Ultrasound ablation enhanced by bubbles formed from cluster compositions administered to a patient

Abstract

The present invention provides a method for enhanced ultrasound ablation and compositions for use therewith, comprising: administering to a subject a cluster composition comprising a microbubble component and a microdroplet component; and creating at least one ablation-assist bubble proximate a target region by activating a phase-shift transition of the microdroplet component of the at least one cluster with ultrasound irradiation to create the at least one ablation-assist bubble, wherein the cluster composition comprises at least one cluster; and activating a phase-shift transition of the microdroplet component of the at least one cluster with ultrasound irradiation to create at least one ablation-assist bubble, wherein expansion from the transition of the at least one cluster into the at least one ablation-assist bubble provides a mechanical stress to the target region to assist in ablation on target tissue within the target region.

Description

[Background technology]

[0001] Tissue ablation therapy In tissue ablation therapy, layers of tissue are locally destroyed by exposure to a destructive environment. Ultrasound is well suited for ablation therapy because it produces both mechanical and thermal energy in the target area and can deliver this energy via pressure waves.

[0002] HIFU High-intensity focused ultrasound (HIFU) induces a disruptive effect, resulting in direct or indirect cell death within a limited target tissue volume. HIFU has two mechanisms of action: thermal ablation and mechanical tissue destruction. The thermal effect can be hyperthermia, where tissue temperature increases. Specifically, the thermal effect of HIFU is heat generation due to absorption of acoustic energy accompanied by a rapid increase in local tissue temperature, leading to instantaneous, irreversible cell death via coagulation necrosis. The mechanical effect is cavitation, where the HIFU acoustic field interacts with gas bubbles within the target tissue. Cavitation refers to a series of complex phenomena involving the creation, oscillation, growth, and collapse of bubbles within a medium.

[0003] The efficacy of HIFU for tissue ablation depends on the frequency of the HIFU sound field and the depth of the target tissue region.For target tissues that are far from the HIFU source or that are located such that there is a strong attenuation medium between the HIFU source and the target tissue, HIFU needs to have a lower effective frequency, for example, a frequency less than 1 MHz.Examples of such target tissues include target tissues inside the skull or target tissues in the mid-abdomen, such as certain areas of the pancreas or liver.For target tissues that are located on the surface of the body or closer to the HIFU source, the optimal frequency is higher, for example, a frequency greater than 10 MHz.

[0004] The length of the HIFU treatment volume can be approximated as being inversely proportional to the HIFU frequency and inversely proportional to the physical size of the HIFU source. Therefore, to achieve efficient thermal ablation by HIFU in thin target tissue that is located far from the HIFU source or with a strong attenuating medium between the HIFU source and the target tissue, the HIFU source needs to have a large physical size to reduce the risk of adverse effects associated with depositing excessive energy into the surrounding healthy tissue volume.

[0005] HIFU with microbubble technology Increasing acoustic intensity and / or prolonging sonication time can alter treatment outcomes, such as more efficient destruction of larger volumes of target tumors. However, if the acoustic intensity is too high, there is a risk of depositing excessive energy in the volume of healthy tissue surrounding the target and / or proximal to the HIFU source, which can lead to adverse effects.

[0006] Thermal techniques, such as HIFU, have primarily been used in conjunction with microbubble technology to reduce damage to surrounding healthy tissue. An example of microbubble technology is preformed lipid-coated microbubbles, which have been primarily developed for ultrasound imaging. Lipid-coated microbubbles can be contrast agents for ultrasound imaging due to their compressible gas core, which makes them echogenic and highly absorbing in a specific frequency band that depends on the microbubble diameter. When insonified with a HIFU field in this frequency band, the microbubbles absorb energy from the HIFU field more efficiently than the surrounding target tissue, thus lowering the acoustic intensity threshold for ablation and thereby minimizing the heat buildup in surrounding tissue that can be associated with HIFU.

[0007] Microbubbles can induce additional heating of the target region through vibration and cavitation, as well as generate shock waves, which deliver additional thermal energy to HIFU alone, so the addition of microbubbles proximal to the HIFU target region can enhance the ablation effect.

[0008] Microbubbles can be injected into a subject and travel through the subject's circulatory system until they reach a target site in proximity. This method can reduce the energy deposition required to achieve tissue ablation, shortening and optimizing treatment times and adverse event rates.

[0009] However, the use of conventional microbubbles in combination with thermal ablation techniques has several limitations. The first limitation is the short circulation time of microbubbles, approximately 2–3 minutes. HIFU requires a fairly long setup and execution time. The microbubbles are likely to dissolve and / or dissipate before the HIFU process can be performed. Another limitation is that these small microbubbles do not efficiently couple with low-frequency ultrasound, such as that used in transcranial applications. Yet another limitation is the poor spatial selectivity of microbubbles, with their residence time in the target tissue being on the order of a few seconds, potentially causing unintended heating at locations distant from the target site.

[0010] Therefore, due to the above-mentioned limitations of HIFU and HIFU combined with diagnostic microbubbles, limitations of ultrasound ablation techniques remain unresolved.

[0011] The present application addresses these above limitations by combining ultrasound technology with Acoustic Cluster Therapy (ACT)®. Summary of the Invention

[0012] According to one aspect of the present invention, there is provided a method for enhanced ultrasound ablation, the method comprising: administering to a subject a cluster composition comprising a microbubble component and a microdroplet component; and activating a phase shift transition of the microdroplet component of at least one cluster by ultrasonic irradiation to create at least one ablation-assist bubble, thereby creating at least one ablation-assist bubble proximal to the target region, wherein the cluster composition comprises at least one cluster; and expanding the at least one cluster from its transition to the at least one ablation-assist bubble to provide mechanical stress to the target region to assist in ablation on target tissue within the target region.

[0013] The at least one ablation-assist bubble may have a diameter of at least 10 micrometers.

[0014] The method may further include insonifying at least one ablation-assist bubble with ultrasound of a predetermined intensity to induce at least one of energy absorption, deposition, vibration, and cavitation of the ablation-assist bubble to provide additional mechanical and / or thermal stress to the target region, thereby assisting in ablation on the target tissue within the target region.

[0015] The predetermined intensity of ultrasound for insonifying ablation-assisted bubbles can be equal to the intensity for non-bubble-assisted ultrasound ablation divided by a factor of 12-24.

[0016] Enhanced ultrasound ablation can be configured to result in temperatures in the target area of ​​30 to 70 degrees Celsius with a continuous exposure time of at least 30 seconds.

[0017] The method further includes using at least one ablation assist bubble for real-time imaging of the target area by insonifying the at least one ablation assist bubble with imaging ultrasound, wherein the at least one ablation assist bubble is induced as a hyperechoic spot.

[0018] The method may further include using unique subject and application specific information to plan a particular ultrasound irradiation regime, where the ultrasound plan includes at least one of a passive ultrasound plan and an active ultrasound plan.

[0019] The passive ultrasound planning may be based on one or more of physiological information, the anatomy of the ablation zone, cross-modality imaging and coregistration, and data defining the subject's anatomy obtained from software.

[0020] Active ultrasound planning may include monitoring the ablation zone during the boost step for real-time feedback of the ablation zone and adjusting a particular ultrasound irradiation regime to achieve predetermined parameters in the ablation zone, the monitoring and adjusting steps being performed continuously over a predetermined period of time.

[0021] The step of monitoring the ablation zone during the augmentation 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 co-registration, real-time monitoring of cluster dynamics and concentration, and real-time monitoring of ablation-assisted bubble dynamics and concentration.

[0022] The step of monitoring the target area including the ablation zone may further include imaging via an image-guided modality, wherein the image-guided modality includes at least one of magnetic resonance guidance, ultrasound guidance, computed tomography guidance, optical guidance, thermocouple guidance, and contrast-enhanced ultrasound guidance.

[0023] The method may further include the co-administration of a therapeutic agent configured to aid in ablation efficacy, wherein the therapeutic agent is administered separately before, simultaneously with, and / or after the cluster composition.

[0024] According to a second aspect of the present invention, there is provided 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 via electrostatic forces, wherein when the method comprises the step of exposing the at least one cluster to effective ultrasonic radiation, each of the at least one cluster is configured to vibrate, expand and coalesce into a single entity to provide an ablation-assisting bubble.

[0025] If the method further comprises exposing the resulting ablation-assist bubbles to ultrasound of a predetermined intensity, the ablation-assist bubbles may be configured to vibrate and / or cavitate to induce mechanical and / or thermal stress in the target region, thereby increasing ablation efficiency in the target region.

[0026] The resulting ablation-assisted bubbles can be configured to induce mechanical and / or thermal stresses comparable to those induced from direct ultrasound application to the target area, where the predetermined intensity is equal to the intensity for non-bubble-assisted ultrasound ablation divided by a factor of 12 to 24.

[0027] Microbubble / microdroplet cluster compositions can be formed from a dispersion of clusters of microdroplets having an average diameter of 2-3 μm stabilized by a lipid membrane having a net positive surface charge, and microbubbles having an average diameter of 2-3 μm stabilized by a lipid shell having a net negative surface charge.

[0028] The net positive surface charge of the microdroplets and the net negative surface charge of the microbubbles may result in electrostatic forces that allow the formation of at least one microbubble / microdroplet cluster.

[0029] The diameter of the resulting clusters can range from 4 to 8 μm.

[0030] The microbubble gas of the at least one microbubble / microdroplet cluster may comprise sulfur hexafluoride, a C3-6 perfluorocarbon, or a mixture thereof.

[0031] The oil phase of the microdroplets of at least one microbubble / microdroplet cluster may comprise a partially or fully halogenated hydrocarbon or mixtures thereof.

[0032] The composition of the second aspect of the invention may be for use in the treatment of one or more of tumors, space-occupying masses, thrombolysis, and neurological disorders. [Brief explanation of the drawings]

[0033] [Figure 1] 1 shows a flow chart of an ACT®-enhanced ultrasound ablation method in accordance with the present invention. [Figure 2] 1 shows a step-by-step diagram of the ACT® enhanced ultrasound ablation method. [Figure 3] 10 shows a graph of the number of ablation-assisted bubbles generated versus mechanical index at different frequencies. [Figure 4a] 1 is a schematic diagram of a first exemplary transducer having a relatively low operating frequency and a relatively large aperture. [Figure 4b] FIG. 10 is a schematic diagram of a second exemplary transducer having a relatively high operating frequency and a relatively large aperture. [Figure 4c] FIG. 10 is a schematic diagram of a third exemplary transducer having a relatively low operating frequency and a relatively small aperture. [Figure 4d] FIG. 10 is a schematic diagram of a fourth exemplary transducer having a relatively high operating frequency and a relatively small aperture. [Figure 5a] FIG. 4C is a schematic diagram of a first exemplary combination of the transducers of FIGS. 4a-4d. [Figure 5b] FIG. 4C is a schematic diagram of a second exemplary combination of the transducers of FIGS. 4a-4d. [Figure 5c] FIG. 4C is a schematic diagram of a third exemplary combination of the transducers of FIGS. 4a-4d. [Figure 5d] FIG. 4C is a schematic diagram of a fourth exemplary combination of the transducers of FIGS. 4a-4d. [Figure 6a] 10A-10C show schematic diagrams of further exemplary configurations of transducers. [Figure 6b] 10A-10C show schematic diagrams of further exemplary configurations of transducers. [Figure 7a] 10A-10C show schematic diagrams of further exemplary configurations of transducers. [Figure 7b] 10 shows a schematic diagram of yet another exemplary configuration of a transducer. [Figure 8a] 10 is a graphical representation of the calculation of the maximum differential volume of an ablation-assist bubble oscillating in the first vibration mode in a free field with a mechanical exponent of 0.4. [Figure 8b] 10 is a graphical representation of the calculation of the maximum differential volume of an ablation-assist bubble oscillating in the first vibration mode in a free field with a mechanical exponent of 0.6. [Figure 8c] 10 is a graphical representation of the calculation of the maximum differential volume of an ablation-assist bubble oscillating in the first vibration mode in a free field with a mechanical exponent of 0.8. DETAILED DESCRIPTION OF THE INVENTION

[0034] definition Unless otherwise defined, all technical terms, notation, and other scientific or technical terms used in this document are intended to have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial departure from what is commonly understood in the art.

[0035] As used herein, "subject" means a human or non-human animal individual selected for treatment or therapy, and includes, but may be limited to, patients, particularly human patients.

[0036] "Insonation" or "ultrasound insonation" is a term used to describe exposure to or treatment with ultrasound.

[0037] The term frequency is defined as the number of (ultrasonic) cycles per second (Hz), and as used herein, designates the center frequency of the applied sound field.

[0038] The term "conventional medical imaging ultrasound" is used to describe ultrasound from commercially available ultrasound scanners and probes intended for medical imaging.

[0039] The term "high intensity ultrasound" or "HIFU" is used to describe ultrasound waves of an intensity that exceeds diagnostic limits.

[0040] The term "microdroplets" is used to describe emulsion droplets with diameters in the range of 0.2 to 10 μm.

[0041] The terms "microbubbles" or "regular, contrast microbubbles" are used to describe gas bubbles with or without a stabilizing shell, ranging in diameter from 0.2 to 10 μm, typically with an average diameter of 2 to 3 μm. "Regular, contrast microbubbles" include commercially available agents such as Sonazoid® (GE Healthcare), Optison® (GE Healthcare), Sonovue® (Bracco Spa.), Definity® (Lantheus Medical Imaging), Micromarker® (VisualSonics Inc.), and Polyson L® (Miltenyi Biotec GmbH).

[0042] 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 microdroplets.

[0043] The term "clustering" refers to the process by which microbubbles of a first component and microdroplets of a second component form clusters.

[0044] The term "cluster" refers to a group of microbubbles and microdroplets in a cluster composition that are permanently held together by electrostatic attraction in a single aggregate.

[0045] The term "phase shift" is used to describe the phase transition of a substance from a liquid state to a gas state. Specifically, it refers to the transition (process) of the oil component of the microdroplets in the clusters from liquid to gas state upon ultrasonic irradiation.

[0046] The term "activation" or "activation step" refers to the induction of a phase shift in microbubble / microdroplet clusters by ultrasound irradiation.

[0047] The term "ablation-assisted bubbles" or "AA bubbles" is used in this document to describe the large (>10 μm) bubbles that form after ultrasound-induced activation of the clusters (i.e., the bubbles that result from the "activation step").

[0048] The term "augmentation" or "augmentation process" refers to the induction of volume vibration and / or cavitation of ablation-assist bubbles and ensuring biomechanical effects by ultrasound irradiation.

[0049] "Acoustic Cluster Therapy (registered trademark)" or "ACT (registered trademark)" refers to a process in which a cluster composition is administered to a subject, and the resulting phase shift of at least one cluster is activated by ultrasound irradiation to generate ablation-assist bubbles, which are used in a further enhancement step. Detailed Description

[0050] The present invention provides methods of enhanced ablation therapy (ACT® Enhanced Ablation Therapy), and in particular methods of enhanced ultrasound ablation (ACT® Enhanced Ultrasound Ablation Therapy). Referring to FIG. 1, Acoustic Cluster Therapy (ACT)® ablation therapy is: (i) administering a cluster composition to a subject in step 10, wherein the cluster composition forms one or more clusters, and the microbubbles and microdroplets are permanently held together by electrostatic attraction; (ii) optionally, imaging one or more clusters using ultrasound imaging to identify regions of interest (target regions) for treatment within the subject; (iii) an activation step 30 comprising activating a phase shift of the diffusible component of the microdroplets of the cluster from step (i) by ultrasonic irradiation at an activation frequency, and optionally an activation mechanical index, to form at least one ablation-assisted (AA) bubble in the target area; (iv) optionally an enhancement step 40 comprising applying ultrasound to at least one AA bubble to induce vibration and / or cavitation of the at least one AA bubble; (v) optionally, a monitoring step comprising monitoring the effect of the ultrasound irradiation during the enhancing step (iv) and adjusting at least one ultrasound parameter according to an appropriate indicator, such as ablation efficiency, temperature of the target region, and / or bubble vibration dynamics in the target region; (vi) optionally repeating steps (iv) and (v) for a predetermined period of time.

[0051] Administration The cluster composition is administered to a subject parenterally, preferably intravenously. The cluster composition forms one or more aggregated clusters due to the electrostatic attraction of the composition components. The one or more clusters can be formed before or after administration to a subject. Preferably, the one or more clusters are formed before administration to a subject.

[0052] In one example, the microbubble and microdroplet cluster composition is formed from a cluster dispersion of lipid membrane-stabilized microdroplets (second component) with a net positive surface charge and lipid shell-stabilized microbubbles (first component) with a net negative surface charge. In one example, the average diameter of both the microdroplets and microbubbles is 2-3 μm. The net positive surface charge of the microdroplets and the net negative surface charge of the microbubbles result in an electrostatic force that allows the formation of at least one cluster.

[0053] In one example, the first component comprises a dispersible gas selected from the group of sulfur hexafluoride, perfluoropropane, perfluorobutane, perfluoropentane, and perfluorohexane, or a mixture thereof, stabilized by a first stabilizer selected from the group of phospholipids, proteins, and polymers. The second component comprises a diffusible component selected from the group of perfluorocarbons, such as perfluorocycloalkanes, stabilized by a second stabilizer selected from the group of surfactants, including phospholipids, polymers, and proteins. More specifically, one of the stabilizers is selected from phospholipids.

[0054] In a specific example, the first component consists of perfluorobutane (PFB) microbubbles stabilized by a hydrogenated egg phosphatidylserine-sodium (HEPS-Na) membrane and embedded in lyophilized sucrose. HEPS-Na has a negatively charged head, which gives the microbubbles a negative surface charge. Each vial of the first component contains approximately 16 μL or 2-10 microbubbles with an average diameter of approximately 2.0 μm. The lyophilized formulation exhibits a long shelf life, more specifically a 3-year shelf life, when stored at ambient room temperature. In this specific example, the second component consists of perfluoromethylcyclopentane (pFMCP) microdroplets stabilized by a 1,2-distearoyl-sn-glycerol-3-phosphocholine (DSPC) membrane with 3% mol / mol stearylamine (SA) added to provide a positive surface charge. The microdroplets in the second component are dispersed in 5 mM TRIS buffer. The standard formulation of the second component, in this specific example, contains approximately 4 μL or 0.8-10 microdroplets per mL, with an average diameter of approximately 1.8 μm. The second component exhibits a long shelf life when refrigerated, more specifically, a shelf life of 18 months or more. The cluster composition can be prepared aseptically by reconstituting a vial of the first component with 2 mL of the second component, followed by manual homogenization for 30 seconds. 2 mL can be withdrawn from the vial of the second component using a sterile, disposable syringe and needle. The contents of the syringe can be added through the stopper of the vial of the first component, and the resulting cluster composition can be homogenized to prepare the composition for administration.

[0055] Imaging The method may include an optional step of imaging the microbubble components of the cluster using a low mechanical index (MI) contrast imaging mode to identify lesion sites for treatment. In the low MI contrast imaging mode, the MI of the ultrasound exposure is less than 0.1. Because the clusters are not activated at low MI (below the activation threshold), standard medical ultrasound contrast imaging can be performed without triggering cluster activation. Thus, the clusters can be used for imaging, for example, to identify microvascular lesions in tumors prior to subsequent steps in the ablation method of the present invention.

[0056] activation After the clusters are formed and administered, they are activated within, at, or near the target region by applying ultrasound energy directed at the target region and the target site. Alternatively, the clusters may be activated in a nutrient artery outside the target region, depositing the activated bubbles in the capillary bed downstream of the activation site closest to the target region. Thus, activated AA bubbles can be spatially localized within a target tissue or organ, such as near a tumor, by applying ultrasound energy spatially localized to activate the clusters.

[0057] During the activation step 30, the cluster microbubbles oscillate and transfer energy to the cluster microdroplets. The oscillating microbubbles initiate a flash evaporation (phase shift) of the attached microdroplets, resulting in the formation of AA bubbles. The AA bubbles are temporarily deposited (settle) in the subject's microvasculature. In particular, activated AA bubbles are temporarily deposited in the nearest capillary bed downstream of the activation site in an amount that correlates with tissue blood perfusion.

[0058] Because the resonant frequency of the microbubble component is typically in the 2-5 MHz range, clusters are easily activated by frequencies in the normal medical imaging range of 1-10 MHz, with M is greater than 0.1. However, the activation frequency of the clusters is application dependent, with frequencies ranging from 50 kHz to 20 MHz being possible.

[0059] In one example, the clusters are activated with standard diagnostic ultrasound imaging pulses (1-10 MHz) typically used in conventional medical ultrasound. Preferably, the ultrasound imaging pulse has an MI of 0.1-0.4, more preferably 0.15-0.3.

[0060] In one embodiment, referring to FIG. 2, the activation process begins immediately after each administration of the cluster composition, such as within 20 seconds, and preferably continues for approximately 60-120 seconds. Activation under medical ultrasound imaging control using imaging pulses allows for spatially targeted activation of clusters within the tissue region being examined by the ultrasound field. After activation, the generated AA bubbles 102 are temporarily confined within the microvasculature 106 of the targeted lesion due to their large size. The AA bubbles 102 are approximately 1000 times the volume of the pre-existing emulsion microdroplets before evaporation. For example, 2 μm diameter AA bubbles can be generated from pre-existing 2 μm diameter oil microdroplets. The diameter of the activated bubbles (AA bubbles) is typically approximately 20 μm. The activated AA bubbles gradually shrink by intermittently settling and detaching, traveling further down the capillary tree before completely disappearing, typically after 5-15 minutes.

[0061] Figure 3 shows a graph 200 of the number of successfully activated AA bubbles per μL versus MI at three different frequencies: 0.5 MHz, 1 MHz, and 2 MHz. The graph shows a peak number of approximately 640 AA bubbles per μL when insonified with an ultrasound field having a frequency of 2 MHz and an MI of 0.5. Preferably, the number of AA bubbles generated per μL exceeds 300. Therefore, according to the graph in Figure 3, an ultrasound field having a frequency of 2 MHz and an MI of 0.29 to 0.6 is suitable. An ultrasound field having a frequency of 1 MHz is suitable for MIs of 0.65 or greater. An ultrasound field having a frequency of 0.5 MHz is suitable for MIs of 0.7 or greater.

[0062] Augmentation The enhancement step 40 includes transmitting ultrasonic energy to the AA bubbles to induce at least one of energy absorption, deposition, vibration, and cavitation of the activated AA bubbles to provide additional mechanical and / or thermal stress to the target region in addition to the mechanical and / or thermal stress resulting directly from the ultrasonic irradiation of the tissue, which has the effect of increasing the ablation efficiency of cells in the target region. The ablation frequency may be the same as 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.

[0063] 2, ultrasound irradiation induces controlled volumetric oscillation 104 of the activated AA bubbles, preferably until cavitation occurs, thereby exerting biomechanical forces on the tissue in the target region. Thus, it has been found that application of ultrasound at or near the cavitation frequency of the AA bubbles can be used to enhance the effectiveness of ablation therapy by creating additional mechanical and / or thermal bioeffect mechanisms in addition to the effects from ultrasound focused directly on the tissue in the target region, thereby increasing targeted tissue destruction.

[0064] The ultrasound exposure depends on the frequency, duration of exposure, transducer characteristics such as geometry and configuration, total power delivered, acoustic pressure and intensity, and energy delivery mode. The specific ultrasound exposure regime is selected based on the tissue type in the target area, the desired ablation effect, and the ultrasound delivery path, as described in more detail below.

[0065] Preferably, the frequency of the applied ultrasound during the boost phase is less than 3 MHz, more preferably less than 1 MHz. However, the frequency may be outside this range depending on the location of the target treatment volume within the subject and the tissue characteristics of that volume. 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.

[0066] The targeted time-averaged intensity of ultrasound used for ablation is up to 5000 W / cm depending on the specific application. 2 When AA bubbles are present in the target tissue, the intensity required to achieve the same amount of ablation is reduced by more than a factor of 1, preferably more than a factor of 8, more preferably more than a factor of 16, even more preferably more than a factor of 24, even more preferably more than a factor of 50, and even more preferably more than a factor of 100.

[0067] The enhancement step 40 may be performed non-invasively or invasively, and may be performed by a focused ultrasound array or a focused single element ultrasound transducer, or by one or more surgically implanted ultrasound transducers.

[0068] The method may include two distinct steps of ultrasound irradiation: an activation step and an enhancement step. After the activation step is completed, ultrasound irradiation may be discontinued before further ultrasound irradiation for the enhancement step is performed. The parameters of the ultrasound field may be modified for the further ultrasound irradiation. Alternatively, the ultrasound field provided for ultrasound irradiation in both the activation step and the enhancement step may not be changed and may have the same parameters (i.e., frequency, intensity, MI) throughout the ACT-augmented ablation therapy process. This is possible because the use of AA bubbles reduces the ultrasound power required to achieve the desired ablation effect. This may have the advantage of simplifying the process, for example, requiring only one transducer setup.

[0069] The combination of ultrasound and AA bubbles has been shown to reduce the acoustic energy levels required for ablation therapy by over 100-fold. The ultrasound field interacts with the AA bubbles through acoustic cavitation, causing them to oscillate, grow, and collapse. Acoustically driven AA bubble oscillations result in heat production, fluid microstreaming near the bubbles, and localized shear stress. Energy absorption as ultrasound propagates through the medium also produces a heating effect. In tissue, absorption increases with frequency. AA bubbles can generate higher harmonics of the excitation frequency, further enhancing the heating effect.

[0070] Ultrasound Planning The optional ultrasound planning step may include a first passive ultrasound planning step and a second active ultrasound planning step.

[0071] In the first passive ultrasound planning step, unique subject- and application-specific information is collected and processed to plan a specific ultrasound irradiation regime. This information includes physiological information and anatomical structures in the ablation zone, and software that defines the anatomical structures can be used. The software that defines the anatomical structures allows for the treatment of various types of patients to deliver precise thermal doses.

[0072] An example of the type of physiological information used in ultrasound planning is the perfusion of various organs. Heat-sensitive organs such as the diaphragm, intestine, and spinal cord are anatomical structures of particular interest in the ablation zone when planning ultrasound exposure.

[0073] In the second active ultrasound planning step, real-time feedback of the ablation zone condition 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 coregistration, real-time monitoring of cluster dynamics and concentration, and real-time monitoring of AA bubble dynamics and concentration.

[0074] Real-time mechanical feedback can be obtained by detecting cavitation using ultrasound. Due to the highly echogenic nature of the generated AA bubbles, ultrasound backscatter from the AA bubbles themselves can be used for imaging to detect cavitation. Real-time mechanical feedback can also be obtained via shear wave monitoring (i.e., using elastography).

[0075] Real-time temperature feedback can be obtained using thermocouples, fiber optic temperature sensors, and magnetic resonance imaging (MRI).

[0076] During the ablation process, ultrasound parameters can be modified based on real-time feedback evaluated against desired ablation zone conditions. For example, ablation efficiency, target region temperature, and bubble oscillation dynamics within the target region can be modified based on real-time feedback. The collection of real-time feedback (monitoring) and corresponding readjustment of ultrasound parameters can be performed in a continuous feedback loop over the duration of the ablation procedure or over a predetermined period of time, such as the duration of the boost step.

[0077] 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, frequencies as low as 0.5 MHz are used for deeper treatments or with large absorption sections in the propagation path (transcranial applications), and frequencies as high as 8 MHz are used for superficial treatments (e.g., prostate and melanoma).

[0078] The threshold heating dose to achieve the desired thermal effect, which includes irreversibly damaging and coagulating vital cellular proteins, tissue structural components, and vasculature, resulting in immediate tissue destruction, varies with tissue type and exposure time. For normal tissue, the temperature range is 30–77°C, while for tumor tissue, the temperature range is 41–64°C. For most applications, the threshold heating dose ranges from 43–65°C for approximately 30 seconds of continuous exposure time.

[0079] monitoring The ablation zone benefits from careful monitoring, providing real-time feedback for the secondary active ultrasound planning step. As discussed above, monitoring the ablation zone can include monitoring temperature, mechanics, cluster, and bubble dynamics and concentration. Various methods can be utilized to monitor the ablation zone.

[0080] A particular method of monitoring the ablation zone uses an image-guided modality, examples of which include magnetic resonance (MR) guidance, ultrasound guidance, computed tomography (CT) guidance, light guidance, thermocouple guidance, contrast-enhanced ultrasound guidance, or a combination of the above.

[0081] The scattering cross section of AA bubbles is several orders of magnitude larger than that of the micron-sized microbubbles contained in the clusters before activation. As a result, AA bubbles produce a large amount of backscattered signal and are easily imaged in basic imaging modes by diagnostic imaging systems. The resonant frequency of AA bubbles is also an order of magnitude lower (approximately 0.2–0.8 MHz) than that of the microbubbles contained in the clusters before activation.

[0082] MRI-guided ablation therapy offers excellent anatomical resolution and high sensitivity, particularly for tumor detection, allowing for precise planning of target tissues. Ultrasound transducers must be specifically designed for compatibility with MRI's high magnetic fields. MR-guided ultrasound offers the added benefit of providing soft-tissue contrast, quantitative temperature measurement, temperature feedback control, and diagnostics, but accessibility can be limited. MRI is highly sensitive to temperature changes and can provide real-time feedback of ongoing temperature data throughout the procedure. MRI is particularly well-suited for ACT-augmented ablation therapy, where biomechanical effects compensate for thermal effects, and thus the temperatures generated from the process can be relatively low in terms of ablation.

[0083] Ultrasound-guided ablation therapy is widely accessible, has good temporal resolution, provides soft tissue contrast and diagnostics, and provides qualitative feedback. Typically, the treatment head incorporates an ultrasound diagnostic transducer, allowing real-time imaging of the ablation process.

[0084] Magnetic resonance-guided focused ultrasound (MRgFUS) is a type of MRI-guided ablation therapy. During the MRgFUS procedure, the patient is conscious and the functional effects of the procedure are clinically assessed throughout. The operator continuously controls and refines the region of interest (target) and selects the attributes of the incident ultrasound field in terms of the level of MI and the number of ultrasound exposures.

[0085] The median duration of the MRgFUS procedure is approximately 1 hour, which includes acquisition of the planned sequence, targeting, and sonication. If necessary, the ACT microcluster composition can be injected or infused repeatedly to cover the duration of the MRgFUS procedure.

[0086] Hardware 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.

[0087] The ultrasound probe provides the ultrasound field for ultrasound irradiation in the activation and enhancement steps, and may comprise a commercially available transducer not specifically designed for HIFU applications, as the use of AA bubbles may negate the need for HIFU.

[0088] Extracorporeal ultrasound devices are typically used for targets within the breast, abdomen, brain, or extremities. Percutaneous procedures require an appropriate acoustic window at the entry site to provide a propagation path for the focused ultrasound beam that is uninterrupted by intervening gases.

[0089] In one embodiment, an external (non-invasive) transducer is used, which offers the opportunity to combine ACT techniques with MRI-guided focused ultrasound (MRgFUS).

[0090] In one example, the selected ultrasound transducer emits ultrasound waves at frequencies ranging from 1 to 5 MHz with a focal intensity of approximately -6 dB, with the -6 dB beam size being approximately 1 to 3 mm in width and 10 mm in length, depending on the geometric size and acoustic parameters.

[0091] The ultrasound transducer may be a fixed transducer that provides a single exposure and is suitable for small volume target areas. The volume of the target area treatable by a fixed transducer also depends on the particular frequency and shape of the transducer, and the location of the target area relative to the transducer. The treatable volume can be approximated as an ellipsoid with major diameters A, B, and C, so the treatment volume is approximately:

[0092]

number

[0093] Example values ​​for major diameters A and B are 1-3 mm, and example value for major diameter C is 10 mm. Thus, example treatment volumes are 5-50 mm. 3 The range is as follows:

[0094] Ultrasonic probes may also include ultrasound transducers that provide the ability to direct ultrasound fields to multiple target regions, either by physically rotating and / or translating the transducer array within the ultrasound probe housing or by electronically exciting specific transducer elements in specific sequences. Thus, the probes are suitable for target regions of larger volumes, e.g., several times the volume range for fixed transducers.

[0095] The probe may be combined with a catheter or encased in a sealed appendage to administer ultrasound within the body, for example, if the target volume is in the prostate and the probe is inserted into the urinary tract or rectum. Other applications may require the use of such a device in a suitable orifice, such as the vaginal canal, nasal cavity, mouth, or esophagus.

[0096] The probe is designed to deliver higher power ultrasound waves and may include a therapeutic transducer that utilizes the same principles as a conventional ultrasound transducer.

[0097] The probe may include two or more transducers or array transducers operating at independent frequencies, with a first set of transducers or transducer array providing ultrasonic radiation in an activation step and a second set of transducers or transducer array providing ultrasonic radiation in an enhancement step.

[0098] 4a is a schematic diagram of a first exemplary 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 indicates the range of the transmitted ultrasound beam on the left, and a second line 303 indicates the range of the transmitted ultrasound beam on the right. Oval 304 indicates the region of highest intensity of the transmitted ultrasound beam.

[0099] 4b is a schematic diagram of a second exemplary transducer 308 having a relatively high operating frequency, e.g., about 2.5 MHz, and a relatively large aperture, e.g., about 50 mm. A first line 309 indicates the range of the transmitted ultrasound beam on the left, and a second line 310 indicates the range of the transmitted ultrasound beam on the right. An oval 311 indicates the region of highest intensity of the transmitted ultrasound beam.

[0100] 4c is a schematic diagram of a third exemplary transducer 305 having a relatively low operating frequency, e.g., about 1.25 MHz, and a relatively small aperture, e.g., about 25 mm. A first line 306 shows the range of the transmitted ultrasound beam on the left side, and a second line 307 shows the range of the transmitted ultrasound beam on the right side.

[0101] 4d is a schematic diagram of a fourth exemplary transducer 312 having a relatively high operating frequency, e.g., about 2.5 MHz, and a relatively small aperture, e.g., about 25 mm. A first line 313 indicates the range of the transmitted ultrasound beam on the left, and a second line 314 indicates the range of the transmitted ultrasound beam on the right. An oval 315 indicates the region of highest intensity of the transmitted ultrasound beam.

[0102] Although transducers 301, 305, 308, and 312 are depicted as planar, they may also have curved shapes.

[0103] 5a-5d are schematic diagrams of examples of how transducers similar to those of FIGS. 4a-4d can be combined in a stacked or co-localized manner to achieve ablation suitable for a particular application.

[0104] In the first example shown in Figure 5a, a relatively high frequency (RHF) transducer 405 is co-localized with a relatively low frequency (RLF) transducer 401. The RHF transducer has a smaller active aperture than the RLF transducer, such that the ranges 402, 403 of the ultrasound beams transmitted at the low frequency are wider than the ranges 406, 407 of the ultrasound beams transmitted at the high frequency. In this example, the high frequency and low frequency ultrasound beams have an area of ​​overlap and equal maximum intensity 404. This configuration is suitable for target treatment volumes between 10 and 500 mm. 3 and may be suitable for applications in which the depth is in the range of about 3 to 7 cm.

[0105] In a second example shown in Figure 5b, an RHF transducer 411 is co-localized with the RLF transducer 408, and the RHF transducer 411 has a larger active aperture than the RLF transducer 408, such that the ranges 412, 413 of the ultrasound beams transmitted at higher frequencies are wider than the ranges 409, 410 of the ultrasound beams transmitted at lower frequencies. In this example, the high frequency ultrasound beams are transmitted at a depth of approximately 1-4 cm and a range of approximately 1-50 mm. 3 The high-frequency beam has a region 414 of maximum intensity suitable for activation in the target volume within the region of 100. In this example, the low-frequency beam is used to enhance within the region 414 determined by the high-frequency beam, even though the range of the low-frequency beam is larger.

[0106] In a further example shown in Figures 5c and 5d, RHF transducers 415, 422 are stacked vertically with RHF transducers 419, 423, respectively. The same principles for activation and enhancement apply as in the previous exemplary transducer setup.

[0107] 6a and 6b are schematic diagrams of two further exemplary transducer configurations in which the RHF transducers 501, 508 and RHF transducers 504, 512 are not co-localized or stacked.

[0108] The example of Figure 6a shows an RHF transducer with an unfocused ultrasound beam 502 and an RHF transducer 504 transmitting an ultrasound beam bounded by lines 505, 506 with a region of maximum intensity 507. In this example, the target tissue is located in region 507.

[0109] In the example of Figure 6b, RLF transducer 508 is configured to transmit a focused ultrasound beam delimited by lines 509, 510, providing a region of maximum intensity 511. RHF transducer 512 is configured to transmit an ultrasound beam delimited by lines 513, 514, providing a region of maximum intensity 515. Target tissue is positioned at the overlap of regions 511 and 515, with activation provided by either RHF transducer 512 or RLF transducer 508, and enhancement provided by either RHF transducer 512 or RLF transducer 508.

[0110] 7a and 7b are schematic diagrams of two further examples of transducer configurations.

[0111] In the first example of FIG. 7a, two RHF transducers 604, 608 are configured to transmit ultrasound beams in ranges 605, 606, 609, and 610, respectively. The RHF transducers 604, 608 each provide regions of maximum intensity 607, 611 that overlap to form a combined region of maximum intensity 612. The RHF transducers 604, 608 are positioned such that the combined region of maximum intensity 612 coincides with the transmitted ultrasound beams separated by lines 602, 603 from the RHF transducer 601. The target volume is defined by the combined region of maximum intensity 612. Activation is provided by either the RHF transducers 604, 608 or the RLF transducer 601. Enhancement is provided by either the RHF transducers 604, 608 or the RLF transducer 601.

[0112] In a second example according to Figure 7b, two RLF transducers 616, 619 configured to transmit respective ultrasound beams in ranges 617, 618, 620, 621 are positioned such that the beams coincide with a region of maximum intensity 615 within the ultrasound beams 613, 614 transmitted by the RHF transducer 612. A target volume is defined by the region of maximum intensity 615. Activation is provided by both the RHF transducer 612 or the RLF transducers 616, 619, and enhancement is provided by both the RHF transducer 612 or the RLF transducers 616, 619.

[0113] A typical system for performing ACT-enhanced ablation is a computer-controlled system adapted to generate ultrasound waves to achieve insonation of AA bubbles within a target region and to achieve an activation step followed by an enhancement step. Computer-controlled ACT-enhanced ablation systems may also utilize planning and treatment feedback.

[0114] A system for performing ACT-augmented ablation may further comprise one or more of a power amplifier, a pulse generator, a 3D positioning system, and an imaging modality such as the US, CT, or MRI imaging modalities described above.

[0115] advantage AA bubbles exhibit several properties that distinguish them from standard microbubbles, allowing ablation therapy to be performed with significantly lower ultrasound energy. First, compared to standard microbubbles, which do not settle in place but instead pass through the capillaries at a rate determined by perfusion velocity, the residence time of AA bubbles settled in place within the capillaries is approximately 5–15 minutes. This is typically on the order of a few seconds, depending on tissue perfusion and volume. This increases the potential exposure time of the target area for ACT-enhanced ablation therapy. Because ultrasound procedures typically take some time to perform (ultrasound ablation typically takes in the range of one hour), the bubbles cannot flow freely, making stationary bubbles a significant advantage. Second, compared to standard contrast microbubbles, which are small and therefore limit the generation of thermal and mechanical effects, the larger size of AA bubbles allows for increased thermal and mechanical effect generation using lower acoustic power.

[0116] AA bubbles also dissipate energy as heat through friction between the settled AA bubble surface area and the capillary wall, and through conduction upon compression. Therefore, combining ultrasound with AA bubbles can effectively reduce the required acoustic energy level.

[0117] AA bubbles are activated under imaging control and deposited within the tissue microvasculature, thus enabling spatial targeting of AA bubbles within tissue. This, combined with the extended residence time of AA bubbles, allows for more efficient and controlled delivery of ablation therapy.

[0118] Because the process is non-invasive and does not involve implanted hardware, the technology poses no risk of infection, has the added benefit of not using ionizing radiation, and can provide immediate results.

[0119] Furthermore, because AA bubbles are triggered as hyperechoic spots, they can provide real-time imaging, which provides additional information about the size and shape of lesions that are not visible in thermally ablated areas on B-mode ultrasound imaging.

[0120] It is often useful to assess the perfusion of the organ to be treated before the procedure begins. ACT techniques can be used to test the perfusion of various organs, thus providing a secondary utility alongside ablation enhancement and a tertiary utility alongside imaging (i.e., the accumulation of AA bubbles in the target tissue can be used for control feedback).

[0121] ACT-enhanced ablation therapy may not reach as high temperatures and requires a shorter cooling time compared to conventional thermal ablation. A cooling period between sonication treatments is often required to prevent unnecessary heating of surrounding tissue. Therefore, a shorter period between sonication treatments is required, thereby reducing the overall ablation time.

[0122] All of the advantages outlined above may lead to the subsequent advantage of reduced side effects and bleeding potential.

[0123] Thermal activation is enhanced only at the acoustic focus, where pressure is sufficient to activate the AA bubbles. Focusing the ultrasound beam allows high intensities only at specific locations within a small volume, minimizing the possibility of thermal damage to tissue outside the focal area. For example, the ultrasound beam may be approximately 1 mm in diameter and 10 mm in length. At the border of the thermally coagulated lesion, tissue dies and is taken up by the immune system within 2–3 days. Ultrasound used in combination with ACT allows for lower intensities, achieving the same or better ablation and reducing the risk of damage to surrounding tissue.

[0124] usefulness ACT-augmented ablation has clinical impact in neurology / surgery, ophthalmology, urology, gynecology, and oncology. In the field of neurology, ACT-augmented ablation may have clinical impact in brain tumors and space-occupying masses, neuromodulation, tremor, tremor-dominant Parkinson's disease (movement disorder symptoms), epilepsy, and stroke. In the field of ophthalmology, ACT-augmented ablation may have clinical impact in glaucoma, intraocular tumors, retinal detachment, and trabeculotomy. In the field of urology, ACT-augmented ablation may have clinical impact in kidney stones, precancerous lesions of the cervix, and adrenal glands. In the field of gynecology, ACT-augmented ablation may have clinical impact in uterine fibroids and ovarian cancer. In the field of oncology, ACT-augmented ablation may have clinical impact primarily in the musculoskeletal system, lung, breast, brain, prostate, kidney, liver, pancreas, brain tumors, renal, and bladder. ACT-augmented ablation may have clinical impact in the treatment of other malignancies, including adrenal tumors, thyroid cancer, skin cancer, bulky tumors (neck, nodules, bone), and a minor role in the treatment of superficial tumors (skin). In the field of cardiovascular disease (blocking irregular electrical signals and restoring normal heartbeat), ACT-augmented ablation may have clinical impact in atrial fibrillation, irregular heartbeat, arrhythmia, and normalization of vascular function. ACT-augmented ablation may also have clinical impact in palliative (metastatic) and chronic pain treatment. Psychiatric disorders may also be treated with ACT-augmented ablation. In the field of cosmetic surgery, ACT-augmented ablation may have clinical impact in the treatment of signs of aging and lifting. ACT-augmented ablation may also have clinical impact in the treatment of complete or partial vascular occlusions, such as deep vein thrombosis, pulmonary embolism, coronary artery occlusion, and arteriosclerosis.

[0125] The ultrasound settings (sonication regime) used in the enhancement step are application specific, particularly with respect to the type of tissue being ablated.

[0126] ACT-enhanced ultrasound ablation for treating tumors The temperature changes are concentrated in a focal zone within and around the tumor. The overall goal of thermal tumor ablation is very similar to that of surgery: to remove the tumor and a 5-10 mm thick margin of apparently normal tissue. In contrast to surgical removal, which consists of physical excision, with thermal ablation, the tissue is killed in situ and then absorbed by the body over several months.

[0127] Specific ultrasound settings for the enhancement step of ACT-enhanced ultrasound when the target area is a tumor include an MI greater than 0.4, preferably greater than 0.6, and more preferably greater than 0.8, and an intensity of up to 5000 W / cm 2 The frequency is less than 3 MHz, preferably less than 1 MHz, and the duration of continuous or pulsed ultrasonic irradiation is about 20 to 30 seconds.

[0128] ACT-enhanced ultrasound ablation is suitable for the treatment of liver tumors and the selective destruction of normal liver, bladder, muscle, and kidneys. Depending on the equipment and parameters used, the volume of the focused ultrasound lesion can be as small as a grain of rice (approximately 10 cubic millimeters). This allows for highly localized treatment and a clear demarcation between treated and untreated areas. For the treatment of larger structures, such as large tumors, multiple treatment volumes can be combined to encompass the entire volume.

[0129] Because tumors are metabolically active, they have high perfusion compared to the relatively low perfusion of surrounding tissue. This higher perfusion rate in tumors compared to surrounding tissue ultimately results in a higher concentration of AA bubbles in tumor tissue than in surrounding areas. As noted above, performing an enhancement step on the AA bubbles destroys adjacent tissue. Therefore, ACT-enhanced ultrasound ablation is particularly suitable for tumor cell removal because the technique can take advantage of the higher perfusion rate in tumors compared to normal tissue.

[0130] ACT-enhanced ultrasound ablation for signs of aging The specific ultrasound settings for the enhancement step of ACT-enhanced ultrasound ablation, where the target area is a sign of aging, are generally similar to those for tumor ablation, except that the ultrasound field is preferably delivered in short bursts instead of continuous insonation.

[0131] Because the target area is normal tissue, the tissue must be exposed to a temperature range of 30-77°C.

[0132] ACT-enhanced ultrasound ablation using transrectal and interstitial ultrasound sources Transrectal and interstitial ultrasound sources can be placed closer to the target volume, operating at lower power and higher frequency and achieving the same ablation efficiency. The preferred ultrasound power range for the transrectal / interstitial source during the enhancement step is up to 5000 W / cm. 2 For the enhancement step, the preferred frequency is less than 4 MHz, more preferably less than 1 MHz. For larger prostates with deeper lesions, the choice of frequency is limited by the required penetration depth.

[0133] ACT-enhanced ultrasound ablation may be combined with chemotherapy, immunotherapy, and / or drug delivery to provide more effective treatment with fewer side effects. ACT-enhanced ultrasound ablation does not exclude other treatment options. Negative cell selection is not present with antibody or hormone therapy.

[0134] ACT-enhanced ultrasound ablation for brain treatments Without combination with AA bubbles, the usefulness of thermal ultrasound ablation for brain procedures is limited, primarily due to the barriers to ultrasound radiation through bony structures.

[0135] ACT-enhanced ultrasound ablation has the advantage of shortening procedure time and allowing temperatures and frequencies to be kept lower than non-ACT-enhanced ultrasound ablation, thereby overcoming the limitations of transcranial ultrasound.

[0136] Furthermore, AA bubbles can be allowed to settle within the vasculature for up to 15 minutes, allowing them to be closer to the endothelial wall and generate an optimal thermal effect. This is in contrast to conventional contrast microbubbles, which are smaller, with an average diameter of approximately 1–3 μm, and therefore clear the vasculature in significantly less time, e.g., a few seconds, depending on tissue perfusion and volume.

[0137] Skull thickness varies with age, gender, and ethnicity. Ultrasound ablation procedures are well suited to treatment through the thick skull barrier. Furthermore, ultrasound ablation may be limited to treatment of target areas in the center of the brain. However, these issues can be resolved by combining this technology with optimal AA bubbles, which achieve functionality at lower ultrasound energy levels. ACT offers the advantage of being temporarily confined to the microcirculation of the target area. This combination allows for the full utilization of MRgFUS technology for extra-central applications in the brain, not only working through thicker bone structures but also opening the blood-brain barrier.

[0138] ACT-enhanced ultrasound ablation for administering thrombolysis ACT-enhanced ablation and ACT-enhanced ultrasound ablation can also be used to treat thrombus formation in the vasculature. The method can include positioning at least one cluster proximal to, and preferably adjacent to, a target thrombus formed in a subject's blood vessel. The cluster is then activated according to the method described above to create at least one AA bubble. The activation process, in which the cluster transitions to an AA bubble, results in the entity expanding and creating mechanical stress on the proximal (adjacent) thrombus. This mechanical stress can be sufficient to cause the thrombus to disintegrate (break down). A method for treating thrombolysis by disintegrating a thrombus can further include utilizing an enhancement step of ACT-enhanced ultrasound ablation, such as the enhancement step described above. A method using ACT-enhanced ultrasound ablation to treat thrombolysis can further include an activation step interleaved with the enhancement step alone or in combination with a thrombolytic or anticoagulant agent.

[0139] AA bubble generation and ACT-enhanced ultrasound ablation can result in thrombus fragmentation or reduce thrombus size, promote thrombus movement, enhance thrombolytic and anticoagulant penetration into the thrombus, and / or remove thrombus degradation products by mechanical or thermal disruption.

[0140] ACT-enhanced ultrasound ablation can be used to treat myocardial infarction, stroke, and venous thromboembolism.

[0141] 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.

[0142] ACT-enhanced ultrasound ablation for thrombolysis treatment has the advantage of reducing the risk of bleeding compared to thrombus disruption using ultrasound irradiation alone or in combination with conventional microbubbles. Bleeding can also be reduced by the lower ultrasound intensity required. Bleeding can also be reduced because the method does not require the use of thrombolytic or anticoagulant drugs or may require lower doses. An additional advantage is that the treatment time can be shortened. [Example]

[0143] Simulation of enhanced fields on bubbles Figures 8a, 8b, and 8c show graphical representations of the calculation of the maximum differential volume of an AA bubble vibrating in the first vibration mode, 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:

[0144]

number

[0145] Preclinical evidence To investigate the effect of MI variation of enhanced ultrasound fields, tumor-specific uptake of the fluorescent dye Evans Blue® was investigated in the SC PC3 mouse model.

[0146] Three mice were selected to receive enhanced ultrasound with a mechanical index of 0.8 (MI=0.8 group). Immediately following intravenous (IV) injection of Evans Blue®, a single IV dose of PS101 (5.1 mg PFMCP / kg [1000 μL PS101 / kg]) was administered, followed by 45 seconds of activated ultrasound (2.5 MHz, MI 0.4) focused on the tumor, followed by 5 minutes of enhanced ultrasound (0.5 MHz, MI 0.8).

[0147] In the MI = 0.8 group, tumors and non-ultrasound-exposed control muscles from the right leg were excised and the amount of Evans Blue® was measured by spectrophotometry at 620 nm. The amount of Evans Blue® detected in the tumors of animals in the MI = 0.8 group was lower than that detected in the other groups with lower enhanced ultrasound MIs. This suggests either potential damage to cells within the tumor or damage to blood vessels, which reduces the blood supply and results in a lower concentration of Evans Blue in the target volume. Therefore, ACT bubbles appear to cause tissue ablation and significant hemorrhage when exposed to an enhanced MI of 0.8. In the MI = 0.8 group, all animals died during or immediately after treatment, showing extensive bleeding in the insonicated area (left thigh and leg). These animals likely died due to the high-intensity ultrasound exposure of a significant portion of the mouse's body weight (approximately 10%, approximately 20 times the typical clinical dose) in combination with a high dose of PS101 (20–40 times the expected clinical dose). It is anticipated that by optimizing the dose of PS101 and the MI of enhanced ultrasound, ablation can be achieved without inducing these effects.

[0148] Although preferred examples of the present invention have been described, it will be apparent to those skilled in the art that other embodiments incorporating the present invention may also be used. These and other examples of the present invention illustrated above are intended for illustrative purposes only, with the actual scope of the invention to be determined from the appended claims.

Claims

1. 1. A method of enhanced ultrasound ablation, said method comprising: administering to a subject a cluster composition comprising at least one cluster, the cluster comprising a microbubble component and a microdroplet component; and activating a phase shift transition of the microdroplet components of the at least one cluster by ultrasonic irradiation to create the at least one ablation-assist bubble; by: creating at least one ablation assist bubble proximal to the target region; The method of claim 1, wherein expansion of the at least one cluster from the transition to the at least one ablation-assist bubble provides mechanical stress to the target region to assist in ablation on target tissue within the target region.

2. The method of claim 1 , wherein the at least one ablation-assist bubble has a diameter of at least 10 micrometers.

3. 3. The method of claim 1 or 2, further comprising insonifying the at least one ablation-assist bubble with ultrasound of a predetermined intensity to induce at least one of energy absorption, deposition, vibration, and cavitation of the ablation-assist bubble, resulting in additional mechanical and / or thermal stress in the target region and assisting in ablation on the target tissue within the target region.

4. 4. The method of claim 3, wherein the predetermined intensity of the ultrasound for insonifying the ablation-assist bubbles is equal to the intensity for non-bubble-assisted ultrasound ablation divided by a factor of 12-24.

5. 5. The method of any one of claims 1 to 4, wherein the enhanced ultrasound ablation is configured to result in a temperature in the target area of ​​30 to 70 degrees Celsius for a continuous exposure time of at least 30 seconds.

6. 6. The method of claim 1, further comprising using the at least one ablation-assist bubble for real-time imaging of the target area by insonifying the at least one ablation-assist bubble with imaging ultrasound, wherein the at least one ablation-assist bubble is induced as a hyperechoic spot.

7. 7. The method of any one of claims 1 to 6, further comprising a further ultrasound planning step that uses unique subject and application specific information to plan a particular ultrasound exposure regime, wherein the ultrasound planning comprises at least one of a passive ultrasound planning and an active ultrasound planning.

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

9. Active ultrasound planning monitoring the ablation zone during the augmentation step for real-time feedback of the ablation zone; adjusting the particular ultrasound exposure regime to achieve predetermined parameters in the ablation zone; 9. The method of claim 7 or 8, wherein the monitoring and adjusting steps are performed continuously for a predetermined period of time.

10. 10. The method of claim 9, wherein monitoring the ablation zone during the enhancement step for real-time feedback of the ablation zone comprises at least one of real-time temperature feedback, real-time mechanical feedback, cross-modality imaging and co-registration, real-time monitoring of cluster dynamics and concentration, and real-time monitoring of ablation-assist bubble dynamics and concentration.

11. 11. The method of claim 9 or 10, wherein monitoring the target area including the ablation zone further comprises imaging via an image-guided modality, wherein the image-guided modality comprises at least one of magnetic resonance guidance, ultrasound guidance, computed tomography guidance, light guidance, thermocouple guidance, and contrast-enhanced ultrasound guidance.

12. The method of any one of claims 1 to 11, further comprising the simultaneous administration of a therapeutic agent configured to assist ablation efficacy, wherein the therapeutic agent is administered separately before, simultaneously with, and / or after the cluster composition.

13. 1. An intravenously administrable composition for use in a method for enhancing ablation at a target area, said intravenously administrable composition comprising: a microbubble / microdroplet cluster composition that forms at least one cluster via electrostatic forces; An intravenously administrable composition configured such that when the method includes exposing the at least one cluster to effective ultrasonic radiation, each of the at least one cluster vibrates, expands, and fuses into a single entity to provide an ablation-assisting bubble.

14. 14. The intravenously administrable composition of claim 13, wherein when the method further comprises exposing the resulting ablation-assist bubbles to ultrasound of a predetermined intensity, the ablation-assist bubbles are configured to vibrate and / or cavitate to induce mechanical and / or thermal stress in the target area, thereby increasing ablation efficiency in the target area.

15. 15. The intravenously administrable composition of claim 13 or 14, wherein the resulting ablation-assisted bubbles are configured to induce mechanical and / or thermal stress comparable to that induced from direct ultrasound application to the target area, and wherein the predetermined intensity is equal to the intensity for non-bubble-assisted ultrasound ablation divided by a factor of 12 to 24.

16. the microbubble / microdroplet cluster composition comprising: a dispersion of clusters of microdroplets having an average diameter of 2-3 μm stabilized by a lipid membrane having a net positive surface charge; 16. The intravenously administrable composition of any one of claims 13 to 15, formed from microbubbles having an average diameter of 2 to 3 μm stabilized with a lipid shell having a net negative surface charge.

17. 17. The intravenously administrable composition of claim 16, wherein the net positive surface charge of the microdroplets and the net negative surface charge of the microbubbles result in electrostatic forces that enable the formation of at least one microbubble / microdroplet cluster.

18. An intravenously administrable composition according to any one of claims 13 to 17, wherein the diameter of the resulting clusters is in the range of 4 to 8 µm.

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

20. 20. An intravenously administrable composition according to any one of claims 17 to 19, for use according to any one of claims 1 to 9, wherein the oil phase of the microdroplets of said at least one microbubble / microdroplet cluster comprises a partially or fully halogenated hydrocarbon or mixtures thereof.

21. 21. An intravenously administrable composition according to any one of claims 13 to 20 for use in the treatment of one or more of tumors, space-occupying masses, thrombolysis, and neurological disorders.

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