Drug-loaded ultrasonic nano-bubble as well as preparation method and application thereof
By developing drug-loaded ultrasonic nanobubbles and combining ultrasonic blasting technology, the problem of difficulty in accumulating drugs in the tumor tissues in the prior art has been solved, achieving more efficient targeted treatment and reducing systemic side effects.
Patent Information
- Application Number
- CN202510077613.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-17
- Publication Date
- 2025-04-22
AI Technical Summary
The prior art is difficult to effectively accumulate drugs in tumor tissues, resulting in poor treatment effects and accompanied by serious systemic side effects.
A drug-loaded ultrasonic nanobubble is developed to achieve targeted drug delivery by coating a paclitaxel-loaded lipid membrane layer outside the gas core, combined with ultrasonic blasting technology.
Drug-loaded ultrasonozoic nanobubbles can penetrate the vascular gaps of tumor tissue, increase the accumulation concentration of drugs in the tumor site, reduce systemic toxicity, and enhance treatment efficiency.
Smart Images
Figure CN119857094A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of medical preparations, and specifically relates to a drug-loaded ultrasonic nanobubble and a preparation method and application thereof. Background Art
[0002] Breast cancer is a disease characterized by abnormal uncontrolled growth of breast cells and the formation of tumors. Being a female is the strongest risk factor for breast cancer. Approximately 99% of breast cancers occur in women, while 0.5-1% occur in men. In 2022, 2.3 million women worldwide will be diagnosed with breast cancer, and 670,000 will die from the disease. Breast cancer can occur at any age, but the incidence rate gradually increases with age. In countries with a high human development index, it is estimated that 1 in 12 women will be diagnosed with breast cancer in their lifetime, and 1 in 71 women will die from breast cancer. Treatment for breast cancer depends on the subtype of cancer and the extent to which the cancer has spread from the breast to the lymph nodes (stage II or stage III) or to other parts of the body (stage IV). Doctors combine different treatments to minimize the likelihood of cancer recurrence, including: 1) surgery to remove the breast tumor; 2) radiation therapy to reduce the risk of recurrence in the breast and surrounding tissues; 3) the use of drugs to kill cancer cells and prevent spread, including hormone therapy, chemotherapy, or targeted biological therapy. However, traditional chemotherapy drugs are difficult to accumulate in tumor tissues and usually require high doses to reach effective concentrations, which can cause serious systemic side effects and affect the health of patients. Long-term low-concentration chemotherapy may also induce tumor cell resistance and limit the effectiveness of treatment.
[0003] Paclitaxel is a discovered natural anticancer drug that has been widely used in the clinic to treat breast cancer, ovarian cancer, some head and neck cancers, and lung cancer. Paclitaxel is poorly soluble in water. The earliest paclitaxel injection used polyoxyethylated castor oil and ethanol as solvents to improve its solubility, but this solvent may affect the effect of the drug and produce serious adverse reactions, such as degradation and release of histamine in the body, leading to allergies. The paclitaxel liposome that was subsequently launched on the market is the world's first approved paclitaxel liposome. By using nanocarriers to embed paclitaxel, its injection toxicity can be significantly reduced.
[0004] Ultrasound-loaded drug-targeted ultrasound nanobubble therapy has the advantages of strong penetration, low toxicity and side effects on normal tissues, and strong selectivity compared to other treatment methods. Traditional ultrasound angiography technology generally uses ultrasound microbubbles as contrast agents, and these microbubbles can also be used as carriers for therapeutic drugs. Ultrasound microbubbles refer to a type of microbubbles with a diameter of 1 to 10 μm, containing gas and covered with a layer of membrane on the outside, which can significantly improve the specificity and sensitivity of ultrasound diagnosis. However, due to the complex vascular structure, dense cells, and lack of blood supply of tumor tissue, it is difficult for micron-level ultrasound microbubbles to pass through the vascular endothelial gap to reach the corresponding tumor target tissue, and the retention time in the body is short, which greatly limits the drug delivery and imaging of specific target tissues. Therefore, there is an urgent need for a nano-ultrasound microbubble with good imaging effect and strong targeting. Summary of the invention
[0005] The present invention aims to overcome the defects of the prior art and provide a drug-loaded ultrasonic nanobubble.
[0006] Another object of the present invention is to provide a method for preparing the above-mentioned drug-loaded ultrasonic nanobubbles.
[0007] Another object of the present invention is to provide applications of the above-mentioned drug-loaded ultrasonic nanobubbles.
[0008] The technical solution of the present invention is as follows:
[0009] A drug-loaded ultrasonic nanobubble comprises a gas core and a lipid membrane layer coated outside the gas core and loaded with paclitaxel, wherein:
[0010] A gas core, wherein the gas is a fluorocarbon gas and / or a fluorine-sulfur gas,
[0011] The lipid film is composed of the drug-loaded liposome loaded with the paclitaxel, and the drug-loaded liposome is prepared from phospholipid material, stabilizer, surfactant, organic solvent, paclitaxel and water.
[0012] In a preferred embodiment of the present invention, the fluorocarbon gas is selected from perfluoropropane, perfluorobutane and perfluorohexane, and the fluorine-sulfur gas is sulfur hexafluoride.
[0013] In a preferred embodiment of the present invention, the phospholipid material is selected from distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE) and dipalmitoylphosphatidylglycerol sodium (DPPG-Na).
[0014] In a preferred embodiment of the present invention, the stabilizer is selected from cholesterol and palmitic acid.
[0015] In a preferred embodiment of the present invention, the surfactant is selected from polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000 and polyethylene glycol 8000.
[0016] In a preferred embodiment of the present invention, the organic solvent is selected from ethanol, tert-butyl alcohol, dichloromethane, isopropanol and n-hexane.
[0017] The method for preparing the drug-loaded ultrasonic nanobubbles comprises the following steps:
[0018] (1) fully mixing the phospholipid material, the stabilizer, paclitaxel and the organic solvent to obtain an organic phase solution; fully mixing the surfactant and water to obtain an aqueous phase solution;
[0019] (2) after removing the organic solvent in the organic phase solution, adding the aqueous phase solution to hydrate the organic phase solution to obtain a suspension;
[0020] (3) Ventilating the suspension obtained in step (2) and simultaneously performing ultrasonic treatment to obtain the drug-loaded ultrasonic nanobubbles.
[0021] In a preferred embodiment of the present invention, in the organic phase solution, the ratio of paclitaxel, phospholipid material and stabilizer is 5wt% to 30wt%: 65wt% to 85wt%: 1wt% to 10wt%; in the aqueous phase solution, the content of surfactant is 10wt% to 40wt%.
[0022] Preferably, the volume ratio of the organic solvent to water in step (1) is 1:1-5.
[0023] Preferably, the method for fully mixing the organic phase solution in step (1) is ultrasonic treatment + heating at 40-70° C. The ultrasonic treatment method is more preferably water bath ultrasonic treatment.
[0024] Preferably, the organic solvent in step (2) is removed by evaporation under reduced pressure, with a vacuum degree of -0.04 MPa to -0.1 MPa.
[0025] Preferably, the hydration temperature in step (2) is 50-80°C.
[0026] Preferably, the ventilation gas flow rate in step (3) is 10 to 100 mL / min.
[0027] Preferably, the ultrasonic treatment in step (3) is carried out by probe ultrasound with a power of 50 to 500 W, an ultrasound duration of 0.1 to 5 s in a single cycle, an interval of 0.1 to 10 s, and an ultrasound cycle of 0.5 to 10 min.
[0028] The use of the drug-loaded ultrasonic nanobubbles in preparing a cancer treatment composition has a therapeutic effect on breast cancer (including triple-negative breast cancer), ovarian cancer, cervical cancer and non-small cell lung cancer.
[0029] The use of the drug-loaded ultrasonic nanobubbles in the preparation of ultrasonic imaging contrast agents.
[0030] The beneficial effects of the present invention are:
[0031] 1. The particle size of conventional ultrasound contrast agent microbubbles is 1-8 μm, which is difficult to penetrate into tumor tissue. However, the particle size of the drug-loaded ultrasound nanobubbles of the present invention is 100-600 nm, which can pass through the loose blood vessel gaps in tumor tissue and penetrate into the tumor tissue, thereby achieving better contrast effects and higher drug delivery efficiency, showing unique superiority in treatment.
[0032] 2. Traditional chemotherapy is mainly carried out by intravenous injection, which lacks targeting, resulting in insufficient drug accumulation in tumor tissues and more serious systemic toxicity. The drug-loaded ultrasonic nanobubbles of the present invention, combined with ultrasonic blasting technology, can be developed at the tumor site and the nanobubbles can be blasted at a fixed point, so that most of the drugs are released at the tumor site, increasing the concentration of the target tissue and reducing the systemic concentration. This not only improves the treatment efficiency, but also reduces systemic toxicity.
[0033] 3. The drug-loaded ultrasonic nanobubbles of the present invention can not only be used as ultrasonic contrast agents for auxiliary diagnosis of tumor tissues, but also can achieve targeted tumor tissue blasting in combination with ultrasound, increase the drug accumulation concentration in target tissues, and reduce the systemic toxicity of drugs, thereby reducing the patient's dosage, improving treatment efficiency, reducing the burden on patients, and improving the patient's quality of life, which has a positive impact on society. BRIEF DESCRIPTION OF THE DRAWINGS
[0034] Figure 1 This is a TEM image of the drug-loaded ultrasonic nanobubbles in Experimental Example 1 of the present invention.
[0035] Figure 2 This is the particle size distribution diagram of the drug-loaded ultrasonic nanobubbles in Experimental Example 1 of the present invention.
[0036] Figure 3 This is an in vivo ultrasound comparison diagram of the drug-loaded ultrasound nanobubbles in Experimental Example 2 of the present invention. From left to right, they are physiological saline, commercially available ultrasound contrast agent microbubbles, and the drug-loaded ultrasound nanobubbles prepared in Example 1 of the present invention.
[0037] Figure 4This is a diagram for verifying the in vivo therapeutic effect of drug-loaded ultrasound nanobubbles in Experimental Example 3 of the present invention. Among them: A shows the comparison of mouse tumor treatment effects, and B shows the changes in mouse tumor volume. Note: control-normal saline group, PTX-free paclitaxel group, NBs-drug-loaded ultrasound nanobubbles group. DETAILED DESCRIPTION
[0038] The technical solution of the present invention is further illustrated and described below through specific implementation modes in combination with the accompanying drawings.
[0039] Example 1
[0040] (1) Distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na) and palmitic acid were dissolved in 4 mL of anhydrous ethanol at a mass ratio of 5:5:1, and ultrasonicated in a water bath at room temperature for 1 min at a power of 40 W until they were completely dispersed; then heated in a water bath (55°C) until the solution was clear and transparent, and then paclitaxel was weighed at a mass ratio of total lipids to paclitaxel of 3:1 and added thereto, and shaken until completely dissolved to obtain a clear and transparent organic phase solution; PEG4000 was weighed and added to 10 mL of purified water, and stirred until completely dissolved to obtain an aqueous phase solution.
[0041] (2) The organic phase solution obtained in step (1) was added to a 50 mL rotary flask, and the ethanol was completely removed by rotary evaporation at 55° C., 30 rpm, and -0.05 MPa. Then, the aqueous phase solution obtained in step (1) was added, and the mixture was rotary hydrated at 60° C., 30 rpm for 30 min to obtain a suspension of crude drug-containing liposomes.
[0042] (3) Transfer the suspension obtained in step (2) to a container while it is still hot. Before starting the ultrasound, ventilate the suspension. The gas used for ventilation is perfluoropropane, and the gas flow rate is adjusted to 30 mL / min. Use probe ultrasound, and the ultrasound parameters are output power accounting for 100%, the cycle is ultrasound 1s and rest 1s, and the total cycle is 2 minutes. Turn on the ultrasound until the ultrasound ends, and obtain drug-loaded ultrasound nanobubbles.
[0043] Comparative Example 1
[0044] The difference between this comparative example and Example 1 is that paclitaxel is not added in step (1), and blank ultrasonic nanobubbles are finally prepared.
[0045] Experimental Example 1: Particle size of drug-loaded ultrasonic nanobubbles
[0046] Take a small amount of the suspension of drug-loaded ultrasonic nanobubbles prepared in Example 1, dilute it with deionized water, and drop a small amount on the copper mesh covered with a support film. After standing for about 5 minutes, use a small piece of filter paper to absorb excess liquid from the edge of the copper mesh, and observe the size and morphology of the nano-ultrasonic microbubbles under a transmission electron microscope. The results are as follows: Figure 1The particle size test results are shown in Figure 2 shown.
[0047] Depend on Figure 1 and 2 It can be seen that the drug-loaded ultrasonic nanobubbles prepared in Example 1 of the present invention are spherical particles with regular morphology and high uniformity.
[0048] Experimental Example 2: Nanobubble in vivo imaging experiment
[0049] To prepare tumor-bearing mice, follow these steps:
[0050] 1) Place the saline-injected mice on an ultrasound machine for imaging;
[0051] 2) 200 μL of commercially available ultrasound contrast agent microbubbles were injected into the tail vein of the mouse, and after 5 minutes, the mouse was placed in an ultrasound instrument for imaging.
[0052] 3) 200 μL of the nanobubbles prepared in Example 1 were injected into the tail vein of the mouse. After 5 minutes, the mouse was placed in an ultrasound instrument for imaging.
[0053] Ultrasound imaging of mice before and after three injections Figure 3 As shown, the imaging of the tumor site after the mice were injected with microbubbles was significantly clearer than that before the injection, indicating that the ultrasonic nanobubbles prepared in Example 1 of the present invention can achieve better imaging effects when performing ultrasonic imaging.
[0054] Experimental Example 3: Verification of the therapeutic effect of drug-loaded ultrasound nanobubbles in vivo
[0055] After nude mice were subcutaneously induced with SK-BR-3 cells, the tumor size was kept at 100 mm. 3 At the same time, 18 nude mice were randomly divided into 3 groups and administered once every 3 days for a total of 18 days. Group 1 was injected with normal saline through the tail vein, group 2 was injected with paclitaxel (10 mg / kg) through the tail vein, and group 3 was injected with paclitaxel-loaded ultrasonic nanobubbles (10 mg / kg in terms of paclitaxel) through the tail vein. Ultra-high resolution small animal ultrasound imaging system Vevo2100 was used for imaging, with an ultrasound frequency of 40 MHz and a power of 100%. The tumor size was measured every 2 days, and the tumor growth status was recorded. On the 18th day, the nude mice were killed by cervical dislocation, and the subcutaneous tumors of the nude mice were removed by dissection.
[0056] Depend on Figure 4 It can be seen that the subcutaneous tumor tissue of the mice in the treatment group is smaller than that in the control group, indicating that the drug-loaded ultrasound nanobubbles prepared in the present invention can play a good role in tumor treatment. And the reduction of tumor tissue in Group 3 is better than that of free paclitaxel in Group 2, indicating that the ultrasound + nanobubble form can improve the targeted treatment effect and enhance the treatment effect.
[0057] Example 2
[0058] (1) Distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na) and palmitic acid were dissolved in 4 mL of tert-butyl alcohol / ethanol mixed solution (v:v=1:1) at a mass ratio of 5:5:1, and ultrasonicated in a water bath at room temperature for 1 min at a power of 40 W until they were completely dispersed; then heated in a water bath (55° C.) until the solution was clear and transparent, and then paclitaxel was weighed at a mass ratio of total lipids to paclitaxel of 4:1 and added thereto, and shaken until completely dissolved to obtain a clear and transparent organic phase solution; PEG4000 was weighed and added to 5 mL of purified water, and stirred until completely dissolved to obtain an aqueous phase solution.
[0059] (2) The organic phase solution obtained in step (1) was added to a 50 mL rotary flask, and the ethanol was completely removed by rotary evaporation at 55° C., 25 rpm, and -0.06 MPa. Then, the aqueous phase solution obtained in step (1) was added, and the mixture was rotary hydrated at 58° C., 25 rpm for 40 min to obtain a suspension of crude drug-containing liposomes.
[0060] (3) Transfer the suspension obtained in step (2) to a container while it is still hot. Before starting the ultrasound, ventilate the suspension. The gas used for ventilation is perfluoropropane, and the gas flow rate is adjusted to 20 mL / min. Use probe ultrasound, and the ultrasound parameters are output power accounting for 100%, the cycle is ultrasound 1s and rest 1s, and the total cycle is 3 minutes. Turn on the ultrasound until the ultrasound ends, and obtain drug-loaded ultrasound nanobubbles.
[0061] Example 3
[0062] (1) Dissolve dipalmitoylphosphatidylcholine (DPPC) and palmitic acid in 4 mL of anhydrous ethanol at a mass ratio of 4:1, and perform water bath sonication at room temperature for 1 min at a power of 40 W until they are completely dispersed; then heat in a water bath (60° C.) until the solution is clear and transparent, then weigh paclitaxel at a mass ratio of total lipids to paclitaxel of 4:1, add the paclitaxel, and shake until it is completely dissolved to obtain a clear and transparent organic phase solution; weigh PEG2000, add it to 10 mL of purified water, and stir until it is completely dissolved to obtain an aqueous phase solution.
[0063] (2) The organic phase solution obtained in step (1) was added to a 25 mL rotary flask, and the ethanol was completely removed by rotary evaporation at 50° C., 40 rpm, and -0.055 MPa. Then, the aqueous phase solution obtained in step (1) was added, and the mixture was rotary hydrated at 58° C. and 30 rpm for 60 min to obtain a suspension of crude drug-containing liposomes.
[0064] (3) Transfer the suspension obtained in step (2) to a container while it is still hot. Before starting ultrasound, ventilate the suspension with perfluorobutane as the gas and adjust the gas flow rate to 30 mL / min. Use probe ultrasound with ultrasound parameters of 70% output power, 2s ultrasound and 1s rest, and a total cycle of 1 min. Start ultrasound until the end of ultrasound to obtain drug-loaded ultrasound nanobubbles.
[0065] Example 4
[0066] (1) Dissolve dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na) and cholesterol in a mass ratio of 5:2:1 in 5 mL of a tert-butyl alcohol / ethanol mixed solution (v:v=1:1), and ultrasonicate in a water bath at room temperature for 1 min at a power of 80 W until they are completely dispersed; then heat in a water bath (60°C) until the solution is clear and transparent, then weigh paclitaxel in a mass ratio of total lipids to paclitaxel of 4:1, add it to the solution, and shake until it is completely dissolved to obtain a clear and transparent organic phase solution; weigh PEG2000, add it to 5 mL of purified water, and stir until it is completely dissolved to obtain an aqueous phase solution.
[0067] (2) The organic phase solution obtained in step (1) was added to a 25 mL rotary flask, and the ethanol was completely removed by rotary evaporation at 55° C., 20 rpm, and -0.07 MPa. Then, the aqueous phase solution obtained in step (1) was added, and the mixture was rotary hydrated at 60° C. and 25 rpm for 40 min to obtain a suspension of crude drug-containing liposomes.
[0068] (3) Transfer the suspension obtained in step (2) to a container while it is still hot. Before starting the ultrasound, ventilate the suspension with sulfur hexafluoride as the gas and adjust the gas flow rate to 20 mL / min. Use probe ultrasound with ultrasound parameters of 50% output power, 2s ultrasound and 2s rest, and a total cycle of 5 min. Start ultrasound until the ultrasound ends to obtain drug-loaded ultrasound nanobubbles.
[0069] Example 5
[0070] (1) Dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE) and palmitic acid were dissolved in 3 mL of anhydrous ethanol at a mass ratio of 6:2:1, and ultrasonicated in a water bath at room temperature for 1 min at a power of 40 W until they were completely dispersed; then heated in a water bath (60° C.) until the solution was clear and transparent, and then paclitaxel was weighed at a mass ratio of total lipids to paclitaxel of 5:1 and added thereto, and shaken until completely dissolved to obtain a clear and transparent organic phase solution; PEG4000 was weighed and added to 10 mL of purified water, and stirred until completely dissolved to obtain an aqueous phase solution.
[0071] (2) The organic phase solution obtained in step (1) was added to a 50 mL rotary flask, and the ethanol was completely removed by rotary evaporation at 50° C., 50 rpm, and -0.08 MPa. Then, the aqueous phase solution obtained in step (1) was added, and the mixture was rotary hydrated at 58° C. and 50 rpm for 60 min to obtain a suspension of crude drug-containing liposomes.
[0072] (3) Transfer the suspension obtained in step (2) to a container while it is still hot. Before starting the ultrasound, ventilate the suspension. The gas used for ventilation is perfluoropropane, and the gas flow rate is adjusted to 25 mL / min. Use probe ultrasound, and the ultrasound parameters are output power accounting for 100%, the cycle is ultrasound for 2 seconds and rest for 2 seconds, and the total cycle is 3 minutes. Turn on the ultrasound until the ultrasound ends, and obtain drug-loaded ultrasound nanobubbles.
[0073] Example 6
[0074] (1) Dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE) and palmitic acid were dissolved in 4 mL of isopropanol at a mass ratio of 6:3:1, and ultrasonicated in a water bath at room temperature for 1 min at a power of 50 W until they were completely dispersed; then heated in a water bath (60° C.) until the solution was clear and transparent, and then paclitaxel was weighed at a mass ratio of total lipids to paclitaxel of 5:1 and added thereto, and shaken until completely dissolved to obtain a clear and transparent organic phase solution; PEG4000 was weighed and added to 10 mL of purified water, and stirred until completely dissolved to obtain an aqueous phase solution.
[0075] (2) The organic phase solution obtained in step (1) was added to a 50 mL rotary flask, and the ethanol was completely removed by rotary evaporation at 50° C., 50 rpm, and -0.08 MPa. Then, the aqueous phase solution obtained in step (1) was added, and the mixture was rotary hydrated at 58° C. and 50 rpm for 60 min to obtain a suspension of crude drug-containing liposomes.
[0076] (3) Transfer the suspension obtained in step (2) to a container while it is still hot. Before starting the ultrasound, ventilate the suspension. The gas used for ventilation is perfluoropropane, and the gas flow rate is adjusted to 25 mL / min. Use probe ultrasound, and the ultrasound parameters are output power accounting for 100%, the cycle is ultrasound for 2 seconds and rest for 2 seconds, and the total cycle is 3 minutes. Turn on the ultrasound until the ultrasound ends, and obtain drug-loaded ultrasound nanobubbles.
[0077] Example 7
[0078] (1) Distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylethanolamine (DPPE) and palmitic acid were dissolved in 4 mL of isopropanol / anhydrous ethanol (v:v=1:1) at a mass ratio of 5:3:1, and ultrasonicated in a water bath at room temperature for 1 min at a power of 50 W until they were completely dispersed; then heated in a water bath (60° C.) until the solution was clear and transparent, and then paclitaxel was weighed at a mass ratio of total lipids to paclitaxel of 5:1 and added thereto, and shaken until completely dissolved to obtain a clear and transparent organic phase solution; PEG4000 was weighed and added to 10 mL of purified water, and stirred until completely dissolved to obtain an aqueous phase solution.
[0079] (2) The organic phase solution obtained in step (1) was added to a 50 mL rotary flask, and the ethanol was completely removed by rotary evaporation at 50° C., 50 rpm, and -0.07 MPa. Then, the aqueous phase solution obtained in step (1) was added, and the mixture was rotary hydrated at 58° C. and 50 rpm for 60 min to obtain a suspension of crude drug-containing liposomes.
[0080] (3) Transfer the suspension obtained in step (2) to a container while it is still hot. Before starting the ultrasound, ventilate the suspension. The gas used for ventilation is perfluoropropane, and the gas flow rate is adjusted to 30 mL / min. Use probe ultrasound, and the ultrasound parameters are output power accounting for 100%, the cycle is ultrasound for 2 seconds and rest for 2 seconds, and the total cycle is 3 minutes. Turn on the ultrasound until the ultrasound ends to obtain drug-loaded ultrasound nanobubbles
[0081] The above description is only a preferred embodiment of the present invention, and therefore cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made according to the patent scope of the present invention and the contents of the specification should still fall within the scope of the present invention.
Claims
1. A drug-loaded ultrasonic nanobubble, characterized in that: It comprises a gas core and a lipid membrane layer coated outside the gas core and loaded with paclitaxel, wherein: A gas core, wherein the gas is a fluorocarbon gas and / or a fluorine-sulfur gas, The lipid film is composed of the drug-loaded liposome loaded with the paclitaxel, and the drug-loaded liposome is prepared from phospholipid material, stabilizer, surfactant, organic solvent, paclitaxel and water.
2. The drug-loaded ultrasonic nanobubble according to claim 1, characterized in that: The fluorocarbon gas is selected from perfluoropropane, perfluorobutane and perfluorohexane, and the fluorine-sulfur gas is sulfur hexafluoride.
3. The drug-loaded ultrasonic nanobubble according to claim 1, characterized in that: The phospholipid material is selected from distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine and dipalmitoylphosphatidylglycerol sodium.
4. The drug-loaded ultrasonic nanobubble according to claim 1, characterized in that: The stabilizer is selected from cholesterol and palmitic acid.
5. The drug-loaded ultrasonic nanobubble according to claim 1, characterized in that: The surfactant is selected from polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000 and polyethylene glycol 8000.
6. The drug-loaded ultrasonic nanobubble according to claim 1, characterized in that: The organic solvent is selected from ethanol, tert-butyl alcohol, dichloromethane, isopropanol and n-hexane.
7. The method for preparing drug-loaded ultrasonic nanobubbles according to any one of claims 1 to 6, characterized in that: The steps include: (1) fully mixing the phospholipid material, the stabilizer, paclitaxel and the organic solvent to obtain an organic phase solution; fully mixing the surfactant and water to obtain an aqueous phase solution; (2) after removing the organic solvent in the organic phase solution, adding the aqueous phase solution to hydrate the organic phase solution to obtain a suspension; (3) Ventilating the suspension obtained in step (2) and simultaneously performing ultrasonic treatment to obtain the drug-loaded ultrasonic nanobubbles.
8. The preparation method according to claim 7, characterized in that: In the organic phase solution, the ratio of paclitaxel, phospholipid material and stabilizer is 5wt%-30wt%: 65wt%-85wt%: 1wt%-10wt%; in the aqueous phase solution, the content of surfactant is 10wt%-40wt%.
9. Use of the drug-loaded ultrasonic nanobubbles according to any one of claims 1 to 6 in preparing a cancer treatment composition, characterized in that: The cancer treatment composition has a therapeutic effect on breast cancer, ovarian cancer and non-small cell lung cancer.
10. Use of the drug-loaded ultrasound nanobubbles according to any one of claims 1 to 6 in the preparation of ultrasound imaging contrast agents.