CN113197859B - Preparation method of polymersome - Google Patents

Preparation method of polymersome Download PDF

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CN113197859B
CN113197859B CN202110438851.4A CN202110438851A CN113197859B CN 113197859 B CN113197859 B CN 113197859B CN 202110438851 A CN202110438851 A CN 202110438851A CN 113197859 B CN113197859 B CN 113197859B
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loaded
peg
hydrophobic
block copolymer
buffer solution
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CN113197859A (en
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王林格
胡菲
刘渊
于倩倩
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South China University of Technology SCUT
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    • 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
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A61K38/385—Serum albumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
    • A61K49/0084—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion liposome, i.e. bilayered vesicular structure
    • A61K49/0086—Polymersome, i.e. liposome with polymerisable or polymerized bilayered-forming substances
    • 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
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes

Abstract

The invention discloses a preparation method of polymer vesicles, and belongs to the field of high polymer materials. The method combines the thin film annealing technology and the hydration method composite technology to prepare the polymer vesicle. Compared with the traditional membrane hydration method which usually prepares the membrane at room temperature or slightly higher than room temperature and rehydrates the membrane to obtain the polymer vesicles, the method disclosed by the invention has the advantages that after the membrane is prepared by using a specific organic solvent, the membrane is subjected to thermal annealing treatment at high temperature to promote the microphase structure in the membrane, so that the subsequent rehydration efficiency is greatly improved, and the nano-scale and narrow-distribution polymer vesicles can be obtained in a controllable and batch manner.

Description

Preparation method of polymersome
Technical Field
The invention belongs to the field of high molecular materials, relates to a preparation method of polymer vesicles, and particularly relates to a method for preparing the polymer vesicles by a composite process of a thin film annealing technology and a hydration method.
Background
The polymer vesicle is a hollow sphere structure formed by orderly self-assembling amphiphilic block copolymers in a solution, and the shape of the polymer vesicle is similar to that of a liposome. In aqueous solution, the membrane structure of the polymer vesicle is similar to a sandwich, the middle layer is a hydrophobic layer formed by closely arranging hydrophobic chain segments, and the inner side and the outer side of the hydrophobic layer are extended by hydrophilic chain segments to form a brush shape. The inner water core of the polymer vesicle can be loaded with hydrophilic molecules, and the hydrophobic membrane layer can be loaded with hydrophobic molecules, so that the polymer vesicle has wide application in the fields of drug delivery, medical diagnosis, food industry, cosmetic industry and the like. Especially, with the rapid development of the biomedical industry and the outbreak of epidemic situations in recent years, the use of polymer vesicles to load biomedical products such as proteins, nucleic acid drugs and nucleic acid vaccines has been highly expected.
The block copolymer with PEG (polyethylene glycol) as a hydrophilic chain segment and PLA (polylactic acid) or PCL (polycaprolactone) as a hydrophobic chain segment has excellent biocompatibility and degradability, and is an optimal candidate system for preparing the polymer vesicle used in the field of biological medicines. The conventional method for preparing the polymer vesicle is a film hydration regeneration method, namely dissolving a polymer in an organic solvent, removing the organic solvent by rotary evaporation, nitrogen blow-drying or other methods, drying the organic solvent in vacuum at room temperature or at the temperature of not higher than 40 ℃ to prepare a film, and adding water or buffer solution to stir the film. However, the vesicles prepared by the method are slow in formation, and the size distribution of the generated vesicles is wide and varies from nanometer to micron, so that the vesicles are not beneficial to delivery of tissues or cells in a human body.
Disclosure of Invention
The present invention aims to overcome the above disadvantages of the prior art and to provide a method for preparing polymersome. The invention firstly utilizes the selected solvent to prepare the film and the film thermal annealing to prepare the film with a certain microphase separation morphology structure, and then prepares the nano-scale narrow-distribution polymer vesicle by the hydration method. The method can be used for preparing the polymer vesicles with nanometer grade and uniform size in a controllable and batch manner.
The purpose of the invention is realized by adopting the following technical scheme:
a preparation method of polymersome comprises the following steps:
1) adding the block copolymer or the block copolymer and hydrophobic molecules to be loaded into an organic solvent, and stirring to prepare a uniform block copolymer solution;
2) removing the organic solvent by rotary evaporation or nitrogen blow drying to obtain a transparent film;
3) placing the film under a vacuum condition for thermal annealing;
4) when the block copolymer is added into the organic solvent in the step 1), adding water or buffer solution and stirring to obtain polymer vesicles; or adding water or buffer solution dissolved with the hydrophilic molecules to be loaded and stirring to obtain the polymer vesicles loaded with the hydrophilic molecules; when the block copolymer and the hydrophobic molecule to be loaded are added into the organic solvent in the step 1), adding water or buffer solution and stirring to obtain the polymer vesicle loaded with the hydrophobic molecule; or adding water or buffer solution dissolved with hydrophilic molecules to be loaded and stirring to obtain the polymer vesicle loaded with the hydrophilic and hydrophobic molecules simultaneously.
The block copolymer in step 1) described in step 1) is preferably at least one of AB type, ABA type, BAB type, BAC type, ABC type, ABABA type and ABACA type block copolymer; wherein, the block A is a hydrophilic chain segment, and the block B and the block C are different hydrophobic chain segments;
the hydrophilic chain segment is preferably polyethylene glycol; the hydrophobic chain segment is preferably polylactic acid or polycaprolactone.
The hydrophobic molecule in step 1) can be a hydrophobic fluorescent dye or a hydrophobic small molecule drug.
The hydrophobic fluorescent dye is preferably Nile red (Nile red); the hydrophobic small molecule drug is preferably Paclitaxel (PTX).
The organic solvent described in step 1) is preferably Tetrahydrofuran (THF).
The ratio of the block copolymer to the organic solvent in the step 1) is preferably 2-15 mg:1 mL.
The stirring condition in the step 1) is preferably 100-500 r/min and 15-30 min.
The thermal annealing condition in the step 3) is preferably 60-80 ℃ for 8-12 h.
The hydrophilic molecule in the step 4) can be a hydrophilic small molecule drug, protein or nucleic acid. The hydrophilic small molecule drug is preferably Doxorubicin (DOX); the protein is preferably Bovine Serum Albumin (BSA); the nucleic acid is preferably plasmid DNA, antisense oligonucleotides, messenger RNA (mRNA), small interfering RNA (siRNA).
The water, the buffer solution and the water or the buffer solution dissolved and needing to load the hydrophilic molecules in the step 4) are preferably calculated according to the proportion of 1mL to 2-15 mg of the block copolymer.
The stirring condition in the step 4) is preferably room temperature, 100-500 r/min and 12-24 h. The room temperature is 20-30 ℃.
A polymersome is prepared by the preparation method.
The method for preparing the polymersome is characterized in that a film with a microphase structure is prepared by using a film annealing technology, and then the polymersome with uniform nano-scale size (the average particle size is 50-300 nm) is obtained by using a hydration method. The film is prepared using a selected solvent, and the effect is equivalent to a specific solvent anneal. And then carrying out thermal annealing to prepare the film with the microphase structure. In the hydration process of the film with the microphase structure, the polymer does not need to be dissolved to a monomer to complete self-assembly, but part of the film falls into water and is bent and then closed into spheres to form vesicles, so that other self-assembly structures are avoided, and the film is more controllable and efficient.
Drawings
FIG. 1 is a schematic illustration of a thin film annealing technique and hydration process; wherein, firstly, the film is prepared by using a specified solvent and then is subjected to thermal annealing treatment, and secondly, water or buffer solution is added and stirred.
FIG. 2 is an atomic force microscope photograph of the film of example 1.
FIG. 3 is a transmission electron micrograph of polymersome prepared in example 1; wherein, (1) is the polymer vesicle prepared by the film thermal annealing and hydration method, and (2) is the polymer vesicle prepared by the common film hydration method.
Fig. 4 is a graph showing a distribution of the particle size of the polymersome of example 1 measured by dynamic light scattering.
FIG. 5 is a confocal microscope photograph showing the doxorubicin-loaded polymersome prepared in example 5 phagocytosed by cells; wherein, (1) is fluorescence signal (red) of adriamycin, (2) is laser confocal microscopic picture of cells under white light condition, and (3) is combined picture of (1) and (2).
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
Example 1:
20mg of block copolymer PEG were weighed 5000 -PLA 12000 Then, the mixture was added to 2mL of THF and stirred (500r/min) for 15 minutes to prepare a 10mg/mL block copolymer solution; removing THF from the block copolymer solution through rotary evaporation to obtain a transparent film; and (3) placing the film in a vacuum drying oven at 80 ℃ and carrying out thermal annealing on the film for 12 hours. Then 2mL of deionized water is added, and the mixture is stirred at room temperature (400r/min) for 12h to prepare the polymersome. The transmission electron microscope image of the polymersome prepared in this example is shown in fig. 3(1), and the result shows that the polymersome prepared by the technology of the present invention (membrane annealing + hydration method) can form uniform nano-scale vesicles under short-time stirring, while the conventional technology (common membrane hydration method, without membrane thermal annealing operation) has the advantages of less vesicle generation amount and irregular aggregates (fig. 3(2)) under the same time, and if more vesicles are obtained, a longer stirring time (usually several days) is often needed. As shown in FIG. 4, the average particle diameter of the vesicles prepared by the technique of the present invention was 95nm, and the particle size distribution (PDI) was 0.014.
Example 2:
20mg of block copolymer PEG were weighed 2000 -PCL 7500 Then, the mixture was added to 2mL of THF and stirred (100r/min) for 30 minutes to prepare a 5mg/mL block copolymer solution; blowing the segmented copolymer solution by nitrogen to remove THF so as to obtain a transparent film; and (3) placing the film in a vacuum drying oven at 70 ℃ and carrying out thermal annealing on the film for 10 hours. Then 2mL of deionized water is added, and the mixture is stirred at room temperature (400r/min) for 18h to prepare the polymersome.
Example 3:
20mg of block copolymer PEG were weighed 4000 -PLA 20000 -PEG 4000 Then, the mixture was added to 2mL of THF and stirred (500r/min) for 15 minutes to prepare a 10mg/mL block copolymer solution; removing THF from the block copolymer solution through rotary evaporation to obtain a transparent film; and (3) placing the film in a vacuum drying oven at 80 ℃ and carrying out thermal annealing on the film for 12 hours. Then 2mL of deionized water is added, and the mixture is stirred (400r/min) at room temperature for 24h to prepare the polymersome.
Example 4:
20mg of block copolymer PEG were weighed 6000 -PLA 8000 -PCL 8000 And 10. mu.g of Nile Red, added to 2mL of THF, stirred (500r/min) for 15 minutes to obtain10mg/mL of a block copolymer solution; removing THF from the block copolymer solution through rotary evaporation to obtain a transparent film; and (3) placing the film in a vacuum drying oven at 80 ℃ and carrying out thermal annealing on the film for 12 hours. Then 2mL of deionized water is added, and the mixture is stirred (400r/min) at room temperature for 24h to prepare the loaded Nile red polymer vesicles.
Example 5:
20mg of block copolymer PEG were weighed 4000 -PCL 10000 Then, the mixture was added to 2mL of THF, and stirred (500r/min) for 15 minutes to prepare a 10mg/mL block copolymer solution; blowing the segmented copolymer solution by nitrogen to remove THF so as to obtain a transparent film; and (3) placing the film in a vacuum drying oven at 70 ℃ and carrying out thermal annealing on the film for 10 hours. Then 2mL of doxorubicin hydrochloride aqueous solution (1mg/mL) is added, and the mixture is stirred at room temperature (400r/min) for 18h to obtain the doxorubicin hydrochloride-loaded polymersome. Cell culture was performed after removing unencapsulated doxorubicin by dialysis (FIG. 5). The specific operation is as follows: to 4T1 cells, 10. mu.L of doxorubicin-loaded polymersome was added at 37 ℃ with 5% CO 2 Co-culturing for 4h in an incubator. In FIG. 5, (1) is the fluorescence signal of doxorubicin (red); (2) is a laser confocal microscope picture of cells under the white light condition; (3) the results, which are a combined graph of (1) and (2), show that the doxorubicin-loaded vesicles successfully delivered doxorubicin into the cells.
Example 6:
20mg of block copolymer PEG were weighed 2000 -PLA 6000 -PEG 2000 -PLA 6000 -PEG 2000 Then, the mixture was added to 2mL of THF, and stirred (500r/min) for 15min to prepare a block copolymer solution of 5 mg/mL; blowing the segmented copolymer solution by nitrogen to remove THF so as to obtain a transparent film; the film was placed in a vacuum oven at 80 ℃ overnight and thermally annealed. 2mL of phosphate buffer containing antisense oligonucleotide (30. mu. mol/L) was added, and the mixture was stirred at room temperature (400r/min) for 18 hours to prepare antisense oligonucleotide-loaded polymersome.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.

Claims (6)

1. A method for producing polymersome, characterized in that: the method comprises the following steps:
1) adding a block copolymer or a block copolymer and a hydrophobic molecule to be loaded into an organic solvent, and stirring to prepare a uniform block copolymer solution;
2) removing the organic solvent by rotary evaporation or nitrogen blow drying to obtain a transparent film;
3) placing the film under a vacuum condition for thermal annealing;
4) when the block copolymer is added into the organic solvent in the step 1), adding water or buffer solution and stirring to obtain polymer vesicles; or adding water or buffer solution dissolved and needing to be loaded with hydrophilic molecules and stirring to obtain the polymer vesicles loaded with the hydrophilic molecules; when the block copolymer and the hydrophobic molecule to be loaded are added into the organic solvent in the step 1), adding water or buffer solution and stirring to obtain the polymer vesicle loaded with the hydrophobic molecule; or adding water or buffer solution dissolved and needing to be loaded with hydrophilic molecules and stirring to obtain the polymer vesicles loaded with the hydrophilic molecules and the hydrophobic molecules simultaneously;
the block copolymer in the step 1) is at least one of PEG-PLA, PEG-PCL, PLA-PEG-PLA, PEG-PLA-PEG, PCL-PEG-PCL and PEG-PCL-PEG;
the organic solvent in the step 1) is tetrahydrofuran;
the thermal annealing condition in the step 3) is 60-80 ℃ for 8-12 h;
the amount of the water, the buffer solution and the water or the buffer solution which is dissolved and needs to be loaded with the hydrophilic molecules in the step 4) is 1mL to 2-15 mg.
2. The method for producing polymersomes according to claim 1, wherein:
the hydrophobic molecule in the step 1) is hydrophobic fluorescent dye or hydrophobic micromolecular medicine;
the hydrophilic molecule in the step 4) is a hydrophilic small molecule drug, protein or nucleic acid.
3. The method for producing polymersomes according to claim 2, wherein:
the hydrophobic fluorescent dye is nile red; the hydrophobic small molecular drug is paclitaxel;
the hydrophilic small molecular drug is adriamycin; the protein is calf serum albumin; the nucleic acid is plasmid DNA, antisense oligonucleotide, messenger RNA or small interfering RNA.
4. The method for producing polymersomes according to claim 1, wherein:
the amount of the water, the buffer solution and the water or the buffer solution which is dissolved and needs to be loaded with the hydrophilic molecules in the step 4) is 1mL to 2-15 mg.
5. The method for producing polymersomes according to claim 1, wherein:
the stirring condition in the step 1) is 100-500 r/min and 15-30 min;
the stirring condition in the step 4) is room temperature, 100-500 r/min and 12-24 h.
6. A polymersome produced by the method for producing a polymersome according to any one of claims 1 to 5.
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