CN108653754B - Hyaluronic acid targeted polydopamine coated phase-change type liquid fluorocarbon nano ultrasonic contrast agent - Google Patents
Hyaluronic acid targeted polydopamine coated phase-change type liquid fluorocarbon nano ultrasonic contrast agent Download PDFInfo
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- CN108653754B CN108653754B CN201810737446.0A CN201810737446A CN108653754B CN 108653754 B CN108653754 B CN 108653754B CN 201810737446 A CN201810737446 A CN 201810737446A CN 108653754 B CN108653754 B CN 108653754B
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- hyaluronic acid
- contrast agent
- liquid fluorocarbon
- polydopamine
- ultrasonic contrast
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Abstract
The invention discloses a hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent. The particle size of the hyaluronic acid targeting polydopamine coated phase change type liquid fluorocarbon nano ultrasonic contrast agent prepared by a film-emulsification method and an oxidation polymerization method is about 248.08nm, and in vitro experiments show that the hyaluronic acid targeting polydopamine coated phase change type liquid fluorocarbon nano ultrasonic contrast agent has good stability. Cytological experiments show that the biocompatibility of the hyaluronic acid targeting polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent is good. In vivo experiments show that the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent has a good ultrasonic imaging effect. Meanwhile, the combined application of the photothermal therapy and the chemotherapy shows good tumor inhibition effect. The hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent prepared by the invention has the advantages of simple and convenient process, good biocompatibility of the used materials and wide application prospect.
Description
Technical Field
The invention relates to the field of medical drugs, in particular to a hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent and a preparation method thereof.
Background
In clinical practice, diagnosis and treatment of disease are two relatively independent processes. However, the separate use of contrast medium and drug in the diagnosis process can lead to the superposition of side effects, increase the pain of patients in drug administration and the like. Therefore, theranostics (theranostics) are gradually developing as a new concept under the combined efforts of clinicians and researchers. Theranostics is a means of combining medication with diagnosis, and under the condition of primary diagnosis, diagnosis and treatment are realized in real time by using a theranostic agent (theranostic agent) so as to enhance the treatment effect and reduce the toxic and side effects on a human body, thereby achieving the effect of achieving twice the result with half the effort. The used theranostic reagent (theranostic agent) carries chemotherapeutic drugs and has a developing imaging function, so that the theranostic reagent has the unique advantages of diagnosing the disease condition in real time and synchronously treating the disease condition, and becomes a new strategy for treating cancers.
Microbubbles have good echogenic effects, and some microbubbles have been approved clinically for use as ultrasound contrast agents, but their excessive particle size and poor stability limit their use in ultrasound contrast. In recent years, in order to solve the problems of too large particle size, poor stability and the like of the ultrasonic microbubbles, nanoscale phase-changeable liquid fluorocarbon nanoparticles are developed. The phase-change liquid fluorocarbon nanoparticles have small particle size and can pass through vascular endothelial cells to reach extravascular targets through the EPR effect or active targeting; compared with microbubbles, the microbubble has better stability, and can generate liquid-gas phase change under external conditions such as focused ultrasound, laser and heating conditions to realize ultrasonic imaging. Although the phase-change liquid fluorocarbon nanoparticles have many advantages, the phase-change liquid fluorocarbon nanoparticles still have the problem of low stability, and according to literature reports, the phase-change liquid fluorocarbon nanoparticles can generate liquid-gas phase change in the storage process; upon entering the systemic circulation, a premature phase change occurs before the target site is reached. Therefore, it is required to prepare a phase-change ultrasound contrast agent with a more stable particle size in the nanometer range.
Photothermal therapy (PTT) is a minimally invasive tumor therapy technology developed in recent years, and mainly kills tumor cells by directly irradiating light energy to a tumor part to increase local temperature of the tumor part, so that systemic toxicity of the whole body is greatly reduced. The materials reported to date for photothermal therapy are mainly inorganic materials (nanoshells, gold nanorods, gold nanocages, copper nanoparticles)]Etc.) and organic polymer materials (polypyrrole, polyaniline, polydopamine, etc.) and near-infrared absorbing small-molecule organic dyes.
Polydopamine is a synthetic polymer inspired by foot adhesion proteins secreted by mussels. Mussel foot adhesion protein is rich in 3, 4-dihydroxy-L-phenylalanine and lysine, which in addition to participating in the bulk curing reaction of the adhesive, 3, 4-dihydroxy-L-phenylalanine can form strong covalent and non-covalent bonds with the substrate. In further studies it was found that the catechol on 3, 4-dihydroxy-L-phenylalanine and the amino group on lysine are critical for adhesion, while dopamine has both common functional groups and in a typical seawater environment, dopamine spontaneously forms polydopamine with adhesions similar to that of adhesion proteins. Polydopamine has good biocompatibility and very low long-term cytotoxicity.
Meanwhile, polydopamine is also a good photothermal therapeutic agent, has higher photothermal conversion efficiency and light stability in the near infrared region, and has been used for photothermal therapy of tumors, but the tumor killing by pure photothermal therapy is limited, and if the polydopamine is combined with chemotherapy, the chemotherapy can enhance the curative effect of photothermal therapy by killing residual tumor cells in a targeted manner or inhibiting damaged tumor blood vessels, so that a new choice is hopefully provided for the treatment of tumors.
Targeted drug delivery systems are one of the hotspots in the field of pharmaceutical research. The targeted drug delivery can selectively deliver the drug to a target position, thereby increasing the curative effect and reducing the toxic and side effects of the drug on normal tissues. Hyaluronic Acid (HA) is a linear high molecular weight glycosaminoglycan made from N-acetyl-D-glucosamine and D-glucuronic acid linked by beta-1, 4 glycosidic bonds. When the molecular weight of the hyaluronic acid is between 20 and 30w, the hyaluronic acid can be generally used as a targeting ligand, is mediated by a CD44 receptor, forms a pit to be taken up by cells, is combined with a lysosome to be taken up by the cells, and releases a medicament in the cells to achieve a therapeutic effect. In addition, HA HAs the advantages of excellent water solubility and biocompatibility, biodegradability, no toxicity, no immunogenicity, good chemical stability, easy chemical modification and the like.
The research designs and prepares a novel polydopamine-coated phase-change liquid fluorocarbon nano ultrasonic contrast agent with a hyaluronic acid targeting function. Firstly, perfluorohexane and an anti-tumor chemotherapeutic drug docetaxel are prepared into phospholipid liquid fluorocarbon nanoparticles, then a layer of poly-dopamine shell with photothermal effect is wrapped outside the phospholipid liquid fluorocarbon nanoparticles, and hyaluronic acid molecules with tumor active targeting function are modified on the shell to finally obtain the hyaluronic acid targeted poly-dopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent. The contrast agent has the characteristics of photothermal therapy, chemotherapy and active targeting mediated by hyaluronic acid and an ultrasonic imaging function, and the used materials are economical, have good biocompatibility and have wide clinical application prospects.
Disclosure of Invention
The invention aims to provide a novel preparation method of a phase-change type nano ultrasonic contrast agent integrating hyaluronic acid targeting with photothermal and chemotherapy, aiming at the problems that phospholipid liquid fluorocarbon nanoparticles are poor in stability as an ultrasonic contrast agent, liquid fluorocarbon nanoparticles wrapped by the existing photothermal material are poor in biodegradability, and the process for modifying active targeting ligands is complex. The novel liquid-carrying medicine-vapor phase modification nanoparticle is small in particle size, and can realize passive targeting through the EPR effect of a tumor part. Meanwhile, the modified hyaluronic acid can realize active targeting on tumor cells, reduce the toxic and side effects of the preparation and enhance the therapeutic effect of the medicine. On the other hand, compared with phospholipid liquid fluorocarbon nanoparticles, the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent prepared by the invention has good stability and a durable ultrasonic contrast effect. The hyaluronic acid targeting polydopamine coated phase-change liquid fluorocarbon nano-ultrasonic contrast agent prepared by a film-emulsification method and an oxidative polymerization method has the advantages of simple and convenient process, economic materials, good biocompatibility and wide clinical application prospect.
The purpose of the invention can be realized by the following technical scheme:
step 1: weighing a proper amount of soybean lecithin and a medicine, dissolving the soybean lecithin and the medicine in dichloromethane, removing the dichloromethane through reduced pressure rotary evaporation to obtain a uniform lipid membrane, then adding a certain amount of Tris buffer solution, and shaking or ultrasonically separating the membrane to obtain a lipid suspension.
Step 2: and (2) carrying out ultrasonic treatment on the lipid suspension obtained in the step (1) for 10min by using an ultrasonic cell disruption instrument for two times to obtain a liposome, and cooling the liposome at 4 ℃.
And step 3: and (3) adding a certain amount of liquid fluorocarbon into the liposome obtained in the step (2), and carrying out ultrasonic treatment by using an ultrasonic cell disruption instrument under the condition of ice-water bath to obtain the liquid fluorocarbon nanoparticles carrying the phospholipid.
And 4, step 4: and (3) dispersing the drug-loaded phospholipid liquid fluorocarbon nanoparticles obtained in the step (3) in a certain amount of Tris buffer solution, enabling the pH value to be alkalescent, adding a proper amount of polyvinylpyrrolidone (PVP) dissolved in the Tris buffer solution and a small amount of ferric trichloride solution, stirring and uniformly mixing, adding a proper amount of dopamine hydrochloride and hyaluronic acid dissolved in the Tris buffer solution, stirring and reacting in an ice-water bath for 12 hours, centrifuging, removing the drug and the polydopamine nanoparticles which are not coated, washing the precipitate with water, and dispersing in the water to obtain the polydopamine-coated phospholipid liquid fluorocarbon nano suspension.
The invention successfully prepares the hyaluronic acid targeted polydopamine coated phase change type liquid fluorocarbon nano ultrasonic contrast agent by using a film-emulsification method and an oxidative polymerization method, and the contrast agent has the advantages of simple synthesis process, less time consumption, good biocompatibility and high specific combination.
Drawings
Fig. 1 is an electron microscope image of the hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent in example 1 of the present invention.
Fig. 2 is a particle size distribution diagram of the hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent in example 1 of the present invention.
Fig. 3 is an infrared spectrum absorption chart of the hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent in example 1 of the present invention.
Fig. 4 is an in vitro stability investigation diagram of the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasound contrast agent in embodiment 2 of the invention.
Fig. 5 is an in vitro photothermal conversion diagram and a thermal stability investigation diagram of the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasound contrast agent in example 2 of the present invention.
Fig. 6 is a graph of in vitro accumulation and release of the hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent in example 2 of the present invention.
Fig. 7 is an experimental cell viability diagram of a hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasound contrast agent MTT in example 2 of the present invention.
Fig. 8 is an in vivo development image of the hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent in example 2 of the present invention.
Fig. 9 is a study of the anti-tumor effect of the hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent in example 2 of the present invention.
Detailed Description
The present invention will be described in detail below with reference to the embodiments shown in the drawings, but the present invention is not limited to the embodiments.
Example 1
1. Preparation of phospholipid liquid fluorocarbon nanoparticles
20mg of soybean lecithin (SPC) and 2mg of the drug were dissolved in 4mL of dichloromethane. Methylene chloride was rapidly removed by evaporation under reduced pressure to form a lipid film. After 2mL of Tris buffer (pH 8.5) was added, the lipid membrane was hydrated in an ultrasonic water bath for 5 minutes to obtain colostrum. Subjecting the colostrum to ultrasonic treatment with ultrasonic cell disruptor for 20min, and cooling in refrigerator at 4 deg.C to obtain liposome. Adding 0.03mL of PFH into the liposome suspension, and then carrying out ultrasonic treatment for 5 minutes by using an ultrasonic cell disruptor under the condition of ice-water bath to obtain the liquid fluorocarbon nanoparticles carrying the phospholipid.
2. Preparation of hyaluronic acid targeted polydopamine coated phase-change type liquid fluorocarbon nano ultrasonic contrast agent
Adding 1mL of PVP (50mg/mL) into 2mL of phospholipid liquid fluorocarbon nano suspension, uniformly stirring, adding 0.1mL of ferric trichloride solution (20mM), then adding 1mL of dopamine hydrochloride (2.5 mg) dissolved in Tris buffer solution and 1mL of sodium hyaluronate (2.5 mg) dissolved in Tris buffer solution, stirring for 12 hours in an ice water bath, centrifugally collecting precipitates, washing for 3 times, and dispersing in water to obtain the phase-change type nano ultrasonic contrast agent integrating hyaluronic acid targeting with photothermal and chemotherapy. Adding methanol to desired volume of 10ml, performing ultrasonic treatment in water bath for 30min, centrifuging, and measuring the content of the supernatant by high performance liquid chromatography to obtain drug loading of 12.67% +/-0.28%.
The prepared suspension of the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasonic contrast agent is diluted by a certain multiple, and the form of the suspension is observed by a transmission electron microscope, as shown in figure 1, the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasonic contrast agent is of a spherical structure. The particle size was measured using a malvern laser particle size analyzer, and the particle size distribution results are shown in fig. 2, where the mean particle size of the hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent was 248.08 ± 5.74 nm. Fourier infrared analysis verifies the successful modification of hyaluronic acid, and as shown in figure 3, (a) shows that hyaluronic acid targets the phase-change nano ultrasonic contrast agent integrating photothermal therapy and chemotherapy. (b) The poly-dopamine coated liquid fluorocarbon nanoparticles carrying the drug phospholipid are shown. (c) Representing liquid fluorocarbon nanoparticles carrying phospholipid. As can be seen from (b) in the figure, at 1622cm-1The position is a stretching vibration peak of carbon-nitrogen double bonds, which indicates that polydopamine is successfully wrapped on the surface of the nanoparticle. As can be seen from (a) in the figure, at 1615cm-1Is located at the stretching vibration peak of carbon-nitrogen double bond, and is 3328cm-1Stretching vibration of a hydrogen-oxygen bond shows that hyaluronic acid is successfully modified on the polydopamine-coated liquid fluorocarbon nanoparticles carrying the medicine phospholipid.
Example 2
1. In-vitro stability of hyaluronic acid targeting polydopamine coated phase-change type liquid fluorocarbon nano ultrasonic contrast agent and photo-thermal conversion effect investigation of nanoparticles
2ml of hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasound contrast agent and 2ml of phospholipid liquid fluorocarbon nano-particle ultrasound contrast agent are placed in a water bath kettle at 37 ℃ for 0, 30, 60 and 90 minutes respectively, and then phase change conditions are observed as shown in figure 4, which shows that the physical stability of the nano-particles coated with polydopamine is enhanced. Meanwhile, the temperature change of 1ml of hyaluronic acid targeting polydopamine coated phase change type liquid fluorocarbon nano ultrasonic contrast agent with different concentrations (0, 50, 100, 250, 500 and 1000 mu g/ml) under laser irradiation is recorded, and as shown in figure 5A, the temperature change is 2.5W/cm2Laser irradiation ofAfter the irradiation for 500s, the highest temperature can reach 45.8 ℃ when the concentration of the nanoparticles is 1000 mug/ml, which shows that the nanoparticles have a certain photo-thermal conversion effect. In addition, the thermal stability of the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasound contrast agent is considered, as shown in fig. 5B, after 4 cycles of laser irradiation, the highest achievable temperature is only slightly reduced, which indicates that the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasound contrast agent has good thermal stability and can be used for photothermal therapy.
2. Hyaluronic acid targeted polydopamine coated phase-change type liquid fluorocarbon nano ultrasonic contrast agent in-vitro drug release experiment
With docetaxel as a model drug, hyaluronic acid targeting polydopamine coated phase change type liquid fluorocarbon nano ultrasonic contrast agent + laser, and docetaxel bulk drug are subjected to in vitro drug release investigation, as shown in fig. 6, the in vitro drug release speed is slow due to the fact that docetaxel bulk drug is difficult to be water-soluble, and the cumulative release degree is 61.3% in 72 hours. Meanwhile, the accumulated release degree of the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent in 72 hours is about 76.1%, and the difference is that the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent + laser has relatively high experimental speed and relatively high accumulated release degree which can reach 86.0%, which indicates that the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent has a certain laser-mediated drug release behavior.
3. Cytotoxicity research of hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent
The toxicity of the blank carrier of the hyaluronic acid targeting polydopamine coated phase-change liquid fluorocarbon nano-ultrasound contrast agent is evaluated by an MTT method by taking 4T1 cells as a research object and cell viability as a research index. As shown in fig. 7, both the hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent and the polydopamine-coated phospholipid liquid fluorocarbon nano-ultrasound contrast agent blank carrier have high biocompatibility.
4. In vivo development experiment of hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent
The prepared hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent is injected into a 4T1 tumor-bearing mouse through a tail vein, and then near-infrared laser is used for irradiating a tumor part and ultrasonic imaging is carried out. As shown in fig. 8, the hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent has a better in-vivo development effect. Due to the tumor targeting mediated by hyaluronic acid, the hyaluronic acid targeted polydopamine coated phase change type liquid fluorocarbon nano ultrasonic contrast agent has stronger contrast effect than a phospholipid liquid fluorocarbon nano ultrasonic contrast agent.
5. Anti-tumor effect research of hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent
Successful tumor-bearing Balb/C mice were divided into 7 groups of 5 mice each. Respectively (1) physiological saline group; (2) saline + laser group; (3) a raw material medicine group; (4) a polydopamine-coated drug-loaded phospholipid liquid fluorocarbon nano-ultrasound contrast agent group; (5) a blank carrier of a hyaluronic acid-targeted polydopamine-coated phase-change liquid fluorocarbon nano ultrasonic contrast agent + laser; (6) the hyaluronic acid targeting polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent; (7) the phase-change liquid fluorocarbon nano ultrasonic contrast agent coated with the targeted polydopamine and the laser. Each group was administered with a different formulation at a dose of 10mg/kg (amount of docetaxel) by tail vein injection in a volume of 0.2mL once every other day for a treatment period of 14 days. Meanwhile, for the group requiring laser irradiation, the power for 24 hours after the administration of the preparation was 2.5W/cm2The tumor part is irradiated by the laser for 5 min. The tumor volume was measured daily and the results are shown in fig. 9. The saline + laser group was not significantly different from the control saline group, indicating that the laser alone did not inhibit tumor growth. The phase-change type nano ultrasonic contrast agent blank carrier and the laser which integrate the photothermal therapy and the chemotherapy in a targeted way by the hyaluronic acid also have obvious tumor treatment effect, and prove that the hyaluronic acid is targeted to gatherThe dopamine-coated phase-change liquid fluorocarbon nano-ultrasound contrast agent blank carrier has a good photo-thermal treatment effect, and can effectively inhibit tumor growth. An experimental group of hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasonic contrast agent and polydopamine coated drug-loaded phospholipid liquid fluorocarbon nano-ultrasonic contrast agent, after the tumor grows for the first few days, the tumor growth is inhibited, but the tumor growth inhibiting effect of the hyaluronic acid targeting polydopamine coated phase change type liquid fluorocarbon nano ultrasonic contrast agent is obviously stronger than that of the polydopamine coated drug-loaded phospholipid liquid fluorocarbon nanoparticle group, the phenomenon shows that the hyaluronic acid targeted polydopamine coated phase change type liquid fluorocarbon nano ultrasonic contrast agent has good tumor targeting property, under the active targeting action mechanism mediated by the hyaluronic acid CD44 receptor, the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasound contrast agent can be more easily reached and enriched at the tumor part, so that the treatment effect of the tumor is enhanced. For the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent + laser group, the tumor volume of the group does not have obvious tumor volume increase in the first few days after treatment, and the tumor volume is reduced in subsequent treatment. The hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent increases the temperature of a tumor part under laser irradiation, and the temperature not only can cause the tumor to generate physical damage, but also can act with chemotherapeutic drugs simultaneously to finally enhance the inhibition effect on the tumor.
Claims (2)
1. A preparation method of a hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano ultrasonic contrast agent is characterized by comprising the following steps:
(1) dissolving 20mg of soybean lecithin and 2mg of medicine in 4mL of dichloromethane, quickly removing the dichloromethane through reduced pressure evaporation to form a lipid membrane, adding 2mL of Tris buffer solution with the pH value of 8.5, hydrating the lipid membrane in an ultrasonic water bath for 5 minutes to obtain colostrum, ultrasonically treating the colostrum for 20 minutes by using an ultrasonic cell disruptor, cooling the colostrum in a refrigerator at the temperature of 4 ℃ to obtain liposome, adding 0.03mL of PFH into the liposome suspension, and ultrasonically treating the liposome suspension for 5 minutes by using an ultrasonic cell disruptor under the condition of an ice-water bath to obtain medicine-carrying phospholipid liquid fluorocarbon nanoparticles;
(2) adding 1mL of PVP solution with the concentration of 50mg/mL into 2mL of drug-loaded phospholipid liquid fluorocarbon nano-suspension, uniformly stirring, adding 0.1mL of ferric trichloride solution with the concentration of 20mM, then adding 1mL of dopamine hydrochloride with the concentration of 2.5mg dissolved in Tris buffer solution and 1mL of sodium hyaluronate with the concentration of 2.5mg dissolved in Tris buffer solution, stirring for 12 hours in ice water bath, centrifuging, collecting precipitate, washing for 3 times, and dispersing in water to obtain the hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasonic contrast agent.
2. The hyaluronic acid targeted polydopamine coated phase-change liquid fluorocarbon nano-ultrasonic contrast agent obtained by the method of claim 1.
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