CN111743862A - Multi-biological activity modified lignin self-assembly drug-loaded nano micelle and preparation method thereof - Google Patents
Multi-biological activity modified lignin self-assembly drug-loaded nano micelle and preparation method thereof Download PDFInfo
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Abstract
The invention provides a multi-bioactivity modified lignin self-assembly drug-loaded nano micelle, which is prepared by modifying acylated lignin after anhydride modification and then modifying a bioactive compound. The bioactive compound has various biological activities, lignin is used for preparing the lignin grafted bioactive compound through reactions such as acylation, esterification and the like, and then the lignin grafted bioactive compound is prepared into the nano micelle, and the nano micelle is used as a good drug carrier and also has various biological activities of the lignin and the bioactive compound; the bioactive compound and the lignin are connected together through chemical bonds, and the nano micelle is self-assembled by utilizing the amphipathy of the lignin, so that the utilization rate of the bioactive compound can be greatly improved; the hydrophobic unit of the bioactive compound is introduced into the lignin, so that the drug loading capacity of the nano micelle on hydrophobic drugs can be greatly improved. The invention also provides a preparation method of the multi-bioactivity modified lignin self-assembled drug-loaded nano micelle, which is simple in process and good in drug-loading capacity of the micelle.
Description
Technical Field
The invention relates to the technical field of lignin modification and utilization, and particularly relates to a multi-bioactivity modified lignin self-assembly drug-loaded nano micelle and a preparation method thereof.
Background
Lignin is an amorphous polymer formed by connecting phenylpropane units through carbon-carbon bonds and ether bonds, and is the second largest biomass resource with the second reserves of cellulose in the plant world. As a typical biomass material, lignin is one of the few renewable resources in aromatic compounds. Lignin, as a biomass material of the second largest resource behind cellulose in the plant kingdom, produces approximately 5000 million tons per year worldwide.
Lignin has a molecular structure containing active groups such as aromatic groups, phenolic hydroxyl groups, alcoholic hydroxyl groups, and carbon-based conjugated double bonds, and thus can undergo many chemical reactions such as oxidation, reduction, hydrolysis, alcoholysis, acidolysis, photolysis, acylation, sulfonation, alkylation, halogenation, nitration, polycondensation, or graft copolymerization. Wherein, the reactions such as oxidation, acylation, sulfonation, polycondensation, graft copolymerization and the like are used for playing an especially important role in the research of the application of the lignin, and are also important ways for expanding the application of the lignin.
Lignin also has applications in the field of drug delivery, such as:
the Chinese patent application with the application number of 201910103932.1 discloses a preparation method of a pH response modified lignin nano micelle, which is characterized in that acryloyl chloride is used for modifying lignin to prepare acryloyl lignin; performing free radical graft copolymerization on the acryloyl lignin and methacrylic acid to prepare an acryloyl lignin graft methacrylic acid copolymer; and dissolving the acryloyl lignin grafted methacrylic acid copolymer in an organic solvent, slowly dripping distilled water while stirring, and uniformly dispersing by ultrasonic waves to obtain the pH response modified lignin nano micelle. The modified lignin nano micelle methacrylic acid has high grafting degree on lignin, and the prepared modified lignin drug-loaded nano micelle shows good pH responsiveness in the aspect of drug release, and has good application prospect in the field of drug sustained-release and controlled-release.
The Chinese patent application with the application number of 201911075226.7 discloses a nano photolysis-resistant controlled-release pesticide with lignin as a wrapping matrix and a preparation method thereof, sodium lignosulfonate is used as the wrapping matrix, the lignin is subjected to intermolecular crosslinking by adding a crosslinking agent, and then pesticide active molecules are wrapped in lignin molecules, so that the preparation method of the nano photolysis-resistant controlled-release pesticide preparation with the lignin as the wrapping matrix is formed.
In addition to this, there have been other studies on lignin. However, the current research only stays in the lignin as a carrier, and no relevant research exists in the field of medicine carrying by applying the combination of the lignin and the active organisms.
Disclosure of Invention
The invention aims to provide a multi-bioactivity modified lignin self-assembled drug-loaded nano micelle, and particularly relates to a nano micelle prepared by combining a bioactive compound and another bioactive macromolecular lignin through a chemical bond, which can be used as a good carrier of a drug and has various bioactivities, simple preparation process, rich raw material sources, and good application prospect in the field of sustained and controlled release of the drug, wherein the specific technical scheme is as follows:
a self-assembled medicine-carrying nano-micelle of multi-bioactivity modified lignin is prepared from acylated lignin modified by anhydride and a bioactive compound.
Preferably, in the above technical solution, the lignin is at least one of alkali lignin, enzymatic hydrolysis lignin, sulfate lignin and kraft paper lignin; the acid anhydride is at least one of maleic anhydride, phthalic anhydride and succinic anhydride; the bioactive compound is at least one of ellagic acid, resveratrol and curcumin.
In the above technical solution, preferably, the mass ratio of the acid anhydride to the lignin is: 1: 100-1: 2; the modification temperature of the anhydride is 20-90 ℃, and the modification time is 0.5-12 h; the mass ratio of the bioactive compound to the acylated lignin is as follows: 1: 30-2: 1; in the modification process of the bioactive compound: the reaction is carried out for 2-6h under the condition of ice water bath at 0-4 ℃, and then the reaction is carried out for 10-30h in constant-temperature water bath at 10-50 ℃.
The technical scheme of the invention has the following beneficial effects:
(1) the multi-bioactivity modified lignin self-assembly drug-loaded nano micelle is prepared by modifying acylated lignin modified by anhydride and then modifying a bioactive compound. The bioactive compound is at least one of ellagic acid, resveratrol and curcumin, the bioactive compound has multiple biological activities such as oxidation resistance, inflammation resistance and cancer resistance, the lignin is also a bioactive substance, the lignin-grafted bioactive compound is prepared through reactions such as acylation and esterification, and then the nano-micelle is prepared.
(2) The bioactive compound used in the invention is a hydrophobic substance, is connected with lignin through chemical bonds, and self-assembles into a nano micelle by utilizing the amphipathy of the lignin, so that the utilization rate of the bioactive compound can be greatly improved; and a bioactive compound hydrophobic unit is introduced into the lignin, so that the drug loading capacity of the nano micelle on hydrophobic drugs can be greatly improved.
The invention also discloses a preparation method of the multi-bioactivity modified lignin self-assembled drug-loaded nano micelle, which comprises the following steps:
dissolving lignin, acid anhydride and 4-dimethylaminopyridine in a ratio into N, N-dimethylformamide for reaction to obtain acylated lignin;
dissolving the acylated lignin, the bioactive compound and 4-dimethylaminopyridine in the N, N-dimethylformamide according to a proportion, uniformly mixing, and dropwise adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride for reaction to obtain the bioactive compound modified lignin;
and step three, dissolving the bioactive compound modified lignin and the medicine in an organic solvent according to a certain proportion, and dropwise adding deionized water to prepare the bioactive compound modified lignin self-assembled medicine-carrying nano micelle.
Preferably, in the above technical solution, in the step one: the mass-volume ratio of the lignin to the N, N-dimethylformamide is as follows: 1-20 g/100 mL; the mass ratio of the acid anhydride to the lignin is as follows: 1: 100-1: 2; the molar ratio of the 4-dimethylamino pyridine to the acid anhydride is as follows: 1: 100-1: 10; reacting for 0.5-12h at the temperature of 20-90 ℃.
Preferably, in the above technical solution, the lignin is at least one of alkali lignin, enzymatic hydrolysis lignin, sulfate lignin and kraft paper lignin; the acid anhydride is at least one of maleic anhydride, phthalic anhydride and succinic anhydride.
Preferably, in the above technical solution, in the second step: the mass-volume ratio of the acylated lignin to the N, N-dimethylformamide is as follows: 1-20 g/100 mL; the mass ratio of the bioactive compound to the acylated lignin is as follows: 1: 30-2: 1; the molar ratio of the 4-dimethylaminopyridine to the bioactive compound is as follows: 1: 100-1: 10; the molar ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the bioactive compound is as follows: 1: 1-2: 1;
dropwise adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride under the ice bath condition, reacting for 2-6h, and transferring to a constant-temperature water bath at 10-50 ℃ for reacting for 10-30 h.
In the above technical solution, preferably, the bioactive compound is at least one of ellagic acid, resveratrol and curcumin.
Preferably, in the above technical solution, in the step three: dissolving bioactive compound modified lignin into an organic solvent according to the weight volume concentration of 0.001-0.1 g/100ml, and adding a medicine with the mass of 0.1-2 times that of the modified lignin for dissolving; slowly dripping distilled water according to the volume ratio of 1: 2-10: 1 of water to the organic solvent, and carrying out ultrasonic treatment for 0.5-2 h;
the organic solvent is at least one of N, N-dimethylformamide, ethanol, pyridine, chloroform, dimethyl sulfoxide, dioxane and tetrahydrofuran;
the drug is a hydrophobic drug.
In the above technical scheme, preferably, the drug is ibuprofen, paclitaxel or doxorubicin.
The method of the invention has rich raw material sources, simple process and low cost; the method comprises the steps of modifying lignin by using anhydride to obtain acylated lignin, reacting the acylated lignin with a bioactive compound to obtain a bioactive compound modified lignin, loading the bioactive compound modified lignin and a medicament to obtain the bioactive compound modified lignin self-assembled medicament-carrying nano micelle, and acting the lignin, the bioactive compound and the loaded medicament together, so that the method has a good application prospect in the field of slow release and controlled release.
In addition to the objects, features and advantages described above, other objects, features and advantages of the present invention are also provided. The present invention will be described in further detail below with reference to the drawings.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 is a transmission electron microscope image of the MAL-g-EA drug-loaded nano-micelle in example 1;
FIG. 2 shows the survival rate of colon cancer cells HT-29 in example 1 under different concentrations of Ibuprofen (IBU) and MAL-g-EA @ IBU;
FIG. 3 is a graph comparing the drug loading of MAL and MAL-g-EA at different initial dosing (IBU) levels in example 1.
Detailed Description
Embodiments of the invention will be described in detail below with reference to the drawings, but the invention can be implemented in many different ways, which are defined and covered by the claims.
Example 1:
a preparation method of a multi-bioactivity modified lignin self-assembled drug-loaded nano micelle specifically comprises the following steps:
step one, 2.00g of lignin and 0.49g (5.0 mmol-CO)2) Adding 25mg (0.2mmol) of 4-Dimethylaminopyridine (DMAP) into 30mL of N, N-Dimethylformamide (DMF), reacting for 4h under stirring in a constant-temperature water bath kettle at 50 ℃, adding 300mL of pure water to precipitate after the reaction is finished, filtering, washing with pure water for three times, washing with absolute ethyl alcohol for three times, and drying in vacuum at 50 ℃ to obtain acylated lignin, namely maleylated lignin (MAL);
step two, dissolving 2.0g of MAL, 0.15g (0.50mmol) of Ellagic Acid (EA) and 3mg (0.025mmol) of 4-Dimethylaminopyridine (DMAP) in 10mL of DMF, adding to a 100mL round-bottomed flask, stirring for 5min, slowly dripping 10mL of DMF solution dissolved with 114mg (0.6mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCL) under the ice bath condition (0 ℃), sealing a plug by using a sealing film after finishing dripping, continuously stirring in an ice water bath at 0-4 ℃ for 2h, transferring to a constant temperature water bath kettle at 25 ℃ for reaction for 24h, after the reaction is finished, adding 300mL of pure water to precipitate, filtering, washing with anhydrous ethanol and pure water for three times, and vacuum drying at 50 deg.C to obtain bioactive compound modified lignin, which is maleylated lignin-g-ellagic acid copolymer (MAL-g-EA);
dissolving 1mg of MAL-g-EA copolymer and 1mg of ibuprofen drug in 2mL of organic solvent, slowly dripping 10mL of distilled water (dripping time is 1-20min) under stirring (200-1200r/min), and performing ultrasonic treatment for 60min to obtain the modified lignin self-assembled drug-loaded nano-micelle, namely the multi-bioactivity MAL-g-EA self-assembled drug-loaded nano-micelle.
Other steps not disclosed in the above preparation method, such as dialysis (dialysis operation is required after ultrasound in step three), etc., can be found in the prior art.
FIG. 1 is a transmission electron microscope image of the MAL-g-EA drug-loaded nano-micelle in example 1. As can be seen from FIG. 1, the micelle is spherical, and the particle size is in the range of 60-120 nm.
FIG. 2 shows the survival rate of colon cancer cells HT-29 at different concentrations of IBU and MAL-g-EA @ IBU in example 1. When the IBU concentration is 300 mug/mL, the survival rate of HT-29 cells is only 92.757%, and under the same concentration, the survival rate of HT-29 cells cultured in the MAL-g-EA @ IBU environment is 46.513%, namely IBU has no cytotoxicity to HT-29 cells basically, while MAL-g-EA @ IBU drug-loaded micelles show stronger cytotoxicity, which indicates that the carrier material MAL-g-EA has a certain anticancer effect.
FIG. 3 is a comparison of the drug loading rates of MAL and MAL-g-EA under different initial dosing (IBU) amounts in example 1. As can be seen from FIG. 3, the drug loading rate of MAL-g-EA is significantly higher than that of MAL, such as: when the initial feeding amount of IBU is 10%, the drug loading rate of the MAL-g-EA is 7.75%, the drug loading rate of the MAL is 6.36%, and the drug loading rate of the MAL-g-EA is 21.8% higher than that of the MAL; when the initial feeding amount of IBU is 50%, the drug loading rate of the MAL-g-EA is 17.55%, the drug loading rate of the MAL is 11.19%, and the drug loading rate is improved by 56.8%; when the initial feeding amount of IBU is 100%, the drug loading rate of the MAL-g-EA is 19.72%, the drug loading rate of the MAL is 12.62%, and the drug loading rate of the MAL-g-EA is improved by about 56.2% compared with the drug loading rate of the MAL.
As can be seen from the combination of FIG. 3, the drug loading capacity of the micelle on the hydrophobic drug IBU is greatly improved after EA is grafted on the MAL in the scheme of the invention.
Examples 2 to 8:
the table for the parameters of example 1 and examples 2-8 is detailed in table 1:
wherein: alkali lignin, enzymatic lignin, kraft lignin and kraft lignin are respectively represented by A1-A4; maleic anhydride, phthalic anhydride and succinic anhydride are represented by B1-B3, respectively; ellagic acid, resveratrol and curcumin are represented by C1-C3, respectively.
TABLE 1 parameter comparison Table for examples 1-8
The process steps and other process parameters of the above examples 2-8 are the same as in example 1.
The drug loading data for examples 1-8 are detailed in table 2.
Table 2 example 1-8 drug loading table for ibuprofen entrapped in product (initial charge of IBU 50%)
| Serial number | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | Example 7 | Example 8 |
| Drug Loading Rate (%) | 17.55 | 15.637 | 15.79 | 15.36 | 16.25 | 15.03 | 16.03 | 15.85 |
| Error (+/-) | 0.48 | 0.35 | 0.81 | 0.66 | 0.64 | 0.24 | 0.43 | 0.57 |
From table 2, the drug loading capacity of the bioactive compound modified lignin self-assembled drug-loaded nano-micelle obtained by the scheme of the invention is greatly improved and a remarkable effect is obtained compared with the scheme (comparative example) which only adopts MAL (11.19%).
Comparative example:
compared with the embodiment 1, the method specifically comprises the following steps: through the steps one to MAL; and (3) carrying out drug loading on the MAL by directly adopting the third step, wherein the drug loading rate is 11.19%.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The self-assembled drug-loaded nano-micelle is characterized by being prepared by modifying acylated lignin modified by anhydride and then modifying a bioactive compound.
2. The multi-bioactive modified lignin self-assembled drug-loaded nanomicelle according to claim 1, wherein the lignin is at least one of alkali lignin, enzymatic lignin, sulfate lignin and kraft paper lignin; the acid anhydride is at least one of maleic anhydride, phthalic anhydride and succinic anhydride; the bioactive compound is at least one of ellagic acid, resveratrol and curcumin.
3. The multi-bioactivity modified lignin self-assembled drug-loaded nanomicelle according to claim 2, wherein the mass ratio of the acid anhydride to the lignin is as follows: 1: 100-1: 2; the modification temperature of the anhydride is 20-90 ℃, and the modification time is 0.5-12 h; the mass ratio of the bioactive compound to the acylated lignin is as follows: 1: 30-2: 1; in the modification process of the bioactive compound: the reaction is carried out for 2-6h under the condition of ice water bath at 0-4 ℃, and then the reaction is carried out for 10-30h in constant-temperature water bath at 10-50 ℃.
4. A preparation method of a multi-bioactivity modified lignin self-assembled drug-loaded nano micelle is characterized by comprising the following steps:
dissolving lignin, acid anhydride and 4-dimethylaminopyridine in a ratio into N, N-dimethylformamide for reaction to obtain acylated lignin;
dissolving the acylated lignin, the bioactive compound and 4-dimethylaminopyridine in the N, N-dimethylformamide according to a proportion, uniformly mixing, and dropwise adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride for reaction to obtain the bioactive compound modified lignin;
and step three, dissolving the bioactive compound modified lignin and the medicine in an organic solvent according to a certain proportion, and dropwise adding deionized water to prepare the modified lignin self-assembled medicine-carrying nano micelle.
5. The preparation method of the multi-bioactivity modified lignin self-assembled drug-loaded nano-micelle according to claim 4, wherein in the first step: the mass-volume ratio of the lignin to the N, N-dimethylformamide is as follows: 1-20 g/100 mL; the mass ratio of the acid anhydride to the lignin is as follows: 1: 100-1: 2; the molar ratio of the 4-dimethylamino pyridine to the acid anhydride is as follows: 1: 100-1: 10; reacting for 0.5-12h at the temperature of 20-90 ℃.
6. The preparation method of the multi-bioactivity modified lignin self-assembled drug-loaded nano-micelle according to claim 5, wherein the lignin is at least one of alkali lignin, enzymatic hydrolysis lignin, sulfate lignin and kraft paper lignin; the acid anhydride is at least one of maleic anhydride, phthalic anhydride and succinic anhydride.
7. The preparation method of the multi-bioactivity modified lignin self-assembled drug-loaded nano-micelle according to claim 4, wherein in the second step: the mass-volume ratio of the acylated lignin to the N, N-dimethylformamide is as follows: 1-20 g/100 mL; the mass ratio of the bioactive compound to the acylated lignin is as follows: 1: 30-2: 1; the molar ratio of the 4-dimethylaminopyridine to the bioactive compound is as follows: 1: 100-1: 10; the molar ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the bioactive compound is as follows: 1: 1-2: 1;
dropwise adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride under the ice bath condition, reacting for 2-6h, and transferring to a constant-temperature water bath at 10-50 ℃ for reacting for 10-30 h.
8. The method for preparing the multi-bioactive modified lignin self-assembled drug-loaded nanomicelle according to claim 7, wherein the bioactive compound is at least one of ellagic acid, resveratrol and curcumin.
9. The preparation method of the multi-bioactivity modified lignin self-assembled drug-loaded nano-micelle of claim 4, wherein in the third step: dissolving the bioactive compound modified lignin in an organic solvent according to the weight volume concentration of 0.001-0.1 g/100ml, and adding a medicine with the mass of 0.1-2 times that of the bioactive compound modified lignin for dissolving; slowly dripping distilled water according to the volume ratio of 1: 2-10: 1 of water to the organic solvent, and carrying out ultrasonic treatment for 0.5-2 h;
the organic solvent is at least one of N, N-dimethylformamide, ethanol, pyridine, chloroform, dimethyl sulfoxide, dioxane and tetrahydrofuran.
10. The preparation method of the multi-bioactivity modified lignin self-assembled drug-loaded nano-micelle of claim 9, wherein the drug is a hydrophobic drug, preferably ibuprofen, paclitaxel or doxorubicin.
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| CN113797175A (en) * | 2021-09-08 | 2021-12-17 | 齐鲁工业大学 | Grape seed lignin nanoparticle, preparation method thereof and application thereof in drug loading |
| CN114177138A (en) * | 2021-12-03 | 2022-03-15 | 华南理工大学 | PH-responsive acetylated histidine modified lignin drug-loaded particle and preparation method thereof |
| CN114507359A (en) * | 2022-02-17 | 2022-05-17 | 浙江大学 | Preparation method of modified material of lignosulfonate and application of modified material in nano pesticide |
| CN114672031A (en) * | 2022-04-15 | 2022-06-28 | 苏州市焕彤科技有限公司 | PH response polymer nano-drug and preparation method thereof |
| CN114854055A (en) * | 2022-03-25 | 2022-08-05 | 华南理工大学 | Lignin colloidal sphere nano-particles based on temperature-induced graded self-assembly and preparation method thereof |
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| CN113797175A (en) * | 2021-09-08 | 2021-12-17 | 齐鲁工业大学 | Grape seed lignin nanoparticle, preparation method thereof and application thereof in drug loading |
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| CN114507359A (en) * | 2022-02-17 | 2022-05-17 | 浙江大学 | Preparation method of modified material of lignosulfonate and application of modified material in nano pesticide |
| CN114854055A (en) * | 2022-03-25 | 2022-08-05 | 华南理工大学 | Lignin colloidal sphere nano-particles based on temperature-induced graded self-assembly and preparation method thereof |
| CN114854055B (en) * | 2022-03-25 | 2024-05-24 | 华南理工大学 | Lignin colloidal sphere nano-particle based on temperature-induced hierarchical self-assembly and preparation method thereof |
| CN114672031A (en) * | 2022-04-15 | 2022-06-28 | 苏州市焕彤科技有限公司 | PH response polymer nano-drug and preparation method thereof |
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