CN108478527B - Preparation method and application of sericin and gamma-polyglutamic acid self-assembly nano micelle - Google Patents
Preparation method and application of sericin and gamma-polyglutamic acid self-assembly nano micelle Download PDFInfo
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Abstract
The invention discloses a preparation method of self-assembly nano-micelle of sericin and gamma-polyglutamic acid, which solves the technical problem that the self-assembly research between sericin and other proteins or polymers is not available at present, and comprises the following steps: 1): selecting sericin with the molecular weight of 12000-24000Da and gamma-polyglutamic acid with the molecular weight of 10-120 ku; 2) preparing a sericin solution and a gamma-polyglutamic acid solution with the same mass concentration: dissolving sericin and gamma-polyglutamic acid in deionized water respectively to prepare solutions with the same mass concentration and the range of 0.3-2%; 3) and preparing a sericin and gamma-polyglutamic acid self-assembly. The invention utilizes gamma-polyglutamic acid and sericin to prepare the gamma-polyglutamic acid and sericin nano self-assembly by an electrostatic assembly method for the first time, and can be applied to the embedding of anticancer drugs and hydrophobic drugs.
Description
Technical Field
The invention relates to the field of research and preparation of drug carriers, in particular to a preparation method and application of a sericin and gamma-polyglutamic acid self-assembly nano drug sustained-release micelle, which is prepared from sericin and gamma-polyglutamic acid with higher molecular weights as raw materials.
Background
Sericin is a natural macromolecular protein wrapped on the surface layer of silk fibroin and is a main protein constituting silk, sericin is used as a byproduct in the textile industry and is discarded, about 50000 tons of sericin is treated as waste every year, and a large amount of natural protein resources are wasted. Sericin has good biological activity, anti-tumor activity and cell adhesion, which lays a foundation for the application of sericin in the fields of biological medicines and health care products, and a novel mucosa adhesion high polymer is prepared by polymerization reaction of sericin and Acrylic Acid (AA), but the polymerization method is a toxic operation process. At present, only reports about the assembly research of sericin in a solution, and no research reports about the self-assembly between sericin and other proteins or polymers exist.
The polyglutamic acid (gamma-PGA) is an ideal drug carrier, has excellent biocompatibility, degradability, fibroblasticity and film forming property, and is also an excellent targeting drug carrier. Is a natural polymer material harmless to human body and environment. At present, the preparation of drug carriers by assembling gamma-polyglutamic acid with high molecular substances such as ethylene glycol, N-trimethyl chitosan and cholesterol has been reported, but the preparation of controllable nano-micelles by assembling gamma-polyglutamic acid with proteins has not been reported.
Disclosure of Invention
The invention aims to solve the technical problem of toxic operation process of polymerization reaction of sericin and Acrylic Acid (AA), and provides a preparation method and application of a non-toxic and pollution-free sericin and gamma-polyglutamic acid self-assembly nano micelle without any study on self-assembly between sericin and other proteins or polymers.
In order to solve the technical problems, the invention adopts the following technical scheme: a preparation method of sericin and gamma-polyglutamic acid self-assembly nano-micelle comprises the following steps: 1): selecting sericin with the molecular weight of 12000-24000Da and gamma-polyglutamic acid with the molecular weight of 10-120 ku; 2) preparing a sericin solution and a gamma-polyglutamic acid solution with the same mass concentration: respectively dissolving sericin with the molecular weight of 12000-24000Da and gamma-polyglutamic acid with the molecular weight of 10-120ku in deionized water to prepare solutions with the same mass concentration and the range of 0.3-2%; 3) and preparing a sericin and gamma-polyglutamic acid self-assembly.
1) Selection and preparation of sericin and gamma-polyglutamic acid
To prepare nano-micelle by self-assembly, the sericin should be selected to ensure both sufficient bioactivity and relative water solubility of the protein molecule, otherwise, the water-soluble nano self-assembly cannot be prepared, and thus the application of the nano-micelle is limited. The molecular weight of the sericin is different from tens of thousands to more than 30 tens of thousands due to different extraction methods, the molecular weight of the easily soluble sericin is between 12000-24000Da, the molecular weight of the common sericin is between 50000-98000Da, and the solubility of the easily soluble sericin powder is much higher than that of the common sericin at low temperature and high temperature, so that very favorable conditions are created for the utilization of the sericin, and the sericin can be used for preparing various types of medical biomaterials. The nano-micelle prepared and used by the invention is used in a liquid environment, so the sericin with the molecular weight of 12000-24000Da is selected as one of the raw materials for preparing the self-assembly nano-micelle, and the sericin and the gamma-polyglutamic acid with the molecular weight range can be directly purchased.
The molecular weight of the gamma-polyglutamic acid is generally between 10 and 2000ku, and in order to assemble and prepare the nano-micelle to obtain a thermodynamically stable self-assembly system, the gamma-polyglutamic acid with smaller molecular weight is used in the invention, and the molecular weight of the gamma-polyglutamic acid is selected to be 10 to 120 ku.
2) Preparing sericin solution and gamma-polyglutamic acid solution with the same mass concentration
Preparing a sericin solution and a gamma-polyglutamic acid solution with the same mass concentration: respectively dissolving sericin with the molecular weight of 12000-24000Da and gamma-polyglutamic acid with the molecular weight of 10-120ku in deionized water to prepare solutions with the same mass concentration and the range of 0.3-2%; the preparation and application environment of the self-assembled micelle should be carried out in an acidic environment (pH is less than or equal to 7).
3) Preparation of self-assemblies of sericin and gamma-polyglutamic acid
The preparation principle is as follows: the isoelectric point of gamma-polyglutamic acid is 2.2, and the isoelectric point of sericin is 3.7When two protein solutions are mixed, if the pH value of the system is adjusted to be between the isoelectric points of the two proteins (pH 2.3-3.6), the gamma-polyglutamic acid can carry negative charges and the sericin can carry positive charges, and through experiments, the two substances can not generate precipitation due to complex interaction and protein conformation change, and are assembled and combined through the mutual attraction of the positive charges and the negative charges to form a novel self-assembled nano micelle. The nanomicelles formed at this time are relatively stable, but they are coupled to each other only by electrostatic interaction, and it is necessary to fix their structures in order to keep them in a relatively stable state in various use environments because gamma-polyglutamic acid is linked with-COOH, -NH2and-CO functional groups, whereas silk fibroin contains-COOH, -NH2Active functional groups such as-OH, -HS, etc., therefore, the covalent network structure can be formed by crosslinking in a molecular chain and among molecular chains by using the active chemical groups and a crosslinking agent, so that the assembly structure is stable.
The preparation process comprises the following steps: the preparation steps of the sericin and gamma-polyglutamic acid self-assembly in the step 3) are as follows: a. mixing the sericin solution with the same mass concentration prepared in the step 2) with the gamma-polyglutamic acid solution according to the mass ratio of (4: 1, 2:1, 1:2, 1: 4) to prepare a mixed solution; b. adding 1-3 times volume of phthalic acid-hydrochloric acid buffer solution (pH2.2-3.8) with concentration of 0.05mol/L, fine adjusting pH value to pH2.2-3.7 with 0.01 mol/L hydrochloric acid, placing in an ultrasonic device, and performing ultrasonic treatment for 1-3 hr with ultrasonic power of 300W and frequency of 40 KHZ; c. and c, filling the mixed solution prepared in the step b into a reactor, respectively carrying out constant temperature assembly for 4-12 hours within the temperature range of (20-50 ℃), then adding 0.005-0.1% of cross-linking agent vinyl sulfone, and carrying out cross-linking for 1-3 hours to fix the structure of the micelle, thereby preparing the self-assembled nano micelle of sericin and gamma-polyglutamic acid.
4) The application of the sericin and gamma-polyglutamic acid self-assembly nano-micelle is to use the prepared sericin and gamma-polyglutamic acid self-assembly nano-micelle for embedding hydrophobic drugs, select curcumin and β -carotene as embedding drugs to detect the embedding and slow-release performance of the drugs, and the appearance of the self-assembly and the drug embedding data are shown in figure 1-figure 3 and table 1.
The invention utilizes the gamma-polyglutamic acid and the sericin to prepare the gamma-polyglutamic acid and sericin nano self-assembly by the electrostatic assembly method for the first time, can be applied to the embedding of anti-cancer drugs and hydrophobic drugs, and has wider application prospect.
Drawings
FIG. 1 is the self-assembly morphology of example 1;
FIG. 2 is the self-assembly morphology of example 2;
FIG. 3 is the morphology of the self-assembly of example 2.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.
Example 1
A preparation method of sericin and gamma-polyglutamic acid self-assembly nano-micelle comprises the following steps:
1) selection of sericin and gamma-polyglutamic acid
The molecular weight of the silk fibroin is selected to be 12000-24000Da, and the molecular weight of the gamma-polyglutamic acid is selected to be 10 ku.
2) Preparation of sericin and gamma-polyglutamic acid solution
Sericin and gamma-polyglutamic acid with certain mass are respectively dissolved in deionized water to prepare aqueous solution with mass concentration of 0.3% for standby.
3) Preparation of self-assemblies of sericin and gamma-polyglutamic acid
Sericin and gamma-polyglutamic acid solution with mass concentration of 0.3% are mixed according to the mass ratio of 4:1, phthalic acid-hydrochloric acid buffer solution (pH2.2-3.8) with 2 times volume (0.05 mol/L) is added, the pH value is finely adjusted to 3.5 within the range by using 0.01 mol/L hydrochloric acid, and the mixture is placed into an ultrasonic device for ultrasonic treatment for 1 hour with the power of 300W and the frequency of 40 KHZ. And (3) putting the mixed solution into a reactor, assembling for 4 hours at a constant temperature within the temperature range of 20 ℃, adding 0.005% of cross-linking agent vinyl sulfone, and crosslinking for 1 hour to fix the micelle structure, thereby preparing the self-assembled nano micelle of sericin and gamma-polyglutamic acid.
4) The prepared sericin and gamma-polyglutamic acid self-assembled nano-micelle is used for embedding and detecting curcumin hydrophobic drugs. The self-assembly morphology and drug encapsulation data are shown in figure 1 and table 1.
Example 2
A preparation method of sericin and gamma-polyglutamic acid self-assembly nano-micelle comprises the following steps:
1) selection of sericin and gamma-polyglutamic acid
The molecular weight of the sericin is 12000-24000Da, and the molecular weight of the gamma-polyglutamic acid is selected to be 70 ku.
2) Preparation of sericin and gamma-polyglutamic acid solution
Dissolving a certain mass of sericin and gamma-polyglutamic acid in deionized water to prepare a solution with the mass concentration of 0.9% for later use.
3) Preparation of self-assemblies of sericin and gamma-polyglutamic acid
The preparation process comprises the following steps: mixing sericin and gamma-polyglutamic acid solution with the same mass concentration of 0.9% and the mass ratio of 2:1, adding phthalic acid-hydrochloric acid buffer solution (pH 2.2-3.8) with 3 times volume (0.05 mol/L), finely adjusting the pH value to 3.0 by using 0.01 mol/L, putting the mixture into an ultrasonic device, and carrying out ultrasonic treatment for 2 hours at the power of 300W and the frequency of 40 KHZ. And (3) putting the mixed solution into a reactor, carrying out constant-temperature assembly for 6 hours at the temperature of 30 ℃, then adding 0.01% of cross-linking agent vinyl sulfone, and carrying out cross-linking for 2 hours to fix the structure of the micelle, thus preparing the self-assembled nano micelle of sericin and gamma-polyglutamic acid.
4) The prepared sericin and gamma-polyglutamic acid self-assembly nano-micelle is used for embedding the hydrophobic drug β -carotene, and the appearance of the self-assembly and drug embedding data are shown in figure 2 and table 1.
Example 3
A preparation method of sericin and gamma-polyglutamic acid self-assembly nano-micelle comprises the following steps:
1) selection of sericin and gamma-polyglutamic acid
The molecular weight of the sericin is selected from 12000-24000Da, and the molecular weight of the gamma-polyglutamic acid is selected from 120 ku.
2) Preparation of sericin and gamma-polyglutamic acid solution
The preparation and application environment of the self-assembled micelle are carried out in an acid environment (the pH is less than or equal to 7), and a solution with the mass concentration of 1.2 percent is prepared by dissolving a certain mass of sericin and gamma-polyglutamic acid in deionized water for later use.
3) Preparation of self-assemblies of sericin and gamma-polyglutamic acid
Mixing sericin with a mass concentration of 1.2% and a gamma-polyglutamic acid solution in a mass ratio of 1:1, adding a phthalic acid-hydrochloric acid buffer solution (pH 2.2-3.8) with a volume of 3 times (0.05 mol/L), finely adjusting the pH value to 3.3 by using hydrochloric acid with a volume of 0.01 mol/L, placing the mixture in an ultrasonic device, and carrying out ultrasonic treatment for 2 hours at a power of 300W and a frequency of 40 KHZ. And (3) putting the mixed solution into a reactor, assembling for 10 hours at a constant temperature within a temperature range of 50 ℃, adding 0.03% of cross-linking agent vinyl sulfone, and crosslinking for 3 hours to fix the structure of the micelle, thereby preparing the self-assembled nano micelle of sericin and gamma-polyglutamic acid.
4) The prepared sericin and gamma-polyglutamic acid self-assembled nano-micelle is used for embedding the hydrophobic drug curcumin and detecting the embedding and slow release performance of the curcumin. The self-assembly morphology and drug encapsulation data are shown in figure 3 and table 1.
Example 4
A preparation method of sericin and gamma-polyglutamic acid self-assembly nano-micelle comprises the following steps: 1): selecting sericin with the molecular weight of 15000-20000Da and gamma-polyglutamic acid with the molecular weight of 100 ku; 2) preparing a sericin solution and a gamma-polyglutamic acid solution with the same mass concentration: dissolving sericin with the molecular weight of 15000-20000Da and gamma-polyglutamic acid with the molecular weight of 100ku in deionized water respectively to prepare solutions with the same mass concentration and the range of 2 percent;
3) preparing a sericin and gamma-polyglutamic acid self-assembly: a. mixing the sericin solution with the same mass concentration prepared in the step 2) with the gamma-polyglutamic acid solution according to the mass ratio of 1:2 to prepare a mixed solution; b. adding 2 times volume of phthalic acid-hydrochloric acid buffer solution (pH 2.2-3.8) into the mixed solution, adjusting pH value to (pH 2.2-3.8) with 0.01 mol/L hydrochloric acid, and placing into an ultrasonic device for ultrasonic treatment for 2 hr with ultrasonic power of 300W and frequency of 40 KHZ; c. and c, filling the mixed solution prepared in the step b into a reactor, respectively carrying out constant temperature assembly for 8 hours within the temperature range of (20-50 ℃), then adding 0.1% of cross-linking agent vinyl sulfone, and carrying out cross-linking for 2 hours to fix the structure of the micelle, thus preparing the self-assembled nano micelle of sericin and gamma-polyglutamic acid.
4) The prepared sericin and gamma-polyglutamic acid self-assembled nano-micelle is used for embedding the hydrophobic medicine curcumin.
Example 5
A preparation method of sericin and gamma-polyglutamic acid self-assembly nano-micelle comprises the following steps: 1): selecting sericin with the molecular weight of 16000-18000Da and gamma-polyglutamic acid with the molecular weight of 80 ku; 2) preparing a sericin solution and a gamma-polyglutamic acid solution with the same mass concentration: dissolving sericin with the molecular weight of 16000-18000Da and gamma-polyglutamic acid with the molecular weight of 80ku in deionized water respectively to prepare solutions with the same mass concentration and the range of 2 percent;
3) preparing a sericin and gamma-polyglutamic acid self-assembly: a. mixing the sericin solution with the same mass concentration prepared in the step 2) with the gamma-polyglutamic acid solution according to the mass ratio of 1:4 to prepare a mixed solution; b. adding 2 times volume of phthalic acid-hydrochloric acid buffer solution (pH 2.2-3.8) with concentration of 0.05mol/L into the mixed solution, finely adjusting pH value to (pH 2.2-3.8) within the range by using 0.01 mol/L hydrochloric acid, and placing the mixture into an ultrasonic device for ultrasonic treatment for 2 hours, wherein the ultrasonic power is 300W, and the frequency is 40 KHZ; c. and c, filling the mixed solution prepared in the step b into a reactor, respectively carrying out constant temperature assembly for 8 hours within the temperature range of (20-50 ℃), then adding 0.3% of cross-linking agent vinyl sulfone, and carrying out cross-linking for 1 hour to fix the structure of the micelle, thus preparing the self-assembled nano micelle of sericin and gamma-polyglutamic acid.
4) The prepared sericin and gamma-polyglutamic acid self-assembled nano-micelle is used for embedding the hydrophobic medicine curcumin.
TABLE 1 embedding and slow releasing performance of sericin and gamma-polyglutamic acid self-assembled nano micelle
As can be seen from FIGS. 1 to 3, the self-assembled nano-micelles of sericin and gamma-polyglutamic acid prepared by assembly under different conditions have different morphologies and particle sizes, but the self-assembled nano-micelles are all between 30 and 95nm and are nano-micelles, the morphologies of examples 1 and 2 are cubic, and the morphology of example 3 is approximately spherical, and experimental detection shows that the self-assembled nano-micelles have higher entrapment rate and drug loading rate for hydrophobic drugs curcumin or β -carotene according to Table 1.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the invention uses soluble sericin with higher molecular weight and gamma-polyglutamic acid with different molecular weights as raw materials
The raw materials, gamma-polyglutamic acid and natural protein substances are firstly used for preparing the self-assembled nano micelle by the self-assembly technology.
2. The sericin used as a raw material is a byproduct in the textile industry, has low price, and can greatly reduce the preparation cost of the drug carrier when being used with the gamma-polyglutamic acid.
3. The preparation raw materials belong to natural high molecular substances, the preparation process belongs to an environment-friendly preparation process, and no harmful substances are added or introduced, so that the preparation method for preparing the composite micelle in an environment-friendly way is provided.
4. Experiments prove that the nano-composite micelle prepared by the method has higher entrapment rate and drug-loading rate, good slow-release performance and good application prospect.
Claims (4)
1. A preparation method of sericin and gamma-polyglutamic acid self-assembly nano-micelle is characterized by comprising the following steps: 1): selecting sericin with the molecular weight of 12000-24000Da and gamma-polyglutamic acid with the molecular weight of 10-120 ku;
2) preparing a sericin solution and a gamma-polyglutamic acid solution with the same mass concentration: respectively dissolving sericin with the molecular weight of 12000-24000Da and gamma-polyglutamic acid with the molecular weight of 10-120ku in deionized water to prepare solutions with the same mass concentration and the range of 0.3-2%;
3) preparing a sericin and gamma-polyglutamic acid self-assembly;
the preparation steps of the sericin and gamma-polyglutamic acid self-assembly in the step 3) are as follows: a. mixing the sericin solution with the same mass concentration prepared in the step 2) with the gamma-polyglutamic acid solution according to the mass ratio of 4:1 to 1:4 to prepare a mixed solution;
b. adding 1-3 times volume of phthalic acid-hydrochloric acid buffer solution (pH2.2-3.8) with concentration of 0.05mol/L, fine-adjusting pH value to pH2.2-3.7 with 0.01 mol/L hydrochloric acid, and placing in an ultrasonic device for ultrasonic treatment for 1-3 hr;
c. b, filling the mixed solution prepared in the step b into a reactor, respectively carrying out constant temperature assembly for 4-12 hours within the temperature range of 20-50 ℃, then adding a cross-linking agent of vinyl sulfone with the total mass of 0.005-0.1% of the mixed solution, and carrying out cross-linking for 1-3 hours to fix the structure of the micelle, thus preparing the self-assembled nano micelle of sericin and gamma-polyglutamic acid;
the preparation and application environment of the self-assembled micelle in the step 3) is carried out in an acidic environment with pH less than or equal to 7.
2. The method for preparing sericin and gamma-polyglutamic acid self-assembly nano-micelles according to claim 1, wherein: the mixed solution in the step 3) is prepared by mixing the sericin solution and the gamma-polyglutamic acid solution with the same mass concentration according to the mass ratio of 4:1, 2:1, 1:2 and 1: 4.
3. The method for preparing sericin and gamma-polyglutamic acid self-assembly nano-micelles according to claim 1, wherein: and c, performing ultrasonic treatment on the mixed solution in the step b in an ultrasonic device at the power of 300W and the frequency of 40 KHz.
4. The application of the sericin and gamma-polyglutamic acid self-assembly nano-micelle prepared by the preparation method of the sericin and gamma-polyglutamic acid self-assembly nano-micelle according to any one of claims 1 to 3 is characterized by being applied to the embedding of the preparation of hydrophobic drugs curcumin and β carotene.
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