CN116212015B - In-situ ultrasonic visual controlled-release phase-change type immune hydrogel and preparation method and application thereof - Google Patents
In-situ ultrasonic visual controlled-release phase-change type immune hydrogel and preparation method and application thereof Download PDFInfo
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- CN116212015B CN116212015B CN202310289818.9A CN202310289818A CN116212015B CN 116212015 B CN116212015 B CN 116212015B CN 202310289818 A CN202310289818 A CN 202310289818A CN 116212015 B CN116212015 B CN 116212015B
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Abstract
The invention relates to the technical field of drug controlled release gel, in particular to in-situ ultrasonic visual controlled release phase-change immune hydrogel and a preparation method and application thereof. The preparation method of the in-situ ultrasonic visual controlled-release phase-change immune hydrogel comprises the following steps: preparing sodium alginate solution and aqueous solution of sound-induced droplet phase-change nanoparticles; the sonoliquid drop phase change nanoparticle consists of a shell formed by PLGA and capable of loading hydrophobic drugs and a liquid fluorocarbon core loaded with hydrophilic drugs; and mixing the sodium alginate solution and the acoustic drop phase change nanoparticle aqueous solution according to a certain proportion to obtain a phase change type hydrogel precursor solution. The technical scheme solves the technical problem that the nano drug delivery system is difficult to rapidly transform and apply in clinical work due to low drug loading, abrupt drug release, poor biocompatibility and the like. If the immune medicines such as tranilast and the like are used as functional medicines, the problems of insufficient immune treatment response rate and poor medicine permeability can be solved, and the application prospect is wide.
Description
Technical Field
The invention relates to the technical field of drug controlled release gel, in particular to in-situ ultrasonic visual controlled release phase-change immune hydrogel and a preparation method and application thereof.
Background
The acoustically induced droplet phase transition (Acoustic Droplet Vaporization, ADV) refers to the fact that ultrasonic energy can excite an acoustically responsive droplet from a liquid state into a bubble, increasing the ultrasonic imaging signal. Recent studies have shown that micro-jets can be created, firing shock waves and ejecting fluids using sonoliquid droplet phase transitions. The high-temperature and high-pressure gas generated by the enlargement and collapse of the liquid drops in the vibration process can be used for acoustic hole effect, ultrasonic permeation promotion, ultrasonic thrombolysis, blood brain barrier opening and even direct killing of tumor cells. In recent years, the unique biological function of acoustically induced droplet phase transitions has received extensive attention from researchers. The liquid fluorocarbon nanoparticle is wrapped as a novel molecular probe, can be targeted to a tumor part efficiently, and can be subjected to phase transition and micro-bubble conversion from small to large under the excitation of focused ultrasound, so that the acoustic environment is changed and the drug permeation is promoted. Thus, the use of focused ultrasound and sonophase-change droplets is expected to provide ultrasound-visualized drug delivery to tumors and promote drug penetration.
Chinese patent CN101780285B discloses a thermally enhanced liquid fluorocarbon loaded polymer nano-ultrasound imaging micelle and a preparation method thereof. The scheme synthesizes the liquid fluorocarbon-loaded nano-particles by the following method: vacuum drying hydroxyl-terminated PEG with molecular weight of 2.0-3.0kg/mol under the protection of argon gas for several hours, cooling to room temperature, and then injecting dried lactide and a small amount of stannous octoate; and (3) drying in vacuum at room temperature, adding anhydrous toluene, and carrying out reflux polymerization. And after the reaction is finished, reprecipitating in anhydrous diethyl ether, filtering, dissolving with dichloromethane, reprecipitating in the anhydrous diethyl ether, filtering and vacuum drying to obtain the polymer nano ultrasonic imaging micelle carrier material PEG-PDLLA. And respectively co-dissolving the copolymer PEG-PDLLA and perfluoropentane in carbon tetrachloride, dispersing in an ice bath under the action of ultrasound, and removing the solvent to obtain the thermally enhanced liquid fluorocarbon-loaded polymer nano ultrasonic imaging micelle. The obtained micelle is nano-scale, has narrower particle size distribution, has obvious in-vitro ultrasonic imaging effect and thermal enhancement effect, can be excited into bubbles from liquid state by phase change under the ultrasonic action, and can generate microjet to realize therapeutic effect. However, the nanoparticles in the prior art have the problems of low drug loading rate, repeated drug administration, drug burst release, potential toxicity and the like, and the rapid conversion and application of the nanoparticles in clinical work are hindered. There is a need to develop a novel controlled release system of drugs based on sonoliquid droplet phase transition to achieve the purposes of increasing drug loading, reducing drug toxicity, realizing effective control over drug release, and improving the clinical transformation potential of the controlled release system of drugs.
Disclosure of Invention
The invention aims to provide a preparation method of in-situ ultrasonic visual controlled-release phase-change immune hydrogel, which aims to solve the technical problem that a nano drug delivery system in the prior art is difficult to rapidly transform and apply in clinical work due to low drug loading, abrupt drug release, biocompatibility and the like.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the preparation method of the in-situ ultrasonic visual controlled-release phase-change immune hydrogel comprises the following steps in sequence:
s1: preparing sodium alginate solution and aqueous solution of sound-induced droplet phase-change nanoparticles; the sonoliquid drop phase change nanoparticle consists of a shell formed by a polymer or lipid membrane material and a liquid fluorocarbon core loaded with hydrophilic drugs;
S2: and mixing the sodium alginate solution and the acoustic droplet phase-change nanoparticle aqueous solution to obtain a phase-change hydrogel precursor solution for forming the hydrogel.
The scheme also provides the hydrogel obtained by the preparation method of the in-situ ultrasonic visual controlled-release phase-change immune hydrogel.
The scheme also provides application of the hydrogel obtained by the preparation method of the in-situ ultrasonic visual controlled-release phase-change immune hydrogel in preparing a drug controlled-release system.
The principle of the technical scheme and the beneficial effects are that:
According to the technical scheme, the drug-loaded acoustic phase-change nanoparticles are combined with sodium alginate in-situ gel forming, various tumor therapeutic drugs are loaded into the drug-loaded acoustic phase-change nanoparticles, and the nanoparticles are dispersed into sodium alginate solution for in-situ injection, so that the in-situ ultrasonic visual drug controlled-release phase-change hydrogel is formed. The technical scheme solves the technical problem that the common sonophase transition nano-drug delivery system in the prior art is difficult to rapidly transform and apply in clinical work due to low drug loading, drug burst, biocompatibility and the like. If the immune medicine is used as an efficacy medicine, the technical scheme can further solve the problems of insufficient response rate and poor medicine permeability of the existing clinical immunotherapy.
Sodium alginate is a natural biological macromolecule separated from brown algae, and under the action of calcium and magnesium ions, sodium alginate molecules can be crosslinked to form porous hydrogel with biocompatibility, and is widely used in the fields of drug delivery, food engineering, tissue engineering and the like. In the technical scheme, the in-situ sodium alginate hydrogel is formed by injecting sodium alginate aqueous solution with a certain concentration and utilizing calcium and magnesium ions with in-situ physiological concentration of tumor, so that the drug loading concentration is greatly improved, the drug toxicity is reduced, and the long-term drug slow release can be realized only by single injection. According to the technical scheme, by utilizing the combination of drug-loaded sonophoresis phase-change nanoparticles and sodium alginate in-situ gel forming, a large amount of phase-change materials can be delivered to tumor in-situ, drugs can be released for a long time, ultrasonic observation can be used, and the application safety of the drugs is improved.
In summary, on the basis of the early-stage research of the acoustic phase-change nano-droplets and the immune hydrogel, the phase-change nano-particles containing the functional drugs are loaded by taking the hydrogel generated in situ as a carrier, so that the in-situ ultrasonic drug controlled-release phase-change hydrogel is developed. Under the excitation of low-energy focused ultrasound, the nanoparticles undergo acoustic phase transition, and the controlled release of the functional drugs and the tumor elimination are visualized. If the functional medicine is an immune medicine (such as TGF-beta inhibitor tranilast), the technical scheme can improve immune microenvironment, normalize tumor blood vessels, enhance oxygen supply, increase the permeability and curative effect of an immune checkpoint blocker in tumors, thoroughly eliminate residual cancers and inhibit recurrence and metastasis, and provides a novel strategy for exploring high-efficiency, safe and accurate tumor treatment for the treatment of breast cancers and the like.
Further, in S1, the functional drug includes at least one of tranilast, imiquimod, resiquimod, cpG oligodeoxynucleotide, lipopolysaccharide, 1-methyltryptophan, doxorubicin, gemcitabine, and paclitaxel.
Further, in S1, the liquid fluorocarbon core material includes at least one of perfluoropropane, perfluoropentane, perfluorohexane, and perfluorobromooctane; the raw materials of the membrane material comprise polylactic acid-glycolic acid copolymer and/or phospholipid material; the phospholipid material comprises at least one of DPPA, DPPC, DPPG, DSPE, DSPE-PEG and DSPG.
The hydrogel of the present embodiment may be loaded with drugs including, but not limited to, tranilast (TRANILAST), imiquimod (R837), resiquimod (R848), cpG oligodeoxynucleotides (CpG-ODN), lipopolysaccharide (LPS), 1-methyltryptophan (1-MT), and common chemotherapeutic drugs (doxorubicin, gemcitabine, paclitaxel), and the like. The perfluoropentane, perfluorohexane, perfluorobromooctane and the like are phase-change materials commonly used in the field, and the polylactic acid-glycolic acid copolymer, liposome and the like are membrane materials commonly used in a nano drug presentation system, and can be used in the preparation of the in-situ ultrasonic visual controlled-release phase-change immune hydrogel in the scheme.
The hydrogel of the technical scheme is particularly suitable for the slow release treatment of immune medicines for tumors or other diseases. Immunotherapy, which is a treatment method that kills tumor cells using the autoimmune system, has shown great potential in preventing tumor recurrence and distant metastasis. Taking an immune checkpoint as an example, the related research and clinical use of antibodies (anti-PD-1/PD-L1) against apoptosis protein 1 and its ligand or antibodies (anti-CTLA-4) against toxic T lymphocyte-associated protein 4 are changing the treatment outcome of tumor patients and are expected to expand and apply to different tumor types. However, studies have shown that the clinical response rate of immune checkpoint therapy is still inadequate, with only 15% of tumor patients benefiting from immune checkpoint therapy. Therefore, there is a need to find new therapeutic approaches to maximize the clinical efficacy of immune checkpoints. The hypoperfusion, hypoxia and immunosuppressive microenvironment of solid tumors are important factors that are difficult to play in immunotherapy. Immune drugs are difficult to penetrate uniformly within the tumor due to its low perfusion, often resulting in tumor remnants and long-term recurrence. In addition, the hypoxia microenvironment induced by tumor hypopriming can induce immunosuppression, such as inhibiting polarization of macrophages to the M1 direction, promoting tumor cell immune checkpoint expression, preventing related antigen presentation and immune cell activation, and the like, and affecting various links of immunotherapy. The hydrogel adopting the technical scheme can promote the uniform permeation of immune medicines and other anti-tumor medicines at tumor cells, improve the tumor treatment effect and avoid tumor recurrence and metastasis.
Among the above drugs, tranilast is an anti-allergic drug of TGF-beta inhibitor approved clinically, and researches show that tranilast can improve the tumor perfusion level, normalize tumor stroma and repair the abnormality of tumor blood vessels, thereby recovering tumor perfusion and oxygenation, and improving the immune check point curative effect and anti-tumor immune treatment effect. How to deliver tranilast safely and efficiently as a hydrophobic drug remains a challenge. The hydrogel adopting the technical scheme can promote the presentation amount of tranilast at the affected part, and can stimulate the drug release according to the actual needs, thereby realizing the safe and efficient delivery of the drug.
Further, in S1, the liquid fluorocarbon is perfluoropentane.
Further, in the phase-change hydrogel precursor solution of S2, the concentration of sodium alginate is 5mg/mL-40mg/mL, the concentration of the sonoliquid drop phase-change nanoparticles is less than or equal to 10mg/mL, and is more than 0mg/mL.
Further, in S1, the sonoliquid droplet phase change nanoparticle is prepared by the following method: dissolving a functional medicine in dichloromethane to obtain a solution B; adding perfluoropentane into the solution B, and obtaining a solution C after acoustic shock treatment; adding PVA solution into the solution C, and obtaining solution D after acoustic shock treatment; adding an isopropanol solution into the solution D, and stirring to obtain a solution E; and (3) centrifuging the solution E, discarding the supernatant to obtain nanoparticles, rinsing the nanoparticles with water, and re-suspending the nanoparticles with water to obtain an aqueous solution of the sonoliquid droplet phase-change nanoparticles.
Further, in S2, the volume ratio of the sodium alginate solution to the aqueous solution of the sound-induced droplet phase-change nanoparticles is 3:2-4:1; when the phase-change hydrogel precursor solution is prepared, the sonoliquid droplet phase-change nanoparticles are added into the sodium alginate solution, and then stirred at 200rpm for 5-10min.
Further, the hydrogel comprises a gel skeleton formed by sodium alginate and sonoliquid drop phase-change nanoparticles attached to the skeleton; the hydrogel is formed by solidifying a phase-change hydrogel precursor solution after being injected into a body.
Further, the drug controlled release system is used for releasing the functional drugs under the excitation of low-energy focused ultrasound; the hydrogel is formed in situ in the living body from a phase-change hydrogel precursor solution, and the phase-change hydrogel precursor solution is free of a cross-linking agent.
To sum up, the beneficial effects of this technical scheme lie in:
The in-situ ultrasonic visual controlled-release phase-change hydrogel provided by the invention has the remarkable advantages of in-situ synthesis, high-efficiency load, simple synthesis, ultrasonic visual drug controlled-release and the like. The tranilast-loaded phase-change type ultra-sound controlled release immune hydrogel prepared by the method has the capabilities of both medicine space-time controlled release and synergistic immune checkpoint therapy. Local ultrasonic visualization tranilast controlled release is performed by utilizing the acoustic drop phase transition and hydrogel in-situ gel forming effects, so that the immunosuppression microenvironment of tumors is improved, the normalization of blood vessels of residual cancer tumors is promoted, the perfusion and oxygenation of the tumors are improved, the permeation of anti-PD-1/PD-L1 antibodies at tumor positions is promoted, immune checkpoint therapy is enhanced, the tumor is prevented from recrudescence and metastasis, and a novel strategy for efficient, safe and economic postoperative recrudescence treatment is explored. In addition, the system can freely adjust various parameters such as the fluidity of the hydrogel, the dosage of the drug, the type of the drug and the like, and has good universality. In a word, the in-situ ultrasonic visual controlled-release phase-change immune hydrogel provided by the invention establishes an in-situ ultrasonic visual drug controlled-release system, realizes the time and space dual controlled release of the hydrophobic drug tranilast, and provides a new idea for local visual delivery of the drug and synergistic immune check point treatment.
Drawings
Fig. 1 is a physical diagram of an in situ ultrasound visualized controlled release phase-change type immune hydrogel.
FIG. 2 is a cryoscanning electron microscope image of in situ ultrasound visualization controlled release phase-change immune hydrogel.
Fig. 3 is an in vitro gel formation verification result image of in situ ultrasound visualization controlled release phase change type immune hydrogel.
Fig. 4 is an in vivo gel formation verification result image of in situ ultrasound visualization controlled release phase change type immune hydrogel.
Fig. 5 is an ultrasound image of in situ ultrasound visualized controlled release phase change immune hydrogels.
FIG. 6 is a cumulative drug release profile of an in situ ultrasound visualized controlled release phase change immune hydrogel.
Fig. 7 is an experimental result of the effect of the mixing speed of comparative example 1 on the state of solution G.
FIG. 8 is the experimental result of the influence of sodium alginate concentration of comparative example 2 on the gelling effect.
FIG. 9 is an experimental result of the effect of the concentration of the phase-change nanoparticles of comparative example 3 on the G state of the solution.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. Unless otherwise indicated, the technical means used in the following examples and experimental examples are conventional means well known to those skilled in the art, and the materials, reagents and the like used are all commercially available.
Example 1
The phase-change type immune hydrogel for in-situ ultrasonic visualization controlled release is prepared by the following method:
100mg of sodium alginate powder was stirred in 3mL of pure water until it was sufficiently dissolved to obtain solution A (sodium alginate solution), which was stored at 4 ℃. 2mg of tranilast and 50mg of PLGA (Jinan Dai, SJ10202, PLGA-COOH,1.2 ten thousand molecular weight) were dissolved in 2mL of methylene chloride, and the dissolution was promoted during the dissolution using conventional ultrasonic treatment, to obtain solution B. Under ice bath conditions, 200 μl of perfluoropentane was added, and the system was emulsified with a conventional sonicator (40% intensity, 50% duty cycle, 5s on,5s off) for 3min to give solution C. 8mL of a 4% PVA solution was added to the solution C, and the mixture was again emulsified for 3 minutes using a sonicator (35%, 50% duty; 5s on,5s off) to give a solution D. 10mL of 2% isopropyl alcohol solution was added to the solution D, and the mixture was magnetically stirred under ice bath conditions for 4 to 6 hours (specifically 5 hours were used in this example) to obtain a solution E. Centrifuging the solution E at 10000rpm and 4 ℃ for 8min, discarding the supernatant, re-dissolving and rinsing with pure water, repeating the rinsing for three times, re-dissolving with 2mL of ultra-pure water to obtain solution F (acoustic droplet phase-change nanoparticle aqueous solution), and preserving at 4 ℃ (needing to be used as soon as possible). The concentration of nanoparticles in solution F may be determined based on the effective concentration of the drug, in this example, a concentration of nanoparticles of about 10mg/mL (in solution G) is used based on the effective concentration.
When in use, the solution A and the solution F are gently stirred and mixed uniformly by magnetic force under the ice bath condition according to the volume ratio of 3:2, so as to obtain the solution G (phase-change hydrogel precursor solution), and the solution G is stored at 4 ℃ and is injected in situ when in use. In the process of mixing the solution A and the solution F, the rotating speed of magnetic stirring is maintained at about 200rpm, and the stirring time is 5-10min. Before stirring and mixing, the solution F needs to be dripped into the solution A, and the reverse dripping can cause the phase change of the nano particles, so that a large number of bubbles appear, and the subsequent in-situ drug release effect is affected. The results of the gel forming ability, ultrasonic imaging effect and in vitro drug release ability experiments are shown in figures 3-6.
The inventors have tried the following way: solution a and solution F were prepared in the manner described in example 1, and when the two solutions were mixed to form solution G, solution a (sodium alginate) was slowly added to solution F (TPP NPs) and the addition was ensured as much as possible to ensure that all of solution a was added to solution F. Then, the mixture was magnetically stirred at 200rpm for 10 minutes to form a solution G. In this process, the inventors found that the above-described material mixing sequence resulted in generation of a large amount of bubbles during the stirring treatment of the solution G, and that the nanoparticles in the finally formed solution G were subjected to a large amount of phase transition, with the presence of many bubbles (similar to the state of the solution G at 1000rpm of fig. 7). After the occurrence of the above phenomenon, the inventors analyzed that the cause of the excessive air bubbles may be that the stirring speed of 200rpm was excessively high, and the stirring speed was randomly adjusted to 100rpm, and repeated the above experiment. As a result, it was found that the phase change of the nanoparticles in the solution G was still not improved, and more bubbles were still present in the solution G, which may affect the in situ gel formation and drug release effects. In addition, the materials are not fully and uniformly mixed due to the too low rotating speed, the morphology of the solution G is not uniform, and obvious layering phenomenon occurs after the solution G is placed for 4 hours. The above attempts indicate that the mixing sequence of solution a and solution F is critical to inhibiting the phase transition of nanoparticles in advance, and that in the case of incorrect mixing sequence, the phase transition of nanoparticles still cannot be effectively avoided by only reducing the rotation speed. The gel preparation of the scheme can realize in-situ ultrasonic visual controlled release of the gel only by solving the problem of incompatibility of sodium alginate and nano particles during mixing. The inventor finds that the above problems can be overcome by adjusting the mixing sequence of the solution A and the solution F through a large amount of experimental researches. When the solution G is prepared, the solution F (TPP NPs) is slowly added into the solution A (sodium alginate), and a phase-change hydrogel precursor solution (solution G) with uniform and stable morphology can be formed under the rotating speed condition of 200rpm, so that the phase-change immune hydrogel with in-situ ultrasonic visualization and controlled release as shown in the embodiment 1 is obtained. It can be seen that the mixing sequence of solution a and solution F has an important impact on the implementation of the present solution, and unexpected technical effects are obtained.
Example 2
This example is basically the same as example 1, except that the amount of sodium alginate is adjusted to 60mg and the volume ratio of solution A to solution F is adjusted to 4:1. The in situ ultrasound visualized controlled release precursor solution prepared in this example showed an appearance consistent with typical results (see fig. 1), and the precursor solution exhibited a morphology similar to that of fig. 2 under a cryo-scanning electron microscope after gelling. And the precursor solution of this example showed gel forming ability, ultrasonic imaging effect and in vitro drug releasing ability similar to those of example 1.
Example 3
This example is substantially the same as example 1, except that tranilast is replaced with doxorubicin in an equivalent amount. The in situ ultrasound visualized controlled release precursor solution prepared in this example showed an appearance consistent with typical results (see fig. 1), and the precursor solution exhibited a morphology similar to that of fig. 2 under a cryo-scanning electron microscope after gelling. And the precursor solution of this example showed gel forming ability, ultrasonic imaging effect and in vitro drug releasing ability similar to those of example 1.
Example 4
This example is substantially the same as example 1, except that tranilast is replaced with an immunostimulant R837 in an equivalent amount. The in situ ultrasound visualized controlled release precursor solution prepared in this example showed an appearance consistent with typical results (see fig. 1), and the precursor solution exhibited a morphology similar to that of fig. 2 under a cryo-scanning electron microscope after gelling. And the precursor solution of this example showed gel forming ability, ultrasonic imaging effect and in vitro drug releasing ability similar to those of example 1.
Example 5
This example is substantially the same as example 1, except that tranilast is replaced with an immunostimulant R848 in an equivalent amount. The in situ ultrasound visualized controlled release precursor solution prepared in this example showed an appearance consistent with typical results (see fig. 1), and the precursor solution exhibited a morphology similar to that of fig. 2 under a cryo-scanning electron microscope after gelling. And the precursor solution of this example showed gel forming ability, ultrasonic imaging effect and in vitro drug releasing ability similar to those of example 1.
Example 6
This example is essentially the same as example 1, except that tranilast is replaced with an immunostimulatory agent CpG oligodeoxynucleotide (CpG-ODN) in an equivalent amount. The in situ ultrasound visualized controlled release precursor solution prepared in this example showed an appearance consistent with typical results (see fig. 1), and the precursor solution exhibited a morphology similar to that of fig. 2 under a cryo-scanning electron microscope after gelling. And the precursor solution of this example showed gel forming ability, ultrasonic imaging effect and in vitro drug releasing ability similar to those of example 1.
The in-situ ultrasonic visualization controlled release phase-change hydrogel precursor solution (namely solution G) is taken for visual observation, the typical result is shown in fig. 1, sodium alginate solution (ALG), acoustic drop phase-change nanoparticle aqueous solution (TPP NPs) and mixed solution (phase-change hydrogel precursor solution, TPP ALG) formed by the two solutions in a certain proportion are shown in the figure, and the three solutions are uniform and stable in appearance.
Typical results of cryoscanning electron microscopy of hydrogels of the present protocol are shown in fig. 2, which is a cryoscanning electron microscopy of in situ ultrasound-visualized controlled release phase-change hydrogels, showing porous network structures inside the gel and nanoparticles therein. Frozen scanning electron microscopy experimental reference (10.1002/adfm.2016670071): a physiologically concentrated calcium-magnesium mixture (1.8 mM Ca 2+、1.5mM Mg2+) was prepared, and 1mL of solution G was injected into 30mL of the calcium-magnesium mixture, followed by filtering the hydrogel out using filter paper, and scanning by cryoelectron microscopy was performed.
Fig. 3 is an in vitro gel formation verification experiment result of in situ ultrasonic visualization controlled release phase-change immune hydrogel, which shows that the phase-change hydrogel can stably form gel in vitro. The upper left image of fig. 3 shows the process of injecting 1mL of an aqueous solution of sonoliquid droplet phase-change nanoparticles (TPP NPs) into 30mL of calcium-magnesium solution, and the lower left image shows the gel formation, and the sonoliquid droplet phase-change nanoparticle drug alone is prone to leakage and is rapidly absorbed and unable to stay in the target area for a long period of time. The upper graph in fig. 3 shows the procedure of injecting 1mL of the phase-change hydrogel precursor solution (i.e., solution G) into 30mL of calcium-magnesium solution, and the lower graph shows the gel formation, using the phase-change hydrogel precursor solution, in vitro. The upper right and lower right of fig. 3 shows the appearance of the gel formed.
Fig. 4 is an in vivo gel formation verification experiment result of the in situ ultrasonic visualization controlled release phase-change type immune hydrogel, which shows that the phase-change type hydrogel can stably form gel in vivo. The mice were subcutaneously injected with 0.1mL of an acoustic droplet phase change nanoparticle aqueous solution (TPP NPs) and 0.1mL of a phase change hydrogel precursor solution (TPP ALG), and after 1h, 24h, 48h and 7 days, gel formation was observed. The sonoliquid drop phase-change nano particles are quickly leaked and dispersed in surrounding tissues after injection, and cannot be fixed in a target area, and the phase-change hydrogel precursor solution quickly forms hydrogel gel after injection, so that the medicine is fixed in a handle area, and the gel state is still maintained within 7 days.
Fig. 5 is a graph of in-vivo ultrasound imaging effects of in-situ ultrasound visualization controlled release, with significant enhancement of ultrasound contrast signals using low energy focused ultrasound. The specific experimental process is as follows: the mice were subcutaneously injected with 0.1mL of aqueous sodium Alginate (ALG), 0.1mL tranilast PLGA ALG solution (non-phase-change hydrogel precursor solution, TP ALG) (equal amount of double distilled water was used instead of PFP) and 0.1mL of phase-change hydrogel precursor solution (TPP ALG), immediately subjected to ultrasound contrast signal observation, and then irradiated with low-energy focused ultrasound (LIFU, 4W) for 180s, before and after excitation of three materials LIFU for ALG/TP ALG/TPP ALG, respectively subjected to B-mode (left side) and ultrasound contrast imaging (CEUS, right side) observation.
Before the above in vivo experiments were carried out, according to the conventional knowledge of the prior art, the inventors predicted that it was difficult to effectively form gel in the living body and controlled release of the drug was difficult to achieve due to the low calcium magnesium concentration of physiological concentration and the presence of certain fluctuation. Thus, the inventors first tried to inject subcutaneously into mice after forming injectable hydrogels in vitro by adding a certain amount of calcium and magnesium ions to the phase-change hydrogel precursor solution (TPP ALG, solution G). Hydrogel-forming re-injection is a conventional procedure employed in the prior art for combinations of hydrogels and nanoparticles. However, for the material of the scheme, the nanoparticles are very easy to change phase by adopting the mode, gel crosslinking is uneven, and the uniform drug release in the body cannot be controlled. As a result of the above-described failed attempts, the inventors have further tried to directly inject a phase-change hydrogel precursor solution (TPP ALG) without any crosslinking agent (e.g., calcium magnesium ions) into the subcutaneous of the mouse, and as a result, unexpectedly found that in situ gel-forming TPP ALG prepared using a physiological concentration of calcium magnesium ions can uniformly and stably fix drug-loaded phase-change nanoparticles to a target region and can monitor drug release behavior using ultrasound visualization.
Fig. 6 is a cumulative drug release profile (arrows are low-energy focused ultrasound excitation) of an in-situ ultrasound visualized controlled-release phase-change immune hydrogel, and the results show that the low-energy focused ultrasound can obviously stimulate drug release. The specific experimental process is as follows: 3mL of the phase-change hydrogel precursor solution (i.e., solution G) was injected into 30mL of an aqueous solution of ethanol (30%) containing calcium (1.8 mM), magnesium (1.5 mM) and Tween-80 (0.01%), and the solution G immediately gelled, followed by in vitro drug release experiments. Performing low-energy focused ultrasound excitation, namely low-energy focused ultrasound (LIFU, 4 w), on an experimental group (repetition) at a designated time point for 180 seconds, and then detecting the release amount of the medicine tranilast by an ultraviolet method and calculating the accumulated release rate; for the control group (control), only the ultrasonic probe was placed without using low-energy focused ultrasonic excitation, the release amount of tranilast drug was directly detected at a designated time point and the release rate was calculated. Cumulative drug release profile experiments were set up with 3 replicates at each time point, error bars in the figure being Standard Deviation (SD).
Comparative example 1
Referring to example 1, the mixing conditions of the solution a and the solution F were studied, and the experimental results are shown in fig. 7. At 1000rpm for 5min, a large number of dense bubbles were visible in the TPP ALG. This indicates that at high rotational speeds, TPP NPs are prone to phase changes. There was still a small amount of bubbles at 600rpm for 5min, and 200rpm for 5min could uniformly disperse TPP NPs without significant bubbles, so the present solution used a 200rpm speed to mix solution A and solution F.
In addition, the inventors adjusted the stirring rotation speed to 100rpm on the basis of example 1. Because the rotating speed is too low, the materials are not fully and uniformly mixed, the morphology of the phase-change hydrogel precursor solution (solution G) is not uniform, and after the phase-change hydrogel precursor solution is placed for 4 hours, obvious layering phenomenon appears, which indicates that the stability of the solution G is poor due to the too low rotating speed.
Comparative example 2
With reference to example 1, the concentration of sodium alginate in solution G (TPP ALG) was explored. TPP ALG 1mL (TPP NPs concentration is fixed to 5 mg/mL) with ALG concentration of 5-20mg/mL is injected into a solution (Ca 2+1.8mM,Mg2+ 1.5.5 mM) simulating physiological calcium magnesium concentration of 50mL, and the strength of the formed hydrogel is better and the injection quantity and direction are easier to control along with the rising of the ALG concentration (see FIG. 8). In the practical application process, the concentration of sodium alginate in the solution A can be 15mg/3mL-200mg/3mL, and the concentration of sodium alginate in the solution G can be 5-40mg/mL. The technical scheme preferably adopts the concentration of sodium alginate of 16-25mg/mL (in the solution G) to fully ensure the solution G to stably form gel.
Comparative example 3
Referring to example 1, the concentration of nanoparticles (TPP NPs) in solution G (TPP ALG) was explored. The concentration of TPP NPs is adjusted according to the effective dose of the actual medicine, and in 0-10mg/mL (the final concentration in solution G), the sodium alginate solution and the nano particles can form uniform mixed solution (see figure 9), so that the gel is realized. 10mg/mL is the maximum concentration of TPP NPs beyond which it is difficult to disperse TPP NPs. The loading capacity of TPP NPs in the solution G of the gel prepared according to the technical scheme can be between 0 and 10mg/mL, and the gel can realize effective gel formation and drug release control. The method shows that the loading of the TPP NPs after gel formation can be changed in a relatively large range, and a user can adjust the loading of the TPP NPs in the range according to actual requirements, so that the method has relatively large freedom.
The foregoing is merely exemplary of the present application, and specific technical solutions and/or features that are well known in the art have not been described in detail herein. It should be noted that, for those skilled in the art, several variations and modifications can be made without departing from the technical solution of the present application, and these should also be regarded as the protection scope of the present application, which does not affect the effect of the implementation of the present application and the practical applicability of the patent. The protection scope of the present application is subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.
Claims (8)
1. The preparation method of the in-situ ultrasonic visual controlled-release phase-change immune hydrogel is characterized by comprising the following steps of: the method comprises the following steps of:
S1: preparing sodium alginate solution and aqueous solution of sound-induced droplet phase-change nanoparticles;
The sonoliquid drop phase change nanoparticle consists of a shell formed by a membrane material and a liquid fluorocarbon core loaded with functional drugs;
the raw materials of the membrane material comprise polylactic acid-glycolic acid copolymer;
the functional medicine comprises at least one of tranilast, imiquimod, resiquimod, cpG oligodeoxynucleotide, lipopolysaccharide, 1-methyl tryptophan, doxorubicin, gemcitabine and paclitaxel;
The liquid fluorocarbon core comprises perfluoropentane as a raw material;
S2: mixing sodium alginate solution and acoustic droplet phase-change nanoparticle aqueous solution to obtain phase-change hydrogel precursor solution for forming hydrogel; when the phase-change hydrogel precursor solution is prepared, the sonoliquid droplet phase-change nanoparticles are added into the sodium alginate solution, and then stirred at 200rpm for 5-10min.
2. The method for preparing the in-situ ultrasonic visual controlled release phase-change immune hydrogel, which is characterized by comprising the following steps of: in S1, the sonoliquid droplet phase change nanoparticle is prepared by the following method: dissolving the functional medicine and the membrane material in dichloromethane to obtain solution B; adding perfluoropentane into the solution B, and obtaining a solution C after acoustic shock treatment; adding PVA solution into the solution C, and obtaining solution D after acoustic shock treatment; adding an isopropanol solution into the solution D, and stirring to obtain a solution E; and (3) centrifuging the solution E, discarding the supernatant to obtain nanoparticles, rinsing the nanoparticles with water, and re-suspending the nanoparticles with water to obtain an aqueous solution of the sonoliquid droplet phase-change nanoparticles.
3. The method for preparing the in-situ ultrasonic visual controlled release phase-change immune hydrogel, which is characterized by comprising the following steps of: in the phase-change hydrogel precursor solution of S2, the concentration of sodium alginate is 5 mg/mL-40 mg/mL, the concentration of the sonoliquid drop phase-change nanoparticles is less than or equal to 10mg/mL, and is more than 0 mg/mL.
4. The method for preparing the in-situ ultrasonic visual controlled release phase-change immune hydrogel according to claim 3, which is characterized in that: in S2, the volume ratio of the sodium alginate solution to the aqueous solution of the sound-induced droplet phase-change nanoparticles is 3:2-4:1.
5. A hydrogel obtainable by the method of preparing an in situ ultrasound visualized controlled release phase-change immune hydrogel according to any one of claims 1 to 4.
6. The hydrogel obtained by the method for preparing the in-situ ultrasonic visual controlled release phase-change immune hydrogel, which is characterized in that: the hydrogel comprises a gel skeleton formed by sodium alginate, and sound-induced liquid drop phase-change nanoparticles attached to the skeleton; the hydrogel is formed by solidifying a phase-change hydrogel precursor solution after being injected into a body.
7. The use of a hydrogel obtained by the method for preparing an in situ ultrasound visualized controlled release phase-change immune hydrogel according to claim 5 or 6 in the preparation of a drug controlled release system.
8. The application of the hydrogel obtained by the preparation method of the in-situ ultrasonic visual controlled-release phase-change immune hydrogel in preparing a drug controlled-release system, which is characterized in that: the medicine controlled release system is used for releasing functional medicines under the excitation of low-energy focused ultrasound; the hydrogel is formed in situ in the living body from a phase-change hydrogel precursor solution, and the phase-change hydrogel precursor solution is free of a cross-linking agent.
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