An acoustically powered thrombolytic system and its use
The sonodynamic synergistic thrombolysis system, which combines TNK-tPA with a sonosensitive agent, solves the problems of low thrombolysis efficiency and insufficient safety in existing technologies, and achieves efficient and safe dissolution of thrombi.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ARMY MEDICAL UNIV
- Filing Date
- 2026-04-30
- Publication Date
- 2026-06-26
Smart Images
Figure CN122272801A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of medical device and pharmaceutical preparation technology, specifically to a sonodynamic synergistic thrombolysis system and its application. Background Technology
[0002] Thrombotic diseases such as acute myocardial infarction, ischemic stroke, and deep vein thrombosis are among the leading causes of death and disability in humans. Currently, commonly used thrombolytic methods in clinical practice mainly include pharmacolytic thrombolysis and mechanical thrombectomy. Pharmacolytic thrombolysis involves intravenous or local injection of thrombolytic agents such as streptokinase, urokinase, and tissue plasminogen activator (tPA) to activate the fibrinolytic system and dissolve the thrombus. However, traditional thrombolytic methods have drawbacks such as low thrombolytic efficiency, high bleeding risk, narrow treatment window, and poor efficacy against old thrombi.
[0003] To enhance thrombolytic efficacy, existing technologies have proposed combining ultrasound with thrombolytic agents. For example, US Patent 5509896A discloses a method for in vitro ultrasound-enhanced thrombolysis, which enhances the thrombolytic effect of thrombolytic agents by applying ultrasound energy to the thrombus area in vitro. This technology mainly promotes the penetration of thrombolytic agents into the thrombus through the physical effects of ultrasound (cavitation effect, microfluidic effect, mechanical vibration), thereby improving thrombolytic efficiency. However, this technology still has the following shortcomings: 1. Single mechanism of action: It only relies on physical effects to promote drug penetration and does not activate the thrombolytic process at the molecular level; 2. High dependence on thrombolytic agents: It still requires relatively high doses of thrombolytic agents, and the risk of bleeding is not substantially reduced; 3. Lack of targeting: Both ultrasound and thrombolytic agents lack specific recognition of thrombus sites; 4. Limited effectiveness on complex thrombi: Platelet-rich arterial thrombi and old thrombi are still difficult to dissolve effectively. Summary of the Invention
[0004] The purpose of this invention is to provide a sonodynamic synergistic thrombolysis system to solve the technical problems of existing ultrasound-synergistic thrombolysis techniques that still rely on high doses of thrombolytic agents and have limited thrombolysis efficiency.
[0005] To achieve the above objectives, the present invention provides the following technical solution: a sonodynamic synergistic thrombolysis system, comprising a tissue plasminogen activator variant, a sonosensitive agent, and an ultrasound source; the tissue plasminogen activator variant is an intravenously injectable formulation; the sonosensitive agent is an intravenously infused formulation; and the ultrasound source is used to emit ultrasound waves during administration of the sonosensitive agent to activate the sonosensitive agent.
[0006] The beneficial effects of this scheme are: (1) Innovation of synergistic effect mechanism: This scheme breaks through the limitation of existing technology that simply relies on the physical effect of ultrasound to promote the penetration of thrombolytic agents. It creatively introduces a sonosensitive agent and forms a dual synergistic thrombolytic mode of "TNK-tPA enzymatic hydrolysis + sonodynamic chemical oxidation". TNK-tPA initially degrades the fibrin network of thrombus. The singlet oxygen generated by sonodynamic therapy can further destroy the insoluble lipid and protein components in the thrombus skeleton at the molecular level. The intervention of this chemical mechanism is an essential enhancement of the thrombolytic process and significantly improves the dissolution efficiency of drug-insoluble thrombi that are difficult to treat by single therapy or physical promotion; (2) Reduce thrombolytic agent dependence and improve safety: Due to the introduction of the sonodynamic chemical thrombolytic mechanism, this invention does not need to rely on high doses of thrombolytic agents. At the same time, it does not need to rely on excessively high power ultrasound. Physical effects effectively avoid the mechanical damage to the vascular wall and bleeding risk that may be caused by high-power ultrasound. While achieving a high recanalization rate, this invention does not cause significant bleeding or tissue damage and has high biosafety. (3) Targeting and precision: The acoustic sensitizer (such as hematoporphyrin) used in this scheme has a certain lipophilicity and affinity for fibrin / platelet. It can be passively targeted to accumulate locally in the thrombus, realizing the specific identification of the thrombus site. The spatiotemporal controllability of ultrasound stimulation further ensures the precision of thrombolysis and reduces systemic side effects. (4) Simple operation and wide application: This scheme uses intravenous injection combined with extracorporeal ultrasound irradiation. The operation is simple and non-invasive. This scheme is not only suitable for acute ischemic stroke, but also has a wide range of clinical application value for various thrombotic diseases such as myocardial infarction, deep vein thrombosis and pulmonary embolism.
[0007] Furthermore, the sound-sensitizing agent is a porphyrin compound.
[0008] Furthermore, the porphyrin compounds include one or more of hematoporphyrin dihydrochloride, hematoporphyrin monomethyl ether, and hematoporphyrin injection.
[0009] Furthermore, the injection time of the tissue plasminogen activator variant is 5 to 10 seconds.
[0010] Furthermore, the tissue plasminogen activator variant is prepared and used immediately after being dissolved from the lyophilized powder of the tissue plasminogen activator variant.
[0011] Furthermore, the parameters of the ultrasound source are: frequency 20kHz~3MHz, power density 1~2W / cm², duration 5-60 minutes, pulse repetition frequency 10Hz, and duty cycle 50%.
[0012] Furthermore, the frequency of the ultrasonic source is 1 MHz and the power density is 2 W / cm².
[0013] This invention also provides an application of a sonodynamic synergistic thrombolysis system, the steps of which are as follows: (1) Obtain body weight parameters and calculate the dosage of tissue plasminogen activator variant based on body weight; (2) After adding the tissue plasminogen activator variant lyophilized powder to the matching sterile water for injection, gently shake until completely dissolved; (3) The dissolved tissue plasminogen activator variant is injected intravenously in a single bolus, with the injection time controlled at 5 to 10 seconds; (4) Calculate the dosage of the sound sensitizer at 5 mg / kg based on the body weight parameters, and prepare the sound sensitizer solution with 250 ml of physiological saline. (5) Infuse the sonosensitive agent solution intravenously through the contrast agent indwelling needle channel, with the infusion time set to 30 minutes; (6) At the same time as the sound-sensitive agent begins to drip, turn on the ultrasonic source to activate the sound-sensitive agent by emitting ultrasonic waves. Attached Figure Description
[0014] Figure 1 This is a schematic diagram of the process of the acoustic-dynamic synergistic thrombolysis system of the present invention; Figure 2 This is a schematic diagram of the acoustic-dynamic synergistic thrombolysis system of the present invention; Figure 3 Comparative Doppler ultrasound images of blood flow velocity on the normal side and the injured side of a rat carotid artery thrombosis model after treatment, where the normal side is the normal side and the injured side is the injured side. Figure 4 for Figure 3 Statistical chart of relative blood flow velocity (%) in each group; Figure 5 H&E staining pathological images of blood vessels in different groups after treatment in a rat common carotid artery thrombosis model animal model; Figure 6 A statistical chart showing the vascular recanalization rate (%) of different groups after treatment in a rat common carotid artery thrombosis model animal model. Figure 7 This image shows the blood routine test results of rats in different doses of hematoporphyrin groups under combined action, where HGB represents hemoglobin, RBC is red blood cell count, HCT is hematocrit, MCV is mean corpuscular volume, MCH is mean corpuscular hemoglobin, MCHC is mean corpuscular hemoglobin concentration, RDW-CV is red blood cell distribution width-coefficient of variation, PLT is platelet count, MPV is mean platelet volume, PDW is platelet distribution width, MXDN% is mixed cell percentage, and NEUT% is neutrophil percentage. Figure 8The graph shows the results of coagulation function testing in rats with different doses of hematoporphyrin under combined action. In the graph, PT is prothrombin time, INR is international normalized ratio, PTA is prothrombin activity, TT is thrombin time, and Fbg is fibrinogen. Figure 9 The images show the H&E staining pathological images of the major organs of rats in different doses of hematoporphyrin under combined action, where Heart is the heart, Liver is the liver, Spleen is the spleen, Lung is the lung, and Kidney is the kidney. Detailed Implementation
[0015] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto. Unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.
[0016] I. Composition of the Acoustodynamic Synergistic Thrombolysis System A thrombolysis system based on acoustic dynamics has the following components:
[0017] II. Evaluation of the Application Effect of Thrombolytic Systems 1. Laboratory animals and models Male SD rats (weighing 200-250 g) were used as subjects, and a common carotid artery thrombosis model was induced using 10% FeCl3 solution. On the 4th day after modeling, thrombolysis was initiated after Doppler ultrasound confirmed that the vessel was still blocked. The experimental groups were as follows:
[0018] 2. Operating Procedures
[0019] 3. Detection indicators and statistical methods Blood flow velocity detection: Doppler ultrasound was used to detect the blood flow velocity of the common carotid artery on the affected and healthy sides before and after treatment. The blood flow velocity recovery rate (%) was calculated as (blood flow velocity on the affected side / blood flow velocity on the healthy side) × 100%.
[0020] Vascular recanalization rate: After treatment, Doppler ultrasound was used to determine whether the blood vessels were patent. The vascular recanalization rate (%) of each group was calculated as follows: (Number of patent animals / Total number of animals in the group) × 100%.
[0021] Pathological and histological examination: After treatment, the animals were euthanized, and the common carotid artery was taken for HE staining. The thrombus dissolution and the area of residual thrombus in the lumen were observed under a microscope.
[0022] Biosafety analysis: Blood was collected after processing for coagulation and routine blood tests. Major organs were taken for HE staining to analyze organ toxicity.
[0023] Statistical analysis: All data were analyzed using SPSS statistical software. Quantitative data were expressed as mean ± standard deviation (Mean ± SD). One-way ANOVA was used for comparisons among multiple groups, and t-tests were used for comparisons between two groups. χ² tests were used for categorical data. A p-value < 0.05 was considered statistically significant. Each experiment was repeated three times, and the results were averaged.
[0024] 4. Experimental Results and Conclusions (1) Doppler ultrasound examination results show (see Figure 3 , Figure 4 The blood flow velocity recovery rate in the Control group was 16.02%±3.21%; the blood flow velocity recovery rate in the TNK-SDT group was 84.97%±10.08%, which was significantly higher than that in the Control group, US group, SDT group, TNK group and TNK-US group (P<0.01). (2) Histopathological examination showed (see Figure 5 In the TNK-SDT group, the thrombus in the common carotid artery was basically dissolved, the lumen was patent, the vessel wall structure was intact, and no obvious damage was observed.
[0025] (3) Results of vascular recanalization rate (see...) Figure 6 The mean patency rate of blood vessels in the TNK-SDT group was 83.69%, which was significantly higher than that in other groups (P<0.01). In summary, the TNK-tPA combined with hematoporphyrin sonodynamic treatment (TNK-SDT) used in this invention can significantly improve the vascular recanalization rate (83.69%) and blood flow velocity recovery rate (86.75%) in the common carotid artery thrombosis model, and the effect is significantly better than single therapy or combination therapy (P<0.01), indicating that the combination of TNK-tPA, hematoporphyrin and ultrasound has a significant synergistic thrombolytic effect.
[0026] III. Biosafety Evaluation of Thrombolytic Systems Male SD rats (weighing 200-250 g) were used as subjects, and a common carotid artery thrombosis model was induced using 10% FeCl3 solution. On the 4th day after modeling, thrombolytic treatment was initiated after Doppler ultrasound confirmed that the blood vessel was still blocked.
[0027] The experimental groups for combined effects are as follows:
[0028] The experimental procedures for each group were performed according to the method of the TNK-SDT group in the above-mentioned experiment on the application effect evaluation of the thrombolytic system. The only difference was that the dose of hematoporphyrin was set according to the groups as 1 mg / kg, 5 mg / kg and 10 mg / kg. After the treatment, the rats in each group were subjected to routine blood tests, coagulation tests and HE staining of major tissues and organs.
[0029] The experimental results are as follows: 1. Blood routine test results (see...) Figure 7 ): Under the combined action of TNK + hematoporphyrin + ultrasound, no significant differences in inflammatory cells were observed among different doses of hematoporphyrin.
[0030] 3. Coagulation test results (see...) Figure 8 ): Under the combined action of TNK + hematoporphyrin + ultrasound, no significant changes in coagulation were observed between different doses of hematoporphyrin.
[0031] 3. Results of HE staining of major organs and tissues (see...) Figure 9 ): Under the combined action of TNK + hematoporphyrin + ultrasound, no obvious histological pathological changes were observed between different doses of hematoporphyrin.
[0032] In summary, no significant hematologic toxicity or organ damage was observed under the combined effects, indicating that the combined effects of TNK-tPA, hematoporphyrin, and ultrasound have good biocompatibility in thrombotic diseases.
[0033] This invention uses a common carotid artery thrombosis model as an example for illustration, but its application scope is not limited to this. The thrombotic diseases mentioned include, but are not limited to, acute ischemic stroke, myocardial infarction, deep vein thrombosis, pulmonary embolism, and peripheral artery disease. In particular, this invention can also be applied to intracranial thrombosis-related diseases, preferably intracranial arterial thrombosis occlusion caused by ischemic stroke. For intracranial thrombosis applications, due to the filtering effects of ultrasound on the skull, such as attenuation, reflection, scattering, and phase distortion, the ultrasound parameters need to be adjusted according to the transcranial sound propagation characteristics. Specifically, the effective ultrasound energy penetrating the skull under different ultrasound parameter conditions can be measured or evaluated to determine the actual effective sound intensity or sound pressure acting on the target vessel / target thrombus region. Based on this, the transmission frequency, power density, pulse repetition frequency, duty cycle, and processing time can be selected or adjusted to ensure effective activation and application safety of the sonosensitive agent.
Claims
1. A thrombolysis system based on acoustic dynamics, characterized in that, The invention includes a tissue plasminogen activator variant, a sonic sensitizer, and an ultrasound source; the tissue plasminogen activator variant is an intravenously administered formulation; the sonic sensitizer is an intravenously administered formulation; and the ultrasound source is used to emit ultrasound waves during administration of the sonic sensitizer to activate the sonic sensitizer.
2. The acoustic-dynamic synergistic thrombolysis system according to claim 1, characterized in that, The sound-sensitizing agent is a porphyrin compound.
3. The acoustic-dynamic synergistic thrombolysis system according to claim 2, characterized in that, The porphyrin compounds include one or more of hematoporphyrin dihydrochloride, hematoporphyrin monomethyl ether, and hematoporphyrin injection.
4. The acoustic-dynamic synergistic thrombolysis system according to claim 3, characterized in that, The injection time for the tissue-type plasminogen activator variant is 5–10 seconds.
5. The acoustic-dynamic synergistic thrombolysis system according to claim 4, characterized in that, The tissue plasminogen activator variant is prepared and used immediately after being dissolved from the lyophilized powder of the tissue plasminogen activator variant.
6. The acoustic-dynamic synergistic thrombolysis system according to claim 5, characterized in that, The parameters of the ultrasound source are: frequency 20kHz~3MHz, power density 1~2W / cm², duration 5-60 minutes, pulse repetition frequency 10Hz, and duty cycle 50%.
7. The acoustic-dynamic synergistic thrombolysis system according to claim 6, characterized in that, The ultrasonic source has a frequency of 1 MHz and a power density of 2 W / cm².
8. The application of the acoustic-dynamic synergistic thrombolysis system according to claim 7, characterized in that, The application steps are as follows: (1) Obtain body weight parameters and calculate the dosage of tissue plasminogen activator variant based on body weight; (2) After adding the tissue plasminogen activator variant lyophilized powder to the matching sterile water for injection, gently shake until completely dissolved; (3) The dissolved tissue plasminogen activator variant is injected intravenously in a single bolus, with the injection time controlled at 5 to 10 seconds; (4) Calculate the dosage of the sound sensitizer at 5 mg / kg based on the body weight parameters, and prepare the sound sensitizer solution with 250 ml of physiological saline. (5) Infuse the sonosensitive agent solution intravenously through the contrast agent indwelling needle channel, with the infusion time set to 30 minutes; (6) At the same time as the sound-sensitive agent begins to drip, turn on the ultrasonic source and activate the sound-sensitive agent by emitting ultrasonic waves.