0.1 mg/mL. Taking 18 clean volumetric flasks of 10mL, adding 0.1mL of 6X 10 bottles into each flask -5 molAdding the series of polymer solutions with different concentrations into the pyrene solution to prepare a test solution, wherein the final concentration of pyrene in the test solution is 6 multiplied by 10 -7 mol/L。
(3) And (3) fluorescence spectrum testing: using 373nm as emission wavelength, testing the excitation spectrum of the solution at 300-350 nm, and using I 339.4 And I 334.6 The ratio is plotted against the logarithm of the concentration, the concentration corresponding to the abrupt change point of the curve is the critical micelle concentration of the polymer, and the critical micelle concentration of PBOOPMA-b-P (HBMA-co-PEGMA) is 3.74mg/L, as shown in FIG. 4.
Example 4
Preparation of reversible acylhydrazone bond core cross-linked micelle system based on amphipathic esterase response linear polymer
Preparing an amphiphilic linear polymer micelle solution by a dialysis method: 30mg of PBOOPMA-b-P (HBMA-co-PEGMA) (product of example 1) was weighed out and dissolved in 30mL of DMSO, and the polymer solution was transferred into a pre-treated dialysis bag (MWCO = 3500), placed in 1L of PBS buffer (20 mmol/L, pH 6.5), and dialyzed at room temperature for 24 hours, with PBS buffer being replaced every 2 hours for the first 12 hours and every 6 hours for the last 12 hours during dialysis. After dialysis, 30mL of the prepared micelle solution is poured into a beaker, 54.64mg of catalyst 2-amino-5-methoxybenzoic acid (the concentration of the catalyst in the micelle solution is 10 mmol/L) is added, a micromolecular cross-linking agent Adipic Dihydrazide (ADH) is dissolved in deionized water to prepare a solution with the concentration of 50mg/mL, and the solution is dropwise added into the micelle solution until the molar ratio of the cross-linking agent to BOOPMA is 1:2, stirring for 24 hours at room temperature, then putting into a dialysis bag, dialyzing with deionized water (pH 7.4) for 12 hours to remove the micromolecule cross-linking agent and the catalyst 2-amino-5-methoxybenzoic acid, changing water every 2 hours, filtering with a 0.45 mu m filter membrane after dialysis to obtain a reversible acylhydrazone bond nuclear cross-linked micelle solution, and freeze-drying at-40 ℃ to obtain a brown solid, namely the reversible acylhydrazone bond nuclear cross-linked micelle.
The particle size and particle size distribution of the self-assembled non-crosslinked micelle were measured by dynamic light scattering, and the particle size was 170.3nm and the PDI was 0.25 (see FIG. 5). 2mL of the acylhydrazone bond-crosslinked micelle solution was filtered through a 0.45 μm filter, and the particle size was 157.5nm and the polydispersity was 0.17 as measured by ZS90 potentiometry (see FIG. 6).
The morphology of the core-crosslinked micelles was determined by Transmission Electron Microscopy (TEM) (see fig. 7). The micelle is spherical in shape by TEM measurement, the particle size is about 130nm, and the Zeta is-5.33 mV.
Example 5
Preparation of reversible imine bond core crosslinked micelle system based on amphiphilic esterase response linear polymer
Preparing an amphiphilic linear polymer micelle solution by a dialysis method: 30mg of PBOOPMA-b-P (HBMA-co-PEGMA) (product of example 1) was weighed and dissolved in 30mL of DMSO, and the polymer solution was transferred to a dialysis bag, and then the DMSO was removed by dialysis at room temperature for 24 hours with PBS buffer (20 mmol/L, pH 8.5) which was replaced every 2 hours for the first 12 hours and every 6 hours for the last 12 hours during the dialysis. And after the dialysis is finished, pouring 30mL of the prepared micelle solution into a beaker, slowly adding an aqueous solution of a small molecular cross-linking agent 1, 2-bis (2-aminoethoxy) ethane (EDE) (which is pre-adjusted to pH 8.5 and has a molar ratio of amino to ketone = 1/2), stirring at room temperature for 24h, then putting into a dialysis bag, dialyzing with deionized water (pH 7.4) for 12h to remove the cross-linking agent, changing water once every 2h, filtering with a 0.45 mu m filter membrane after the dialysis is finished to obtain a reversible imine bond core cross-linked micelle solution, and freeze-drying at-40 ℃ to obtain a white solid, namely the reversible imine bond core cross-linked micelle.
2mL of the imine-bonded cross-linked micelle solution was filtered through a 0.45 μm filter, and the resulting filtrate was measured to have a particle size of 141.3nm and a polydispersity of 0.23 by using a ZS90 potential particle sizer (see FIG. 8).
The morphology of the imine bond core crosslinked micelle was determined by Transmission Electron Microscopy (TEM) (see fig. 9). The micelle is spherical in TEM measurement, the particle size is about 110nm, and the Zeta is-16.64 mV.
Example 6
Esterase responsiveness of core-crosslinked micelles
2mL of acylhydrazone bond core-crosslinked micelle solution (1 mg/mL, obtained in example 4) was taken, 8mg of esterase was added, the mixture was placed in a homomixer at a constant temperature of 37 ℃ for reaction, and the distribution of micelle particle size was measured by dynamic light scattering. The results are shown in FIG. 10.
The results show that: after the core cross-linked micelle is added with esterase, a particle size distribution curve shows double peaks after 5min, and the particle size exceeds 1000nm after 12h, which indicates that the micelle structure is damaged and is disintegrated under the action of the esterase, and the disintegrated substances are further obviously aggregated. It can be seen that the micelle had excellent esterase responsiveness.
Example 7
Preparation of reversible acylhydrazone bond core cross-linked drug-loaded micelle system based on amphipathic esterase response linear polymer
30mg of PBOOPMA-b-P (HBMA-co-PEGMA) (product of example 1) and 10mg of Camptothecin (CPT) were added to 30mL of DMSO, stirred well for 4 hours to dissolve, transferred to a dialysis bag, dialyzed against PBS buffer (20 mmol/L, pH 6.5) for 24 hours to remove DMSO, and replaced every 2 hours for the first 12 hours and every 6 hours for the last 12 hours during the dialysis. After completion of dialysis, 30mL of the micelle solution in the dialysis bag was poured into a beaker, and 54.64mg of 2-amino-5-methoxybenzoic acid catalyst (to give a concentration of 10mmol/L in the micelle solution) was added. Dissolving a small molecular cross-linking agent Adipic Dihydrazide (ADH) in deionized water to prepare a solution with the concentration of 50mg/mL, and slowly dropwise adding the solution into the micelle solution until the molar ratio of the cross-linking agent to the BOOPMA is 1:2, stirring for 24h at room temperature, then filling into a dialysis bag, dialyzing with deionized water (pH 7.4) for 12h to remove the small molecule cross-linking agent and the catalyst, changing water every 2h, finally filtering through a 0.45 mu m filter membrane, and freeze-drying. The drug loading was 5.9% as determined by uv spectroscopy.
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 (10)

1. An esterase-responsive amphiphilic linear polymer characterized by the structural formula:
Figure FDA0003948105190000011
wherein x =15 to 25; y =8 to 10; z =9 to 13.
2. A process for preparing an esterase-responsive amphiphilic linear polymer according to claim 1, comprising the steps of:
(1) Dissolving glycidyl methacrylate in a solvent, adding benzoic acid and a catalyst, and carrying out reflux reaction at the temperature of 80-85 ℃ for 16-24 h to obtain a monomer 2-hydroxy-3- (methacryloyloxy) propyl benzoate;
(2) Adding pyridinium chlorochromate and silica gel into a solvent, adding 2-hydroxy-3- (methacryloyloxy) propyl benzoate under an ice bath condition, and carrying out oxidation reaction at room temperature to obtain a monomer 3- (methacryloyloxy) -2-oxopropyl benzoate;
(3) Dissolving an initiator and a catalyst in a solvent, adding the monomer 3- (methacryloyloxy) -2-oxypropylbenzoate obtained in the step (2) and the ligand 1,4,7, 10-hexamethyltriethylenetetramine, uniformly mixing, adding a reducing agent, and carrying out heating reaction; after the monomer is completely converted, adding the monomer 2-hydroxybutyl methacrylate and the monomer monomethoxypolyethylene glycol methacrylate to continue reacting to obtain the polymer.
3. The method of claim 2, wherein the molar ratio of glycidyl methacrylate, benzoic acid, and catalyst in step (1) is 1: 1.2-1.5: 0.03 to 0.06; the catalyst is tetrabutylammonium bromide;
the molar ratio of the 2-hydroxy-3- (methacryloyloxy) propylbenzoate to pyridinium chlorochromate in the step (2) is 1:1.2 to 1.5;
the mass ratio of the pyridinium chlorochromate to the silica gel in the step (2) is 0.8-1: 1.
4. the method of claim 2, wherein the initiator, catalyst, ligand 1,4,7, 10-hexamethyltriethylenetetramine, reducing agent, 3- (methacryloyloxy) -2-oxopropyl benzoate, 2-hydroxybutyl methacrylate and monomethoxypolyethylene glycol methacrylate are present in the molar ratio of 1: 0.04-0.06: 0.4 to 0.6: 0.4-0.6: 15 to 25: 8-10: 9 to 13;
the initiator in the step (3) is ethyl 2-bromoisobutyrate; the catalyst is copper bromide; the reducing agent is stannous isooctanoate.
5. The method of claim 2, wherein the oxidation reaction time of step (2) is 12-16 hours;
the heating reaction temperature in the step (3) is 65-70 ℃, and the reaction time of the monomer 3- (methacryloyloxy) -2-oxypropylbenzoate is 10-12 h; adding monomer 2-hydroxy butyl methacrylate and monomer monomethoxy polyethylene glycol methacrylate, and reacting at 65-70 deg.c for 2-3 days.
6. The method of claim 2, wherein the solvent in step (1) is at least one of acetonitrile and dichloromethane, and the molar volume ratio of the glycidyl methacrylate to the solvent is 0.2 to 0.4mmol/mL;
the solvent in the step (2) is dichloromethane; the molar volume ratio of the 2-hydroxy-3- (methacryloyloxy) propyl benzoate to the solvent is 0.25-0.375 mmol/mL;
the solvent in the step (3) is anisole, and the mass volume ratio of the 3- (methacryloyloxy) -2-oxypropylbenzoate to the solvent is 0.2-0.25 g/mL.
7. An esterase-response amphiphilic linear polymer nano micelle is characterized by being prepared by the following method:
dissolving the esterase-responsive amphiphilic linear polymer of claim 1 in a solvent, uniformly mixing, dialyzing in phosphate buffered saline solution to obtain micellar solution, adding a small-molecular cross-linking agent adipic dihydrazide and a catalyst, or only adding a small-molecular cross-linking agent 1, 2-bis (2-aminoethoxy) ethane, stirring at room temperature for reaction, dialyzing with deionized water, filtering, and drying to obtain the esterase-responsive amphiphilic linear polymer reversible covalent bond crosslinked nano-micelle.
8. The esterase-responsive amphiphilic linear polymer nanomicelle according to claim 7, wherein the molar ratio of ketone groups to small molecule cross-linking agent adipic dihydrazide or 1, 2-bis (2-aminoethoxy) ethane in the esterase-responsive amphiphilic linear polymer is 1-2: 1; the concentration of the catalyst in the micellar solution is 8-12 mmol/L; the catalyst is 2-amino-5-methoxybenzoic acid;
the room-temperature stirring reaction time is 24-36 h; when the cross-linking agent is adipic acid dihydrazide, the pH of the phosphate buffered saline solution is = 6.5-6.8; when the crosslinking agent is 1, 2-bis (2-aminoethoxy) ethane, the phosphate buffered saline solution has a pH = 8.5-9;
the solvent is dimethyl sulfoxide; the mass-to-volume ratio of the esterase-responsive amphiphilic linear polymer to the solvent is 0.5-1 mg/mL;
the dialysis in phosphate buffered saline solution refers to transferring the uniformly mixed solution into a dialysis bag with molecular weight cut-off (MWCO = 3500), and then dialyzing in phosphate buffered saline solution for 24-36 h;
the dialysis with deionized water means that the reaction product is transferred into a dialysis bag with molecular weight cutoff MWCO =3500, and then dialyzed in deionized water for 12-24 h.
9. The use of an esterase-responsive amphiphilic linear polymer according to claim 1 for loading poorly water-soluble drugs,
dissolving the esterase-responsive amphiphilic linear polymer and the poorly water-soluble drug in a solvent, uniformly mixing, dialyzing in phosphate buffered saline solution to obtain micellar solution, adding a small-molecular cross-linking agent adipic dihydrazide and a catalyst or only adding a small-molecular cross-linking agent 1, 2-bis (2-aminoethoxy) ethane, stirring at room temperature for reaction, dialyzing with deionized water, filtering, and drying to obtain the esterase-responsive amphiphilic linear polymer reversible covalent bond crosslinked nano-micelle.
10. The application of the esterase-responsive amphiphilic linear polymer in loading poorly water-soluble drugs according to claim 9, wherein the mass ratio of the esterase-responsive amphiphilic linear polymer to the poorly water-soluble drugs is (3-6): 1; the water-insoluble drug is camptothecin;
the molar ratio of ketone group to micromolecular cross-linking agent adipic dihydrazide or 1, 2-bis (2-aminoethoxy) ethane in the esterase response amphiphilic linear polymer is 1-2: 1; the concentration of the catalyst in the micellar solution is 8-12 mmol/L; the catalyst is 2-amino-5-methoxybenzoic acid;
the room-temperature stirring reaction time is 24-36 h; when the cross-linking agent is adipic acid dihydrazide, the pH of the phosphate buffered saline solution is = 6.5-6.8; when the crosslinking agent is 1, 2-bis (2-aminoethoxy) ethane, the phosphate buffered saline solution has a pH = 8.5-9;
the solvent is dimethyl sulfoxide; the mass-volume ratio of the esterase-responsive amphiphilic linear polymer to the solvent is 0.5-1 mg/mL;
the dialysis in phosphate buffered saline solution means that the uniformly mixed solution is transferred into a dialysis bag with molecular weight cut-off MWCO =3500, and then is dialyzed in phosphate buffered saline solution for 24-36 h;
the dialysis with deionized water means transferring the reaction product into a dialysis bag with MWCO =3500, and then dialyzing in deionized water for 12-24 h.
CN202210052436.XA 2022-01-18 2022-01-18 Esterase-response amphiphilic linear polymer and preparation method and application thereof Active CN114605600B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210052436.XA CN114605600B (en) 2022-01-18 2022-01-18 Esterase-response amphiphilic linear polymer and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210052436.XA CN114605600B (en) 2022-01-18 2022-01-18 Esterase-response amphiphilic linear polymer and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN114605600A CN114605600A (en) 2022-06-10
CN114605600B true CN114605600B (en) 2023-01-06

Family

ID=81857926

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210052436.XA Active CN114605600B (en) 2022-01-18 2022-01-18 Esterase-response amphiphilic linear polymer and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN114605600B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115010913B (en) * 2022-06-17 2023-05-26 广东工业大学 PH/reduction dual-response polymer micelle and preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104231155A (en) * 2014-08-19 2014-12-24 华南理工大学 Cholesterol modified amphiphilic pH response pennicuius copolymer as well as preparation and micelle of copolymer
WO2014206044A1 (en) * 2013-06-29 2014-12-31 华南理工大学 Amphiphilic 4/6 miktoarm star-shaped ph-responsive copolymer and preparation method thereof
CN106084156A (en) * 2016-06-07 2016-11-09 华南理工大学 A kind of amphipathic four arm star polymer and shell reversible crosslink micellar system based on it and preparation method and application
CN106589271A (en) * 2016-11-30 2017-04-26 华南理工大学 Degradable reversible crosslinking polymer based on dynamic chemical bond and micelle thereof, preparation method and application

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3641730B1 (en) * 2017-06-22 2021-03-03 SNBioscience Inc. Particle and pharmaceutical composition comprising an insoluble camptothecin compound with double core-shell structure and method for manufacturing the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014206044A1 (en) * 2013-06-29 2014-12-31 华南理工大学 Amphiphilic 4/6 miktoarm star-shaped ph-responsive copolymer and preparation method thereof
CN104231155A (en) * 2014-08-19 2014-12-24 华南理工大学 Cholesterol modified amphiphilic pH response pennicuius copolymer as well as preparation and micelle of copolymer
CN106084156A (en) * 2016-06-07 2016-11-09 华南理工大学 A kind of amphipathic four arm star polymer and shell reversible crosslink micellar system based on it and preparation method and application
CN106589271A (en) * 2016-11-30 2017-04-26 华南理工大学 Degradable reversible crosslinking polymer based on dynamic chemical bond and micelle thereof, preparation method and application

Also Published As

Publication number Publication date
CN114605600A (en) 2022-06-10

Similar Documents

Publication Publication Date Title
Liu et al. Bio-functional micelles self-assembled from a folate-conjugated block copolymer for targeted intracellular delivery of anticancer drugs
CN106265509B (en) A kind of pH and Redox double-bang firecracker answers amphipathic nature block polymer and its preparation method and application
CN104758247B (en) A kind of pH responsive polymers mixed micelle and its application
CN104231155B (en) Cholesterol modifies amphipathic pH response brush copolymer and preparation and micella thereof
Wang et al. Stimulus-responsive polymeric micelles for the light-triggered release of drugs
CN111991563A (en) PH response type nano-drug delivery system and preparation method thereof
Cheng et al. Water-soluble single-chain polymeric nanoparticles for highly selective cancer chemotherapy
CN114605600B (en) Esterase-response amphiphilic linear polymer and preparation method and application thereof
CN114507326B (en) pH response crosslinking bond-based hydrophilic side chain-adjustable triblock polymer and preparation and application thereof
CN111154084A (en) Preparation of PVA reversible crosslinked drug-loaded micelle with triple response
CN106581647B (en) PH-responsive insulin sustained-release nanoparticles and preparation method and application thereof
CN109134870A (en) A kind of pH responsive polymer carrier and its micella, the preparation method and application of preparation
CN109400830B (en) PH dissociable lightly crosslinked polymer nano material and preparation method and application thereof
CN113912841A (en) PH and Redox dual-response diblock amphiphilic polymer prodrug and preparation method thereof
CN110563863B (en) Amphiphilic pH/reduction dual-response four-arm star-shaped nano polymer, reversible cross-linked micelle, preparation and application thereof
CN106565962B (en) Cholesterol grafted pH-responsive triblock amphiphilic copolymer and preparation method and application thereof
CN104415342A (en) Self-assembled drug carrier microcapsule system containing polypyrrolidone
Huang et al. Toward understanding polymeric micelle stability regulated by diverse physico-chemical strategies and their stabilized mechanism
CN113101278B (en) Targeting nanoparticle with GSH and esterase tumor microenvironment dual response and preparation method and application thereof
CN104414999A (en) Anti-tumor targeted nanometer drug-loaded microcapsule preparation method
CN103977417A (en) Preparation method of amphiphilic drug-loaded nanoparticles
CN113881002B (en) Amphiphilic block copolymer and preparation thereof, and preparation and application of nano micelle
CN104415003A (en) Polymer nano drug microcapsule containing polypyrrolidone
CN104415344A (en) Polymer drug microcapsule containing polyacrylic acid
CN115010913B (en) PH/reduction dual-response polymer micelle and preparation method and application thereof

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