CN115737538A - Chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel and preparation method and application thereof - Google Patents
Chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel and a preparation method and application thereof, wherein when the hydrogel is prepared, a chitosan solution, a dopamine hydrochloride solution, a dialdehyde sodium alginate solution and a sodium periodate solution are prepared by respectively using deionized water; and then uniformly mixing the chitosan solution and the dopamine hydrochloride solution, dropwise adding dialdehyde sodium alginate and the sodium periodate solution, uniformly mixing, finally adding ferroferric oxide nano particles, uniformly mixing, and crosslinking at 37 ℃ to obtain the black hydrogel. The ferroferric oxide nano particles in the invention endow hydrogel targeting, dopamine participates in crosslinking to enhance adhesion, and dialdehyde sodium alginate is used as a crosslinking agent. The preparation process is simple and easy to operate, accords with green synthetic chemistry, and does not introduce toxic or expensive cross-linking agents, photoinitiators or enzymes. Does not need expensive and complex equipment, has lower cost and obvious effect, and can be used as a targeted hydrogel drug delivery system for treating tumors.
Description
Technical Field
The invention relates to the technical field of hydrogel drug delivery systems, in particular to chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel and a preparation method and application thereof.
Background
Cancer treatment mainly includes surgery, chemotherapy, radiotherapy and immunotherapy. Chemotherapy is effective to a certain extent, but adverse reactions, drug resistance and targeting of the drug are poor, so that the wide application of the drug is limited. In order to improve the effect of chemotherapy and reduce the cost of administration, researchers have proposed many new administration strategies in recent years, such as nano-therapeutic drugs, drug-loaded hydrogels, and the like. Hydrogel is an effective drug delivery strategy comprising a large amount of water and a cross-linked polymer network, has excellent biocompatibility, negligible cytotoxicity and outstanding drug encapsulation ability, and thus has been widely used for cancer treatment in recent years.
Taking bladder cancer as an example, the treatment method of bladder cancer is intravesical immunotherapy or chemotherapy after transurethral resection, but the bladder cancer is easy to relapse after the operation. Intravesical BCG infusion is a well-established and effective treatment regimen, but can only be treated by means of large, multiple infusions of BCG. The treatment mode has a plurality of defects, for example, excessive BCG can strongly stimulate the mucous membrane of the bladder, so that patients have symptoms of hematuria, frequent micturition, urgent micturition, odynuria and the like; the drug cannot be accurately released at the cancerous site; and poor adhesion, which causes the drug to be discharged out of the body with intermittent urinary and urinary discharge, directly resulting in low drug utilization rate, etc. In order to relieve the pain of patients and improve the therapeutic effect of drugs, it is necessary to develop a drug delivery system which can adhere to the cancerous part of the bladder at a fixed point and can be continuously and slowly released.
The hydrogel based on chitosan and sodium alginate is an outstanding medical auxiliary material at present, and the chitosan and sodium alginate have good biocompatibility and a plurality of excellent properties, so that the hydrogel has great application potential in the fields of drug encapsulation and transfer, tissue engineering and the like. The hydrogel is added with the drug, so that the hydrogel becomes a system for slowly releasing the drug, and the retention time of the anti-tumor drug in the body is prolonged. It also has the following drawbacks: firstly, the hydrogel adhesion is insufficient; secondly, the hydrogel has no targeting property and cannot accurately reach a cancerous part for fixed-point adhesion; thirdly, the hydrogel can not be degraded in the human body and discharged out of the human body.
We note the strategies that researchers have proposed to solve these problems. Zhang et al, in A magnetic chitosan hydrogel for both preserved and preserved delivery of Bacillus CalmeteGuerin in the treatment of lamellar cancer, use beta-glycerophosphate as a cross-linking agent to form a temperature responsive hydrogel with chitosan and magnetic ferroferric oxide nanoparticles, which can use an external magnetic field to direct the hydrogel to the cancerous site, and can also extend the residence time of BCG in the bladder. One study by Xu et al has attracted our attention, in Genipin-crosslinked chitosan-chitosan hydrogel for transdermal drug delivery using dopamine to covalently graft onto chitosan chains, followed by the preparation of a well-adhering hydrogel for oral administration using Genipin (GP) as a crosslinking agent, which is attributed to the adhesion properties of the catechol moiety. However, the two important properties of magnetic targeting and adhesion are not combined in the current hydrogel, so that the prepared hydrogel has a single function.
Disclosure of Invention
The invention provides a chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel as well as a preparation method and application thereof.
The technical scheme of the invention is that a preparation method of chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel is characterized by comprising the following steps:
s1, preparing 10 to 30mg/mL chitosan solution, 10 to 30mg/mL dopamine hydrochloride solution, 5 to 25mg/mL dialdehyde sodium alginate solution and 5 to 25mg/mL sodium periodate solution by using deionized water respectively;
s2, uniformly mixing a chitosan solution and a dopamine hydrochloride solution, dropwise adding dialdehyde sodium alginate and a sodium periodate solution, uniformly mixing, adding ferroferric oxide nanoparticles, uniformly mixing, adding a loaded drug, and crosslinking at 36-37.5 ℃ to obtain the black drug-loaded hydrogel.
Further, the volume ratio of the chitosan solution, the dopamine hydrochloride solution, the dialdehyde sodium alginate solution and the sodium periodate solution in the S2 is 2 to 3:2 to 3:1:1; (ii) a The adding amount of the ferroferric oxide nano particles accounts for 0.2-0.5% of the mass of the solution.
Further, the dialdehyde sodium alginate in the dialdehyde sodium alginate solution is prepared by dissolving sodium alginate as a raw material by deionized water, adding an oxidant to carry out a light-resistant reaction, dialyzing the reaction solution after the reaction is stopped, and freeze-drying the permeate liquid.
Further, the oxidant is sodium periodate, ammonium persulfate or potassium permanganate, and the mass ratio of the sodium alginate to the oxidant is 1 to 2.
Further, keeping away from light for 2-10h, and adding ethylene glycol to terminate the reaction after the reaction is finished; the reaction solution was dialyzed using a 3500D dialysis bag for 3 to 5 days.
Further, feCl is adopted in the preparation of the ferroferric oxide nano particles 3 ·6 H 2 O and FeCl 2 ·4H 2 Dissolving O in deionized water, and dropping hydro-oxidation under heating and stirringAnd (3) reacting and curing the sodium solution, collecting black precipitate, and cleaning and drying to obtain the sodium-containing water-soluble sodium sulfate.
Further, feCl 3 ·6 H 2 O and FeCl 2 ·4H 2 Dissolving O in a mass ratio of 3.
Further, adding 1 to 3mol/L sodium hydroxide solution, adjusting the pH value to 9 to 11, stirring and curing at the temperature for 5 to 9 hours, collecting the generated black precipitate by using an external magnet, washing the black precipitate to be neutral by using deionized water, and drying the black precipitate in vacuum at 70 to 90 ℃.
The invention also relates to the chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel prepared by the preparation method.
The invention also relates to application of the chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel in a targeted hydrogel drug delivery system for tumor treatment.
The process and mechanism of the present invention is largely divided into three sections. The first part is the preparation of dialdehyde sodium alginate: the sodium alginate monomer has a large amount of ortho-dihydroxy, the ortho-dihydroxy can be oxidized into dialdehyde by reacting with oxidants such as sodium periodate, sodium persulfate, ammonium persulfate and the like, and then the dialdehyde sodium alginate is obtained by dialysis, freeze drying; the second part is preparation of ferroferric oxide nano particles: the solution of ferrous chloride and ferric chloride can generate nano ferroferric oxide particles under the alkaline condition, and products are collected by an external magnet; the third part is the preparation of targeted drug-loaded hydrogel: the chitosan and the dopamine contain amino groups and can form Schiff base bonds with aldehyde groups of dialdehyde sodium alginate so as to be crosslinked into hydrogel, and the hydrogel is endowed with targeting property by adding the nano ferroferric oxide particles.
The invention has the beneficial effects that:
the hydrogel preparation strategy which has good adhesion and magnetic responsiveness and can be used for transferring tumor treatment drugs provided by the invention comprises the steps of firstly oxidizing sodium alginate with an oxidizing agent to obtain dialdehyde sodium alginate; then using FeCl 3 、FeCl 2 Preparing nano ferroferric oxide particles under an alkaline condition; finally, the dissolved chitosan, dopamine andmixing dialdehyde sodium alginate, sodium periodate and nano ferroferric oxide particles to prepare the hydrogel. The ferroferric oxide nanoparticles endow hydrogel targeting, dopamine participates in crosslinking to enhance adhesion, and dialdehyde sodium alginate is used as a crosslinking agent. The preparation process is simple and easy to operate, accords with green synthetic chemistry, and does not introduce toxic or expensive cross-linking agents, photoinitiators or enzymes. Expensive and complicated equipment is not needed, the cost is low, and the effect is obvious.
The hydrogel prepared by the invention has good magnetic responsiveness, adhesiveness, degradability, bacteriostasis and biocompatibility, and can realize fixed-point adhesion in vivo and sustained release of drugs.
The hydrogel provided by the invention can be used as a targeted hydrogel drug delivery system for tumor treatment, for example, the hydrogel is applied to bladder cancer, can be adhered to a bladder cancer change part and release drugs, and solves the problems of low utilization rate of the traditional treatment drugs and the like.
Drawings
FIG. 1 is a diagram illustrating the therapeutic principle of the hydrogel in the bladder and the principle of the preparation of dialdehyde sodium alginate and hydrogel; wherein a is a schematic diagram of a hydrogel treatment process, and b is a diagram of a gel forming mechanism.
FIG. 2 is an electron micrograph of the hydrogel obtained in examples 1 and 2 of the present invention, wherein the left side is GelDA10 of example 1, and the right side is GelDA20 of example 2.
Fig. 3 is a graph showing the results of rheological property tests of hydrogels used in examples 1 and 2 of the present invention, wherein the left side of the graph is the graph of example 1, and the right side of the graph is the graph of example 2.
FIG. 4 is a schematic diagram showing the targeting of hydrogel and the sticking to the porcine bladder in examples 1 and 2 of the present invention, wherein 1 is hydrogel before the magnetic field is applied, 2 is hydrogel after the magnetic field is applied, 3 is hydrogel after the magnetic field is applied, and 4 is hydrogel stuck to a specific part of the porcine bladder membrane after the magnetic field is removed.
FIG. 5 shows the inhibition rate of the hydrogel of examples 1 and 2 of the present invention against Escherichia coli and Staphylococcus aureus.
FIG. 6 is a graph showing the results of the cytotoxicity test of the hydrogels of examples 1 and 2 of the present invention on Hela cells.
FIG. 7 is a graph showing the release rate of hydrogels at different pH's of examples 1 and 2 of the present invention.
FIG. 8 is an infrared spectrum of a product obtained by oxidizing sodium alginate with sodium periodate in step A of example 2.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention.
Example 1:
as shown in FIG. 1, the first embodiment of the present invention is based on the bladder with cancer lesion, the hydrogel can reach the cancer site under the guidance of external magnetic field, and realize the site-specific adhesion and the slow release of the drug. Dialdehyde sodium alginate, chitosan and dopamine are adopted to prepare hydrogel through Schiff base reaction between aldehyde groups and amino groups. A multifunctional medicine-carrying hydrogel is constructed at a bladder canceration part, and the method comprises the following steps:
A. preparation of Dialdehyde Sodium Alginate (DSA): 2.0 g sodium alginate was dissolved in 250ml deionized water and then 2.1g sodium periodate was added to the solution while magnetically stirring at 25 ℃. The oxidation process is carried out at room temperature for 24 hours and is kept in the dark to prevent the oxidation reaction of the sodium periodate under the illumination of light. The process was terminated by adding an excess of ethylene glycol (mass ratio of ethylene glycol to sodium periodate 3). The reaction mixture was then purified in deionized water using dialysis bags (mwco 3.5 kda) for 3 days, with daily changes of deionized water. Finally, freeze-drying the purified reaction mixture at-50 ℃ for 24 hours to obtain dialdehyde sodium alginate containing a dialdehyde structure, wherein the product is white flocculent powder for later use;
B. ferroferric oxide nanoparticles (Fe) 3 O 4 NPs) preparation: the ferroferric oxide nano particles are prepared from the following components in percentage by mass of 3:2 FeCl 3 ·6 H 2 O and FeCl 2 ·4H 2 O is dissolved in 100ml of deionized water and stirred for 120 minutes at the temperature of 80 ℃ at 2000r/min, and then sodium hydroxide is added. Hydrogen hydroxideSodium solution (3M) was added drop by drop to the above mixture and the pH of the mixture was adjusted to 11. Continuously stirring and curing for 6 hours, collecting the generated black precipitate by using an external magnet, thoroughly washing the black precipitate into neutrality by using deionized water, and drying the neutral precipitate in vacuum at 90 ℃ for 24 hours to finally obtain black magnetic powder, namely ferroferric oxide nano particles for later use;
C. a simulation experiment was performed using porcine bladder, and a drug-loaded hydrogel was introduced at the presumed site of porcine bladder carcinogenesis: preparing 30mg/ml chitosan, 10mg/ml dopamine, 5mg/ml dialdehyde sodium alginate solution and 5mg/ml sodium periodate solution, wherein the volume ratio of the raw materials is 2.
Example 2:
referring to fig. 1, a second embodiment of the present invention is that, based on the bladder with a cancerous lesion, the hydrogel can reach the cancerous site under the guidance of an external magnetic field, and achieve site-specific adhesion and sustained drug release, and according to the drug release rate of fig. 7, the hydrogel with different drug release time or drug release effect can be obtained by using dopamine in different proportions. Dialdehyde sodium alginate, chitosan and dopamine are adopted to prepare hydrogel through Schiff base reaction between aldehyde groups and amino groups. A multifunctional medicine-carrying hydrogel is constructed at a bladder canceration part, and the method comprises the following steps:
A. preparing dialdehyde sodium alginate: 2.0 g sodium alginate was dissolved in 250ml deionized water and then 2.1g sodium periodate was added to the solution while magnetically stirring at 25 ℃. The oxidation process is carried out at room temperature for 24 hours and is kept away from light to prevent the sodium periodate from oxidation reaction under the irradiation of light. The process was terminated by adding an excess of ethylene glycol (mass ratio of ethylene glycol to sodium periodate 3). The reaction mixture was then purified in deionized water using dialysis bags (mwco3.5 kda) for 3 days, with deionized water being changed daily. Finally, freeze-drying the purified reaction mixture at-50 ℃ for 24 hours to obtain dialdehyde sodium alginate containing a dialdehyde structure, wherein the product is white flocculent powder for later use;
B. preparing nano ferroferric oxide: the ferroferric oxide nano particles are prepared from FeCl with the proportion of 3 3 ·6 H 2 O and FeCl 2 ·4H 2 O was dissolved in 100ml of deionized water at 80 ℃ for 120 minutes with vigorous stirring. Sodium hydroxide solution (3M) was added drop by drop to the above mixture, and the pH of the mixture was adjusted to 9 to 11. Continuously stirring and curing for 6 hours, collecting the generated black precipitate by using an external magnet, thoroughly washing the precipitate to be neutral by using deionized water, and drying the precipitate in vacuum at 90 ℃ for 24 hours to finally obtain black magnetic powder for later use;
C. a simulation experiment was performed using porcine bladder, and a drug-loaded hydrogel was introduced at the presumed site of porcine bladder carcinogenesis: preparing a 30mg/ml chitosan solution, a20 mg/ml dopamine solution, a 5mg/ml dialdehyde sodium alginate solution and a 5mg/ml sodium periodate solution, wherein the volume ratio of the raw materials is 2. Mixing chitosan, dopamine, dialdehyde sodium alginate andsolution(s)The nano ferroferric oxide particles with the total mass of 0.5 percent are uniformly mixed with 10mg of bovine serum albumin serving as a model drug, hydrogel can be formed under the human body condition of 37 ℃, the hydrogel is introduced into the bladder, the cancerization part is determined according to cystography, the drug-loaded hydrogel is moved to the cancerization part under the guidance of an external magnetic field, and fixed-point adhesion and drug slow release are carried out.
We characterized the morphological features of the hydrogels and the possible cross-linking. The adhesion performance, targeting performance and release performance of the hydrogel with different dopamine hydrochloride proportions and the bovine serum albumin of a model drug are evaluated by using a pig bladder simulation experiment.
As shown in FIG. 3, the hydrogel has a porous interconnected structure, the size of the pore structure is about 200 microns, and the uniform through microporous structure is beneficial to the embedding and delivery of water and macromolecular substances. As shown in figure 4, 1 is that the hydrogel is in the pig bladder, 2 is that a magnetic field is added to the hydrogel and the hydrogel slowly moves, 3 is that the hydrogel reaches a designated position, 4 is that the hydrogel can be attached to the wall of the pig bladder at a fixed point without falling after the magnetic field is removed, and then the drug release is carried out. As shown in FIG. 5, the hydrogel has an inhibition rate of over 95% on Escherichia coli and Staphylococcus aureus. As shown in fig. 6, the hydrogel had little cytotoxicity. As shown in fig. 7, the hydrogel with pH =4.0 released drug for 10 hours, and the hydrogel with pH =7.4 released drug for 27 hours in normal physiological environment.
Example 2 in step a sodium alginate was oxidized by sodium periodate and the presence of aldehyde groups was determined by infrared spectroscopy. In particular, 1734cm as shown in FIG. 8 -1 Aldehyde group absorption peak at wavenumber.
Example 3:
based on example 2, when the concentration of dopamine is 0%, the hydrogel prepared under the same conditions cannot produce a black hydrogel, but exists in a solution state, and does not have sufficient adhesiveness, which fully shows that the hydrogel takes dopamine as a core and provides a skeleton component and an adhesive support of the hydrogel.
Claims (10)
1. A preparation method of chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel is characterized by comprising the following steps:
s1, preparing 10 to 30mg/mL chitosan solution, 10 to 30mg/mL dopamine hydrochloride solution, 5 to 25mg/mL dialdehyde sodium alginate solution and 5 to 25mg/mL sodium periodate solution by using deionized water respectively;
s2, uniformly mixing the chitosan solution and the dopamine hydrochloride solution, dropwise adding dialdehyde sodium alginate and the sodium periodate solution, uniformly mixing, adding the ferroferric oxide nanoparticles, uniformly mixing, adding the medicine to be loaded, and crosslinking at 36-37.5 ℃ to obtain the chitosan/sodium periodate composite material.
2. The method for producing the hydrogel according to claim 1, wherein: s2, the volume ratio of the chitosan solution to the dopamine hydrochloride solution to the dialdehyde sodium alginate solution to the sodium periodate solution is 2 to 3:2 to 3:1:1; the adding amount of the ferroferric oxide nano particles accounts for 0.2-0.5% of the mass of the solution.
3. The method for producing the hydrogel according to claim 1, wherein: the dialdehyde sodium alginate in the dialdehyde sodium alginate solution is prepared by dissolving sodium alginate as a raw material by deionized water, adding an oxidant to carry out a light-resistant reaction, dialyzing reaction liquid after the reaction is stopped, and freeze-drying the permeated liquid.
4. The method for producing the hydrogel according to claim 3, wherein: the oxidant is sodium periodate, ammonium persulfate or potassium permanganate, and the mass ratio of the sodium alginate to the oxidant is 1 to 2.
5. The method for producing the hydrogel according to claim 3, wherein: the reaction time is 2-10h away from light, and ethylene glycol is added to terminate the reaction after the reaction is finished; the reaction solution was dialyzed using a 3500D dialysis bag for 3 to 5 days.
6. The method for producing the hydrogel according to claim 1, wherein: feCl is adopted in the preparation of the ferroferric oxide nano particles 3 ·6 H 2 O and FeCl 2 ·4H 2 Dissolving the O with deionized water, dripping sodium hydroxide solution under the condition of heating and stirring, collecting black precipitate after reaction and curing, and cleaning and drying to obtain the product.
7. The method for producing the hydrogel according to claim 6, wherein: feCl 3 ·6H 2 O and FeCl 2 ·4H 2 The mass ratio of O is 3.
8. The method for producing the hydrogel according to claim 7, wherein: adding 1-3 mol/L sodium hydroxide solution, adjusting the pH value to 9-11, stirring and curing at the temperature for 5-9 h, collecting the generated black precipitate by using an external magnet, washing the black precipitate to be neutral by using deionized water, and drying the black precipitate in vacuum at 70-90 ℃.
9. The chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel prepared by the preparation method of any one of claims 1 to 8.
10. The use of the chitosan/dialdehyde sodium alginate/dopamine magnetic hydrogel of claim 9 in a targeted hydrogel drug delivery system for tumor therapy.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117100716A (en) * | 2023-08-29 | 2023-11-24 | 广东龄值生物科技有限公司 | Nano microsphere containing iNKT cells and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117100716A (en) * | 2023-08-29 | 2023-11-24 | 广东龄值生物科技有限公司 | Nano microsphere containing iNKT cells and preparation method thereof |
| CN117100716B (en) * | 2023-08-29 | 2024-03-12 | 广东龄值生物科技有限公司 | Nano microsphere containing iNKT cells and preparation method thereof |
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