CN105395486A - Macromolecule vesicle and complexing method thereof - Google Patents
Macromolecule vesicle and complexing method thereof Download PDFInfo
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- CN105395486A CN105395486A CN201510824570.7A CN201510824570A CN105395486A CN 105395486 A CN105395486 A CN 105395486A CN 201510824570 A CN201510824570 A CN 201510824570A CN 105395486 A CN105395486 A CN 105395486A
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- 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
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Abstract
The invention belongs to the technical field of macromolecule vesicle preparation, and discloses a macromolecule vesicle and a complexing method thereof. The method includes the steps of firstly, adding segmented copolymers or segmented copolymers and fluorescent dyes to organic solvent to be stirred and dissolved to obtain a macromolecule solution; secondly, filling a storage container of a high-voltage static generation device with the macromolecule solution, and conducting electronic injection through a high-voltage static spraying method to obtain solid particles; thirdly, adding the solid particles to water or a PBS buffer solution to be subjected to a hydration reaction to obtain the macromolecule vesicle or adding the solid particles and substances to be buried or loaded to water or a PBS buffer solution to be subjected to a hydration reaction to obtain the macromolecule vesicle. The method is simple, feasible, high in production efficiency and repeatability and suitable for macromolecule vesicle large-scale production of different requirements; meanwhile, the macromolecule vesicle is uniform in size and medicine carrying effect and can be used for fields of biological medicine delivery, nanometer reactors and fluorescent probes.
Description
Technical field
The invention belongs to technical field prepared by macromolecular vesicles, relate to a kind of preparation method of macromolecular vesicles, be specifically related to a kind of macromolecular vesicles and employing electrostatic spraying and the hydration legal system method for macromolecular vesicles.
Technical background
Macromolecular vesicles (polymervesicles or polymersomes) is a class hollow sphere, and the molecular film of similar spherical shell is formed by amphipathic nature block polymer sequential combination, and size is generally between tens nanometers are to tens microns.In aqueous, macromolecular vesicles film is a kind of structure of similar sandwich, and together intermediate layer is formed by hydrophobic segment tight clusters, hydrophilic segment be distributed in water-repellent layer inside and outside both sides and in the molecule brush of unfolding.The structure of macromolecular vesicles and the characteristic of film bring many-sided potential application perhaps to it, and such as medicine embedding, drug conveying, medicament slow release, nano-reactor etc., receive the concern of many scholars in recent decades.Particularly at biomedicine field, inclusions (medicine or gene) can be discharged into cell interior carry out target administration and gene therapy by cell endocytic by the macromolecular vesicles of some small sizes (about 200nm).In this field, scientists starting with on the one hand from raw material (block copolymer) of formation macromolecular vesicles, by Design and synthesis specific function block, preparation have specific response " intelligent macromolecule vesicle " and for medicine carrying and release, as having the macromolecular vesicles of pH response, temperature-responsive, photoresponse etc.Start with from the preparation method of macromolecular vesicles on the other hand, improve medicine carrying efficiency.The macromolecular vesicles method of preparing of block copolymer generally comprises, the extrusion molding etc. of hydration method, solvent exchange method, electrotyping forming method, ultrasonic method, high shear.The size often heterogeneity (distributing wide from tens nm to several microns) of this type of conventional preparation method gained macromolecular vesicles, the quality of different batches is also not quite similar, and causes the effect of medicine carrying and efficiency to have difference like this.
Summary of the invention
In order to overcome the shortcoming and defect of prior art, the object of the present invention is to provide complex method prepared by the macromolecular vesicles of a kind of nanoscale, size uniformity, narrowly distributing.The present invention first utilize electrostatic spraying legal system for constant weight, size block copolymer microgranule again with these block copolymer microgranules for raw material, prepared the nano-high molecule vesicle of narrow ditribution by hydration method.
A complex method for macromolecular vesicles, concrete steps are:
1) add in organic solvent by block copolymer or block copolymer and fluorescent dye, stirring and dissolving, obtains macromolecular solution;
2) macromolecular solution is loaded high-voltage electrostatic generator with in the storage capsule of injector head, then carry out EFI by high-pressure electrostatic spurt method, obtain solid particle; Step 2) actual conditions that sprays of described high-pressure electrostatic is: high-pressure electrostatic voltage is 5 ~ 30kV, distance between injector head and dash receiver is 5 ~ 50cm, solution is 0.1 ~ 15mL/h from the rate of outflow of injector head, and ambient temperature is 15 ~ 50 DEG C, and relative air humidity is 30 ~ 90%; Describedly prepare the schematic diagram of solid particle as shown in Figure 1 by electrostatic spraying;
3) solid particle is added in water or PBS buffer solution and carry out hydration reaction, obtain macromolecular vesicles; Or by solid particle with need to embed or the material of load adds in water or PBS buffer solution and carries out hydration reaction, obtain the macromolecular vesicles being loaded with loaded article.
Step 3) described in the mass volume ratio of solid particle and water (or PBS buffer) be 50mg:(5 ~ 10) mL; Described solid particle with need embed or the material mass of load than for 1000:(5 ~ 100).
Step 3) described hydration reaction refer to stirring reaction or first ultrasonic reaction again stirring reaction or first stirring reaction again ultrasonic reaction or stir ultrasonicly to stir again; Described ultrasonic time is 5 ~ 15min, and described ultrasonic power is 40 ~ 100W, and supersonic frequency is 20 ~ 500kHz; Described mixing time is 4 ~ 48h, and described speed of agitator is 100 ~ 800r/min.
Describedly need to embed or the material of load is medicine, antibody, albumen, genetic fragment or somatomedin.Described medicine is preferably amycin (DOX); Described antibody is preferably Victibix (Vectibix), T-DM1 (Kadcyla), antibody immunoglobulinG; Described albumen is preferably bovin serum albumin (BSA).
Step 1) described in block copolymer be diblock copolymer or segmented copolymer.
Described block copolymer is polyethylene glycol-polylactic acid (PEG-PLA), PEG-PCL (PEG-PCL), PLA-PEG-PLA (PLA-mPEG-PLA) or PCL-PEG-PCL (PCL-mPEG-PCL).Described block copolymer is reacted under the effect of catalyst by Polyethylene Glycol and caprolactone or lactide to prepare.
The preparation method of described PEG-PCL is: be dissolved in by PEG in organic solvent (as: toluene), add micro-stannous octoate simultaneously, under argon shield, slowly add caprolactone monomer, 48h (rotating speed is 300r/min) is stirred, vacuum rotary steam removing organic solvent, precipitating in excessive cold diethyl ether in 110 DEG C of constant temperature, sucking filtration, obtains PEG-PCL block copolymer; The mol ratio of described PEG and caprolactone is 1:0.2 ~ 5.
The preparation method of described PEG-PLA: take PEG and lactide, the mol ratio of PEG and lactide is 1:0.2 ~ 5); PEG, lactide are added in organic solvent (as: toluene) together with stannous octoate (trace), 18h (rotating speed is 350r/min) is stirred in 150 DEG C of constant temperature under blanket of nitrogen, then precipitating in excessive cold diethyl ether, sucking filtration, obtains PEG-PLA block copolymer.
The preparation method of described PLA-PEG-PLA: take PEG and lactide, the mol ratio of PEG and lactide is 10:1 ~ 2; PEG, lactide are added in organic solvent (as: toluene) together with stannous octoate (trace), in 140 DEG C of isothermal reaction 24h, then precipitating in cold diethyl ether under blanket of nitrogen, after vacuum drying, namely obtains PLA-PEG-PLA triblock copolymer.
The preparation method of described PCL-PEG-PCL: by PEG and caprolactone monomer, the mol ratio of PEG and caprolactone is 10:1 ~ 2; Add in organic solvent (as: toluene) together by PEG, caprolactone and stannous octoate (trace), in 140 DEG C of isothermal reaction 8h under nitrogen protection, excessive ice ether sedimentation sucking filtration, obtains PCL-PEG-PCL triblock copolymer.
Step 1) described in fluorescent dye be rhodamine (Rhodamine), Nile red (Nilered), phycoerythrin (PE) or Fluorescein isothiocyanate (FITC).Described rhodamine comprises rhodamine B.
Step 1) described in organic solvent be oxolane (THF), DMF (DMF), N,N-dimethylacetamide (DMAC), dichloromethane (DCM), chloroform (CHCl
3), more than one in methyl acetate (methylacetate), methyl cyanide (Acetonitrile), ethanol (Ethanol), methylisobutylketone (MIBK), hexafluoroisopropanol (HFIP) or acetone (Acetone).
Step 1) described in stir rotating speed be 100 ~ 800r/min;
Step 1) described in mixing time be 15 ~ 60min; The consumption of described block copolymer is 5 ~ 50wt% of organic solvent weight, and the weight ratio of described block copolymer and fluorescent dye is 1000:(1 ~ 50).
Described macromolecular vesicles is prepared by above-mentioned complex method.Macromolecular vesicles mean diameter prepared by the present invention is 50 ~ 300nm.
Described high-voltage electrostatic generator forms primarily of high-voltage generator, solution storage device, injection apparatus (i.e. injector head) and gathering-device (i.e. dash receiver).
Compared with prior art, tool of the present invention has the following advantages and beneficial effect:
(1) the present invention is by changing polymer copolymerization substrate concentration, dicyandiamide solution and electrostatic spraying condition, just can control weight and the size of microgranule; Again by water legal processes, the macromolecular vesicles with nanoscale, size uniformity just can be obtained; It is comparatively homogeneous that the present invention prepares macromolecular vesicles size, substantially maintains about 200nm;
(2) cavity closed that in macromolecular vesicles, amphiphilic macromolecular is formed can be used for packaging medicine or gene etc., and therefore macromolecular vesicles can be used as a kind of new drug carrier; And because the materials such as medicine and microgranule can obtain good dispersion in aqueous phase solution, so the medicine carrying uniform in effect of macromolecular vesicles, even if the quality of different batches also can be substantially identical, the effect of medicine carrying and efficiency do not have obvious difference;
(3) preparation process technique simple possible of the present invention, production efficiency is high, reproducible, is suitable for the macromolecular vesicles scale of mass production of different demand;
(4) macromolecular vesicles of the present invention can be used for that biological medicine is sent, nano-reactor and fluorescent probe association area.
Accompanying drawing explanation
Fig. 1 is that the present invention prepares the schematic diagram of solid particle by electrostatic spraying; 1 is charged solution and macromolecular solution, and 2 is EFI liquid stream, and 3 is ground connection gathering-device and dash receiver;
Fig. 2 is the stereoscan photograph of solid particle prepared by embodiment 1;
Fig. 3 is the transmission electron microscope photo of macromolecular vesicles prepared by embodiment 3; Wherein (1) is the TEM figure of 1500 times, and (2) are the TEM figure of 10000 times;
Fig. 4 is that the grafting fluorophor macromolecular vesicles load DOX of embodiment 4 preparation is by the Laser Scanning Confocal Microscope photo (630 times) after cytophagy; Wherein (1) is by the laser confocal microscope photo of the vesicle of FITC labelling, (2) be the laser confocal microscope photo of DOX, (3) be laser confocal microscope photo under the white light conditions of DOX, (4) are the merging figure of this three of (1) ~ (3).
Specific implementation method
Explain this explanation further below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.
Embodiment 1
Take 0.5g diblock copolymer PLA
2000-PEG
2000, join in the THF of 1g, mechanical agitation 15min (rotating speed of stirring is 100r/min), obtain block macromolecular solution (consumption of block copolymer is the 50wt% of organic solvent); Block macromolecular solution is loaded and carries out EFI with in the syringe of injector head by high-pressure electrostatic spurt method, the actual conditions of described EFI is: high-pressure electrostatic voltage is 5kV, distance between injector head and dash receiver is 10cm, solution is 0.1mL/h from the rate of outflow of injector head, ambient temperature is 15 DEG C, and relative air humidity is 45%; After EFI completes, by powder collection on collecting board, leave standstill and organic solvent is volatilized naturally, obtain solid particle; Get the solid particle of 50mg, add in 7.5mL deionized water, after ultrasonic 5min (ultrasonic power is 40W, and supersonic frequency is 20kHz), Keep agitation 4h (rotating speed of stirring is 100r/min), obtained macromolecular vesicles.The mean diameter of the solid particle prepared by the present embodiment is 20 μm, macromolecular vesicles particle diameter average out to 100nm.The stereoscan photograph of solid particle prepared by the present embodiment as shown in Figure 2.
Embodiment 2
Take 0.05g triblock copolymer PCL
2000-mPEG
4000-PCL
2000, join in the THF of 1g, mechanical agitation 60min (rotating speed of stirring is 800r/min), obtained block macromolecular solution (consumption of block copolymer is the 5wt% of organic solvent); Block macromolecular solution is loaded and carries out EFI with in the syringe of injector head by high-pressure electrostatic spurt method, the actual conditions of described EFI is: high-pressure electrostatic voltage is 20kV, distance between injector head and dash receiver is 30cm, solution is 15mL/h from the rate of outflow of injector head, ambient temperature is 30 DEG C, and relative air humidity is 85%; After EFI completes, by powder collection on collecting board, leave standstill and organic solvent is volatilized naturally, obtain solid particle; Take off the microgranule of 50mg, join in 7.5mL deionized water, (rotating speed of stirring is 100r/min) i.e. obtained macromolecular vesicles after Keep agitation 48h.The mean diameter of the solid particle prepared by the present embodiment is 30 μm, and macromolecular vesicles mean diameter is 150nm.
Embodiment 3
Take 0.05g diblock copolymer PLA
5000-PEG
5000, join in 1g acetone/DMAC (volume ratio 2:1) double solvents, mechanical agitation 60min (rotating speed of stirring is 100r/min), obtain block macromolecular solution (consumption of block copolymer is the 5wt% of organic solvent); Block macromolecular solution is loaded and carries out EFI with in the syringe of injector head by high-pressure electrostatic spurt method, the actual conditions of described EFI is: high-pressure electrostatic voltage is 20kV, distance between injector head and dash receiver is 30cm, solution is 15mL/h from the rate of outflow of injector head, ambient temperature is 25 DEG C, and relative air humidity is 85%; After EFI completes, by powder collection on collecting board, leave standstill and organic solvent is volatilized naturally, obtain solid particle; Take off the microgranule of 50mg, join in 7.5mL deionized water, ultrasonic 5min (ultrasonic power is 40w, and supersonic frequency is 20kHz) after mechanical agitation 4h, then (rotating speed of stirring is 100r/min) i.e. obtained macromolecular vesicles after Keep agitation 4h.The mean diameter of the solid particle prepared by the present embodiment is 40 μm, and macromolecular vesicles mean diameter is 200nm.The transmission electron microscope photo of macromolecular vesicles prepared by the present embodiment as shown in Figure 3.
Embodiment 4
Take 0.5g triblock copolymer PCL
2000-mPEG
4000-PCL
2000join in the THF organic solvent of 1g together with the FITC stain of 25mg, mechanical agitation 60min (rotating speed of stirring is 100r/min), has dissolved rear obtained 50wt% block macromolecular solution (consumption of block copolymer is the 50wt% of organic solvent); Block macromolecular solution is loaded and carries out EFI with in the syringe of injector head by high-pressure electrostatic spurt method, the actual conditions of described EFI is: high-pressure electrostatic voltage is 20kV, distance between injector head and dash receiver is 30cm, solution is 15mL/h from the rate of outflow of injector head, ambient temperature is 25 DEG C, and relative air humidity is 85%; After EFI completes, by powder collection on collecting board, leave standstill and organic solvent is volatilized naturally, obtain solid particle; The solid particle and the 0.4mg amycin (DOX) that take off 50mg join in the PBS solution of 7.5mL in the lump, after ultrasonic 15min (ultrasonic power is 100w supersonic frequency is 700kHz), (rotating speed of stirring is 100r/min) i.e. obtained macromolecular vesicles after Keep agitation 48h, carries out cell culture (Fig. 4) after the not wrapped DOX of dialysis removing.In Fig. 4, (1) is that vesicle demonstrates green by the laser confocal microscope photo of the vesicle of FITC labelling; (2) be the laser confocal microscope photo of DOX, DOX demonstrates redness; (3) be laser confocal microscope photo under the white light conditions of DOX, (4) are the merging figure of this three of (1) ~ (3).The mean diameter of the solid particle prepared by the present embodiment is 30 μm, and macromolecular vesicles mean diameter is 150nm.
Embodiment 5
Take 0.05g diblock copolymer PLA
5000-PEG
5000join in the THF organic solvent of 1g together with the rhodamine B stain of 0.1mg, mechanical agitation 15min (rotating speed of stirring is 800r/min), obtain macromolecular solution (consumption of block copolymer is the 5wt% of organic solvent); Macromolecular solution is loaded and carries out EFI with in the syringe of injector head by high-pressure electrostatic spurt method, the actual conditions of described EFI is: high-pressure electrostatic voltage is 20kV, distance between injector head and dash receiver is 30cm, solution is 0.1mL/h from the rate of outflow of injector head, ambient temperature is 30 DEG C, and relative air humidity is 45%; After EFI completes, by powder collection on collecting board, leave standstill and organic solvent is volatilized naturally, obtain solid particle; The molecular weight of the solid particle and 15 μ Μ of getting 50mg is that the DNA fragmentation of 500daltons joins in the PBS solution of 7.5mL jointly, under super-clean environment, after ultrasonic 15min, (ultrasonic power is specially 40W, supersonic frequency is specially 20kHz) (rotating speed of stirring is 100r/min) i.e. obtained macromolecular vesicles after Keep agitation 48h, carries out cell culture after the not wrapped DNA fragmentation of dialysis removing.The mean diameter of the solid particle prepared by the present embodiment is 40 μm, and macromolecular vesicles mean diameter is 200nm.
Claims (10)
1. a complex method for macromolecular vesicles, is characterized in that: concrete steps are:
1) add in organic solvent by block copolymer or block copolymer and fluorescent dye, stirring and dissolving, obtains macromolecular solution;
2) macromolecular solution is loaded high-voltage electrostatic generator with in the storage capsule of injector head, then carry out EFI by high-pressure electrostatic spurt method, obtain solid particle; The actual conditions that described high-pressure electrostatic sprays is: high-pressure electrostatic voltage is 5 ~ 30kV, distance between injector head and dash receiver is 5 ~ 50cm, solution is 0.1 ~ 15mL/h from the rate of outflow of injector head, and ambient temperature is 15 ~ 50 DEG C, and relative air humidity is 30 ~ 90%;
3) solid particle is added in water or PBS buffer solution and carry out hydration reaction, obtain macromolecular vesicles; Or by solid particle with need to embed or the material of load adds in water or PBS buffer solution and carries out hydration reaction, obtain the macromolecular vesicles being loaded with loaded article.
2. the complex method of macromolecular vesicles according to claim 1, is characterized in that: step 1) described in block copolymer be more than one in PEG-PLA, PEG-PCL, PLA-mPEG-PLA or PCL-mPEG-PCL.
3. the complex method of macromolecular vesicles according to claim 2, is characterized in that: described block copolymer is reacted under the effect of catalyst by Polyethylene Glycol and caprolactone or lactide to prepare.
4. the complex method of macromolecular vesicles according to claim 1, is characterized in that: step 3) described hydration reaction be stirring reaction or first ultrasonic reaction again stirring reaction or first stirring reaction again ultrasonic reaction or stir ultrasonicly to stir again.
5. the complex method of macromolecular vesicles according to claim 3, it is characterized in that: described ultrasonic time is 5 ~ 15min, described ultrasonic power is 40 ~ 100W, and supersonic frequency is 20 ~ 500kHz; Described mixing time is 4 ~ 48h, and described speed of agitator is 100 ~ 800r/min.
6. the complex method of macromolecular vesicles according to claim 1, it is characterized in that: step 1) described in organic solvent be oxolane, N, more than one in dinethylformamide, N,N-dimethylacetamide, dichloromethane, chloroform, methyl acetate, methyl cyanide, ethanol, methylisobutylketone, hexafluoroisopropanol or acetone;
Step 1) described in fluorescent dye be rhodamine, Nile red, phycoerythrin or Fluorescein isothiocyanate.
7. the complex method of macromolecular vesicles according to claim 1, is characterized in that: step 1) described in mixing time be 15 ~ 60min; Step 1) described in stir rotating speed be 100 ~ 800r/min; The consumption of described block copolymer is 5 ~ 50wt% of organic solvent weight, and the weight ratio of described block copolymer and fluorescent dye is 1000:(1 ~ 50).
8. the complex method of macromolecular vesicles according to claim 1, is characterized in that: step 3) described in the mass volume ratio of solid particle and water or PBS buffer be 50mg:(5 ~ 10) mL; Described solid particle with need embed or the material mass of load than for 1000:(5 ~ 100).
9. the complex method of macromolecular vesicles according to claim 8, is characterized in that: describedly need to embed or the material of load is medicine, antibody, albumen, genetic fragment or somatomedin.
10. the macromolecular vesicles prepared by complex method described in any one of claim 1 ~ 9, is characterized in that: described macromolecular vesicles mean diameter is 50 ~ 300nm.
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Cited By (5)
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CN105716923A (en) * | 2016-04-21 | 2016-06-29 | 华南理工大学 | Preparation method of scanning electron microscope sample for polymer vesicae |
CN106913524A (en) * | 2017-03-24 | 2017-07-04 | 清华大学 | Multifunctional load stimulation vesica based on framework induction self assembly and preparation method thereof |
CN107281105A (en) * | 2017-05-27 | 2017-10-24 | 华南理工大学 | A kind of method that macromolecular vesicles electroporation is loaded into loaded article |
CN114349976A (en) * | 2021-12-16 | 2022-04-15 | 华南理工大学 | Method for preparing nano-scale macromolecular vesicles through electrostatic-assisted microfluidics |
CN115717279A (en) * | 2022-11-23 | 2023-02-28 | 华南理工大学 | Preparation method of narrow-distribution macromolecular vesicles |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105716923A (en) * | 2016-04-21 | 2016-06-29 | 华南理工大学 | Preparation method of scanning electron microscope sample for polymer vesicae |
CN106913524A (en) * | 2017-03-24 | 2017-07-04 | 清华大学 | Multifunctional load stimulation vesica based on framework induction self assembly and preparation method thereof |
CN107281105A (en) * | 2017-05-27 | 2017-10-24 | 华南理工大学 | A kind of method that macromolecular vesicles electroporation is loaded into loaded article |
CN114349976A (en) * | 2021-12-16 | 2022-04-15 | 华南理工大学 | Method for preparing nano-scale macromolecular vesicles through electrostatic-assisted microfluidics |
CN114349976B (en) * | 2021-12-16 | 2023-08-18 | 华南理工大学 | Method for preparing nanoscale high-molecular vesicles through electrostatic auxiliary microfluidic |
CN115717279A (en) * | 2022-11-23 | 2023-02-28 | 华南理工大学 | Preparation method of narrow-distribution macromolecular vesicles |
CN115717279B (en) * | 2022-11-23 | 2024-07-19 | 华南理工大学 | Preparation method of narrow-distribution macromolecular vesicles |
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