CN114426656A - Polymer nano hydrogel, drug delivery system comprising same and preparation method thereof - Google Patents
Polymer nano hydrogel, drug delivery system comprising same and preparation method thereof Download PDFInfo
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- CN114426656A CN114426656A CN202210107248.2A CN202210107248A CN114426656A CN 114426656 A CN114426656 A CN 114426656A CN 202210107248 A CN202210107248 A CN 202210107248A CN 114426656 A CN114426656 A CN 114426656A
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Classifications
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- 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
- C08F293/005—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 using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- 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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
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- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Radiology & Medical Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Preparation (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a polymer nano hydrogel, a drug delivery system containing the polymer nano hydrogel and a preparation method of the polymer nano hydrogel. The polymer can be self-assembled in an aqueous solution to form a micro-nano structure, the micro-nano structure can be coated with a medicament at a low temperature, hydrogel is formed at a high temperature, so that the defect of photothermal therapy, namely the problem of damage to surrounding tissues, is improved in a heat transfer mode, and meanwhile, the polymer has temperature sensitivity, biocompatibility and biodegradability, the critical solution temperature of the micro-nano structure can be continuously adjusted through the hydrophilic-hydrophobic proportion, and the material has a wide prospect in the aspects of diagnosis and treatment of cancers.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a polymer nano hydrogel, a drug delivery system comprising the polymer nano hydrogel and a preparation method of the polymer nano hydrogel.
Background
Tumors are one of the biggest killers threatening human life and how to effectively diagnose and treat them is a major challenge facing the current biomedical research field. At present, 3 methods for treating tumors in clinic mainly comprise surgery, radiation and chemotherapy, but the methods have high risk, lack specificity, damage immune system, increase the incidence rate of second tumors and greatly limit the application due to the generation of chemical drug resistance.
Photothermal therapy has attracted much attention as a new therapeutic method in the treatment of tumors. The photothermal therapy based on the nano material adopts near infrared light with stronger tissue penetrating capacity as a light source, the early photothermal therapy plays a role in treating tumors by radiating the nano material with photothermal conversion capacity to generate heat, and tumor cells are directly destroyed and eliminated mainly by high heat. In recent years, a plurality of researchers find that the heat generated by the nano materials has the function of directly killing tumor cells, and can also play the role of resisting tumors by inhibiting tumor metastasis and overcoming chemotherapy resistance.
At present, the photo-thermal materials which are researched more mainly comprise inorganic nano materials and organic nano materials, and are modified and modified to endow the photo-thermal materials with new functions, such as targeting, diagnosis and treatment integration and the like. Although nanoparticles have many advantages in targeted delivery, some of them have burst release, poor bioadhesive properties and irreversible deformation, and are therefore not suitable for long-term administration.
Disclosure of Invention
The invention aims to solve the problems in the prior art, and provides a polymer nano hydrogel, a drug delivery system comprising the polymer nano hydrogel and a preparation method of the polymer nano hydrogel.
The technical scheme of the invention is as follows:
aiming at the requirements that single-drug therapy is easy to generate drug resistance, drugs are difficult to enter the interior of a tumor and the like, the invention synthesizes a polymer by using monomer acrylamide (AAM), Acrylonitrile (AN), N-isopropylacrylamide (NIPAM) and N, N-Dimethylacrylamide (DMAA) through a reversible addition-fragmentation chain transfer method (RAFT), the polymer can be self-assembled in AN aqueous solution to form a micro-nano structure, the micro-nano structure can be loaded with AN anti-cancer drug and a photosensitizer in a physical packaging mode at a low temperature, and the micro-nano structure is cracked at a high temperature to release the drugs and form hydrogel, thereby forming a nano hydrogel drug delivery system.
Based on the structure, the polymer nano hydrogel is formed by a micro-nano structure formed by self-assembling a polymer with a structure shown in a formula (IV), an isomer, pharmaceutically acceptable salt, a hydrate or a solvate thereof in an aqueous solution at high temperature;
in the formula (IV), the compound is shown in the specification,
r14, R14' is selected from O, N or S;
l is an olefin monomer containing a hydrophilic group and a hydrophobic group, respectively;
x is an N-substituted or N, N-substituted acrylamide monomer;
t1 and t2 are independently selected from integers of 0-500, and t3 is selected from integers of 1-10;
r13 is selected from any one of H, a halogen atom, a hydrocarbon group, a cycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, an alcohol group, an ether group, an aldehyde group, a carboxyl group, an amide group, an ester group, or an amino group.
Further, the R14 is O or S, and the R14' is O or S;
further, L is
One or more than one of the above, q is independently selected from an integer of 0-12;
further, X is
Each q is independently selected from an integer of 0-12.
Further, the polymer is synthesized from the monomers acrylamide (AAM) and Acrylonitrile (AN), N-isopropylacrylamide (NIPAM) and N, N-Dimethylacrylamide (DMAA) by a reversible addition fragmentation chain transfer method (RAFT).
The invention also provides a drug delivery system containing the polymer nano hydrogel, wherein the drug delivery system is composed of the polymer nano hydrogel loaded with an anticancer drug and a photosensitizer, and the loading is completed in a physical packaging mode.
The drug delivery system is characterized in that an anticancer drug and a photosensitizer are loaded in a polymer nano hydrogel in a physical packaging mode. The temperature stimulation response type nano hydrogel drug delivery system is small in size, and can enter a tumor part through a tumor high permeability and retention effect (EPR effect) when being circulated to the tumor part through the tail vein, and the micro-nano structure has strong Near Infrared (NIR) absorption capacity due to the fact that the photosensitizer is loaded in the micro-nano structure. When the drug enrichment amount reaches the maximum, infrared light irradiation is carried out on the tumor part of the mouse, and the temperature of the part is gradually increased, so that the micro-nano structure is stimulated to change, and the anti-cancer drug is released. Meanwhile, the micro-nano structure can form hydrogel at high temperature, and the formed hydrogel can improve the defects of photo-thermal treatment in a heat transfer mode.
Furthermore, the micro-nano structure of the polymer nano hydrogel is uniform in size, the size is 50-200 nm, and the polymer nano hydrogel has good hydrophilicity and variable temperature control size.
The micro-nano structure of the polymer has the property of temperature stimulation response, namely the micro-nano structure can be damaged by temperature rise, so that the drug release is realized, the temperature continues to rise, the hydrogel is formed, and the defect of photo-thermal treatment is overcome.
Hydrogels are chemically and structurally versatile and may be composed of a network of covalently cross-linked polymer chains. The covalent bonds between the polymer chains form a network structure that wraps the water by surface tension at a sufficient crosslink density. For biomedical applications, the most common bonds are those formed by "click chemistry" reactions, as these bonds can crosslink rapidly under ambient conditions. Including copper-catalyzed or strain-promoted azide-alkyne cycloaddition reactions, michael addition reactions of michael donors and acceptors, thiol-ene reactions, diels-alder cycloaddition reactions, disulfide bond formation, and oxime bond formation. Meanwhile, covalent crosslinking has also been investigated as a way to form polymer-nanoparticle hydrogels.
At the same time, thermal triggering is well suited for many basic scientific and clinical applications. When the sol-gel transformation occurs in the temperature range (about 4-41 ℃) generally used in biomedicine, the method has extremely high application value. In this temperature range, thermal triggering is most often used to initiate the formation of non-covalent interactions, leading to gelation.
The invention also provides a preparation method of the drug delivery system of the polymer nano hydrogel, which comprises the following steps:
(1) and (2) mixing the chain transfer agent, the N-isopropylacrylamide, the N, N-dimethylacrylamide and the initiator according to the weight ratio of 1: (75-85): (25-35): (2-3) adding the substances into a dimethyl sulfoxide solution according to the mass ratio, mixing and dissolving, removing air in a reaction system for 0.1-2 h at 0-50 ℃, and heating the reaction system to 50-100 ℃ to react for 8-16 h under an anaerobic condition to obtain an initial product;
(2) mixing the initial product obtained in the step (1) with acrylamide, acrylonitrile and an initiator according to the ratio of 1: (90-95): (100-120): (0.2-0.3) mixing the substances in a proper amount of dimethyl sulfoxide, removing air in the reaction system for 0.1-2 h at 0-50 ℃, and heating the reaction system to 50-100 ℃ to react for 20-28 h under the oxygen-free condition to obtain a copolymer product;
(3) and (3) drying the copolymer obtained in the step (2) at 0-50 ℃ in vacuum, and then mixing the anti-cancer drug, the photosensitizer and the copolymer according to a mass ratio of 1: (1-3): (4-10), mixing the copolymer with an anticancer drug and a photosensitizer, dissolving the mixture in a small amount of dimethyl sulfoxide, dropwise adding deionized water, and stirring at room temperature; then removing the non-encapsulated anticancer drug and photosensitizer by dialysis separation, and vacuum drying at 25 deg.C to obtain the drug delivery system.
According to the temperature stimulus response type nano hydrogel drug delivery system loaded with the anticancer drug and the photosensitizer, provided by the invention, by utilizing the temperature stimulus response characteristic of the polymer, the micro-nano structure can be damaged by temperature rise, so that the drug release process is realized.
The thermo-sensitive polymer is used as a drug carrier, the thermo-sensitive polymer is combined with a micromolecular photosensitizer, the photo-controlled thermo-sensitive polymer is separated, the low-temperature drug is used for drug wrapping, and the high-temperature drug is released to form hydrogel, so that the defect that normal cells are damaged while cancer cells are killed in photothermal therapy is overcome.
Further, the initiator in the step (1) and the step (2) is any one of azobisisobutyronitrile, azobisisoheptonitrile, dibenzoyl peroxide, lauroyl peroxide, ferrous salt and sodium sulfite;
the chain transfer agent in the step (1) is any one of EGditCTA, aliphatic mercaptan, dodecyl mercaptan, water, alcohol, ether, acid, ester and quinone.
Further, the anticancer drug in the step (3) is a drug having the function of preventing the growth of cancer tissues, and includes at least one of CPT, an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor agent, an antitumor platinum complex, an antitumor camptothecin derivative, an antitumor tyrosine kinase inhibitor, a monoclonal antibody, an interferon, a biological response modifier, a hormonal antitumor agent, an antitumor virus agent, an angiogenesis inhibitor, a differentiation inducer, a PI3K/Mtop/AKT inhibitor, a cell cycle inhibitor, an apoptosis inhibitor, a topoisomerase inhibitor, a taxane, a Her-2 targeting drug, a hormone antagonist, a targeting growth factor receptor or a pharmaceutically acceptable salt thereof; the photosensitizer has excellent near infrared light absorption performance and comprises one or more of Cy7TCF, N-heteroporphyrin dye, polyaniline, polypyrrole and polythiophene. Cy7TCF is one of cyanine dyes, is developed by the inventor in the laboratory and is published.
The invention has the beneficial effects that:
(1) the polymer provided by the invention can be self-assembled in an aqueous solution to form a micro-nano structure, the micro-nano structure can be loaded with an anti-cancer drug and a photosensitizer in a physical packaging mode at a low temperature, and the micro-nano structure is cracked at a high temperature to release the drug and form hydrogel, so that a nano hydrogel drug delivery system is formed. The photosensitizer loaded in the nano hydrogel drug delivery system has good photo-thermal conversion efficiency and photo-acoustic imaging effect, and has the synergistic effect of targeted tumor chemotherapy-photo-thermal treatment after being loaded with the anti-cancer drug, so that the tumor treatment effect is improved, and the nano hydrogel drug delivery system has good application prospect.
(2) The hydrogel nano-drug delivery system has low cytotoxicity; the phase transition temperature of the hydrogel can be well controlled by changing the molar mass ratio of the monomers; the drug release of the drug has temperature sensitivity, namely, the temperature-controlled drug release is realized; compared with the simple anticancer drugs and auxiliary agents and clinical anticancer drug sustained release preparations, the compound preparation has better characteristic of inhibiting the growth of tumors.
Drawings
FIG. 1 is a schematic diagram of a process for preparing a drug delivery system provided in example 1 of the present invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum of an initial product prepared in example 1 of the present invention;
FIG. 3 is a nuclear magnetic hydrogen spectrum of a copolymer product prepared in example 1 of the present invention;
FIG. 4 is a graph of photothermal effect of the polymer synthesized in example 1 of the present invention, wherein FIG. 4A is a graph of photothermal effect at different concentrations, and FIG. 4B is a graph of photothermal effect at different powers;
FIG. 5 is a test chart for drug release in example 1 of the present invention;
FIG. 6 is a DLS particle size distribution diagram of a micro-nano structure of a polymer encapsulated drug and photosensitizer synthesized in example 1 of the present invention;
FIG. 7 is a TEM image of the micro-nano structure of the polymer encapsulated drug and photosensitizer synthesized in example 1 of the present invention;
FIG. 8 is a photothermal characterization of a nanogel prepared in accordance with the invention;
FIG. 9 shows the results of cell co-localization experiments of micro-nano structures prepared in the present invention;
FIG. 10 is a fluorescence image of a mouse experiment provided by the present invention;
FIG. 11 is a diagram of photothermal therapy experiments in a mouse experiment provided by the present invention;
FIG. 12 is a data plot of a mouse experiment provided by the present invention;
FIG. 13 is a chart of a blood routine and liver function test data table for a mouse experiment provided by the present invention;
FIG. 14 is a graph showing the results of the in vivo safety test of mice according to the present invention.
Detailed Description
For further understanding of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The raw materials or reagents involved in the examples and experimental examples are all known substances, and can be obtained commercially or prepared by conventional means in the field; unless otherwise indicated, all operations involved are conventional.
Example 1
As shown in fig. 1, this example provides a method for preparing a drug delivery system comprising a polymer nanohydrogel, comprising the steps of:
step (1): this example uses reversible addition-fragmentation transfer (RAFT) polymerization techniques to prepare functional polymers. RAFT polymerization is used to produce P (NIPAM-co-DMAA) bifunctional macroscopic CTAs with different Degrees of Polymerization (DPs) from EGditCTA. EGditCTA (0.14g, 0.24mmol), NIPAM (2.17g, 19.15mmol), DMAA (711.9mg, 7.18mmol) and AIBN (9.83mg, 0.59mmol) were typically charged to a Schlenk flask and dissolved in 6g of dimethyl sulfoxide to prepare hydrophilic P (NIPAM-co-DMAA). The reaction mixture was degassed using three freeze pump cycles and polymerized at 70 ℃ for 12 hours. After 12 hours, the Schlenk flask was immersed in liquid nitrogen to stop the polymerization. To remove unpolymerized monomers, the polymerization solution was diluted in DCM and precipitated three times in methanol and diethyl ether. The final product was dried in a vacuum oven at room temperature overnight, resulting in a solid precipitate. The nuclear magnetic spectrum is shown in figure 2.
Step (2): p (NIPAM-co-DMAA) is taken as a macromolecule RAFT reagent to synthesize the P (AAM-co-AN) -b-P (NIPAM-co-DMAA) -b-P (AAM-co-AN) triblock copolymer. P (NIPAM-co-DMAA) (1.4g, 0.12mmol), AAM (0.8g, 11.16mmol), AN (0.7g, 13.2mmol) and AIBN (0.005g, 0.03mmol) were charged into a Schlenk flask containing 4ml of DMSO. The reaction mixture was degassed using three freeze pump-thaw cycles and polymerized at 70 ℃ for 24 hours. After 24 hours, the Schlenk flask was immersed in liquid nitrogen to stop the polymerization. To produce a residue, the mixture was precipitated into excess ether, the residue was dissolved in dimethyl sulfoxide and precipitated into ether, and the above dissolution-precipitation cycle was repeated three times. The finished product was dried in a vacuum oven overnight at room temperature to give a solid powder. The nuclear magnetic spectrum is shown in figure 3.
And (3): medicine wrapping: membrane dialysis was used to prepare P (AAm-co-AN) -b-P (NIPAM-co-DMAa) -b-P (AAm-co-AN) micelles and Cy7-TCF/CPT drug-loaded nanoparticles. CPT (5mg), Cy7TCF (5mg) and copolymer (20mg) were dissolved in 2ml of dimethyl sulfoxide. While magnetically stirring, the mixture was dropped into 10mL of deionized water for 30 minutes. The solution was then dialyzed against deionized water for 24 hours to remove the solvent as well as free CPT and Cy7 TCF. In the absence of CPT and Cy7TCF, a similar method was used to create free micelles.
The prepared polymer is subjected to a photothermal effect experiment, and as can be seen from fig. 4, the polymer has good photothermal effect; in the drug release test chart shown in fig. 5, the drug release can reach about 60% when irradiated with 808 nm.
DLS (digital Living SoftSpecification) particle size distribution measurement and TEM (Transmission Electron microscope) test are respectively carried out on the micro-nano structure of the polymer-encapsulated drug and the photosensitizer synthesized in the embodiment, as shown in fig. 6 and 7, the test structure shows that the prepared micro-nano structure has uniform particle size and the average size of about 100 nm.
Example 2
This example provides a method of making a drug delivery system comprising a polymeric nanohydrogel, comprising the steps of:
step (1): this example uses reversible addition-fragmentation transfer (RAFT) polymerization techniques to prepare functional polymers. RAFT polymerization is used to generate P (NIPAM-co-DMAA) bifunctional macroscopic CTAs with different Degrees of Polymerization (DPs) from EGditCTA. EGditCTA (0.14g, 0.24mmol), NIPAM (2.034g, 18.00mmol), DMAA (594.00mg, 6.00mmol) and AIBN (78.72mg, 0.48mmol) were typically charged to a Schlenk flask and dissolved in 6g of dimethyl sulfoxide to prepare hydrophilic P (NIPAM-co-DMAA). The reaction mixture was degassed using three freeze pump cycles and polymerized at 50 ℃ for 16 hours. After 16 hours, the Schlenk flask was immersed in liquid nitrogen to stop the polymerization. To remove unpolymerized monomers, the polymerization solution was diluted in DCM and precipitated three times in methanol and diethyl ether. The final product was dried in a vacuum oven at room temperature overnight, resulting in a solid precipitate.
Step (2): p (NIPAM-co-DMAA) is taken as a macromolecule RAFT reagent to synthesize the P (AAM-co-AN) -b-P (NIPAM-co-DMAA) -b-P (AAM-co-AN) triblock copolymer. P (NIPAM-co-DMAA) (1.4g, 0.12mmol), AAM (0.767g, 10.80mmol), AN (0.636g, 12.00mmol) and AIBN (3.93mg, 0.024mmol) were charged in general to a Schlenk flask containing 4ml DMSO. The reaction mixture was degassed using three freeze pump-thaw cycles and polymerized at 50 ℃ for 28 hours. After 28 hours, the Schlenk flask was immersed in liquid nitrogen to stop the polymerization. To produce a residue, the mixture was precipitated into excess diethyl ether, the residue was dissolved in dimethyl sulfoxide and precipitated into diethyl ether, and the above dissolution-precipitation cycle was repeated three times. The finished product was dried in a vacuum oven overnight at room temperature to give a solid powder.
And (3): medicine wrapping: membrane dialysis was used to prepare P (AAm-co-AN) -b-P (NIPAM-co-DMAa) -b-P (AAm-co-AN) micelles and Cy7-TCF/CPT drug-loaded nanoparticles. CPT (5mg), Cy7TCF (10mg) and copolymer (30mg) were dissolved in 2ml of dimethyl sulfoxide. While magnetically stirring, the mixture was dropped into 20mL of deionized water for 30 minutes. The solution was then dialyzed against deionized water for 24 hours to remove the solvent as well as free CPT and Cy7 TCF. In the absence of CPT and Cy7TCF, a similar method was used to create free micelles.
Example 3
This example provides a method of making a drug delivery system comprising a polymeric nanohydrogel, comprising the steps of:
step (1): this example uses reversible addition-fragmentation transfer (RAFT) polymerization techniques to prepare functional polymers. RAFT polymerization is used to generate P (NIPAM-co-DMAA) bifunctional macroscopic CTAs with different Degrees of Polymerization (DPs) from EGditCTA. EGditCTA (0.14g, 0.24mmol), NIPAM (2.305g, 20.40mmol), DMAA (831.6mg, 8.40mmol) and AIBN (0.118g, 0.72mmol) were typically charged to a Schlenk flask and dissolved in 6g of dimethyl sulfoxide to prepare hydrophilic P (NIPAM-co-DMAA). The reaction mixture was degassed using three freeze pump cycles and polymerized at 100 ℃ for 8 hours. After 8 hours, the Schlenk flask was immersed in liquid nitrogen to stop the polymerization. To remove unpolymerized monomers, the polymerization solution was diluted in DCM and precipitated three times in methanol and diethyl ether. The final product was dried in a vacuum oven at room temperature overnight, resulting in a solid precipitate.
Step (2): p (NIPAM-co-DMAA) is taken as a macromolecule RAFT reagent to synthesize the P (AAM-co-AN) -b-P (NIPAM-co-DMAA) -b-P (AAM-co-AN) triblock copolymer. P (NIPAM-co-DMAA) (1.4g, 0.12mmol), AAM (0.810g, 11.40mmol), AN (0.763g, 14.40mmol) and AIBN (0.006g, 0.036mmol) were charged in general to a Schlenk flask containing 4ml of DMSO. The reaction mixture was degassed using three freeze pump-thaw cycles and polymerized at 100 ℃ for 20 hours. After 20 hours, the Schlenk flask was immersed in liquid nitrogen to stop the polymerization. To produce a residue, the mixture was precipitated into excess ether, the residue was dissolved in dimethyl sulfoxide and precipitated into ether, and the above dissolution-precipitation cycle was repeated three times. The finished product was dried in a vacuum oven overnight at room temperature to give a solid powder.
And (3): medicine wrapping: membrane dialysis was used to prepare P (AAm-co-AN) -b-P (NIPAM-co-DMAa) -b-P (AAm-co-AN) micelles and Cy7-TCF/CPT drug-loaded nanoparticles. CPT (5mg), Cy7TCF (15mg) and copolymer (50mg) were dissolved in 2ml of dimethyl sulfoxide. While magnetically stirring, the mixture was dropped into 20mL of deionized water for 30 minutes. The solution was then dialyzed against deionized water for 24 hours to remove the solvent as well as free CPT and Cy7 TCF. In the absence of CPT and Cy7TCF, a similar method was used to create free micelles.
Examples of the experiments
The product prepared in example 1 was assayed and subjected to a mouse experiment. As shown in FIG. 8, it can be concluded from the photo-thermal characterization of nanogel that when the photosensitizer with the same concentration is injected into the chicken breast with the same volume, the photo-thermal effect in the chicken breast with the same volume shows that the nanogel can better transfer heat. As can be seen from the test results shown in the cell co-localization experiment of fig. 9, the micro-nano structure is able to reach the lysosome of the cell. FIG. 10 is fluorescence imaging data of the micro-nano structure, and as shown in the figure, the fluorescence part of the tumor part is increased along with the increase of time, and after 114 hours, other parts in the body have no other compounds and are all enriched in the tumor part, so that the compound is proved to be applied to the tumorThe targeting of the site is very good, and the body of the nude mouse does not have abnormal reactions such as spasm, convulsion and the like within 24 hours, which proves that the biological safety of the compound is high. As can be analyzed from FIGS. 11 and 12, the tumor volume before photothermal therapy was 70mm3On the left and right sides, after photo-thermal treatment, the tumor broke, and no obvious tumor growth was seen with the time increase, and the tumor broke starts to heal, and the tumor broke heals completely on day 16. Tumor volume changes as shown in fig. 12a, the mice in the experimental group had tumor elimination after laser irradiation and had no recurrence within 20 days. While the tumor volume of the control mice increased continuously and became 25-fold larger within 20 days. The change of the body weight of the mice is shown in fig. 12b, and the body weight of the mice in the experimental group and the control group has no abnormal change and has no obvious side effect. The micro-nano structure is proved to have excellent photo-thermal treatment capability, no damage to viscera, small side effect, and relative safety and reliability. As can be seen from the results of the safety test in mice in fig. 13 and 14, the blood general indicators of lymphocytes, mean corpuscular volume and corpuscular volume distribution width are within the normal range, and the liver function indicators of albumin, cholesterol, alkaline phosphatase and blood sugar are within the normal range. The results show that the polymer has higher safety, does not damage the liver in a short time, and is relatively safe and reliable.
All the experimental test results show that the drug delivery system of the stimulus response type nano hydrogel has the advantages of both the hydrogel and the nanoparticle delivery system, and the drug release efficiency of the nano hydrogel is remarkably improved under the photo-thermal condition. Meanwhile, the system also has the characteristics of hydrophilicity, flexibility, biocompatibility, high water absorption and the like of hydrogel, and can control the release of the medicine through temperature stimulus response. The method has simple synthetic process, and can reach higher loading capacity when being used as a drug carrier. In addition, the materials used in the invention have good biocompatibility and low toxicity, and the synthesis process is simple, so the material has good biological application prospect, and has important research significance for researching the preparation field of the drug delivery system material.
Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the present invention. Any modification, equivalent replacement, or modification made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The polymer nano hydrogel is characterized in that the polymer nano hydrogel is formed by a micro-nano structure formed by self-assembling a polymer with a structure shown in a formula (IV), an isomer, pharmaceutically acceptable salt, a hydrate or a solvate thereof in an aqueous solution at high temperature;
in the formula (IV), the compound is shown in the specification,
r14, R14' are selected from O, N or S;
l is an olefin monomer containing a hydrophilic group and a hydrophobic group, respectively;
x is an N-substituted or N, N-substituted acrylamide monomer;
t1 and t2 are independently selected from integers of 0-500, and t3 is selected from integers of 1-10;
r13 is selected from any one of H, a halogen atom, a hydrocarbon group, a cycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, an alcohol group, an ether group, an aldehyde group, a carboxyl group, an amide group, an ester group, or an amino group.
2. The polymer nanohydrogel of claim 1, wherein R14 is O or S and R14' is O or S.
3. The polymer nanohydrogel of claim 1, wherein L is
And each q is independently selected from an integer of 0-12.
4. The polymer nanohydrogel of claim 1, wherein X is
Or
Each q is independently selected from an integer of 0-12.
5. The polymer nanohydrogel of claim 1, wherein the polymer is synthesized from the monomers acrylamide and acrylonitrile, N-isopropylacrylamide and N, N-dimethylacrylamide by a reversible addition-fragmentation chain transfer method.
6. A drug delivery system comprising the polymer nanohydrogel of any one of claims 1 to 5, wherein the drug delivery system is composed of the polymer nanohydrogel loaded with an anticancer drug and a photosensitizer, and the loading is performed by physical encapsulation.
7. The drug delivery system of claim 6, wherein the micro-nano structure of the polymer is uniform in size, and the size of the micro-nano structure is 50-200 nm.
8. Method for the preparation of a drug delivery system according to any of claims 6 or 7, comprising the steps of:
(1) and (2) mixing the chain transfer agent, the N-isopropylacrylamide, the N, N-dimethylacrylamide and the initiator according to the weight ratio of 1: (75-85): (25-35): (2-3) adding the substances into a dimethyl sulfoxide solution according to the mass ratio, mixing and dissolving, removing air in a reaction system for 0.1-2 h at 0-50 ℃, and heating the reaction system to 50-100 ℃ to react for 8-16 h under an anaerobic condition to obtain an initial product;
(2) mixing the initial product obtained in the step (1) with acrylamide, acrylonitrile and an initiator according to the ratio of 1: (90-95): (100-120): (0.2-0.3) mixing the substances in a proper amount of dimethyl sulfoxide, removing air in the reaction system for 0.1-2 h at 0-50 ℃, and heating the reaction system to 50-100 ℃ to react for 20-28 h under the oxygen-free condition to obtain a copolymer product;
(3) and (3) drying the copolymer obtained in the step (2) at 0-50 ℃ in vacuum, and then mixing the anti-cancer drug, the photosensitizer and the copolymer according to a mass ratio of 1: (1-3): (4-10), mixing the copolymer with an anti-cancer drug and a photosensitizer, dissolving the mixture in a small amount of dimethyl sulfoxide, dropwise adding deionized water, and stirring at room temperature; then removing the non-encapsulated anticancer drug and photosensitizer by dialysis separation, and vacuum drying at 25 deg.C to obtain the drug delivery system.
9. The method according to claim 8, wherein the initiator in the steps (1) and (2) is any one of azobisisobutyronitrile, azobisisoheptonitrile, dibenzoyl peroxide, lauroyl peroxide, a ferrous salt, and sodium sulfite;
the chain transfer agent in the step (1) is any one of EGditCTA, aliphatic mercaptan, dodecyl mercaptan, water, alcohol, ether, acid, ester and quinone.
10. The process according to claim 8, wherein the anticancer drug in step (3) comprises at least one of CPT, an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor agent, an antitumor platinum complex, an antitumor camptothecin derivative, an antitumor tyrosine kinase inhibitor, a monoclonal antibody, an interferon, a biological response modifier, a hormonal antitumor agent, an antitumor virus agent, an angiogenesis inhibitor, a differentiation inducer, a PI3K/Mtop/AKT inhibitor, a cell cycle inhibitor, an apoptosis inhibitor, a topoisomerase inhibitor, a taxane, a Her-2 targeting drug, a hormone antagonist, a targeting growth factor receptor or a pharmaceutically acceptable salt thereof; the photosensitizer comprises one or more of Cy7TCF, N-heteroporphyrin dye, polyaniline, polypyrrole and polythiophene.
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| CN114524955A (en) * | 2022-02-24 | 2022-05-24 | 中国药科大学 | Method for singly regulating and controlling mechanical property of acid response nanogel and application |
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