A drug enrichment system and method

Abstract

This invention discloses a drug enrichment system, comprising: a sound field generating device, which includes a focusing transducer for generating a focused sound field, the transmitter of which faces a fluid cavity within a human or animal body to be enriched; drug-loaded particles are injected into the fluid cavity, and the focusing transducer is controlled to generate a frequency-adjustable focused sound field, thereby enriching the drug-loaded particles at a preset target location. The preset target location is located on the plane of the focusing transducer's emission focal point. The sound field generating device further includes a signal generator and a power amplifier. The sound field generating device, through the signal generator and power amplifier, controls the focusing transducer to emit a swept-frequency sound field that causes sound field nodes to move directionally along the sound wave propagation direction, causing the drug-loaded particles to migrate directionally with the moving sound field nodes under the action of the acoustic radiation force generated by the swept-frequency sound field.

Description

Technical Field

[0001] This disclosure belongs to the field of biomedical technology, and specifically relates to a drug enrichment system and method. Background Technology

[0002] In the field of drug delivery, a core challenge is how to target therapeutic drugs to the intended site of action. To address this challenge, numerous studies have focused on modifying active pharmaceutical ingredients or biologics to better regulate their pharmacological activity and in vivo metabolic processes. One strategy is to develop prodrugs, which involve conjugating active pharmaceutical ingredients with targeting groups to enable the former to specifically recognize specific cellular receptors. However, these prodrugs often face the problem of rapid clearance and premature degradation in vivo. To address these challenges, researchers have conducted extensive studies to better control drug delivery and increase its accumulation at lesion sites. To this end, the possibility of using external field manipulation (such as magnetism, light, and sound) to deliver drugs to specific sites has been explored to improve drug delivery performance and further enhance the accumulation rate of drug-loaded microparticles in diseased tissues.

[0003] Externally manipulated drug delivery typically utilizes various external physical fields to act on specific drug-carrying substances, actively and relatively efficiently enriching the drug-carrying substances into diseased tissues. Compared to traditional drug delivery methods, externally manipulated drug delivery strategies exhibit higher drug utilization rates and show great application potential in the field of drug delivery. Currently, there are various in vivo drug-directed enrichment methods based on external physical fields, including magnetocontrol, optical field control, and ultrasonic field control.

[0004] Magnetic field-driven drug delivery offers improvements in delivery efficiency and drug utilization compared to traditional drug delivery. However, the magnetic guidance system in magnetic manipulation technology is relatively complex, requiring the integration of superparamagnetic components into the structure in addition to carrying the target drug. Secondly, the field resolution of magnetic fields is relatively low, primarily at the centimeter level, posing challenges to high-precision control of drug delivery. Finally, magnetic fields cannot be focused, making it difficult to construct anisotropic magnetic fields, and all matter within the magnetic field experiences forces in the same direction, which limits its application scope to some extent.

[0005] The light field has poor penetrability in opaque tissues, making it only suitable for surface or transparent tissues, and it is difficult to counteract physiological flow within the body and help drug-carrying substances penetrate biological barriers.

[0006] Ultrasound manipulation is a manipulation method with good tissue penetration depth, excellent biocompatibility, high control precision, and wide material application, and has been proven to be used for in vivo drug enrichment. Ultrasound primarily enriches drug-loaded substances by generating acoustic radiation force and acoustic flow. Currently, the main challenges of ultrasound-manipulated in vivo drug enrichment include achieving ultrasound-mediated drug enrichment at lesions in vivo; and achieving in vivo therapeutic drug enrichment mediated by focused ultrasound. Summary of the Invention

[0007] The purpose of this disclosure is to achieve drug enrichment via a carrier. Specifically, it relates to a disease treatment system and method that utilizes a focused sound field to achieve targeted enrichment of drug-loaded microparticles in vivo. This disclosure primarily addresses the problem that existing drug delivery technologies struggle to achieve large-scale targeted enrichment of drugs at lesions within the body.

[0008] One aspect of this disclosure is a drug enrichment method based on focused ultrasound, comprising the following steps:

[0009] The drug-loaded substance is introduced into a biological cavity or flow field cavity containing a lesion area, and the drug-loaded substance can migrate under the action of acoustic radiation force;

[0010] A focused ultrasonic field is formed in the biological cavity or flow field cavity using a focusing transducer, and the sound field nodes are moved directionally along the direction of sound wave propagation by periodically adjusting the ultrasonic emission frequency to form a swept frequency sound field.

[0011] The acoustic radiation force generated by the frequency sweep sound field is used to capture and drive the drug-loaded substance to migrate with the moving acoustic node, so that the drug-loaded substance can achieve large-scale directional enrichment in the target lesion area.

[0012] A reflective interface is provided within the biological cavity or flow field cavity, allowing the incident ultrasound waves and reflected waves to interfere and form a standing wave field. The acoustic field nodes are the sound pressure nodes within this standing wave field, which are used to capture and migrate the drug-loaded substance. By adjusting the focal position of the focusing transducer relative to the lesion region, the enrichment location can be spatially controlled. During the enrichment process, a real-time ultrasound imaging device monitors the relative position of the drug-loaded substance's enrichment location to the lesion region in real time, adjusting the focal position of the focusing transducer accordingly.

[0013] One aspect of this disclosure is a drug enrichment therapy system based on focused ultrasound, comprising:

[0014] A sound field generating device, including a signal generator, a power amplifier and a focusing transducer, is used to generate a focused ultrasonic field and adjust the ultrasonic frequency to form a swept-frequency sound field;

[0015] The acoustically responsive drug carrier can migrate with the sound field nodes under the action of the acoustic radiation force generated by the swept frequency sound field.

[0016] A robotic arm, including a fixture and a multi-degree-of-freedom axis, is used to fix the focusing transducer and adjust its spatial position.

[0017] A real-time ultrasound imaging device is used to observe in real time the relative position of the enrichment location of the drug-loaded substance and the lesion area.

[0018] The terminal device is communicatively connected to the sound field generating device, the robotic arm, and the real-time ultrasound imaging device, and is used to control the coordinated operation of each device to achieve the directional enrichment of the drug-loaded substance in the lesion area.

[0019] The terminal device controls the signal generator to perform the frequency sweep operation and simultaneously receives feedback signals from the real-time ultrasound imaging device to control the enrichment process in a closed loop.

[0020] The focused ultrasonic field generated by the sound field generating device has a frequency range of 0.01 MHz to 10 MHz. The particle size of the acoustically responsive drug-loaded substance ranges from 100 nanometers to 50 micrometers, including at least one of microspheres, bubbles, liposomes, or cells. The terminal device is used to control the signal generator to perform a frequency sweep operation, and the frequency sweep range of the frequency sweep sound field is set according to the center frequency of the focused transducer, with a sweep interval of 0.5 MHz. The frequency sweep range is set between 3.5 MHz and 4.0 MHz, and the frequency scan time is 1.5 seconds.

[0021] This disclosure presents a disease treatment system based on focused ultrasound for in vivo drug enrichment, which achieves large-scale enrichment of drug-loaded substances at the lesion site and improves the efficiency of drug enrichment. Attached Figure Description

[0022] The above and other objects, features, and advantages of this disclosure will become readily apparent from the following detailed description of exemplary embodiments, taken in conjunction with the accompanying drawings. Several embodiments of this disclosure are illustrated in the drawings by way of example and not limitation, in which:

[0023] Figure 1 A schematic diagram of an experimental apparatus according to one embodiment of this disclosure.

[0024] Figure 2 A schematic diagram of particle enrichment at a target location in a focused sound field according to one embodiment of the present disclosure.

[0025] Figure 3 A schematic diagram of material enrichment in a static standing wave acoustic field according to one embodiment of this disclosure.

[0026] Figure 4A schematic diagram of silent field particles according to one embodiment of the present disclosure.

[0027] Figure 5 A schematic diagram of an experimental apparatus according to one embodiment of this disclosure.

[0028] Figure 6 A schematic diagram of the enrichment of drug substance by a focused sound field according to one embodiment of the present disclosure.

[0029] Figure 7 A schematic diagram of the adhesion of drug-eluting microparticles to cell slices under silent field modulation according to one embodiment of this disclosure.

[0030] Figure 8 A schematic diagram illustrating the enrichment of microparticles to the location of a bladder tumor in a live mouse bladder using a focused acoustic field, according to one embodiment of this disclosure.

[0031] Figure 9 A schematic diagram of an ultrasound image (scale bar 2mm) during the treatment of orthotopic bladder cancer in mice according to one embodiment of this disclosure.

[0032] Figure 10 A schematic diagram of a bladder tumor image (scale bar, 2 cm) after treatment for bladder cancer in a mouse, according to one of the embodiments of this disclosure.

[0033] Figure 11 A schematic diagram of a drug-loaded substance in vivo enrichment technology control system under a focused sound field according to one embodiment of the present disclosure. Detailed Implementation

[0034] Currently, in vivo drug enrichment faces challenges such as difficulty in overcoming biological barriers, premature drug leakage, and low drug enrichment rates, making it difficult to concentrate large quantities of drugs at the intended site. Acoustic manipulation offers advantages such as good biocompatibility, non-invasiveness, centimeter-level tissue penetration depth, and high sub-millimeter spatial resolution, enabling precise manipulation of particles of various sizes. However, the main difficulty in existing ultrasound-mediated targeted drug enrichment is its low enrichment efficiency. Current in vivo acoustic manipulation-based targeted drug delivery and enrichment only enriches the drug-loaded material near its focal point (within approximately two wavelengths), failing to enrich most other substances distributed in fluids.

[0035] To address the aforementioned challenges, this disclosure proposes a solution for the large-scale targeted enrichment of in vivo drugs using focused ultrasound. It utilizes a focused sound field to achieve large-scale targeted enrichment of drug-loaded substances for in vivo treatment. The purpose of this disclosure is to achieve large-scale enrichment of drug-loaded substances at the lesion site, improve drug enrichment efficiency, reduce drug exposure in normal tissues, thereby enhancing efficacy and reducing toxic side effects.

[0036] According to one or more embodiments, an in vivo drug enrichment therapy system based on focused ultrasound, such as Figure 11 As shown, the system includes a sound field generating device, a sound-responsive drug-loaded substance, a robotic arm, a real-time ultrasound imaging device, and a terminal device. The sound field generating device includes a signal generator, a power amplifier, and a transducer for emitting a focused sound field and adjusting sound field parameters. The sound-responsive drug-loaded substance includes sound-responsive drug-loadable substances such as microspheres, bubbles, liposomes, and cells. The robotic arm includes a fixator and a multi-degree-of-freedom axis for fixing the transducer and adjusting its spatial position. The real-time ultrasound imaging device is a medical imaging device used to observe the relative position of the sound field enrichment location and the treatment target location in real time. The terminal device is a computer device used to control the sound field generating device, the robotic arm, and the real-time ultrasound imaging device. The applicable ultrasound frequency for the focused sound field is between 0.01 MHz and 10 MHz. The sound field enrichment method uses a focusing transducer, and the spatial position of the enrichment location in the focused sound field is controllable. The focused sound field is used for the directional enrichment of drug-loaded substances in vivo. The size of the drug-loaded substance enriched by the focused sound field is between 100 nanometers and 50 micrometers.

[0037] According to one or more embodiments, a focused ultrasound drug enrichment system for disease treatment is disclosed. To demonstrate the universality of the manipulation method, the focused ultrasound provided in this disclosure is used for the directional enrichment of substances within a flow field cavity. This disclosure compares the substance enrichment efficiency at a target location using a silent field, a static standing wave sound field, and a focused ultrasound sound field. The substance manipulated by the ultrasound in this disclosure is polystyrene (PS) microparticles with a diameter of 20 micrometers.

[0038] In the system of this embodiment, the target sound field is generated by a focusing transducer. The focal position of the transducer is determined according to the target location where the drug substance needs to be enriched. The transducer is an adjustable frequency focusing transducer with a center frequency of 4.0 MHz, a focusing distance of 20 mm, and an aperture of 18.4 mm. The target location is located in the plane of the transducer focal position. A reflecting interface is formed at the top of the fluid cavity, causing the incident wave and the reflected wave to interfere with each other, forming a standing wave field. Here, for the human body, a fluid cavity refers to a cavity with significant acoustic differences from the surrounding tissues, including blood vessels, bladders, etc. Significant acoustic differences mainly refer to the significant differences between fluid cavities (blood vessels, bladders, cysts, gallbladders, stomach cavities, uterine cavities, or pleural cavities, etc.) and surrounding solid tissues in terms of acoustic impedance, echogenicity, and dynamic characteristics, which are common in human organs or tissues.

[0039] A focusing transducer, serving as the sound field emission source, is installed at the bottom of the fluid cavity to generate a focused ultrasonic field. This disclosure uses a swept-frequency sound field in an ultrasonic focused sound field. The swept-frequency sound field is set with a sweep range of 3.5-4.0 MHz, a frequency scan time of 1.5 s, and an electrical signal amplitude of 2.5 Vpp driving the transducer. As a control, a non-ultrasonic sound field is used, where no ultrasonic sound field is set within its fluid cavity. As a control, a static standing-wave sound field is set within the fluid cavity, with a frequency of 4.0 MHz and an electrical signal amplitude of 2.5 Vpp driving the transducer. A schematic diagram of the experimental setup is shown below. Figure 1 .

[0040] Standing wave sound fields can propel particles to sound pressure nodes or anti-nodes through acoustic radiation forces. Compared to static standing wave sound fields, frequency-sweeping sound fields based on focused ultrasound have acoustic nodes that move along the propagation direction due to changes in node distance. During each incremental frequency shift iteration, the node distance decreases, and the acoustic nodes move towards the reflecting interface. Matter in the sound field is trapped at these acoustic nodes and moves towards the interface. At the end of the iteration, when the frequency changes from its maximum to its minimum, matter is trapped at adjacent acoustic nodes and then moves towards the interface in the new iteration. Frequency-sweeping sound fields can be used to enrich drug-loaded substances at the acoustic focus, thereby improving the efficiency of targeted drug enrichment and providing therapeutic effects.

[0041] The expected enrichment location and direction of the drug-loaded substance are determined by the position and direction set by the transducer used. Adjustment of the enrichment location and direction can be achieved using a robotic arm or control platform. The enrichment area is affected by the position and movement rate of the acoustic nodes. The movement of the acoustic nodes varies depending on the signal amplitude, frequency range, and sweep period. The signal amplitude is positively correlated with voltage. The rate of change of the acoustic node position in the sound field is affected by the sweep period and frequency range. The sweep period is inversely proportional to the frequency change; the shorter the period, the faster the frequency change, and vice versa. The frequency is determined by the center frequency of the transducer used, and the frequency range is directly proportional to the node movement rate. The larger the sweep range, the faster the frequency change, and the faster the node movement rate. When the node movement is too fast, the velocity of the captured particles cannot keep up with the node movement rate, resulting in particle loss during the enrichment process and a poorer enrichment effect. When the node movement is too slow, the particles are easily affected by the fluid environment and gravity, leading to a poorer enrichment effect.

[0042] In this embodiment, the fluid cavity is used to contain the drug-loaded fluid to be treated, and the drug-loaded fluid can be directly injected into the fluid cavity through a conduit. Here, PS microparticles with a particle size of 20 μm are selected as the manipulated object, and the drug-loaded microparticles are dispersed in pure water. The microparticles are captured at the acoustic nodes under the action of acoustic radiation force and migrate with the movement of the nodes. This ultimately achieves a directional enrichment effect at the acoustic focal point, such as... Figure 2The enrichment efficiency of microparticles was measured by statistically analyzing the enrichment area. Within 5 minutes, the enrichment area of ​​the microparticles was 200 times that of the group without ultrasound. Figure 3 As shown, this is a static sound field group ( Figure 4 10 times (as shown).

[0043] According to one or more embodiments, a focused ultrasound drug loading system enriches drug loading in an external bladder model using focused ultrasound. By testing the model, the enrichment efficiency of drug loading at target locations is improved. This disclosure also provides a comparison of drug loading efficiency at target locations on cell smears with and without an ultrasound field versus a focused sound field.

[0044] In the sound field setup of this embodiment, the reflecting surface is a cell-covered sheet. The cell-covered sheet forms a reflecting interface, causing the incident wave and the reflected wave to interfere with each other, forming a standing wave field. A schematic diagram of the experimental setup is shown below. Figure 5 .exist Figure 5 The diagram shows that the focusing transducer was placed in water to avoid acoustic impedance mismatch caused by the arc-shaped transducer not making sufficient contact with the bottom of the culture dish during the experiment, which would prevent sound waves from effectively entering the culture dish. Here, the sound field manipulation material was set as drug-loaded microparticles. The microparticles were 20 μm diameter PS microparticles, and the drug was doxorubicin (DOX). Within the same operating time, the drug enrichment area of ​​the focused ultrasound group (…) Figure 6 As shown, it is approximately 40 times that of the non-focused ultrasound group. Figure 7 (As shown). It should be noted that whether the enrichment system, including the transducer, should be placed inside the fluid cavity depends on the situation, as long as the acoustic impedance of each component is matched during the transmission of the sound wave. For example, in in vivo experiments, an ultrasonic coupling agent can be applied to the surface of the transducer to avoid the acoustic impedance mismatch problem caused by air.

[0045] According to one or more embodiments, a method for targeted enrichment of drug-loaded substances in vivo using a focused ultrasound field is disclosed. The fluid cavity used is a mouse bladder, and the drug-loaded substance is drug-loaded microparticles. The microparticles are PS microparticles with a diameter of 20 μm, and the drug is doxorubicin (DOX).

[0046] The drug-loaded substance is injected into the bladder via intravesical instillation. Focused ultrasound is used to concentrate the drug-loaded substance at the bladder tumor site. An ultrasound image of the bladder under focused ultrasound is shown below. Figure 8 Under the influence of a focused sound field, the drug-loaded substance accumulates at the tumor site.

[0047] According to one or more embodiments, an in vivo disease treatment method combining a focused sound field with a drug-loaded substance is disclosed. Here, the fluid cavity is a mouse bladder, and the drug-loaded substance is drug-eluting microparticles. The microparticles are PS microparticles with a diameter of 20 μm, and the drug is doxorubicin (DOX). A mouse orthotopic bladder cancer tumor model is used. The mice are female Balb / c-nu nude mice (6-8 weeks old, 18-20 grams), and the drug-loaded microparticles are injected into the bladder via intravesical instillation. The experiment is divided into a control group, a chemotherapy drug group, and a sound field + drug-loaded microparticle group.

[0048] Focused sound fields are used to concentrate drug-loaded microparticles at the bladder cancer tumor site for treatment. Treatment is administered every two days for a total of four sessions. Ultrasound imaging is used to acquire images of the bladder tumor during the treatment. Figure 9 (As shown). Tumor growth rate under different conditions was measured by the percentage of bladder area occupied by the tumor at the end of treatment. Results showed that tumor growth was uncontrolled in the blank control group during the experiment. On day 8 of treatment, the tumor in the blank group occupied 100% of the bladder area. The chemotherapy drug group occupied 56.5% of the bladder area. The sound field + drug-loaded microparticle group showed a significant anti-tumor effect, with a significantly slower tumor growth rate during treatment. At the end of treatment, the tumor area occupied 22% of the bladder area. After treatment, all experimental mice were euthanized, and tumor images were recorded and weighed (…). Figure 10 (As shown). In the control group, the tumors grew rapidly over time. After 8 days of administration, compared with the blank group, the tumor weight in the sound field + drug-loaded microparticle group decreased by 83.90%. Compared with traditional chemotherapy, the tumor weight in the sound field + drug-loaded microparticle group decreased by 72.43%.

[0049] The beneficial effects of this disclosure include:

[0050] 1. The focused ultrasound field disclosed herein enables the enrichment of drug-loaded substances in vivo.

[0051] 2. In the drug enrichment system disclosed herein, the focused sound field can enrich most of the drug-carrying material in the flow field. Within 5 minutes, the enrichment area of ​​the material is 200 times that of the group without ultrasound and 10 times that of the static sound field group.

[0052] It should be understood that in the embodiments of this disclosure, the term "and / or" is merely a description of the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A existing alone, A and B existing simultaneously, and B existing alone. Additionally, the character " / " in this document generally indicates that the preceding and following related objects have an "or" relationship.

[0053] It is worth noting that although the foregoing has described the spirit and principles of this disclosure with reference to several specific embodiments, it should be understood that this disclosure is not limited to the disclosed specific embodiments, and the division of aspects does not imply that the features in these aspects cannot be combined; such division is merely for the convenience of expression. This disclosure is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

Claims

1. A drug enrichment system, characterized in that, The system includes, A sound field generating device, the device including a focusing transducer for generating a focused sound field, the transmitter of the focusing transducer facing a fluid cavity in a human or animal body to be enriched with a drug. The fluid cavity is injected with drug-loaded particles, and the focusing transducer is controlled to generate a frequency-adjustable focused sound field, so that the drug-loaded particles are concentrated at a preset target location.

2. The system according to claim 1, characterized in that, The preset target position is located on the plane where the focusing transducer's emission focal point is located.

3. The system according to claim 1, characterized in that, The sound field generating device further includes a signal generator and a power amplifier. The sound field generating device uses the signal generator and power amplifier to control the focusing transducer to emit a swept frequency sound field that causes the sound field nodes to move directionally along the direction of sound wave propagation. This causes the drug-loaded particles to migrate directionally with the moving sound field nodes under the action of the acoustic radiation force generated by the swept frequency sound field.

4. The system according to claim 1, characterized in that, The system also includes a robotic arm for setting the focusing transducer and adjusting the spatial position of the focusing transducer.

5. The system according to claim 1, characterized in that, The system also includes a real-time imaging device for observing the relative position of the drug-loaded enrichment location to the lesion area in real time.

6. The system according to claim 1, characterized in that, The system includes a terminal device that is communicatively connected to the sound field generating device, the robotic arm, and the real-time imaging device, and is used to control the coordinated operation of each device to achieve the directional enrichment of the drug-loaded particles in the lesion area.

7. The system according to claim 1, characterized in that, The drug-loaded particles are at least one of microspheres, bubbles, liposomes, or cells.

8. A method for drug enrichment, characterized in that, The method includes the following steps: Introducing acoustically responsive drug-loaded particles into a fluid cavity within a human or animal body containing a lesion area; A focused sound field is formed inside the fluid cavity using a focusing transducer, and a swept sound field is formed by adjusting the sound field emission frequency to make the sound field nodes move directionally along the sound wave propagation direction. The drug-loaded particles are captured and driven to migrate with the moving acoustic nodes by the acoustic radiation force generated by the frequency sweep sound field, so that the drug-loaded particles can be directionally enriched in the lesion area.

9. The method according to claim 8, characterized in that, The frequency modulation range of the focused sound field is from 0.01 MHz to 10 MHz.

10. The method according to claim 9, characterized in that, The sweep frequency range of the sweep frequency sound field is set according to the center frequency of the focusing transducer, with a sweep frequency interval of 0.5MHz.

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