CN116606461A - Method for preparing polymer nano particles by micro-channels - Google Patents
Method for preparing polymer nano particles by micro-channels Download PDFInfo
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- C08J3/00—Processes of treating or compounding macromolecular substances
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- B82—NANOTECHNOLOGY
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- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
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- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
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- C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
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Abstract
The invention provides a method for preparing polymer nano particles by a micro-channel, which is a preparation method capable of accurately regulating and controlling the sizes of the polymer nano particles. According to the method, a polymer solution, an antisolvent and gas are respectively introduced into three inlets of a cross-shaped inlet microchannel, a gas is utilized to strengthen the mass transfer process of nano precipitation, and polymer nano particles are continuously prepared by a nano precipitation method. Compared with the traditional nano precipitation method, the method can accurately regulate the size of the polymer nano particles, and can prepare the nano particles with the particle size of less than 20nm, so that the steric hindrance caused by the large-size nano particles can be reduced, the transmission capacity of the nano particles can be improved, the targeting specificity and the binding affinity of the nano particles can be enhanced, and the application of the polymer nano particles in the fields of biomedicine and the like can be greatly promoted.
Description
Technical Field
The invention belongs to the technical field of nano materials, in particular to a preparation method of polymer nano particles, and particularly relates to a method for preparing polymer nano particles by a micro-channel.
Background
In recent years, emerging nanotechnology has become a very effective tool for studying life sciences. Nanoparticles (NPs) in which specific properties are produced by changing the size can be applied in the fields of biology, medicine, pharmacy, etc. Nanoparticles have shown greater efficiency as drug delivery vehicles when used in the diagnosis and treatment of diseases than micro-sized particles that can be rapidly eliminated by the immune system.
Polymeric Nanoparticles (PNPs) have shown great potential as carriers for drug delivery. PNPs have dimensions in the nanometer range, thus making PNPs unique in nature, and can penetrate blood vessels, penetrate tissues, and enter target cells. In addition, PNPs with modified surfaces can be targeted to lesion sites, and drug targeted release is very effective for many diseases (such as cancers). The cancer cells can be visually identified by utilizing the receptor response of specific expression through the nanotechnology, and then various PNPs with modified surfaces wrap medical drugs, so that the advantage of small volume is beneficial to targeted delivery of the drugs to specific parts, high drug concentration and biological activity are achieved only at the specific parts or organs, detection and medical treatment of the specific parts are realized, and adverse side effects and toxicity of the existing treatment method are overcome.
However, the transport of PNPs from blood to tissues and into pathological cells is strongly dependent on the size of the dimensions. Changing the size of PNPs can significantly alter its controlled transport in vivo by affecting circulation time, interception rate by the immune system, etc. Generally, PNPs with larger size are easy to be cleared by organs such as liver and spleen, but the particle size of PNPs prepared by the conventional nano precipitation method is more than 20nm, so that development of a method capable of controllably preparing PNPs with smaller size is needed.
According to the invention, a continuous controllable microfluidic nano precipitation method is adopted, gas is introduced into the cross-shaped inlet microchannel, and the polymer nano particles are successfully prepared by utilizing the nano precipitation process of the gas reinforced polymer solution and the antisolvent, so that the size of the polymer nano particles can be accurately regulated and controlled, and the preparation of the nano particles below 20nm is realized.
Disclosure of Invention
The invention aims to prepare nano particles with small particle size and good monodispersity in a highly controllable way, solve the problems of steric hindrance caused by large-size nano particles, interference of targeting specificity and binding affinity of grafted biomolecules and other functions, and provide a process method for preparing polymer nano particles by using a microfluidic nano precipitation method.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a method for preparing polymer nano particles in a microchannel includes the steps of respectively introducing a polymer solution, an antisolvent and gas into three inlets of a cross-shaped inlet microchannel, utilizing the gas to strengthen the nano precipitation mass transfer process, continuously preparing nano particles with required particle size by a nano precipitation method, communicating a fourth inlet of the cross-shaped inlet microchannel with a receiving tube, and collecting the nano particles. The method specifically comprises the following steps:
step 1, dissolving a polymer in an organic solvent at room temperature, and diluting to obtain a polymer solution with a specific concentration.
The polymer comprises polylactic acid-glycolic acid copolymer (PLGA), poly (9, 9-dioctylfluorene-co-benzothiadiazole) (PFBT), polyethylene glycol (PEG), gelatin (Gelatin), chitosan (Chitosan) and the like;
the organic solvent comprises Tetrahydrofuran (THF), acetonitrile (ACN), acetone (AC), dioxane (EEW), and the like;
the concentration of the polymer solution obtained by dilution with an organic solvent is 1 to 1000. Mu.g/mL, preferably 10 to 200. Mu.g/mL.
And 2, constructing a cross-shaped inlet microchannel, wherein the cross-shaped inlet microchannel comprises three inlets and one outlet, and a microchannel nano precipitation mass transfer section is arranged from the cross point to the outlet.
The cross-shaped inlet micro-channel consists of two cross-shaped crossed and mutually communicated tubular structures, and the materials comprise glass, metal and rubber. The pipe diameter of the tubular structure is 1-1000 mu m.
Step 3, two ends of the same circular tube of the cross-shaped inlet micro-channel are respectively communicated with an injector where the antisolvent and the polymer solution are located through a tetrafluoro tube, and the injector is connected with an injection pump; two ends of the other round tube are respectively communicated with the gas flowmeter and the receiving tube, one end of the receiving tube is connected with a cross-shaped inlet micro-channel outlet, and the receiving tube outlet is arranged in the sample bottle to collect samples.
The injector is a glass injector, an organic plastic injector and the like.
Step 4, firstly, introducing gas into the whole cross-shaped inlet micro-channel, controlling the flow of the gas through a gas flowmeter, and starting an injection pump when the whole micro-channel is in a stable state, wherein the reaction starts: and (3) continuously introducing gas, simultaneously introducing a polymer solution and an antisolvent into the other two inlets, converging and mixing the polymer solution and the antisolvent at a cross intersection point, flowing in the direction of an outlet, reacting at room temperature in the section, reinforcing a nano precipitation mass transfer process by using gas, collecting at the outlet, and then performing aftertreatment to remove the organic solvent to obtain the product.
In the reaction process, the gas flow is regulated by a gas flowmeter, the fluid flow of the polymer solution and the antisolvent is regulated by a flow pump, and then different flow patterns (Taylor flow, stirring flow, annular flow and the like) are regulated, and the nano particles are prepared by utilizing the gas reinforced nano precipitation mass transfer process. And the particle size and distribution of the nano particles can be detected by a dynamic light scattering instrument (DLS) and a Transmission Electron Microscope (TEM), so that the particle size and distribution of the nano particles can be below 20 nm.
The gas flow is 1-80 mL/min; the fluid flow of the polymer solution is 0.005-0.32 mL/min; the flow rate of the anti-solvent fluid is 0.5-8 mL/min. The antisolvent comprises water, methanol (MeOH), ethanol (EtOH), preferably water.
In the invention, gas is introduced into the micro-channel, and the nano precipitation mass transfer process is enhanced under different flow patterns (Taylor flow, stirring flow, annular flow and the like), so that nano particles with the required particle size can be continuously and controllably prepared. The introduction of gas may provide greater flexibility in nanoparticle size regulation.
At the end of the reaction, the collected sample is purged by nitrogen to remove the organic solvent in the sample.
Compared with the prior art, the invention has the following beneficial effects:
(1) According to the microfluidic nano precipitation method for preparing the polymer nano particles, provided by the invention, the small-size nano particles can be prepared on the premise of not reducing the concentration of the polymer solution by utilizing the enhanced mass transfer effect of gas under different flow patterns (Taylor flow, stirring flow, annular flow and the like), so that the mass concentration of the nano particles in the aqueous solution is improved.
(2) The microfluidic nano-precipitation method for preparing the polymer nano-particles overcomes experimental errors caused by manual injection in the traditional nano-precipitation method, realizes accurate regulation and control of the particle size of the polymer nano-particles, and improves the repeatability of results.
(3) According to the microfluidic nano precipitation method for preparing the polymer nano particles, the particle size of the polymer nano particles prepared by the method is smaller and can reach below 20nm under the same preparation conditions, and the controllability is better.
(4) The microfluidic nano-precipitation method for preparing the polymer nano-particles is simple to operate, has certain universality and can be used for preparing other types of polymer nano-particles.
In conclusion, the technical scheme of the invention can solve the problems of large particle size, poor controllability and the like in the process of preparing the nano particles by the traditional method, and has a certain contribution to promoting the application of the polymer nano particles in the biomedical field.
For the reasons, the invention can accurately regulate the size of the polymer nano-particles, improve the repeatability of experimental results, realize the preparation of the polymer nano-particles below 20nm, and can be applied to the preparation of other polymer nano-particles.
Drawings
FIG. 1 is a schematic diagram of a system for precisely controlling the size of polymer nanoparticles to achieve nanoparticle preparation below 20 nm.
FIG. 2 is a flow pattern in the microchannel when nanoparticles were prepared by the method described above in example 1: taylor flow.
Fig. 3 is a graph of TEM results of nanoparticles prepared using the above method in example 1.
Detailed Description
The invention is further illustrated below with reference to specific examples.
Example 1
The preparation method of the polymer nanoparticle of the embodiment comprises the following steps:
1. solution preparation: 1mg of polylactic-co-glycolic acid (PLGA) was dissolved in 1mL of Tetrahydrofuran (THF), and diluted to give a polymer solution of PLGA 100. Mu.g/mL for experimental use.
2. Preparation before experiment: a glass syringe with a measuring range of 1mL was used to aspirate 0.5mL of a polymer solution with a concentration of 100. Mu.g/mL, the syringe was fixed on a syringe pump and connected to a cross-shaped inlet microchannel apparatus via a tetrafluoro tube with an inner diameter of 0.5 mm. 40mL of deionized water was aspirated with a 50mL range glass syringe, and the syringe was mounted on a syringe pump and also connected to a cross-shaped inlet microchannel apparatus via a 0.5mm inner diameter tetrafluoro tube. The last inlet of the cross-shaped inlet microchannel is connected with a gas flowmeter through a tetrafluoro tube with the inner diameter of 0.5 mm. The outlet of the cross-shaped inlet microchannel is connected with a tetrafluoro tube receiving tube with the length of 5cm and the inner diameter of 0.8mm, and the sample is collected into a sample bottle through the receiving tube. And preparing to observe and record the flow pattern at the 1cm position of the mass transfer section of the micro-channel nano-precipitate by using an OLYMPUS microscope.
3. The experiment was started: firstly, the air flow rate of the air flow meter is regulated to 8mL/min, and the air flow meter is stabilized for 3min. And then setting the flow rate of the polymer solution injection pump to be 0.08mL/min, setting the flow rate of the deionized water injection pump to be 8mL/min, starting to collect samples after stabilizing for 3min, setting the volume of the dropwise added polymer solution to be 0.1mL, and simultaneously observing and recording the flow pattern in the micro-channel by using an OLYMPUS microscope. And finally, sequentially closing the injection pump and the gas flowmeter.
4. Sample treatment: after the reaction was completed, the collected sample was purged with nitrogen at 50 ℃ until THF was removed from the sample. Finally, polymer nano particles suspended in deionized water are obtained.
5. Sample characterization: the particle size of the obtained sample after THF is removed is 5nm by a dynamic light scattering instrument (DLS) and a Transmission Electron Microscope (TEM), and the sample is spherical nano particles with uniform sphericity.
Example 2
The preparation method of the polymer nanoparticle of the embodiment comprises the following steps:
1. solution preparation: 1mg of polylactic-co-glycolic acid (PLGA) was dissolved in 1mL of Tetrahydrofuran (THF), and diluted to give a polymer solution of PLGA 100. Mu.g/mL for experimental use.
2. Preparation before experiment: a glass syringe with a measuring range of 1mL was used to aspirate 0.7mL of a polymer solution with a concentration of 100. Mu.g/mL, the syringe was fixed on a syringe pump and connected to a cross-shaped inlet microchannel apparatus via a tetrafluoro tube with an inner diameter of 0.5 mm. 40mL of deionized water was aspirated with a 50mL range glass syringe, and the syringe was mounted on a syringe pump and also connected to a cross-shaped inlet microchannel apparatus via a 0.5mm inner diameter tetrafluoro tube. The last inlet of the cross-shaped inlet microchannel is connected with a gas flowmeter through a tetrafluoro tube with the inner diameter of 0.5 mm. The outlet of the cross-shaped inlet microchannel is connected with a tetrafluoro tube receiving tube with the length of 5cm and the inner diameter of 0.8mm, and the sample is collected into a sample bottle through the receiving tube. And preparing to observe and record the flow pattern at the 1cm position of the mass transfer section of the micro-channel nano-precipitate by using an OLYMPUS microscope.
3. The experiment was started: firstly, the air flow rate of the air flow meter is adjusted to 18mL/min, and the air flow meter is stabilized for 3min. And then setting the flow rate of the polymer solution injection pump to be 0.12mL/min, setting the flow rate of the deionized water injection pump to be 6mL/min, starting to collect a sample after stabilizing for 3min, setting the volume of the dropwise added polymer solution to be 0.2mL, and simultaneously observing and recording the flow pattern in the micro-channel by using an OLYMPUS microscope. And finally, sequentially closing the injection pump and the gas flowmeter.
4. Sample treatment: after the reaction was completed, the collected sample was purged with nitrogen at 50 ℃ until THF was removed from the sample. Finally, polymer nano particles suspended in deionized water are obtained.
5. Sample characterization: the particle size of the obtained sample after THF is removed is 15nm by a dynamic light scattering instrument (DLS) and a Transmission Electron Microscope (TEM), and the sample is spherical nano particles with uniform sphericity.
Example 3
The preparation method of the polymer nanoparticle of the embodiment comprises the following steps:
1. solution preparation: 1mg of poly (9, 9-dioctylfluorene-co-benzothiadiazole) (PFBT) was dissolved in 1mL of Tetrahydrofuran (THF) and diluted to give a polymer solution with PFBT of 100. Mu.g/mL for experimental use.
2. Preparation before experiment: a glass syringe with a measuring range of 1mL was used to aspirate 0.5mL of a polymer solution with a concentration of 100. Mu.g/mL, the syringe was fixed on a syringe pump and connected to a cross-shaped inlet microchannel apparatus via a tetrafluoro tube with an inner diameter of 0.5 mm. 30mL of deionized water was aspirated with a 50mL range glass syringe, and the syringe was mounted on a syringe pump and also connected to a cross-shaped inlet microchannel apparatus via a 0.5mm inner diameter tetrafluoro tube. The last inlet of the cross-shaped inlet microchannel is connected with a gas flowmeter through a tetrafluoro tube with the inner diameter of 0.5 mm. The outlet of the cross-shaped inlet microchannel is connected with a tetrafluoro tube receiving tube with the length of 5cm and the inner diameter of 0.8mm, and the sample is collected into a sample bottle through the receiving tube. And preparing to observe and record the flow pattern at the 1cm position of the mass transfer section of the micro-channel nano-precipitate by using an OLYMPUS microscope.
3. The experiment was started: firstly, the air flow rate of the air flow meter is regulated to 9mL/min, and the air flow meter is stabilized for 3min. And then setting the flow rate of the polymer solution injection pump to be 0.06mL/min, setting the flow rate of the deionized water injection pump to be 3mL/min, starting to collect samples after stabilizing for 3min, setting the volume of the dropwise added polymer solution to be 0.2mL, and simultaneously observing and recording the flow pattern in the micro-channel by using an OLYMPUS microscope. And finally, sequentially closing the injection pump and the gas flowmeter.
4. Sample treatment: after the reaction was completed, the collected sample was purged with nitrogen at 50 ℃ until THF was removed from the sample. Finally, polymer nano particles suspended in deionized water are obtained.
5. Sample characterization: the particle size of the obtained sample after THF is removed is 20nm by a dynamic light scattering instrument (DLS) and a Transmission Electron Microscope (TEM), and the sample is spherical nano particles with uniform sphericity.
The examples described above represent only embodiments of the invention and are not to be understood as limiting the scope of the patent of the invention, it being pointed out that several variants and modifications may be made by those skilled in the art without departing from the concept of the invention, which fall within the scope of protection of the invention.
Claims (7)
1. A method for preparing polymer nano particles by using a micro channel is characterized in that a polymer solution, an antisolvent and gas are respectively introduced into three inlets of the cross-shaped inlet micro channel, and the nano precipitation mass transfer process is reinforced by the gas, so that the nano particles with the required particle size are continuously prepared.
2. A method for preparing polymer nanoparticles by a microchannel according to claim 1, comprising the steps of:
step 1, dissolving a polymer in an organic solvent at room temperature, and diluting to obtain a polymer solution with the concentration of 1-1000 mug/mL; the polymer comprises polylactic acid-glycolic acid copolymer, poly (9, 9-dioctylfluorene-co-benzothiadiazole), polyethylene glycol, gelatin and chitosan;
step 2, constructing a cross-shaped inlet microchannel, wherein the cross-shaped inlet microchannel comprises three inlets and one outlet, and the part from the cross-shaped intersection point to the outlet is a microchannel nano precipitation mass transfer section; the pipe diameter of the tubular structure is 1-1000 mu m;
step 3, two ends of the same circular tube of the cross-shaped inlet micro-channel are respectively communicated with an injector where the antisolvent and the polymer solution are located through a tetrafluoro tube, and the injector is connected with an injection pump; two ends of the other round tube are respectively communicated with the gas flowmeter and the receiving tube, one end of the receiving tube is connected with a cross-shaped inlet microchannel outlet, and the receiving tube outlet is arranged in a sample bottle for collecting samples;
and 4, firstly, introducing gas into the whole cross-shaped inlet microchannel, when the whole microchannel is in a stable state, continuously introducing the gas, starting the injection pump, namely, introducing the polymer solution and the antisolvent into the other two inlets, regulating the gas flow through a gas flowmeter in the reaction process, regulating the fluid flow of the polymer solution and the antisolvent through a flow pump, further regulating different flow patterns, and preparing the nano particles with the particle size of less than 20nm by utilizing the gas-reinforced nano precipitation mass transfer process.
3. The method for preparing polymer nanoparticles by using a microchannel according to claim 2, wherein the organic solvent in step 1 comprises tetrahydrofuran, acetonitrile, acetone, dioxane.
4. The method for preparing polymer nano-particles by using the micro-channel according to claim 2, wherein the cross-shaped inlet micro-channel in the step 2 is composed of two cross-shaped and mutually communicated tubular structures, and the materials comprise glass, metal and rubber.
5. The method for preparing polymer nano-particles by using the micro-channel according to claim 2, wherein the gas flow rate in the step 4 is 1-80 mL/min; the fluid flow of the polymer solution is 0.005-0.32 mL/min; the flow rate of the anti-solvent fluid is 0.5-8 mL/min.
6. A method for preparing polymer nanoparticles by a microchannel according to claim 2, wherein said antisolvent in step 4 comprises water, methanol, ethanol.
7. A method for preparing polymer nanoparticles by means of a microchannel according to claim 6, wherein the antisolvent of step 4 is preferably water.
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