CN111363170A - Preparation and application of hydroxyethyl cellulose-sodium alginate hydrogel - Google Patents
Preparation and application of hydroxyethyl cellulose-sodium alginate hydrogel Download PDFInfo
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Abstract
The invention provides a preparation method and application of hydroxyethyl cellulose-sodium alginate hydrogel, the hydroxyethyl cellulose-sodium alginate hydrogel provided by the invention is used as a drug-carrying carrier, and has the characteristics of simple synthesis method, high encapsulation efficiency and the like.
Description
Technical Field
The invention relates to preparation and application of hydroxyethyl cellulose-sodium alginate hydrogel, belonging to the field of medicines.
Background
Drug delivery systems refer to pharmaceutical preparations that improve the therapeutic effect of a drug by different administration forms. The conventional dosage forms, such as injection, tablet, capsule, etc., have been unable to meet the clinical treatment requirement due to the defect of short maintenance time of effective concentration. In order to overcome the defect, a novel drug delivery system such as hydrogel drug loading attracts extensive attention of researchers, the molecular weight of a product obtained after the hydrogel polymer carrier is degraded is lower than the excretion limit of the kidney (<30kDa), and the safety is improved. Among the properties of sodium alginate which are particularly noteworthy are its bioaffinity and its bioabsorbability, which, when implanted in the body of an organism, causes little reaction in the organism tissue and is slowly absorbed by enzymes in the tissue.
Hydroxyethyl cellulose is a white, nontoxic and tasteless polymer, has the function of a protective colloid within the pH value of 2-8, has strong stability, can slow down the loss of blood platelets as a thick colloid, and accelerates the healing of wounds, so that a hydrogel is designed to reach intestinal tumors through highly acidic stomachs to release medicines, repair mucous membranes and the like, and has great potential application value in the field of medicine.
Disclosure of Invention
The invention relates to a preparation and application of hydroxyethyl cellulose-sodium alginate hydrogel, the hydroxyethyl cellulose-sodium alginate hydrogel provided by the invention is used as a drug-carrying carrier, has simple synthesis method, can encapsulate and convey anti-tumor drugs, has high encapsulation efficiency, has a group with high affinity to organisms and low biological toxicity, is an orally-taken hydrogel carrier, the acidic condition of the stomach can protect the medicine inside from being released, so that the medicine targets the intestinal tumor, the hydroxyethyl cellulose in the hydrogel can promote the repair function of the intestine and effectively reduce the side effects of hematochezia and the like caused by intestinal tumors, the decomposed hydroxyethyl cellulose has no acidic or basic groups and no neurotoxicity, and is completely absorbed by a human body 7-14 days after being decomposed into monosaccharide in vivo; the hydrogel is indicated to have wide practical application as a novel drug-loaded carrier hydrogel.
The invention aims to provide a preparation method of hydroxyethyl cellulose-sodium alginate hydrogel.
The invention further aims to provide application of the hydroxyethyl cellulose-sodium alginate hydrogel.
The invention further aims to provide application of the hydroxyethyl cellulose-sodium alginate hydrogel in drug loading and tumor growth inhibition, wherein the drug is an anti-tumor drug rich in electron-withdrawing groups, and the tumor cells are PC3 prostate cancer cells and HCT-8 intestinal cancer cells.
The structural formula of the hydroxyethyl cellulose-sodium alginate hydrogel is shown as the formula (I):
wherein n is 20-50; and m is 20-50.
The structural formula of the sodium alginate is shown as the formula (II):
wherein m is 20-50.
The structural formula of the 3, 3-dithiodipropionic acid is shown as a formula (III):
the structural formula of the hydroxyethyl cellulose is shown as (V).
Wherein n is 20 to 50.
The synthesis steps of the hydroxyethyl cellulose-sodium alginate hydrogel are as follows:
(1) reacting the compound with the structure shown in the formula (II) with the compound with the structure shown in the formula (III) to obtain the following compound with the structure shown in the formula (IV):
wherein n is 20 to 50.
Reacting a compound with a structure shown in a formula (IV): formula (III) (8.41g, 40mmol), formula (II) (1.93g, 5mmol) and 4-dimethylaminopyridine (0.0386g, 0.316mmol) were dissolved in 20mL anhydrous tetrahydrofuran. Dicyclohexylcarbodiimide (3.09g, 15mmol) was then added to anhydrous tetrahydrofuran (5mL) and added dropwise to the ice bath. Stirring the resulting mixture at 20-40 ℃ for 8-16 h, filtering the reaction, removing the solvent by rotary evaporation, and purifying the product by recrystallization from ethyl acetate to give the product of formula (IV).
(2) Reacting a compound having the structure of formula (IV) with formula (V) to obtain a compound having the structure of formula (I):
reacting a compound with a structure shown in a formula (I): 2g (3.5mmol) of formula (IV) and 1.32g EDC (6.9mmol) were dissolved in 20mL of absolute ethanol and the reaction was stirred for 50 minutes to activate the carboxyl group. Formula (V) (3.0mmol) and 0.8g NHS (6.9mmol) were dissolved in 20mL deionized water to activate the hydroxyl group, and the activated formula (V) (3.0mmol) was slowly added to the aqueous solution of formula (IV) after the carboxyl group was activated, and the dropping time was controlled to 5-10 min. Stirring for 6-10 h in a dark place. Dialyzing with 8000-14000 molecular weight dialysis bag for 2 days, and freeze drying to obtain green solid (I).
The preferred synthesis steps of the hydroxyethyl cellulose-sodium alginate hydrogel are as follows:
(1) reacting the compound with the structure shown in the formula (II) with the compound with the structure shown in the formula (III) to obtain the compound with the structure shown in the formula (IV).
Reacting a compound with a structure shown in a formula (IV): formula (III) (8.41g, 40mmol), formula (II) (1.93g, 5mmol) and 4-dimethylaminopyridine (0.0386g, 0.316mmol) were dissolved in 20mL anhydrous tetrahydrofuran. Dicyclohexylcarbodiimide (3.09g, 15mmol) was then added to anhydrous tetrahydrofuran (5mL) and added dropwise to the ice bath. The resulting mixture was stirred at 30 ℃ for 10h, the reaction was filtered, the solvent was removed by rotary evaporation, and the product was purified by recrystallization from ethyl acetate to give the product formula (iv).
(2) Reacting the compound with the structure shown in the formula (IV) with the compound with the structure shown in the formula (V) to obtain the compound with the structure shown in the formula (I).
Reacting a compound with a structure shown in a formula (I): 2g (3.5mmol) of formula (IV) and 1.32g EDC (6.9mmol) were dissolved in 20mL of absolute ethanol and the reaction was stirred for 50 minutes to activate the carboxyl group. Formula (V) (3.0mmol) and 0.8g NHS (6.9mmol) were dissolved in 20mL deionized water to activate the hydroxyl group, and the activated formula (V) (3.0mmol) was slowly added to the aqueous solution of formula (IV) after the carboxyl group was activated, with the dropping time controlled within 5 min. Stirring for 8h in the dark. Dialyzing with 8000-14000 molecular weight dialysis bag for 2 days, and freeze drying to obtain green solid (I).
Has the advantages that: the invention provides a preparation and application of hydroxyethyl cellulose-sodium alginate hydrogel, the polymer provided by the invention is used as a drug-carrying carrier, hydroxyethyl cellulose has no acidic or alkaline group, has no neurotoxicity, is decomposed into monosaccharide in vivo, is completely absorbed by a human body within 7-14 days, and has a certain anti-acid decomposition effect and is not decomposed in the stomach environment; the critical micelle concentration calculation shows that the drug loading capacity is large and the drug loading efficiency is high. In addition, the polymer has the diameter of 130nm grade, is easy to enter tumor cells, and the carrier has no toxicity to the cells, so that the carrier is an excellent nano drug-carrying carrier.
The following will clearly and completely describe the technical scheme of the embodiment of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Drawings
FIG. 1 is a morphology picture of a TEM-captured hydroxyethylcellulose-sodium alginate hydrogel.
FIG. 2 is a size distribution diagram of hydroxyethyl cellulose-sodium alginate hydrogel measured by DLS.
FIG. 3 is a bar chart of cytotoxicity of drug-loaded hydroxyethylcellulose-sodium alginate hydrogel (1-50 mg/mL) and PC3 prostate cancer cells and HCT-8 intestinal cancer cells.
FIG. 4 is a bar chart of cytotoxicity of hydroxyethylcellulose-sodium alginate hydrogel (1-50 mg/mL) and normal epidermal cells Hacat and intestinal cancer cells HCT-8.
Detailed description of the preferred embodiments
Example 1
The synthesis method of the hydroxyethyl cellulose-sodium alginate hydrogel comprises the following steps:
(1) formula (III) (8.41g, 40mmol), formula (II) (1.93g, 5mmol) and 4-dimethylaminopyridine (0.0386g, 0.316mmol) were weighed out and dissolved in 20mL dry tetrahydrofuran. Dicyclohexylcarbodiimide (3.09g, 15mmol) was then added to anhydrous tetrahydrofuran (5mL) and added dropwise to the ice bath. The resulting mixture was stirred at 30 ℃ for 10h, the reaction was filtered, the solvent was removed by rotary evaporation, and the product was purified by recrystallization from ethyl acetate to give the product formula (iv);
(2) 2g of formula (IV) (3.5mmol) and 1.32g of EDC (6.9mmol) were dissolved in 20mL of absolute ethanol and reacted for 50 minutes with stirring to activate the carboxyl group; formula (V) (3.0mmol) and 0.8g NHS (6.9mmol) were dissolved in 20mL deionized water to activate the hydroxyl group, and the activated formula (V) (3.0mmol) was slowly added to the aqueous solution of formula (IV) after the carboxyl group was activated, with the dropping time controlled within 5 min. Stirring for 8h in the dark. Dialyzing with 8000-14000 molecular weight dialysis bag for 2 days, and freeze-drying to obtain green solid of formula (I).
Example 2
Preparation of nedaplatin-loaded hydroxyethyl cellulose-sodium alginate hydrogel
Nedaplatin is encapsulated in the crosslinked network of hydroxyethylcellulose-sodium alginate hydrogel. 50mg of hydroxyethyl cellulose-sodium alginate hydrogel, 10mg of nedaplatin dissolved in a volume ratio of 1: 9 was stirred at room temperature for 24 hours, desalted, slowly added dropwise to a large amount of ultrapure water (500mL), and then rapidly stirred at room temperature for 1 hour. The solution was dialyzed with ultrapure water and filtered through a 0.45 μm needle filter to obtain a nedaplatin-loaded hydrogel.
Example 3
Nedaplatin-loaded hydroxyethylcellulose-sodium alginate hydrogel Drug Loading Capacity (DLC) and Drug Loading Efficiency (DLE)
The appearance is as follows: and uniformly dropping a drop of hydrogel solution on a copper net with a carbon film, and then drying the hydrogel solution at room temperature, and capturing morphology pictures of the micelles by using a TEM (transmission electron microscope). Particle size: the average size and size distribution of the micelles was determined by DLS. Fig. 1 is a morphology picture of TEM-captured nedaplatin-loaded hydroxyethylcellulose-sodium alginate hydrogel, and fig. 2 is a size distribution diagram of DLS-determined nedaplatin-loaded hydroxyethylcellulose-sodium alginate hydrogel.
Drug Loading (DLC) and Drug Loading Efficiency (DLE): freezing the nedaplatin-loaded hydroxyethyl cellulose-sodium alginate hydrogel to obtain faint yellow solid powder, dissolving the powder in methanol, repeatedly preparing 4 batches of nedaplatin-loaded hydroxyethyl cellulose-sodium alginate hydrogel, and recording the absorbance value at 488nm by UV-vis. Similarly, a gradient DOX solution was prepared, 4 batches of nedaplatin hydroxyethylcellulose-sodium alginate loaded hydrogel were prepared repeatedly, and the absorbance values obtained were plotted as standard working curves to calculate DLC and DLE of drug loaded hydrogel. Table 1 below is the drug-loaded hydrogel encapsulation efficiency and drug-loading measurement results.
DLC% (% DOX mass/Polymer mass in hydrogel) × 100 (1)
DLE% ((mass of DOX in hydrogel/mass of DOX charge)) × 100% (2)
Table 1: hydroxyethyl cellulose-sodium alginate hydrogel encapsulation efficiency and drug loading measurement
| Batches of | 1 | 2 | 3 | 4 |
| Encapsulation efficiency% | 68.9 | 67.4 | 66.9 | 68.3 |
| Drug loading rate% | 10.5 | 11.03 | 10.9 | 11.4 |
Example 4
Cytotoxicity test of nedaplatin-loaded hydroxyethyl cellulose-sodium alginate hydrogel
Cell culture: inoculating PC3 prostate cancer cell and HCT-8 intestinal cancer cell in cell culture bottle at 37 deg.C and 5% CO2Culturing in environment, wherein the culture medium is selected from 1640 culture medium containing 10% fetal calf serum and 0.5% double antibody. Cell inoculation: the cultured cells were seeded in 96-well plates at a cell density of 8000 cells/mL, and continued at 37 ℃ with 5% CO2Cultivation in the environmentAnd (5) cultivating for 48 hours. Adding gradient compound solution: removing culture medium from 96-well plate, washing with precooled PBS for 3 times, adding 1640 complete culture medium containing different gradient carrier nedaplatin hydroxyethylcellulose-sodium alginate hydrogel, continuing to perform cell culture at 37 deg.C and 5% CO2And culturing for 24 hours in the environment. Adding an MTT solution: the culture medium in the 96-well plate is removed, 200 μ L of MTT solution diluted to 5mg/ml with complete medium is added to each well, the solution is removed after 4 hours of incubation with tinfoil wrap, and 100 μ L of DMSO is added to fully dissolve the formazan that adheres to the 96-well plate. Measuring cell viability: and (3) transferring the 96-well plate into a microplate reader, setting the scanning wavelength to be 577nm, measuring the absorbance of the 96-well plate, and determining the survival rate of the cells according to the value of the absorbance.
FIG. 3 is a bar chart of cytotoxicity of Nedaplatin-loaded hydroxyethylcellulose-sodium alginate hydrogel (1-50 mg/mL) and PC3 prostate cancer cells and HCT-8 intestinal cancer cells. The nedaplatin-loaded hydroxyethyl cellulose-sodium alginate hydrogel disclosed by the invention quickly penetrates through cell membranes to bring a medicament into cells, and the hydrogel is slowly melted under the acidic condition of tumors, so that the time of the medicament acting on the tumors is prolonged, and the purpose of killing the cells is achieved.
Example 5
Toxicity test of hydroxyethyl cellulose-sodium alginate hydrogel leaching liquor on cells
Firstly, normal epidermal cells Hacat and intestinal cancer cells HCT-8 are planted in a 96-well plate with the density of 104Wells each containing 200 μ L of complete medium. The plates were placed in a carbon dioxide incubator (37 ℃, 5% CO)2) Culturing for 24 hr, removing old culture medium, adding 200 μ L hydroxyethyl cellulose-sodium alginate hydrogel leaching solution into each well, adding CO2The incubation was continued in the incubator. The plates were removed at the scheduled time points, the old media was aspirated, washed twice with PBS, and then 360. mu.L of serum free DMEM cell media and 40. mu.L of MTT was added to each well and placed in the incubator for further incubation for 4 h. After the cells reacted well with MTT, the medium was aspirated, 400. mu.L of DMSO was added to each well, and the mixture was shaken for 30min at 37 ℃ in the dark to completely dissolve the precipitate. Then detecting the light absorption value by an enzyme-labeling instrument at the wavelength of 577nmEach sample was replicated three times.
FIG. 4 is a bar chart of cytotoxicity of hydroxyethylcellulose-sodium alginate hydrogel (1-50 mg/mL) and normal epidermal cells Hacat and intestinal cancer cells HCT-8. The hydroxyethyl cellulose-sodium alginate hydrogel has no cytotoxicity to tumor cells under the condition of no drug loading, and shows that the hydroxyethyl cellulose-sodium alginate hydrogel is nontoxic.
Example 6
Animal anti-tumor assay
In the experiment, male mice with five weeks are selected to carry out abdominal subcutaneous injection of HCT-8 intestinal cancer cells, and the in vivo anti-tumor effect of the drug-loaded delivery system is tested and researched. After injecting HCT-8 intestinal cancer cells, when the tumor volume of the mice reaches about 100mm3In the experimental process, the mouse tumor is measured by using a vernier caliper every 2 days, the tumor volume calculation formula is V ═ L × W2/2, wherein L is the longest tumor diameter, W is the shortest tumor diameter perpendicular to L, the average body weight of each group is simultaneously measured to be used as an index for evaluating the toxicity of the system, and the excretion of the mouse is observed every two days, and whether the symptom of hematochezia is observed.
| Dose (. mu.) ofg) | |
4 |
8 days | 12 days | 16 days | |
| Drug-loaded hydrogel | 400 | 1 | 1.26 | 1.89 | 2.09 | 2.26 |
| Pure water gel | 400 | 1 | 1.49 | 2.78 | 3.49 | 3.81 |
| |
0 | 1 | 1.59 | 2.86 | 3.44 | 3.82 |
In the experiment, the nedaplatin-loaded polyhydroxyethyl cellulose-sodium alginate hydrogel has obvious inhibition effect on HCT-8 intestinal cancer. The tumor 16 days after the test sample carrying the nedaplatin hydroxyethylcellulose-sodium alginate hydrogel is administered with 400 mu g of the nedaplatin-sodium alginate hydrogel is 0.8 times smaller than that of a negative control group and a pure hydrogel group without any medicine, which indicates that the nedaplatin hydrogel can be released in the intestine by an oral administration mode through the stomach to inhibit the tumor; in addition, no hematochezia is observed in the excrement, a small amount of hematochezia exists in the pure hydrogel group, and the hematochezia is serious in the negative control group, which indicates that the hydroxyethyl cellulose-sodium alginate hydrogel can repair damaged intestinal tissues or mucous membranes and reduce the hematochezia.
Claims (3)
1. The preparation method of the hydroxyethyl cellulose-sodium alginate hydrogel is characterized by comprising the following steps: the chitosan-sodium alginate hydrogel is synthesized by hydroxyethyl cellulose, 3-dithiodipropionic acid and sodium alginate:
the structural formula of the hydroxyethyl cellulose-sodium alginate hydrogel is shown as the formula (I):
wherein n is 20-50; m is 20-50;
the structural formula of the sodium alginate is shown as a formula (II):
wherein m is 20-50;
the structural formula of the 3, 3-dithiodipropionic acid is shown as a formula (III):
the structural formula of the hydroxyethyl cellulose is shown as (V);
wherein n is 20-50;
the synthesis steps of the hydroxyethyl cellulose-sodium alginate hydrogel are as follows:
(1) reacting the compound with the structure shown in the formula (II) with the compound with the structure shown in the formula (III) to obtain the following compound with the structure shown in the formula (IV):
wherein n is 20-50;
reacting a compound with a structure shown in a formula (IV): dissolving formula (III) (8.41g, 40mmol), formula (II) (1.93g, 5mmol) and 4-dimethylaminopyridine (0.0386g, 0.316mmol) in 20mL anhydrous tetrahydrofuran; then dicyclohexylcarbodiimide (3.09g, 15mmol) was added to anhydrous tetrahydrofuran (5mL) and dropped into an ice bath; stirring the formed mixture at 20-40 ℃ for 8-16 h, filtering the reactant, removing the solvent through rotary evaporation, and recrystallizing and purifying the product through ethyl acetate to obtain a product shown in formula (IV);
(2) reacting a compound having the structure of formula (IV) with formula (V) to obtain a compound having the structure of formula (I):
reacting a compound with a structure shown in a formula (I): 2g of formula (IV) (3.5mmol) and 1.32g of EDC (6.9mmol) were dissolved in 20mL of absolute ethanol and reacted for 50 minutes with stirring to activate the carboxyl group; dissolving the formula (V) (3.0mmol) and 0.8g NHS (6.9mmol) in 20mL deionized water to activate hydroxyl, slowly adding the activated formula (V) (3.0mmol) into the carboxyl-activated water solution of the formula (IV), and controlling the dropping time to be 5-10 min; stirring for 6-10 h in a dark place; dialyzing with 8000-14000 molecular weight dialysis bag for 2 days, and freeze drying to obtain green solid of formula (I).
2. The preparation of hydroxyethyl cellulose-sodium alginate hydrogel according to claim 1, wherein: the preferred synthesis steps of the hydroxyethyl cellulose-sodium alginate hydrogel are as follows:
(1) reacting a compound with a structure shown in a formula (II) with a compound with a structure shown in a formula (III) to obtain a compound with a structure shown in a formula (IV);
reacting a compound with a structure shown in a formula (IV): dissolving formula (III) (8.41g, 40mmol), formula (II) (1.93g, 5mmol) and 4-dimethylaminopyridine (0.0386g, 0.316mmol) in 20mL anhydrous tetrahydrofuran; then dicyclohexylcarbodiimide (3.09g, 15mmol) was added to anhydrous tetrahydrofuran (5mL) and dropped into an ice bath; the resulting mixture was stirred at 30 ℃ for 10h, the reaction was filtered, the solvent was removed by rotary evaporation, and the product was purified by recrystallization from ethyl acetate to give the product formula (iv);
(2) reacting a compound with a structure shown in a formula (IV) with a compound with a structure shown in a formula (V) to obtain a compound with a structure shown in a formula (I);
reacting a compound with a structure shown in a formula (I): 2g of formula (IV) (3.5mmol) and 1.32g of EDC (6.9mmol) were dissolved in 20mL of absolute ethanol and reacted for 50 minutes with stirring to activate the carboxyl group; dissolving formula (V) (3.0mmol) and 0.8g NHS (6.9mmol) in 20mL deionized water to activate hydroxyl, slowly adding activated formula (V) (3.0mmol) into the carboxyl-activated water solution of formula (IV), and controlling the dropping time within 5 min; stirring for 8h in a dark place; dialyzing with 8000-14000 molecular weight dialysis bag for 2 days, and freeze drying to obtain green solid of formula (I).
3. The application of the hydroxyethyl cellulose-sodium alginate hydrogel is characterized in that: the hydrogel is used as a carrier of PC3 prostate cancer cells, breast cancer, fallopian tube cancer, ovarian cancer, pancreatic cancer, non-small cell lung cancer, HCT-8 intestinal cancer cells, acute myelogenous leukemia, indolent lymphoma and liver cancer.
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| CN112897658A (en) * | 2021-01-18 | 2021-06-04 | 广州博芳环保科技股份有限公司 | Method for preparing polyaluminum chloride composite flocculant by using sludge from aluminum profile plant |
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