CN111072877B - Method for self-assembling protein conjugate into nano-microsphere by polymerization initiation - Google Patents
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Abstract
The invention discloses a method for self-assembling a polymerization-initiated protein conjugate into nano microspheres. The method takes lipase CALB as a carrier, modifies the carrier into a macroinitiator through ammonolysis reaction, adopts controllable free radical polymerization LRP regulated and controlled by Cu (0) to respectively polymerize hydrophilic and hydrophobic monomers in an aqueous solution and a water/methanol mixed solution, and explores the activity. Under the mild action condition, the polymerization-initiated conjugate is self-assembled into the nano-microspheres, the catalytic activity of the protein is improved, and the protein-immobilized chitosan nano-microsphere has a wide application prospect in the field of protein immobilization.
Description
Technical Field
The invention belongs to the technical field of biomacromolecules, and relates to a method for self-assembling a polymerization-initiated protein conjugate into nano microspheres.
Background
In recent years, polymerization-initiated self-assembly (PISA) has a wide application prospect in the fields of catalysis and biotechnology as a simple and convenient method for synthesizing polymer nano materials. Compared with a solvent and a pH value adopted by a traditional self-assembly method, PISA does not have complicated reaction and purification processes, and has the characteristics of simplicity, high repetition rate, high solid content and the like, and researches show that in Controllable Radical Polymerization (CRP), reversible addition-fragmentation chain transfer polymerization (RAFT) is widely adopted to synthesize the amphiphilic block polymer with a specific morphology. However, since Atom Transfer Radical Polymerization (ATRP) is limited by aqueous systems, there are few reports that mention is made of the investigation of polymerization-initiated self-assembly behavior by the ATRP process. Self-assembly of protein-polymer conjugates into highly ordered nanoparticles is widely used in protein therapeutics and nanocapsules. With the development of science and technology, aqueous solution PISA is widely applied to in-situ RAFT and ATRP polymerization as a polymerization method for efficiently synthesizing protein-polymer conjugates. Lipases are a class of enzymes capable of hydrolyzing triglycerides at oil-water interfaces, widely used in the field of biotechnology, especially the synthesis of polymers. In many reports, lipases are Immobilized on the surface of polymer matrices or porous materials by adsorption or chemical coupling, thereby improving the Activity and reusability of proteins (Sun X, Zhu W, Matyjaszewski K. protection of open lipids: Very High Catalytic Activity of lipid Immobilized on Core-Shell Nanoparticles [ J ]. Macromolecules,2018,51(2):289 296). Currently, very few lipase-polymer conjugates synthesized by PISA are reported in the literature. Therefore, the amide monomers are polymerized in the aqueous solution by CRP regulated by Cu (0) by using lipase as a macroinitiator, and the self-assembly behavior of the amphiprotic macromolecules in the aqueous solution is explored.
Disclosure of Invention
The invention aims to provide a method for self-assembling a polymerization-initiated protein conjugate into a nano microsphere.
The technical scheme for realizing the purpose of the invention is as follows:
a method for preparing nano-microspheres by self-assembling protein-polymer conjugates initiated by controllable free radical polymerization comprises the following steps of forming a biomacromolecule initiator by succinimidyl modified protein, forming the protein-polymer conjugates by controllable free radical polymerization, and finally polymerizing and inducing the self-assembly of the protein-polymer conjugates to obtain the nano-microspheres, wherein the method comprises the following steps:
further, in step 1, the content of N-succinimidyl 2-bromo-2-methylpropionate was 25% by weight.
Further, in step 1, the pH value of the aqueous solution system is 8.
Further, in step 1, the preparation temperature of the protein solution macroinitiator is 4 ℃.
Further, in step 1, the freeze-drying time was 48 hours.
Further, in step 2, the concentration of the monomer was 50% by weight.
Further, in step 2, the concentration of the catalyst was 2 wt%.
Further, in step 2, the polymerization temperature was 0 ℃.
Further, in step 2, the polymerization time was 24 hours.
Further, in step 2, the freeze-drying time was 48 hours.
Compared with the prior art, the invention has the following advantages:
(1) the preparation process is simple and convenient, and large instruments and complex sample pretreatment are not needed;
(2) when the lipase-hydrophobic polymer conjugate is prepared by controllable free radical polymerization regulated and controlled by Cu (0), the lipase-hydrophobic polymer conjugate can be self-assembled into nano microspheres, so that the complex steps of the traditional self-assembly are overcome, the termination interference on the reaction is avoided, the repeatability is good, and the process is controllable;
(3) the protein-polymer conjugate maintains good enzyme activity, overcomes the influence of covalent bond immobilized enzyme on the activity, particularly improves the enzyme activity of the conjugate nano-microsphere after self-assembly, can realize the embedding and transmission of the drug, and has good application prospect in the field of enzyme immobilization and nano-reactors.
Drawings
FIG. 1 is an aqueous gel permeation chromatogram of the lipase macroinitiator prepared in example 1 with the original lipase.
FIG. 2 is a graph of nuclear magnetic conversion of the protein-polymer conjugates prepared in example 2 (a. HEAA; b. NIPAM).
FIG. 3 is an infrared image of the lipase macroinitiator (CALB-Br) and conjugate (CALB-poly (NIPAM)) prepared in example 2.
FIG. 4 is a graph of UV absorption as a function of temperature for the protein-polymer conjugate (CALB-poly (NIPAM)) prepared in example 2.
FIG. 5 is a graph showing the change in particle size of the protein-polymer conjugate (CALB-poly (NIPAM)) prepared in example 2 with an increase in temperature.
FIG. 6 is a graph of nuclear magnetic conversion of the protein-polymer conjugate (CALB-poly (TBA)) prepared in example 2.
FIG. 7 is a transmission electron micrograph of a protein-polymer conjugate (CALB-poly (TBA)) prepared in example 2.
FIG. 8 is a graph of the particle size of the protein-polymer conjugate (CALB-poly (TBA)) prepared in example 2.
FIG. 9 is a schematic representation of the activity of enzymes in the protein-polymer conjugates prepared in example 2.
FIG. 10 is a graph of nuclear magnetic conversion of the protein-polymer conjugate (CALB-poly (HEAA)) prepared in comparative example 1.
Detailed Description
The present invention is further described with reference to the following specific examples and accompanying drawings, but should not be construed as limiting the scope of the invention. Any insubstantial modifications or adaptations of the invention from the foregoing disclosure by those skilled in the art are intended to be covered by the present invention.
Example 1
(1) Dissolving lipase in 10mL of phosphoric acid buffer solution to prepare 0.018mmol of protein solution, and then uniformly stirring the protein solution at 25 ℃ on a magnetic stirrer;
(2) dissolving N-succinimidyl 2-bromo-2-methylpropionate in 1ml of dimethyl sulfoxide solution to prepare 0.055mmol of organic solution, and uniformly stirring the organic solution on a magnetic stirrer at 25 ℃;
(3) taking out the organic solution in the step (2), slowly dropwise adding the organic solution into the protein solution obtained in the step (1), and uniformly stirring the organic solution on a magnetic stirrer at 4 ℃ to react for one day;
(4) dissolving the macroinitiator obtained in the step (3) in an aqueous solution, adding 50 wt% of water-soluble monomers (HEAA, NIPAM) to perform degassing for 15min to obtain a reaction bottle A, taking another reaction bottle B, filling deionized water (1ml), a catalyst (CuBr) and a ligand into the other reaction bottle B, uniformly mixing the mixture on a stirrer to perform degassing treatment, and slowly introducing the reaction bottle A into the reaction bottle B to perform reaction for 24h at room temperature;
FIG. 1 is an aqueous gel permeation chromatogram of the lipase macroinitiator prepared in example 1 and the original lipase, and it can be seen that the original lipase shows multiple peaks at 10-14min, and the elution time of the column is obviously shifted to an earlier time by grafting a bromine-containing initiator (CALB-Br) on the surface of the lipase, which indicates that the hydrodynamic volume of the lipase is increased after modifying the initiator compared with the original lipase.
FIG. 2 is a graph of nuclear magnetic conversion of the protein-polymer conjugates prepared in example 1 (a. HEAA; b. NIPAM). It clearly shows that the integrated area of the vinyl groups decreases at 5.5-6.5ppm and that a polymer backbone peak appears at 1.4-2.3ppm, demonstrating that polymerization occurs efficiently and that the conversion after 24h is about 91%, 92%, respectively, indicating successful grafting of the polymer to the lipase surface to form the conjugate.
FIG. 3 is an infrared image of the lipase macroinitiator (CALB-Br) and conjugate (CALB-poly (NIPAM)) prepared in example 1, which is seen at 2973cm-1Here, the IR spectrum still shows the typical IR absorption peak of the polymer due to stretching vibration of methyl group, and the original absorption peak of CALB-Br is not significant, probably due to the dense surface coating of the polymer.
FIG. 4 is a graph of UV absorption as a function of temperature for the protein-polymer conjugate (CALB-poly (NIPAM)) prepared in example 1, and it can be seen that the temperature sensitivity of the conjugate (CALB-poly (NIPAM)) is 38 ℃ which is slightly higher than the temperature sensitivity (32 ℃) of the homopolymer (poly (NIPAM)), due to the fact that the temperature sensitivity of the polymer is increased by the effective contact of the polymer with the protease.
Fig. 5 is a graph of the particle size of the protein-polymer conjugate (CALB-poly (nipam)) prepared in example 1 as temperature increases, and it can be seen that as the temperature increases from 25 ℃ to 35 ℃ and 50 ℃, the hydrophobicity of the conjugate increases, affecting its self-assembly behavior in water, nanoparticles with a diameter of 172nm (dispersity of 0.25) are formed in the temperature-sensitive temperature range, and when the temperature increases to 50 ℃, the size decreases to 64nm (dispersity of 0.40), which may be caused by aggregation of the polymer (poly (nipam)) at high temperature.
Example 2
This example is essentially the same as example 1, except that a hydrophobic polymer (poly (tba)) is grafted from the lipase surface to form an amphiphilic protein-polymer conjugate and self-assembled into nanospheres.
(1) Dissolving lipase in 10mL of phosphoric acid buffer solution to prepare 0.018mmol of protein solution, and then uniformly stirring the protein solution on a magnetic stirrer at 25 ℃;
(2) dissolving N-succinimidyl 2-bromo-2-methylpropionate in 1ml of dimethyl sulfoxide solution to prepare 0.055mmol of organic solution, and uniformly stirring the organic solution on a magnetic stirrer at 25 ℃;
(3) taking out the organic solution in the step (2), slowly dropwise adding the organic solution into the protein solution obtained in the step (1), and uniformly stirring the organic solution on a magnetic stirrer at 4 ℃ to react for one day;
(4) dissolving the macroinitiator obtained in the step (3) in an aqueous solution, adding 40mg of hydrophobic monomer (TBA) to degas for 15min to obtain a reaction bottle A, taking another reaction bottle B, putting deionized water (1ml), a catalyst (CuBr) and a ligand in the other reaction bottle B, uniformly mixing the mixture on a stirrer to degas, and slowly introducing the reaction bottle A into the reaction bottle B to react for 24h at room temperature;
fig. 6 is a graph of nuclear magnetic conversion (c.tba) of the protein-polymer conjugates prepared in example 1. It clearly shows that the integrated area of vinyl groups decreases at 5.5-6.5ppm and that a polymer backbone peak appears at 1.4-2.3ppm, which demonstrates the efficient occurrence of polymerization, with a conversion of about 30% after 24h, indicating successful grafting of the polymer to the lipase surface to form a conjugate, and a lower conversion of hydrophobic polymerization, probably due to the lower solubility of the polymer (poly (tba)) in the solvent compared to the monomer, making the polymerization process similar to precipitation polymerization. At the same time, the occurrence of polymerization induces self-assembly, and thus may inhibit further effective contact of TBA monomer with the initiation site of the nanoparticles in the suspension.
FIG. 7 is a transmission electron micrograph of the protein-polymer conjugate (CALB-poly (TBA)) prepared in example 2, which clearly shows that the polymerization process induces the self-assembly behavior of the conjugate, and clearly shows that the spherical nanoparticles with the diameter of 100-400 nm exist in the suspended water.
FIG. 8 is a graph of the particle size of the protein-polymer conjugate (CALB-poly (TBA)) prepared in example 2, showing that the nanoparticles having an average particle size of about 400nm are in a monodispersed state (dispersion degree of 0.62).
FIG. 9 is a schematic representation of the enzymatic activity of the protein-polymer conjugates prepared in example 2, as determined by the degradation behavior of the conjugates to p-nitrophenylpalmitate. Self-assembly of the grafted hydrophobic polymer (poly (tba)) to form an amphiphilic conjugate may encapsulate a portion of the enzyme within the core of the nanoparticle, which prevents efficient contact of the substrate with the lipase active site, and thus slightly reduces enzyme activity.
Comparative example 1
This comparative example is essentially the same as example 1, except that the amount of initiator is halved. The conversion of the protein-polymer conjugate obtained is low because there is not enough bromine in the reaction system to initiate the chain ends, resulting in inefficient initiation of the living radicals.
FIG. 10 is a nuclear magnetic conversion plot (CALB-poly (HEAA)) of the protein-polymer conjugate prepared in comparative example 1. It clearly shows that the integrated area of the vinyl groups decreases at 5.5-6.5ppm and that a polymer backbone peak appears at 1.4-2.3ppm, which demonstrates the efficient occurrence of polymerization, with a conversion after 24h of about 55% each, indicating that halving the initiator leads to a decrease in the conversion efficiency of the conjugate.
Comparative example 2
The comparative example is essentially the same as example 1, except that the drying mode is room temperature drying. The protein-polymer conjugate prepared is slightly low in activity, and the reason for the result is probably that the activity of the protein is damaged due to room-temperature drying, and the structure of the protein can be better maintained by low-temperature freezing, so that the enzyme activity is effectively kept, and the aim of quickly and stably dehydrating is fulfilled.
In conclusion, the method utilizes the characteristic that polymerization induces the conjugate to self-assemble into the nano-microsphere, overcomes the difficulty that the activity of protease is damaged after coupling, takes the lipase modified by succinimidyl as a macromolecular initiator, utilizes a method of Cu (0) to regulate and control free radical polymerization to form polymers with different hydrophilicities on the surface of the lipase, and prepares the lipase-polymer conjugate nano-microsphere by initiating the self-assembly behavior of the conjugate for the polymerization of hydrophobic monomers. The soluble protein initiator initiates hydrophobic monomers in aqueous solution to perform chain extension, so that the prepared polymer is gradually insoluble, and the conjugate is driven to self-assemble in situ to form the amphiphilic protein conjugate nano-microsphere. Meanwhile, the PISA has the advantages of simple operation, good reproducibility, no need of multiple treatment and purification and the like, and can be synthesized and prepared under the condition of higher solid content.
Claims (9)
1. The preparation method of the nano-microsphere by self-assembly of the polymerization initiation protein-polymer conjugate is characterized by comprising the following specific steps:
step 1, reacting lipase with N-succinimidyl 2-bromo-2-methylpropionate to obtain a lipase initiator, and freeze-drying to obtain a water-soluble lipase macroinitiator;
and 2, polymerizing a temperature sensitive monomer NIPAM and a hydrophobic monomer TBA by Cu (0) controllable free radical polymerization respectively, and freeze-drying to obtain the lipase-polymer conjugate.
2. The method according to claim 1, wherein the content of N-succinimidyl 2-bromo-2-methylpropionate in the step 1 is 25% by weight.
3. The method according to claim 1, wherein the temperature for preparing the protein solution macroinitiator in step 1 is 4 ℃.
4. The method according to claim 1, wherein the freeze-drying time in step 1 is 48 hours.
5. The method according to claim 1, wherein the concentration of the monomer in the step 2 is 50 wt%.
6. The method according to claim 1, wherein the concentration of the catalyst in the step 2 is 2 wt%.
7. The method according to claim 1, wherein the polymerization temperature in the step 2 is 0 ℃.
8. The method according to claim 1, wherein the polymerization time in step 2 is 24 hours.
9. The method according to claim 1, wherein the freeze-drying time in step 2 is 48 hours.
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| Coating Titania Nanoparticles with Epoxy-Containing Catechol Polymers via Cu(0)-Living Radical Polymerization as Intelligent Enzyme Carriers;Donghao Wang等;《Biomacromolecules》;20180508;第2979−2990页 * |
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