Enhanced ultrasound ablation by bubbles formed from cluster compositions administered to patients

Abstract

Methods of enhancing ultrasound ablation and compositions for use thereof are provided. The method comprises: generating at least one ablation assisting bubble near a target region by: administering to a subject a cluster composition comprising a microbubble component and a droplet component, wherein the cluster composition comprises at least one cluster; and activating a phase change transformation of the droplet components of the at least one cluster by the action of an ultrasonic sound wave to produce at least one ablation assist bubble; wherein the expansion of the at least one cluster to the at least one ablation assist bubble provides mechanical stress on the target region to assist ablation on the target tissue in the target region.

Description

Background Art

[0001] Tissue ablation therapy

[0002] In tissue ablation therapy, tissue layers are locally destroyed as a result of exposure to a destructive environment. Ultrasound is well suited for ablation therapy because it can generate both mechanical and thermal energy in a targeted area and can transmit this energy via pressure waves.

[0003] HIFU

[0004] High Intensity Focused Ultrasound (HIFU) induces destructive effects in a defined target tissue volume to achieve direct or indirect cell death. HIFU has two mechanisms of action: thermal ablation and mechanical tissue destruction. The thermal effect can be hyperthermia, in which the temperature of the tissue increases. In particular, the thermal effect of HIFU is a rapid increase in temperature in the local tissue due to the generation of heat by the absorption of acoustic energy, resulting in instantaneous and irreversible cell death through coagulative necrosis. The mechanical effect is cavitation, in which the HIFU acoustic field interacts with bubbles in the targeted tissue. Cavitation refers to a complex series of phenomena involving the generation, oscillation, growth and collapse of bubbles within the medium.

[0005] The effectiveness of HIFU for tissue ablation depends on the frequency of the HIFU field and the depth of the target tissue area. For target tissues that are far from the HIFU source or located so that there is a strong attenuating medium between the HIFU source and the target tissue, the HIFU must have a lower frequency (e.g., a frequency less than 1 MHz) to ensure effectiveness. Some examples of such target tissues include target tissues within the skull or target tissues in the mid-abdomen, such as certain areas of the pancreas or liver. For target tissues located on the surface of the body or closer to the HIFU source, the optimal frequency is higher, such as a frequency greater than 10 MHz.

[0006] The HIFU treatment volume length can be approximated to be inversely proportional to the HIFU frequency, and inversely proportional to the physical size of the HIFU source. Therefore, in order to achieve effective thermal ablation with HIFU in target tissue that is far from the HIFU source, or located so that there is a strong attenuating medium between the HIFU source and the target tissue, and the thickness is small, the HIFU source must have a large physical size to reduce the risk of adverse effects associated with depositing too much energy into the volume of surrounding healthy tissue.

[0007] HIFU with Microbubble Technology

[0008] Increasing the acoustic intensity and / or extending the duration of sonication can change the outcome of the treatment, such as more effectively destroying a larger volume of the target tumor. However, if the acoustic intensity is too high, there is a risk of depositing too much energy into the healthy tissue volume surrounding the target and / or close to the HIFU source. This can lead to adverse effects.

[0009] Mainly, thermal techniques such as HIFU have previously been combined with microbubble techniques to reduce damage to surrounding healthy tissue. Some examples of microbubble techniques are preformed lipid-coated microbubbles that are primarily developed for ultrasound imaging. Due to the compressible gas core of the lipid-coated microbubbles, the microbubbles echo and have strong absorptivity in a specific frequency band that depends on the diameter of the microbubbles, so the lipid-coated microbubbles can be contrast agents for ultrasound imaging. When insonated with a HIFU field in this frequency band, the microbubbles absorb energy from the HIFU field more effectively than the surrounding target tissue, and thus the acoustic intensity threshold for ablation can be reduced, thereby minimizing the thermal accumulation of heat in the surrounding tissue that can be associated with HIFU.

[0010] Microbubbles can induce additional heating of the target area through oscillation and cavitation, as well as generate shock waves, which deliver additional thermal energy to the HIFU alone.Thus, the addition of microbubbles near the HIFU target area can enhance the ablation effect.

[0011] The microbubbles can be injected into a subject and travel through the subject's circulatory system until they are close to the target site. The method can reduce the energy deposition required to achieve tissue ablation, shorten and optimize treatment time and adverse event rates.

[0012] However, there are several limitations to using conventional microbubbles together with thermal ablation techniques. The first limitation is that microbubbles have a short circulation time of about 2 to 3 minutes. HIFU requires significantly longer time to set up and perform. Before implementing the HIFU method, the microbubbles may have dissolved and / or dissipated. Another limitation is that these small microbubbles cannot be effectively coupled with low-frequency ultrasound (e.g., low-frequency ultrasound for transcranial application). Another limitation is that microbubbles have low spatial selectivity, have a residence time of the order of seconds in the target tissue, and can cause unintended heating away from the target site.

[0013] Therefore, due to the above-mentioned limitations of HIFU and HIFU in combination with diagnostic microbubbles, the limitations of ultrasound ablation technology remain unsolved.

[0014] This application combines ultrasound technology with acoustic cluster therapy (ACT) combination to solve the above limitations. Summary of the invention

[0015] According to one aspect of the present invention, a method for enhancing ultrasonic ablation is provided, which includes: generating at least one ablation assisting bubble near a target area by: administering to an object a cluster composition comprising a microbubble component and a microdroplet component, wherein the cluster composition comprises at least one cluster; and activating a phase change transformation of the microdroplet component of at least one cluster by ultrasonic sound wave action to generate at least one ablation assisting bubble; wherein expansion of the transformation from at least one cluster to at least one ablation assisting bubble provides mechanical stress on the target area to assist ablation on target tissue in the target area.

[0016] The at least one ablation assisting bubble may have a diameter of at least 10 microns.

[0017] The method may also include subjecting at least one ablation assisting bubble to insonation with ultrasound of a predetermined intensity to induce at least one of energy absorption, deposition, oscillation and cavitation of the ablation assisting bubble to provide additional mechanical stress and / or thermal stress on the target area to assist ablation on the target tissue in the target area.

[0018] The predetermined intensity of ultrasound used to insonate the ablation-assisting bubble may be equal to the intensity of non-bubble-assisted ultrasound ablation divided by a factor of 12 to 24.

[0019] The enhanced ultrasound ablation may be configured to provide a resulting temperature of 30 to 70 degrees Celsius in the target region for a continuous exposure time of at least 30 seconds.

[0020] The method may further include using the at least one ablation assisting bubble for real-time imaging of the target area by insonating the at least one ablation assisting bubble with imaging ultrasound, and wherein the at least one ablation assisting bubble is induced as a hyperechoic spot.

[0021] The method may further include a further step of ultrasound planning, which includes planning a specific ultrasound exposure protocol using the unique subject and application specific information, wherein the ultrasound planning includes at least one of passive ultrasound planning and active ultrasound planning.

[0022] Passive ultrasound planning may be based on one or more of: physiological information, anatomical structures in the ablation zone, cross-modality imaging and co-registration, and data defining the subject's anatomy retrieved from software.

[0023] Active ultrasound planning may include: monitoring the ablation zone during the enhancement step for real-time feedback of the ablation zone; and adjusting a specific ultrasound exposure regimen to achieve predetermined parameters in the ablation zone; wherein the steps of monitoring and adjusting are performed on a continuous basis for a predetermined duration.

[0024] Monitoring the ablation zone during the enhancement step for real-time feedback of the ablation zone may include at least one of real-time temperature feedback, real-time mechanical feedback, cross-modality imaging and registration, real-time monitoring of cluster dynamics and concentration, and real-time monitoring of ablation-assisting bubble dynamics and concentration.

[0025] Monitoring the target area (including the ablation zone) may also include imaging by an image-guided modality, wherein the image-guided modality includes at least one of the following: magnetic resonance guidance, ultrasound guidance, computed tomography guidance, optical guidance, thermocouple guidance, and contrast-enhanced ultrasound guidance.

[0026] The method may further include co-administering a therapeutic agent configured to assist in the effectiveness of ablation, the therapeutic agent being administered prior to the cluster composition, and / or concurrently with the cluster composition, and / or separately after the cluster composition.

[0027] According to a second aspect of the present invention, there is provided an intravenously administrable composition for use in a method for enhancing ablation at a target area, the composition comprising: a microbubble / microdroplet cluster composition that forms at least one cluster by electrostatic force; and wherein, when the method comprises exposing the at least one cluster to effectively exposed ultrasound, each of the at least one cluster is configured to oscillate, expand and fuse into a single entity, thereby providing an ablation-assisting bubble.

[0028] When the method further comprises exposing the resulting ablation assisting bubble to ultrasound of a predetermined intensity, the ablation assisting bubble may be configured to oscillate and / or cavitate to induce mechanical and / or thermal stress on the target area to improve ablation efficiency in the target area.

[0029] The resulting ablation-assisted bubble can be configured to induce mechanical and / or thermal stress on the target area comparable to that induced from direct ultrasonic insonation, wherein the predetermined intensity is equal to the intensity of non-bubble-assisted ultrasonic ablation divided by a factor of 12 to 24.

[0030] The microbubble / microdroplet cluster composition can be formed from: a cluster dispersion of microdroplets having a median diameter of 2 to 3 μm, which are stabilized by a lipid membrane with a net positive surface charge; and microbubbles having a median diameter of 2 to 3 μm, which are stabilized by a lipid shell with a net negative surface charge.

[0031] The net positive surface charge of the microdroplets and the net negative surface charge of the microbubbles may provide electrostatic forces that enable at least one microbubble / microdroplet cluster to form.

[0032] The resulting clusters formed may be 4 to 8 μm in diameter.

[0033] The gas of the microbubbles in at least one microbubble / microdroplet cluster may comprise sulfur hexafluoride or a C3-6 perfluorocarbon or a mixture thereof.

[0034] The oil phase of the microdroplets in at least one of the microbubble / microdroplet clusters may comprise a partially halogenated hydrocarbon or a fully halogenated hydrocarbon or a mixture thereof.

[0035] The composition of the second aspect of the invention may be used to treat one or more of a tumor, a space occupying mass, thrombolysis and a nervous system disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The invention is shown for Flowchart of a method for enhanced ultrasound ablation;

[0037] Figure 2 Shown for A step-by-step schematic diagram of the method for enhanced ultrasound ablation;

[0038] Figure 3 A graph showing the number of ablation-assisted bubbles generated at different frequencies versus the mechanical index is shown;

[0039] Figure 4a is a schematic diagram of a first example transducer having a relatively low operating frequency and a relatively large aperture;

[0040] Figure 4b is a schematic diagram of a second example transducer having a relatively high operating frequency and a relatively large aperture;

[0041] Figure 4c is a schematic diagram of a third example transducer having a relatively low operating frequency and a relatively small aperture;

[0042] Figure 4d is a schematic diagram of a fourth example transducer having a relatively high operating frequency and a relatively small aperture;

[0043] Figure 5a yes Figures 4a to 4d A schematic diagram of a first example combination of transducers;

[0044] Figure 5b yes Figures 4a to 4d a schematic diagram of a second example combination of transducers;

[0045] Figure 5c yes Figures 4a to 4d a schematic diagram of a third example combination of transducers;

[0046] Figure 5d yes Figures 4a to 4d a schematic diagram of a fourth example combination of transducers;

[0047] Figure 6a is a schematic diagram of another example configuration of a transducer;

[0048] Figure 6b is a schematic diagram of another example configuration of a transducer;

[0049] Figure 7a is a schematic diagram of another example configuration of a transducer;

[0050] Figure 7b is a schematic diagram of yet another example configuration of a transducer;

[0051] Figure 8a is a graphical representation of the calculation of the maximum differential volume of an ablation assisting bubble oscillating in the first oscillation mode in a free field with a mechanical index of 0.4;

[0052] Figure 8b is a graphical representation of the calculation of the maximum differential volume of an ablation assist bubble oscillating in a first oscillation mode in a free field with a mechanical index of 0.6; and

[0053] Figure 8c is a graphical representation of the calculation of the maximum differential volume of an ablation assist bubble oscillating in the first oscillation mode in a free field with a mechanical index of 0.8.

[0054] definition

[0055] Unless otherwise defined, all technical terms, symbols and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those skilled in the art to which the invention belongs. In some cases, for clarity and / or for ease of reference, terms with commonly understood meanings are defined herein, and the inclusion of such definitions herein should not necessarily be construed as representing a significant difference beyond what is commonly understood in the art.

[0056] As used herein, "subject" means any human or non-human animal individual selected for treatment or therapy, and encompasses and may be limited to patients, particularly human patients.

[0057] "Sonication" or "ultrasonic insonation" are terms used to describe exposure to or treatment with ultrasound.

[0058] The term frequency is defined as the number of (ultrasound) cycles per second (Hz). As used herein, this term refers to the central frequency of the applied acoustic field.

[0059] The term "conventional medical imaging ultrasound" is used to describe ultrasound from commercially available ultrasound scanners and probes used for medical imaging.

[0060] The term "high-intensity ultrasound" or "HIFU" is used to describe ultrasound with intensities above the diagnostic limit.

[0061] The term "droplet" is used to describe emulsion droplets having a diameter of 0.2 to 10 μm.

[0062] The term "microbubbles" or "conventional contrast microbubbles" is used to describe gas bubbles with or without a stabilizing shell, which have a diameter of 0.2 to 10 μm, typically with an average diameter of 2 to 3 μm. "Conventional contrast microbubbles" include commercially available agents, such as (GE Healthcare), (GE Healthcare), (Bracco Spa.), (Lantheus Medical Imaging), (VisualSonics Inc.) and Polyson (Miltenyi Biotec GmbH).

[0063] The terms "microbubble / microdroplet cluster composition", "microbubble and microdroplet cluster composition" or "cluster composition" refer to a composition having a first component of microbubbles and a second component of microdroplets, particularly oil droplets.

[0064] The term "clustering" refers to the process by which microbubbles in the first component and microdroplets of the second component form clusters.

[0065] The term "cluster" refers to groups of microbubbles and microdroplets in a cluster composition that are permanently held together by electrostatic attraction to form a single aggregated entity.

[0066] The term "phase change" is used to describe the phase transition of a substance from a liquid state to a gaseous state. Specifically, the oil component of the droplets in the cluster changes state from a liquid state to a gaseous state under the action of ultrasonic sound waves.

[0067] The term "activation" or "activation step" refers to the induction of a phase transition of the microbubble / microdroplet clusters by ultrasonic insonation.

[0068] The term "ablation-assisted bubble" or "AA bubble" is used herein to describe the large (>10 μm) bubbles formed following ultrasound-induced cluster activation (ie, bubbles resulting from the "activation step").

[0069] The term "enhancing" or "enhancing step" refers to the induction of volume oscillations and / or cavitation of the ablation-assisting bubble by ultrasound insonation and the resulting biomechanical effects.

[0070] Acoustic Cluster Therapy or "ACT The invention relates to a process of administering a cluster composition to a subject, activating a phase change of at least one of the generated clusters by ultrasonic insonation to generate an ablation-assisting bubble, and using the ablation-assisting bubble in an additional enhancement step. DETAILED DESCRIPTION

[0071] The present invention provides enhanced ablation therapy ( Enhanced ablation therapy), especially enhanced ultrasound ablation ( Enhanced ultrasound ablation therapy).

[0072] Reference Figure 1 , sound cluster therapy Enhanced ablation therapy includes:

[0073] (i) administering to a subject 10 a cluster composition, the cluster composition forming one or more clusters in which microbubbles and microdroplets are permanently held together by electrostatic attraction;

[0074] (ii) optionally, imaging 20 the one or more clusters using ultrasound imaging to determine a region of interest (target region) within the subject for treatment;

[0075] (iii) an activation step 30 comprising activating a phase change of a diffusible component of the droplets of the cluster from step (i) by ultrasonic insonation at an activation frequency and optionally an activation mechanical index to form at least one ablation-assisting (AA) bubble in the target area;

[0076] (iv) optionally, a enhancing step 40 comprising insonifying the at least one AA bubble with ultrasound to induce oscillation and / or cavitation of the at least one AA bubble;

[0077] (v) optionally, a monitoring step comprising monitoring the effects of the insonation during the enhancing step (iv) and adjusting at least one ultrasound parameter based on a suitable metric (e.g., ablation efficacy, temperature in the target region, and / or bubble oscillation dynamics in the target region); and

[0078] (vi) Optionally, an iterative step, wherein steps (iv) and (v) are repeated for a specified period of time.

[0079] Application

[0080] The cluster composition is administered parenterally, preferably intravenously, to a subject. Due to the attractive electrostatic forces of the composition components, the cluster composition forms one or more clusters of agglomeration. One or more clusters may be formed before or after administration in a subject. Preferably, one or more clusters are formed before administration in a subject.

[0081] In one example, the microbubble and microdroplet cluster compositions are formed by cluster dispersions of microdroplets (second component) stabilized by lipid membranes with a net positive surface charge and microbubbles (first component) stabilized by lipid shells with a net negative surface charge. In one example, the median diameter of both microdroplets and microbubbles is 2 to 3 μm. The net positive surface charge of the microdroplets and the net negative surface charge of the microbubbles provide electrostatic forces that enable at least one cluster to form.

[0082] In one example, the first component comprises a dispersed gas selected from sulfur hexafluoride, perfluoropropane, perfluorobutane, perfluoropentane, and perfluorohexane, or a mixture thereof, which is stabilized by a first stabilizer selected from phospholipids, proteins, and polymers. The second component comprises a diffusible component selected from perfluorocarbons (e.g., perfluorocycloalkanes), which is stabilized with a second stabilizer selected from surfactants (e.g., including phospholipids, polymers, and proteins). More specifically, any one of the stabilizers is selected from phospholipids.

[0083] In one specific example, the first component consists of perfluorobutane (PFB) microbubbles stabilized by a hydrogenated egg phosphatidyl serine-sodium (HEPS-Na) membrane and embedded in freeze-dried sucrose. HEPS-Na carries a negatively charged head group, so the microbubbles have a negative surface charge. Each vial of the first component contains about 16 μL or 2·109 microbubbles with an average diameter of about 2.0 μm. The freeze-dried preparation shows a long shelf life when stored at ambient room temperature, more specifically 3 years. In this specific example, the second component consists of perfluoromethyl-cyclopentane (pFMCP) droplets stabilized by a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) membrane and 3% mol / mol stearylamine (SA) is added to provide a positive surface charge. The droplets in the second component are dispersed in 5mM TRIS buffer. In this specific example, the standard formulation of the second component contains about 4 μL or 0.8·109 droplets / mL, and its average diameter is about 1.8 μm. The second component shows a long shelf life when stored in a refrigerator, more specifically 18 months or longer. The cluster composition is aseptically prepared by reconstructing the vial of the first component with 2mL of the second component and then manually homogenizing for 30 seconds. 2mL is taken out from the vial of the second component using a sterile, disposable syringe and needle. The contents of the syringe are added through the stopper of the vial of the first component, and the resulting cluster composition is homogenized to prepare a composition for administration.

[0084] Imaging

[0085] The method may include an optional step of imaging the microbubble component of the cluster using a low mechanical index (MI) contrast agent imaging mode to determine the pathological location for treatment. In the low MI contrast agent imaging mode, the MI of the ultrasound used for insonation is less than 0.1. Since the cluster is not activated at low MI (below the activation threshold), standard medical ultrasound contrast agent imaging can be performed without triggering cluster activation. Therefore, the cluster can be used for imaging, for example, to determine the tumor microvascular pathology before the subsequent steps of the ablation method of the present invention.

[0086] activation

[0087] After cluster formation and administration, clusters can be activated within, at, or near the target area by applying ultrasonic energy to the target area and target site. Alternatively, clusters can be activated in feeding arteries outside the target area, and activated bubbles can be deposited in the capillary bed closest to the target area downstream of the activation site. Thus, by spatially localizing the application of ultrasonic energy to activate clusters, activated AA bubbles can be spatially localized in a target tissue or organ, such as near a tumor.

[0088] During the activation step 30, the cluster microbubbles oscillate and transfer energy to the cluster microdroplets. The oscillating microbubbles induce transient vaporization (phase change) of the attached microdroplets, resulting in the formation of AA bubbles. The AA bubbles temporarily deposit (reside) in the microvasculature of the subject. Specifically, the activated AA bubbles are temporarily deposited in the capillary bed closest to the downstream of the activation site in an amount related to the blood perfusion of the tissue.

[0089] Since the resonant frequency of the microbubble components is typically 2 to 5 MHz, the clusters are easily activated by frequencies of conventional medical imaging of 1 to 10 MHz with MI above 0.1. However, the activation frequency of the clusters is application dependent, and frequencies of 50 kHz to 20 MHz are possible.

[0090] In one example, the clusters are activated with standard diagnostic ultrasound imaging pulses (1 to 10 MHz) commonly used in conventional medical ultrasound.Preferably, the ultrasound imaging pulses have a MI of 0.1 to 0.4, more preferably 0.15 to 0.3.

[0091] In one embodiment, and with reference to Figure 2, the activation step begins immediately after each application of the cluster composition, for example within 20 seconds, and preferably lasts for about 60 to 120 seconds. Activation under medical ultrasound imaging control using imaging pulses allows spatially targeted activation of clusters in tissue regions interrogated by ultrasound fields. After activation, the generated AA bubbles 102 are temporarily captured in the microvasculature 106 of the target pathological condition due to their large size. The AA bubbles 102 are about 1000 times the volume of the pre-existing emulsion droplets before vaporization. For example, AA bubbles with a diameter of 20 μm can be generated by pre-existing oil droplets with a diameter of 2 μm. The diameter of the activation bubble (AA bubble) is typically about 20 μm. The activated AA bubble can gradually shrink and move further down in the capillary tree by intermittent stays and movements, and then is completely cleared after typically 5 to 15 minutes.

[0092] Figure 3 A graph 200 of the number of successfully activated AA bubbles / μL versus MI at three different frequencies is shown. The frequencies are 0.5 MHz, 1 MHz, and 2 MHz. The graph shows that when insonation is performed with an ultrasound field having a frequency of 2 MHz and an MI of 0.5, the peak number per μL is about 640 AA bubbles / μL. Preferably, the number of AA bubbles produced per μL is greater than 300. Thus, according to Figure 3 , an ultrasonic field with a frequency of 2 MHz and an MI of 0.29 to 0.6 is suitable. In the case of an MI of 0.65 and above, an ultrasonic field with a frequency of 1 MHz is suitable. In the case of an MI of 0.7 and above, an ultrasonic field with a frequency of 0.5 MHz is suitable.

[0093] Enhancement

[0094] The enhancement step 40 includes transmitting ultrasonic energy to the AA bubble to induce at least one of energy absorption, deposition, oscillation and cavitation of the activated AA bubble to provide additional mechanical stress and / or thermal stress on the target area, in addition to the mechanical stress and / or thermal stress directly derived from the ultrasonic insonation on the tissue that has the effect of increasing the effectiveness of cell ablation in the target area. The ablation frequency can be the same or different from the ultrasonic frequency used in the activation step. In some examples, the pulse amplitude of the ultrasound associated with the enhancement step is different from the pulse amplitude of the activation step.

[0095] Further references Figure 2, the ultrasound insonation induces controlled volume oscillations 104 of the activated AA bubbles, preferably until cavitation, thereby exerting biomechanical forces on tissue in the target area. Thus, it has been discovered that applying ultrasound at or close to the cavitation frequency of the AA bubbles can be used to generate additional mechanical and / or thermal bioaction mechanisms to enhance the ablation therapy efficacy along with the effects from focusing ultrasound directly onto tissue in the target area. This results in enhanced destruction of the target tissue.

[0096] Ultrasound exposure depends on the frequency, exposure time, transducer characteristics (e.g., geometry and configuration - total power delivered), acoustic pressure and intensity, and energy delivery mode. A specific ultrasound exposure regimen is selected based on the tissue type of the target area, the desired ablation effect, and the ultrasound delivery pathway, as will be explained in more detail below.

[0097] Preferably, the frequency of the ultrasound insonation during the boost phase is less than 3 MHz, and more preferably less than 1 MHz. However, depending on the location of the target treatment volume in the subject and the tissue characteristics of the volume, the frequency may be outside this range. In the target volume, the target MI of the ultrasound field is preferably greater than 0.4, more preferably greater than 0.6, and even more preferably greater than 0.8.

[0098] Depending on the specific application, the target time-averaged intensity of ultrasound for ablation is up to 5000 W / cm 2 In the case where AA bubbles are present in the target tissue, the intensity required to achieve the same ablation amount is reduced to less than 1 times, preferably less than 1 / 8, more preferably less than 1 / 16, further preferably less than 1 / 24, further preferably less than 1 / 50, and further preferably less than 1 / 100.

[0099] The enhancing step 40 is performed non-invasively or invasively, and may be performed by a focused ultrasound array or a focused mono-element ultrasound transducer, or by one or more surgically implanted ultrasound transducers.

[0100] The method may include steps of two different insonifications for an activation step and an enhancement step. After the activation step is completed, the insonification may be stopped before an additional insonification occurs in the enhancement step. The parameters of the ultrasound field may be modified for the additional insonification. Alternatively, the ultrasound field provided for the insonification in both the activation step and the enhancement step may remain unchanged and have the same parameters (i.e., frequency, intensity, MI) throughout the ACT enhanced ablation treatment. This is possible because the use of AA bubbles reduces the ultrasound power required to achieve the desired ablation effect. This may be advantageous because it simplifies the process, for example, only one sensor device is required.

[0101] It has been shown that the combination of ultrasound and AA bubbles can reduce the acoustic energy level required for ablation therapy to 1 / 100 or less. The ultrasound field interacts with the AA bubbles in the form of acoustic cavitation. This causes the AA bubbles to oscillate, grow, and collapse. Acoustically driven AA bubble oscillations lead to heat generation, fluid microflows near the bubbles, and local shear stresses. The absorption of energy when ultrasound propagates through the medium also produces a thermal effect. In tissue, the absorption rate increases with frequency. AA bubbles can produce higher harmonics of the excitation frequency, further enhancing the thermal effect.

[0102] Ultrasound plan

[0103] The optional ultrasound planning step may include a first passive ultrasound planning step and a second active ultrasound planning step.

[0104] In the first passive ultrasound planning step, unique subject and application specific information is collected and processed to plan a specific ultrasound exposure protocol. This information may include physiological information and anatomical structures in the ablation zone, and uses anatomy determination software. The software used to define the anatomy enables treatment of different types of patients to deliver the exact thermal dose.

[0105] An example of a type of physiological information used in ultrasound planning is the perfusion of different organs. When planning ultrasound exposures, heat sensitive organs, such as the diaphragm, bowel, and spinal cord, are anatomical structures of particular interest in the ablation zone.

[0106] In the second active ultrasound planning step, real-time feedback of conditions in the ablation zone can be used to adjust ultrasound parameters in an iterative process to ensure optimal conditions throughout the ACT enhanced ultrasound ablation method. Real-time feedback can include: real-time temperature feedback, real-time mechanical feedback, cross-modality imaging and registration, real-time monitoring of cluster dynamics and concentration, and real-time monitoring of AA bubble dynamics and concentration.

[0107] Real-time mechanical feedback can be obtained by using ultrasound for cavitation detection. Since the generated AA bubbles are highly echogenic, ultrasound backscatter from the AA bubbles themselves can be used in imaging for cavitation detection. Real-time mechanical feedback can also be obtained by shear wave monitoring (i.e., using elastography).

[0108] Real-time temperature feedback can be obtained using thermocouples, fiber optic thermal sensors, and Magnetic Resonance Imaging (MRI).

[0109] During the ablation process, ultrasound parameters may be modified based on real-time feedback evaluated for desired ablation zone conditions. For example, ablation efficacy, temperature in the target area, and bubble oscillation dynamics in the target area may be modified based on real-time feedback. Collecting real-time feedback (monitoring) and re-adjusting ultrasound parameters accordingly may be implemented in a continuous feedback loop for the duration of the ablation treatment or for a predetermined duration (e.g., the duration of an enhancement step).

[0110] The optimal choice of ultrasound frequency is application specific and represents a compromise between treatment depth and desired heating rate. Frequencies around 1 MHz have been found to be most useful for heat deposition, with frequencies as low as 0.5 MHz used for deep treatments or with large absorption portions in the propagation path (transcranial application), and frequencies as high as 8 MHz used for surface treatments (e.g., prostate and melanoma).

[0111] The threshold thermal dose for achieving the desired thermal effects, which include irreversible damage and coagulation of key cellular proteins, tissue structural components, and vasculature, leading to immediate tissue destruction, varies with tissue type and exposure time. For normal tissue, the temperature range is 30°C to 77°C, while for tumor tissue, the temperature range is 41°C to 64°C. For most applications, the threshold thermal dose is in the range of 43°C to 65°C, and the exposure time is about 30 seconds.

[0112] monitor

[0113] The ablation zone benefits from careful monitoring and provides real-time feedback for the second active ultrasound planning step. As described above, monitoring of the ablation zone may include monitoring temperature, mechanics, dynamics and concentration of clusters and bubbles. A variety of methods may be used to monitor the ablation zone.

[0114] A particular method of monitoring the ablation zone is to use an image-guided modality. Examples of image-guided modalities include magnetic resonance (MR) guidance, ultrasound guidance, computer tomography (CT) guidance, optical guidance, thermocouple guidance, and contrast-enhanced ultrasound guidance, or a combination thereof.

[0115] The scattering cross section of AA bubbles is several orders of magnitude larger than the scattering cross section of the micron-sized microbubbles contained in the cluster before activation. Therefore, AA bubbles generate a large amount of backscattered signal and are easily imaged with a diagnostic imaging system in a basic imaging mode. The resonant frequency of AA bubbles is also one order of magnitude lower (about 0.2 to 0.8 MHz) than the resonant frequency of the microbubbles contained in the cluster before activation.

[0116] MRI-guided ablation therapy has excellent anatomical resolution and, in particular, high sensitivity for tumor detection, providing accurate planning of the tissue to be targeted. In order to be used in the high magnetic fields of MRI, ultrasound transducers must be specially designed for compatibility. MR-guided ultrasound has the additional advantages of providing soft tissue contrast, quantitative temperature measurement, temperature feedback control, and diagnosis, but its accessibility is limited. MRI is very sensitive to temperature changes and therefore can provide continuous, real-time thermal data feedback throughout the procedure. MRI is particularly suitable for ACT-enhanced ablation therapy, in which biomechanical effects compensate for thermal effects and, therefore, the temperatures generated by the process can be relatively low in terms of ablation.

[0117] Ultrasound guided ablation therapy is widely available, has good temporal resolution, provides soft tissue contrast and diagnosis, and provides qualitative feedback. An ultrasound diagnostic transducer is often incorporated into the treatment tip, which allows real-time imaging of the ablation process.

[0118] Magnetic Resonance-guided Focused Ultrasound (MRgFUS) is a type of MRI-guided ablation therapy. During the MRgFUS procedure, the patient is awake and the functional effects of the procedure are clinically assessed throughout. The operator continuously controls and refines the area of ​​interest (target) and selects the properties of the incident ultrasound field with respect to MI level and number of insonation events.

[0119] The median duration of a MRgFUS procedure, which includes acquisition of the planning sequence, targeting, and sonication, is approximately 1 hour. If necessary, injections or infusions of the ACT microcluster composition can be repeated to cover the MRgFUS procedure time span.

[0120] hardware

[0121] ACT enhanced ultrasound ablation may use one or more ultrasound transducers or transducer arrays to provide the ultrasound field for the activation step, and optionally, for the imaging, enhancement, and monitoring steps of the procedure.

[0122] The ultrasound probe provides the ultrasound field for insonation during the activation step and the enhancement step. The use of AA bubbles may not require HIFU, so the ultrasound probe may include a commercially available transducer that is not specifically designed for HIFU applications.

[0123] Extracorporeal ultrasound devices are typically used for targets located within the breast, abdomen, brain, or limbs. Percutaneous treatment requires an appropriate acoustic window over the access site that provides a propagation path for the focused ultrasound beam that is not disturbed by intervening gases.

[0124] In one embodiment, an external (non-invasive) transducer is used. Such an external transducer provides the opportunity to combine the ACT technique with MRI-guided focused ultrasound (MRgFUS).

[0125] In one example, the selected ultrasound transducer transmits ultrasound waves at a frequency of 1 to 5 MHz with focused intensity and about a -6 dB beam size, where the -6 dB beam size is about 1 to 3 mm in width and about 10 mm in length depending on the geometry and acoustic parameters.

[0126] The ultrasound transducer may be a static transducer that provides a single exposure and is suitable for a small volume of target area. The volume of the target area that can be treated by a static transducer depends on the specific frequency and geometry of the transducer, and also the position of the target area relative to the transducer. The treatable volume can be approximated as an ellipsoid with principal diameters A, B, C, so the treatment volume is approximately:

[0127]

[0128] Example values ​​for major axis diameters A and B are 1 to 3 mm, and an example value for major axis diameter C is 10 mm. Thus, an example treatment volume is 5 to 50 mm 3 .

[0129] The ultrasound probe may also include an ultrasound transducer that provides the ability to direct the ultrasound field toward multiple target areas by one of the following means: physically rotating and / or translating the transducer array within the ultrasound probe housing; or electronically exciting specific transducer elements in a specific sequence. Thus, the probe is suitable for target areas of larger volumes, for example, a volume range that is several times that of a static transducer.

[0130] The probe can be used in combination with a catheter or in a closed enclosure for in vivo administration of ultrasound, such as when the volume of interest is in the prostate and the probe is inserted into the urethra or rectum. Other applications may require such a device to be inserted into a suitable orifice (e.g., vagina, nasal cavity, oral cavity, or esophagus) for use.

[0131] The probe may include a therapeutic transducer designed to deliver ultrasound at higher power and relying on the same principles as conventional ultrasound transducers.

[0132] The probe may include two or more transducers or array transducers operating at independent frequencies, wherein a first set of transducers or transducer array provides insonification during the activation step and a second set of transducers or transducer array provides insonification during the enhancement step.

[0133] Figure 4a30 is a schematic diagram of a first example transducer 301 having a relatively low operating frequency, e.g., about 1.25 MHz, and a relatively large aperture, e.g., about 50 mm. Line 302 represents the range of an ultrasound beam emitted to the left, and a second line 303 represents the range of an ultrasound beam emitted to the right. Oval 304 represents the area where the intensity of the emitted ultrasound beam is highest.

[0134] Figure 4b 30 is a schematic diagram of a second example transducer 308 having a relatively high operating frequency, such as about 2.5 MHz, and a relatively large aperture, such as about 50 mm. A first line 309 represents the range of an ultrasound beam emitted to the left, and a second line 310 represents the range of an ultrasound beam emitted to the right. An ellipse 311 represents the area where the intensity of the emitted ultrasound beam is the highest.

[0135] Figure 4c is a schematic diagram of a third example transducer 305 having a relatively low operating frequency, such as about 1.25 MHz, and a relatively small aperture, such as about 25 mm. A first line 306 represents the range of an ultrasound beam emitted to the left, and a second line 307 represents the range of an ultrasound beam emitted to the right.

[0136] Figure 4d 31 is a schematic diagram of a fourth example transducer 312 having a relatively high operating frequency, such as about 2.5 MHz, and a relatively small aperture, such as about 25 mm. A first line 313 represents the range of an ultrasound beam emitted to the left, and a second line 314 represents the range of an ultrasound beam emitted to the right. An ellipse 315 represents the area where the intensity of the emitted ultrasound beam is the highest.

[0137] Transducers 301 , 305 , 308 , and 312 are depicted as being planar, but may also have curved shapes.

[0138] Figures 5a to 5d is similar to Figures 4a to 4d Schematic diagram of an example of how transducers in FIG. 5 are combined in a stacked or co-located manner to achieve ablation suitable for a particular application.

[0139] exist Figure 5aIn the first example shown in FIG. 4 , a relatively high frequency (RHF) transducer 405 is co-located with a relatively low frequency (RLF) transducer 401. The RHF transducer has a smaller effective aperture than the RLF transducer, so that the range of ultrasound beams (402, 403) emitted at a lower frequency is wider than the range of ultrasound beams (406, 407) emitted at a higher frequency. In this example, the higher and lower frequency ultrasound beams have overlapping and equivalent maximum intensity regions 404. This configuration may be suitable for target treatment volumes between 10 and 500 mm 3 Application within a range and at a depth of about 3 to 7 cm.

[0140] exist Figure 5b In the second example shown in FIG. 4 , the RHF transducer 411 is co-located with the RLF transducer 408, and the RHF transducer 411 has a larger effective aperture than the RLF transducer 408, so that the range of the ultrasound beam (412, 413) transmitted at the higher frequency is wider than the range of the ultrasound beam (409, 410) transmitted at the lower frequency. In this example, the higher frequency ultrasound beam has a maximum intensity region 414, which is suitable for a maximum intensity region 414 of about 1 to 50 mm at a depth of about 1 to 4 cm. 3 In this example, the lower frequency beam is used for enhancement in the region 414 determined by the higher frequency beam, even though the lower frequency beam has a greater range.

[0141] exist Figure 5c and 5d In other examples shown in FIG. 4 , RLF transducers 415, 422 are vertically stacked with RHF transducers 419, 423, respectively. The same principles for activation and enhancement apply to the previous example sensor devices.

[0142] Figure 6a and 6b are schematic diagrams of two additional example transducer configurations in which the RLF transducers 501 , 508 and the RHF transducers 504 , 512 are not co-located or stacked.

[0143] Figure 6a The example of shows an RLF transducer with an unfocused ultrasound beam 502, and an RHF transducer 504 emitting an ultrasound beam bounded by lines 505, 506 with a region of maximum intensity 507. In this example, the target tissue would be located in region 507.

[0144] exist Figure 6bIn the example of FIG. 5 , the RLF transducer 508 is configured to transmit a focused ultrasound beam defined by lines 509, 510 and to provide a maximum intensity region 511. The RHF transducer 512 is configured to transmit an ultrasound beam defined by lines 513, 514 and to provide a maximum intensity region 515. The target tissue will be located in the overlap of regions 511 and 515, with activation provided by either the RHF transducer 512 or the RLF transducer 508, and enhancement provided by either the RHF transducer 512 or the RLF transducer 508.

[0145] Figure 7a and 7b are schematic diagrams of two further examples of transducer configurations.

[0146] In accordance with Figure 7a In the first example, two RHF transducers 604, 608 are configured to transmit ultrasound beams of ranges 605, 606, 609, 610, respectively. The RHF transducers 604, 608 provide respective maximum intensity regions 607, 611, which overlap to form a combined maximum intensity region 612. The placement of the RHF transducers 604, 608 makes the combined maximum intensity region 612 coincide with the transmitted ultrasound beam defined by the lines 602, 603 from the RLF transducer 601. The target volume is defined by the combined maximum intensity region 612. Activation is provided by one of the RHF transducers 604, 608 or the RLF transducer 601. Enhancement is provided by one of the RHF transducers 604, 608 or the RLF transducer 601.

[0147] In accordance with Figure 7b In a second example, two RLF transducers 616, 619 configured to transmit respective ultrasound beams of ranges 617, 618, 620, 621 are placed so that the beams coincide with a maximum intensity region 615 in an ultrasound beam 613, 614 transmitted by an RHF transducer 612. A target volume is defined by the maximum intensity region 615. Activation is provided by the RHF transducer 612 or the two RLF transducers 616, 619, and enhancement is provided by the RHF transducer 612 or the two RLF transducers 616, 619.

[0148] A common system for performing ACT enhanced ablation is a computer controlled system and is adapted to generate ultrasound waves to effect insonation of AA bubbles in the target area to effect the activation step and subsequently the enhancement step as described above. A computer controlled ACT enhanced ablation system may also utilize planning and treatment feedback.

[0149] A system for performing ACT enhanced ablation may also include one or more of the following: a power amplifier, a pulse generator, a 3D positioning system, and an imaging modality, such as the above-mentioned US, CT, or MRI imaging modalities.

[0150] Advantages

[0151] AA bubbles exhibit several characteristics that are different from conventional microbubbles, and this feature enables ablation therapy to be performed at relatively low ultrasound energy. The first feature is that the residence time of AA bubbles in the capillaries is about 5 to 15 minutes, in contrast, conventional microbubbles do not stay in place and pass through the capillaries at a rate determined by the perfusion rate. Depending on tissue perfusion and volume, this is usually on the order of seconds. This increases the potential exposure time of the target area relative to ACT enhanced ablation therapy. Having static bubbles is a major advantage because ultrasound procedures usually take some time to perform (usually, ultrasound ablation is performed in the range of one hour), and free-flowing bubbles do not allow this. The second feature is that AA bubbles are larger, which enables the use of lower acoustic power to increase the generation of thermal and mechanical effects, compared to conventional contrast microbubbles, which are smaller and therefore limited in the generation of thermal and mechanical effects.

[0152] The AA bubbles will also dissipate energy in the form of heat due to friction between the surface area of ​​the resting AA bubbles and the capillary walls and by conduction during compression.Thus, the required acoustic energy level can be effectively reduced by combining ultrasound with AA bubbles.

[0153] AA bubbles are activated and deposited in tissue microvasculature under imaging control. Therefore, AA bubbles in tissue can be spatially targeted. This, combined with the extended residence time of AA bubbles, allows for more effective and controllable ablation therapy.

[0154] The procedure is non-invasive and does not use any implantable hardware, so the technique carries no risk of infection. Another benefit is that it does not use ionizing radiation. In addition, it also provides immediate results.

[0155] Furthermore, because AA bubbles can be induced as hyperechoic spots, they can provide real-time imaging. This yields more information on lesion size and shape, where thermal ablation areas are not visible in B-mode ultrasound imaging.

[0156] Before starting treatment, it is often useful to assess the perfusion of the organ to be treated. ACT technology can be used to test the perfusion of different organs, thus providing a second use along with ablation enhancement, and a third use along with imaging (i.e., AA bubble accumulation at the target tissue can be used for control feedback).

[0157] Compared to conventional thermal ablation, ACT-enhanced ablation therapy may not reach such high temperatures and has a reduced cool-down time. A cool-down period is usually required between sonication treatments to prevent undesired heating of surrounding tissue. Therefore, less time is required between sonication treatments, resulting in an overall reduction in ablation time.

[0158] All of the above advantages may lead to the subsequent advantage of reduced side effects and bleeding potential.

[0159] Thermal activity is only enhanced at the acoustic focus where the pressure is sufficient to activate the AA bubble. Ultrasound beam focusing can only achieve high intensity at specific locations within a small volume, which minimizes the possibility of thermal damage to tissue outside the focal area. For example, the diameter of the ultrasound beam can be about 1 mm and the length is about 10 mm. At the border of the thermally coagulated lesion, the tissue will die and be taken up by the immune system within 2 to 3 days. The combination of ultrasound and ACT can reduce the intensity and achieve the same or better ablation with reduced risk of damage to surrounding tissue.

[0160] use

[0161] ACT-enhanced ablation has clinical impact in neurology / surgery, ophthalmology, urology, gynecology, and oncology. In neurology, ACT-enhanced ablation can have clinical impact in the following: brain tumors and space-occupying masses, neuromodulation, tremor, tremor-dominant Parkinson's disease (dyskinesia symptoms), epilepsy, and stroke. In ophthalmology, ACT-enhanced ablation can have clinical impact in the following: glaucoma, intraocular tumors, retinal detachment, and trabeculotomy. In urology, ACT-enhanced ablation can have clinical impact in the following: kidney stones, cervical precancerous lesions, and adrenal glands. In gynecology, ACT-enhanced ablation can have clinical impact in uterine fibroids and ovarian cancer. In oncology, ACT-enhanced ablation can have clinical impact in the following: mainly musculoskeletal system, lung, breast, brain, prostate, kidney, liver, pancreas, brain tumors, renal, and bladder. Other malignancies where ACT-enhanced ablation can have a clinical impact are: adrenal tumors, thyroid cancer, skin cancer, secondary role in the treatment of bulky tumors (neck, nodules, bones) and superficial (skin). In the field of cardiovascular disorders (blocking irregular electrical signals and restoring normal heartbeat), ACT-enhanced ablation can have a clinical impact on: atrial fibrillation, irregular heart rhythm, arrhythmias and normalization of vascular function. ACT-enhanced ablation can also have a clinical impact in pain treatment: palliative (metastatic) and chronic. Psychiatric disorders can also be treated with ACT-enhanced ablation. In the field of aesthetics, ACT-enhanced ablation can have a clinical impact on: signs of aging and enhancement. ACT-enhanced ablation can also have a clinical impact on complete or partial vascular occlusions (such as deep vein thrombosis, pulmonary embolism, coronary artery occlusion and atherosclerosis).

[0162] The ultrasound settings (ultrasound exposure protocol) used in the enhancement step are application specific. Specifically, application specificity refers to the type of tissue to be ablated.

[0163] ACT-enhanced ultrasound ablation for tumors

[0164] The temperature changes are concentrated to a focal zone in and around the tumor. The overall goal of thermal tumor ablation is very similar to that of surgery: to remove the tumor and a 5 to 10 mm thick margin of normal-looking tissue. In contrast to surgical removal, which consists of physical excision, during thermal ablation, tissue is killed in situ and subsequently absorbed by the body over a period of several months.

[0165] Specific ultrasound settings for the enhancement step of ACT enhanced ultrasound where the target area is a tumor are: MI above 0.4, preferably above 0.6, and further preferably above 0.8; intensity up to 5000 W / cm 2 ; a frequency below 3 MHz, and preferably below 1 MHz; and continuous or pulsed insonation lasting about 20 to 30 seconds.

[0166] ACT-enhanced ultrasound ablation is suitable for the treatment of liver tumors and the selective destruction of normal liver, bladder, muscle and kidney. Depending on the equipment and parameters used, the volume of the focused ultrasound lesion can be as small as a grain of rice (about 10 cubic millimeters). This allows for extremely localized treatment and a clear boundary between the treated area and the untreated area. For the treatment of larger structures (such as large tumors), multiple treatment volumes can be combined to cover the entire volume.

[0167] Because tumors are metabolically active, their perfusion is high compared to the relatively low perfusion of surrounding tissues. The higher perfusion rate of the tumor compared to the surrounding tissues ultimately results in a higher concentration of AA bubbles in the tumor tissue than in the surrounding areas. As described above, the enhancement step of AA bubbles results in the destruction of adjacent tissues. Therefore, ACT-enhanced ultrasound ablation is particularly well suited for removing tumor cells because the technique can take advantage of the higher perfusion rate in tumors than in normal tissues.

[0168] ACT-enhanced ultrasound ablation for signs of aging

[0169] The specific ultrasound settings for the enhancement step of ACT enhanced ultrasound ablation where the target area shows signs of senescence are substantially similar to those used for tumor ablation. However, the ultrasound field is preferably delivered in short bursts rather than continuous insonation.

[0170] Since the target area is normal tissue, the tissue should be subjected to a temperature within the temperature range of 30°C to 77°C.

[0171] ACT-enhanced ultrasound ablation using transrectal and interstitial ultrasound sources

[0172] The transrectal and interstitial ultrasound sources can be placed closer to the target volume, allowing them to operate at lower power and higher frequency and achieve the same ablation effectiveness. The preferred ultrasound power range for the transrectal / interstitial sources during the boost step is up to 5000 W / cm2 For the enhancement step, the preferred frequency is below 4 MHz, more preferably below 1 MHz. For larger prostates with deeper lesions, the frequency choice is limited by the required penetration depth.

[0173] ACT-enhanced ultrasound ablation can be combined with chemotherapy, immunotherapy and / or drug delivery to make the treatment more effective and with fewer side effects. ACT-enhanced ultrasound ablation does not exclude other treatment options. There is no negative cell selection when it comes to antibody or hormone therapy.

[0174] ACT-enhanced ultrasound ablation for brain treatment

[0175] In the absence of combination with AA bubbles, thermoultrasound ablation of the brain has limited utility, primarily due to the barrier of insonation across bony structures.

[0176] The advantages of ACT-enhanced ultrasound ablation are that the treatment time is shortened, and the temperature and frequency can be kept lower than those of non-ACT-enhanced ultrasound ablation, thus overcoming the limitations of transcranial ultrasound.

[0177] Additionally, since the bubbles reside in the vasculature for up to 15 minutes, the AA bubbles can be close to the endothelial wall to allow for optimal thermal effects. This is in contrast to small conventional contrast agent microbubbles, which have an average diameter of approximately 1 to 3 μm and therefore clear the vasculature in a significantly shorter time (e.g., on the order of seconds), depending on tissue perfusion and volume.

[0178] The thickness of the skull varies by age, sex, and across ethnic groups. Ultrasound ablation treatments are well suited for treatment through the skull with thick barriers. In addition, ultrasound ablation can be limited to treating target areas located in the center of the brain. However, combining this technology with optimal AA bubbles, which can function at lower ultrasound energies, can address these issues. ACT offers the advantage of transient retention in the microcirculation of the target area. This combination makes it possible to fully utilize the MRgFUS technology, even when working through thicker bone structures, and also provides for opening the blood-brain barrier for applications outside the center of the brain.

[0179] ACT-enhanced ultrasound ablation for thrombolysis

[0180] ACT-enhanced ablation and ACT-enhanced ultrasonic ablation can also be used to treat the formation of blood clots in the vascular system. The method may include positioning at least one cluster near a target blood clot formed in a subject's blood vessel, preferably adjacent to the blood clot. Then, the cluster is activated according to the above method to produce at least one AA bubble. The activation process (wherein the cluster is converted into an AA bubble) causes the expansion of the entity, which produces mechanical stress on the nearby (adjacent) blood clot. The mechanical stress may be sufficient to cause the blood clot to rupture (decompose). The method of treating thrombolysis by rupturing the blood clot may also include an enhancement step using ACT-enhanced ultrasonic ablation, such as the above-mentioned enhancement step. The method of treating thrombolysis using ACT-enhanced ultrasonic ablation may also include alternating activation steps with enhancement steps, which are used alone or in combination with thrombolytic drugs or anticoagulants.

[0181] The generation of AA bubbles and ACT-enhanced ultrasound ablation can fragment clots or reduce clot size, promote clot movement, enhance the penetration of thrombolytics and anticoagulants into the clot, and / or remove clot degradation products by mechanical or thermal destruction.

[0182] ACT-enhanced ultrasound ablation can be used to treat myocardial infarction, stroke, and venous thromboembolism.

[0183] The ultrasound source used to provide the ultrasound field to achieve ACT-enhanced ultrasound ablation for treating thrombolysis can be an external ultrasound probe or a catheter-based probe.

[0184] The advantage of ACT-enhanced ultrasound ablation therapy for thrombolysis is that the risk of bleeding is reduced compared to using ultrasound insonation alone or in combination with conventional microbubbles to break up blood clots. Bleeding may also be reduced because lower ultrasound intensities are required. Bleeding may also be reduced because the method may not require or require the use of lower doses of thrombolytic drugs or anticoagulants. Another advantage is that treatment time may be reduced.

[0185] Example

[0186] Simulation of enhanced field on a bubble

[0187] Figure 8a , 8b 8c shows a graphical representation of the calculation of the maximum differential volume of an AA bubble oscillating in the first oscillation mode in a free field, i.e. the difference between the volume at peak expansion and the volume at rest. The calculation is based on a simulation of the modified Rayleigh-Plesset equation:

[0188]

[0189] Where R is the bubble radius, p L is the pressure in the liquid at the bubble surface, p 0 is the environmental pressure, pi is the incident driving pressure, ρ is the density of the surrounding fluid, and c is the speed of sound in the surrounding fluid. The variables c, ρ, and p 0 is a constant, and p i 、p L and R are functions of time, and the dot operator represents differentiation with respect to time. The effects of the bubble gas and shell parameters are included in the surface pressure p L , which is the boundary condition for solving the radial oscillation equation R. The number of periods of the simulated insonation pressure wave is 2 periods. The maximum differential volume is shown on the ordinate axis, and the AA bubble diameter is shown on the abscissa axis. Figures 8a to 8c It reflects the maximum differential volume for different mechanical indices in the acoustic field. Figure 8a The mechanical index is 0.4. Figure 8b The mechanical index is 0.6, and Figure 8c The mechanical index is 0.8. Figures 8a to 8c As shown in the legend of each of the , the frequency of the insonation field is 0.3, 0.5 and 1.0 MHz. These figures show the advantage of using lower frequencies to achieve larger volume oscillations of the AA bubble for larger AA bubble diameters. They also show that increasing the MI has the effect of increasing the maximum differential volume. For higher MIs, the AA bubble will undergo inertial cavitation, a process that causes the bubble size to gradually increase through inward diffusion of dissolved gases from the surrounding fluid, and ultimately leads to drastic bubble collapse. Stable and inertial cavitation will impose varying degrees of thermal and mechanical stress on the surrounding tissue.

[0190] Preclinical evidence

[0191] The fluorescent dye Evans was studied in the SC PC3 mouse model To investigate the role of enhanced ultrasound fields in MI changes, we used the tumor-specific uptake of 400 mM NSCLC cells.

[0192] Three mice were selected to receive enhanced ultrasound, where the mechanical index was 0.8 (MI=0.8 group). Evans was injected intravenously (IV) Immediately thereafter, a single IV dose of PS101 (5.1 mg PFMCP / kg [1000 μL PS101 / kg]) was administered, followed by 45 seconds of activated ultrasound (at 2.5 MHz, MI 0.4), and then 5 minutes of enhanced ultrasound (at 0.5 MHz, MI 0.8), focused on the tumor.

[0193] For the MI=0.8 group, non-sonicated control muscle and tumor were removed from the right leg, and the Evans Evans was detected in the tumors of animals in the MI=0.8 group. The amount was lower than that detected in other groups with lower enhanced ultrasound MI. This indicates potential damage to cells in the tumor, or damage to the vasculature, which reduces blood supply and therefore reduces the concentration of Evans blue in the target volume. Therefore, it is shown that when subjected to an enhancement of MI of 0.8, ACT bubbles cause tissue ablation and significant bleeding. For the MI=0.8 group, all animals died during or immediately after treatment, and the area of ​​insonation (left thigh and leg) showed extensive bleeding. These animals may die due to the combination of high-power ultrasound insonation of a significant portion of the mouse body weight (about 10%, about 20 times the typical clinical situation) and high-dose PS101 (20 to 40 times the expected clinical dose). By optimizing the dose of PS101 and the MI of enhanced ultrasound, it is expected that ablation can be achieved without causing these effects.

[0194] Having described some preferred embodiments of the present invention, it will be apparent to those skilled in the art that other embodiments incorporating the present invention may be used. These and other embodiments of the present invention illustrated above are intended to be exemplary only and the actual scope of the present invention is determined by the appended claims.

Claims

1. A method for enhancing ultrasound ablation, wherein include: At least one ablation assist bubble is generated near the target area by: administering to a subject a cluster composition comprising a microbubble component and a microdroplet component, wherein the cluster composition comprises at least one cluster; and activating a phase change transformation of droplet components of the at least one cluster by ultrasonic insonation to produce the at least one ablation-assisting bubble; Wherein the expansion of the at least one cluster into the at least one ablation assisting bubble provides mechanical stress on the target area to assist ablation on target tissue in the target area.

2. The method of claim 1, wherein the at least one ablation assisting bubble has a diameter of at least 10 microns.

3. The method of claim 1 or claim 2 further comprises subjecting the at least one ablation assisting bubble to the action of acoustic waves using ultrasound of a predetermined intensity to induce at least one of energy absorption, deposition, oscillation and cavitation of the ablation assisting bubble to provide additional mechanical stress and / or thermal stress on the target area to assist ablation on the target tissue in the target area. 4 . The method of claim 3 , wherein the predetermined intensity of ultrasound used to insonate the ablation-assisting bubble is equal to the intensity of non-bubble-assisted ultrasound ablation divided by a factor of 12 to 24.

5. The method of any preceding claim, wherein the enhanced ultrasound ablation is configured to provide a resulting temperature in the target region of 30 to 70 degrees Celsius for a continuous exposure time of at least 30 seconds.

6. The method of any preceding claim, further comprising using the at least one ablation assisting bubble to perform real-time imaging of the target area by insonifying the at least one ablation assisting bubble with imaging ultrasound, and wherein the at least one ablation assisting bubble is induced as a hyperechoic spot.

7. The method of any preceding claim, further comprising a further step of ultrasound planning, wherein the ultrasound planning comprises using unique subject and application specific information to plan a specific ultrasound exposure protocol, wherein the ultrasound planning comprises at least one of passive ultrasound planning and active ultrasound planning.

8. The method of claim 7, wherein the passive ultrasound planning is based on one or more of: physiological information, anatomical structures in the ablation zone, cross-modality imaging and registration, and data defining the subject's anatomy retrieved from software.

9. The method of claim 7 or claim 8, wherein the active ultrasound plan include: monitoring the ablation zone during the enhancing step for real-time feedback of the ablation zone; as well as adjusting the specific ultrasound exposure protocol to achieve predetermined parameters in the ablation zone; The monitoring and regulating steps are performed on a continuous basis for a predetermined duration.

10. The method of claim 9, wherein monitoring the ablation zone during the enhancement step for real-time feedback of the ablation zone includes at least one of: real-time temperature feedback, real-time mechanical feedback, cross-modal imaging and alignment, real-time monitoring of cluster dynamics and concentration, and real-time monitoring of ablation-assisted bubble dynamics and concentration.

11. The method of claim 9 or claim 10, wherein monitoring the target area including the ablation zone also includes imaging through an image-guided modality, wherein the image-guided modality includes at least one of the following: magnetic resonance guidance, ultrasound guidance, computed tomography guidance, optical guidance, thermocouple guidance, and contrast-enhanced ultrasound guidance.

12. The method of any preceding claim, further comprising co-administering a therapeutic agent configured to assist in ablative efficacy, wherein the therapeutic agent is administered prior to, and / or concurrently with, and / or separately after the cluster composition.

13. An intravenously administrable composition for use in a method of enhancing ablation at a target area, the composition comprising: a microbubble / microdroplet cluster composition that forms at least one cluster by electrostatic forces; and in, When the method includes exposing the at least one cluster to ultrasound effective to expose, each of the at least one cluster is configured to oscillate, expand, and fuse into a single entity, thereby providing an ablation-assisting bubble.

14. The composition of claim 13, in, When the method further comprises exposing the resulting ablation assisting bubble to ultrasound of a predetermined intensity, the ablation assisting bubble is configured to oscillate and / or cavitate to induce mechanical and / or thermal stress on the target area to enhance ablation effectiveness in the target area.

15. A composition as described in claim 13 or 14, wherein the resulting ablation-assisted bubble is configured to induce mechanical stress and / or thermal stress on the target area that is comparable to the mechanical stress and / or thermal stress induced from direct ultrasonic insonation, wherein the predetermined intensity is equal to the intensity of non-bubble-assisted ultrasonic ablation divided by a factor of 12 to 24.

16. The composition of any one of claims 13 to 15, wherein the microbubble / microdroplet cluster composition is formed from: A cluster dispersion of droplets having a median diameter of 2 to 3 μm stabilized by a lipid membrane with a net positive surface charge; and Microbubbles have a median diameter of 2 to 3 μm and are stabilized with a lipid shell with a net negative surface charge.

17. The composition of claim 16, wherein the net positive surface charge of the microdroplets and the net negative surface charge of the microbubbles provide electrostatic forces that enable at least one microbubble / microdroplet cluster to form.

18. The composition of any one of claims 13 to 17, wherein the resulting formed clusters have a diameter of 4 to 8 μm.

19. The composition of claim 17 or 18 for use according to any one of claims 1 to 9, wherein the gas of the microbubbles in the at least one microbubble / microdroplet cluster comprises sulfur hexafluoride or C3-6 perfluorocarbon or a mixture thereof.

20. The composition of any one of claims 17 to 19 for use according to any one of claims 1 to 9, wherein the oil phase of the droplets in the at least one microbubble / microdroplet cluster comprises a partially halogenated hydrocarbon or a fully halogenated hydrocarbon or a mixture thereof.

21. The composition of any one of claims 13 to 20, for use in treating one or more of a tumor, a space-occupying mass, thrombolysis, and a nervous system disease.

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