JPWO2019002940A5 - - Google Patents

Description

(Cross reference to related applications)
This application is based on U.S. patent application Ser. No. 15/637,163 (filed June 29, 2017), No. 62/597,073 (filed December 11, 2017), and No. 62/ 597,076 (filed Dec. 11, 2017), and claims the benefit thereof. The entire disclosure of these priority documents is incorporated herein by reference.

The present invention relates generally to targeted drug delivery, and more particularly to systems and methods for enhancing targeted drug delivery using ultrasound techniques.

Drug delivery systems are often developed with the goal of lowering the overall administered therapeutic dose of a drug, increasing its residence time, prolonging its release over time, and enhancing targeting to diseased tissues. It is Toxic effects of a drug can be reduced by limiting concentration or dose in non-target areas while increasing concentration or dose in target areas. Thus, targeted drug delivery systems direct relatively high levels of drug to the focal site, thereby minimizing drug uptake by non-target organs or tissues and reducing the cost of treatment.

One conventional approach to enhancing targeted drug delivery involves the use of ultrasound. For example, exposing a target tissue to ultrasound may increase its penetration rate, allowing a higher percentage of the drug dose to produce a therapeutic effect on the target area. In another approach, drugs are encapsulated within "nanobubbles" that are injected into the target area. Application of ultrasound can cause local increases in temperature and bubble cavitation, thereby inducing release of the encapsulated drug. Similarly, ultrasonic energy may be applied to chemically activate the drug administered into the target area. Although these conventional approaches can improve targeted drug delivery, a number of challenges remain.

For example, to ensure that the application of ultrasound results in increased permeability only in the target tissue (and does not have a clinically significant effect on the permeability of non-target tissues), the ultrasound beam is directed over the target location. is required to be precisely focused at . However, due to the heterogeneous anatomy of the body (e.g., with skin, skull, or ribs located between the ultrasound transducer array and the target area), targeting the ultrasound beam, for example, during an earlier preparatory stage. It is difficult to focus precisely as planned on the area. Additionally, since the size of the target area is generally larger than that of the ultrasound focal zones, multiple ultrasound vibrations are required to generate multiple focal zones that collectively cover the target area. However, because the human body is flexible and moves (e.g., due to breathing or minor involuntary movements) even when the patient is positioned to remain stationary, multiple ultrasound waves Focused regions created over time by vibration can deviate from the target region even when delivered within seconds of each other. Deviation of the focal region from the target region is undesirable and can lead to increased penetration in non-target regions, with adverse therapeutic consequences.

Thus, there is a need for improved targeted drug delivery approaches that adapt to patient anatomy and locomotion during therapeutic drug delivery, release, and/or activation.

The present invention provides systems and methods for increasing tissue permeability within a target area using ultrasound techniques. Tissue regions with altered permeability are accurately tracked through the use of permeability maps. In various embodiments, the permeability map is generated using an MRI contrast agent selected based on the molecular size of the therapeutic agent to be administered for treatment. For example, target tissue may be permeable to molecules having a size of less than 400 daltons, whereas therapeutic agents have a size of 1,000 daltons and thus block entry into the target area. can be In response to the application of ultrasound, tissue within the target area may be disrupted so that its permeability may be increased. The level of permeability and/or the size of the tissue region with increased permeability may depend on the intensity and/or duration of the ultrasound application. Thus, by adjusting the ultrasound parameters, the tissue permeability of the target area can be increased to the desired degree to allow the therapeutic agent to penetrate and/or diffuse therein. An MRI contrast agent, having substantially the same molecular weight (or other size metric) as the therapeutic agent (i.e., 1,000 Daltons in this example), is then applied to the target area to generate a tissue permeability map. can be injected into The size of the MRI contrast agent ensures that it can penetrate the target tissue being sonicated and cause a visible contrast change in the MRI image. Thus, by monitoring contrast changes in MRI images, a map of tissue permeability in target and/or non-target regions can be generated.

In one embodiment, microbubbles are optionally generated (eg, acoustically) at and/or injected into the target area according to conventional practice. Application of ultrasound pulses to microbubbles can result in a series of behaviors known as acoustic cavitation, which can aid in tissue disruption and thereby increase tissue permeability in the target area. Thus, in one embodiment, a tissue permeability map is derived, at least in part, from local acoustic responses (e.g., instantaneous acoustic response levels, cumulative acoustic response levels, dose, and/or the spectral distribution of the acoustic response).

Additionally or alternatively, the permeability map may be created using computer simulation. For example, the simulation may include tissue models of target and/or non-target tissue material properties (e.g., thermal sensitivity and/or thermal energy tolerance), microbubble properties (e.g., dosing profile, size distribution, concentration, etc.), and/or Alternatively, a permeability map may be generated based on ultrasound parameters (eg, amplitude, frequency, duration, etc. of ultrasound vibration pulses). These properties may be determined experimentally, by reference to the literature, and the like.

In various embodiments, the tissue region with increased permeability within the permeability map is compared to the target region defined prior to the ultrasound procedure (e.g., registered to the image), Verify that the tissue penetration rate within the defined target area is increased to allow penetration of the therapeutic agent therein. In addition, tissue permeability within non-targeted regions preferably remains substantially unchanged (e.g., any permeability change is such that any resulting drug penetration has no clinically detrimental effect). not clinically significant in the sense that it does not occur), thereby blocking the therapeutic agent's pathway of entry so as to ensure precise delivery, release, and/or activation of the therapeutic agent only in the desired target area do. In some embodiments, if the tissue area with increased permeability (as revealed by the map) is smaller than the defined target area, additional ultrasonic vibrations are applied to encompass the target area. Additionally, it may be implemented to increase the volume of tissue permeability that is increased. However, if the mapped area is larger than the defined target area, the patient will be treated until the tissue in the target area regenerates and loses the induced permeability (and can therefore be disrupted again from baseline levels). , may rest for 1 or 2 days. Once the mapped area is verified to substantially (e.g., ±5% or ±10% by volume) match the defined target area, the therapeutic agent is administered to the target area for treatment. may be

Alternatively, if the therapeutic agent has already been administered based on the permeability map, there may be no need to acquire and validate new maps for subsequent administrations. For example, a therapeutic agent may be administered into the target area based on the tissue permeability map generated after the first series of ultrasonic vibrations. Subsequent ultrasonic vibrations may be applied to the target area having the therapeutic agent therein. Since the therapeutic agent itself may also exhibit responsiveness to ultrasonic vibrations and/or enhance the destruction rate of the target tissue, the present approach advantageously favors the uptake rate of the therapeutic agent within the target region (e.g., permeation rate, release rate, and/or activation rate).

Thus, the present invention provides an approach for creating tissue permeability maps of target and optionally non-target regions. Based thereon, therapeutic agents can be administered with enhanced targeting. In addition, using ultrasound to increase tissue penetration can be an effective treatment modality because ultrasound can penetrate deep into the body and produce a beam that is focused to a desired area in a controlled manner. It allows the drug to be precisely delivered and/or activated within the target area.

Thus, in one aspect, the invention relates to a system for ablating target tissue for treatment and assessing target tissue destruction . In various embodiments, the system includes an imaging device for obtaining a digital representation of one or more portions of a target volume of target tissue and corresponding target volume to increase tissue permeability therein. an ultrasonic transducer for generating and delivering one or more ultrasonic vibrations of the shaped energy beam to the target volume to cause destruction of the target tissue within the region; generating a tissue permeability map indicating the area of tissue permeability to be affected and an estimate of tissue permeability resulting from the disruption , and computationally assessing disruption of the target tissue within the target volume based on the tissue permeability map a controller configured to: In one implementation, the controller is further to generate a tissue permeability map based, at least in part, on the acoustic response of the target volume during MRI contrast imaging, planning or simulating ultrasound vibrations, and/or destruction . Configured.

In some embodiments, the controller is further configured to computationally determine whether tissue within the target volume can receive the therapeutic agent based on the tissue permeability map. For example, the controller may be configured to computationally determine whether tissue within the target volume is capable of receiving the therapeutic agent based on its molecular size and estimated tissue permeability. Additionally, the controller may be further configured to computationally verify, based on the tissue permeability map, that tissue outside the target volume is unable to receive the therapeutic agent to a clinically significant extent. In one embodiment, the controller is further configured to compare the target volume within the tissue permeability map and the target volume acquired using the imaging device. In some embodiments, the system further provides treatment only when tissue within the target volume is capable of receiving a therapeutic agent and the target volume substantially matches the target volume obtained using the imaging device. Including a dosing device for administering the drug.

Additionally or alternatively, the system may include an administration device for administering the therapeutic agent into the target volume based on the tissue permeability map. The controller may be further configured to cause the ultrasound transducer to generate and deliver a second ultrasound oscillation of the shaped energy beam to the target volume after administration of the therapeutic agent. In various embodiments, the tissue permeability map includes a plurality of permeability levels, each permeability level being associated with a tissue region within the target volume and the number of molecules capable of entering the associated tissue region. Indicates maximum size. The administration device may then be configured to administer the therapeutic agent based on the permeability level. Therapeutic drugs include busulfan, thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), temozolomide, methotrexate, topotecan, cisplatin, etoposide, irinotecan/SN-38, carboplatin, doxorubicin, vinblastine, vincristine, procarbazine, paclitaxel. , fotemustine, ifosfamide/4-hydroxyifosfamide/aldoifosfamide, bevacizumab, 5-fluorouracil, bleomycin, hydroxyurea, docetaxel, and/or cytarabine (cytosine arabinoside, ara-C)/ara-U good.

In some embodiments, the imaging device is further configured to acquire images of the target volume during delivery of the ultrasonic vibrations, and the controller further determines, based on the images, parameters associated with the subsequent ultrasonic vibrations. is configured to regulate the Additionally, the controller may be further configured to cause the ultrasonic transducer to generate a plurality of ultrasonic vibrations, each delivering shaped acoustic energy to one focal zone within the target volume, are collectively coextensive with the target volume. Ultrasonic vibrations can cause the generation of microbubbles and cavitation within the target volume. Additionally or alternatively, the system may further include a dosing device for dosing the microbubble seeds into the target volume, wherein the ultrasonic vibration and the microbubble seeds cause generation of the microbubbles. Additionally, the system may further include a dosing device for dosing the microbubbles into the target volume, where the ultrasonic vibrations may then cause cavitation of the microbubbles.

In another aspect, the invention relates to a method of destroying target tissue for treatment and assessing target tissue destruction . In various embodiments, the method comprises the steps of: (a) identifying a target volume of the target tissue; and (b) extracting the target tissue within a region corresponding to the target volume so as to increase tissue permeability therein. (c) computationally generating a tissue permeability map indicating regions of increased tissue permeability and an estimate of tissue permeability resulting from the disruption ; (d) at least partially Computationally assessing destruction of the target tissue within the target volume based on the tissue permeability map and the identified target volume. In one implementation, the tissue permeability map is generated based, at least in part, on MRI contrast imaging, planning or simulating ultrasound vibrations, and/or acoustic response of the target volume during step (b).

In some embodiments, the method further comprises computationally determining whether tissue within the target volume can receive the therapeutic agent based on the tissue permeability map. For example, whether tissue within a target volume is capable of receiving a therapeutic agent may be computationally determined based on its molecular size and estimated tissue permeability. Additionally, the method may include computationally verifying, based on the tissue permeability map, that tissue outside the target volume is unable to receive the therapeutic agent to a clinically significant extent. In one embodiment, step (d) includes comparing the target volume in the tissue permeability map and the target volume identified in step (a) to determine a match therebetween. The therapeutic agent is administered only when tissue within the target volume is capable of receiving the therapeutic agent and the target volume substantially matches the target volume identified in step (a).

Additionally or alternatively, the method may include administering the therapeutic agent into the target volume based on the tissue permeability map. The method may further include generating and delivering a second ultrasonic oscillation of the shaped acoustic energy beam to the target volume after administering the therapeutic agent. In various embodiments, the tissue permeability map includes a plurality of permeability levels, each permeability level being associated with a tissue region within the target volume and the number of molecules capable of entering the associated tissue region. Indicates maximum size. A therapeutic agent may then be administered based on the permeability level. Therapeutic drugs include busulfan, thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), temozolomide, methotrexate, topotecan, cisplatin, etoposide, irinotecan/SN-38, carboplatin, doxorubicin, vinblastine, vincristine, procarbazine, paclitaxel. , fotemustine, ifosfamide/4-hydroxyifosfamide/aldoifosfamide, bevacizumab, 5-fluorouracil, bleomycin, hydroxyurea, docetaxel, and/or cytarabine (cytosine arabinoside, ara-C)/ara-U good.

In some embodiments, the method further comprises generating and delivering one or more ultrasonic vibrations of the shaped energy beam to the target volume to increase tissue penetration. A plurality of ultrasonic vibrations, when generated, each deliver shaped acoustic energy to a focal zone within the target volume, the focal zones being collectively coextensive with the target volume. Additionally, the method includes imaging the target volume during delivery of a first one of the ultrasonic vibrations and adjusting parameters associated with subsequent ones of the ultrasonic vibrations based thereon. It's okay. In one embodiment, the method includes causing cavitation of microbubbles within a target volume to increase tissue penetration therein. Microbubbles may be generated by an acoustic energy beam that is injected and/or shaped into the target volume. In one implementation, microbubbles are generated by microbubble seeds and shaped acoustic energy beams that are injected into the target volume.

As used herein, the term "substantially" means ±10% tissue volume, in some embodiments ±5% tissue volume. "Clinically significant" has an undesirable effect on tissue that is considered significant by a clinician, e.g., inducing the development of damage thereto (sometimes lacking the desired effect). ) means that Throughout this specification, references to "an example,""anexample,""anembodiment," or "an embodiment" refer to the specific features, structures, or features described in connection with the example. or that the characteristic is included in at least one embodiment of the technology. Thus, appearances of the phrases "in one embodiment,""in one embodiment,""in one embodiment," or "an embodiment" in various places throughout this specification do not necessarily all refer to the same It does not refer to an embodiment. Furthermore, certain features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or more embodiments of the technology. The headings provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology.
The present invention provides, for example, the following.
(Item 1)
A system for destroying target tissue for treatment and assessing destruction of said target tissue, said system comprising:
an imaging device for obtaining a digital representation of at least a portion of a target volume of the target tissue;
generating at least one ultrasonic vibration of a shaped energy beam to cause destruction of the target tissue within a region corresponding to the target volume so as to increase tissue permeability within the target volume; , an ultrasound transducer for delivery to said target volume;
generating, in response to the imaging device, a tissue permeability map indicating regions of increased tissue permeability and an estimate of the tissue permeability resulting from the disruption ; A system comprising: a controller configured to computationally assess disruption of target tissue within a volume.
(Item 2)
2. The system of item 1, wherein the controller is further configured to computationally determine whether tissue within the target volume is capable of receiving a therapeutic agent based on the tissue permeability map.
(Item 3)
3. The system of item 2, wherein the controller is further configured to compare a target volume within the tissue permeability map and the target volume acquired using the imaging device.
(Item 4)
for administering the therapeutic agent only when tissue within the target volume is capable of receiving the therapeutic agent and the target volume substantially matches the target volume obtained using the imaging device; 4. The system of item 3, further comprising an administration device.
(Item 5)
the controller is further configured to computationally determine whether tissue within the target volume is capable of receiving the therapeutic agent based on the molecular size of the therapeutic agent and the estimated tissue permeability; The system of item 2.
(Item 6)
Item 2, wherein the controller is further configured to computationally verify, based on the tissue permeability map, that tissue outside the target volume is incapable of receiving the therapeutic agent to a clinically significant extent. The system described in .
(Item 7)
3. The system of item 2, further comprising an administration device for administering the therapeutic agent into the target volume based on the tissue permeability map.
(Item 8)
Item 7, wherein the controller is further configured to cause the ultrasonic transducer to generate and deliver at least a second ultrasonic oscillation of the shaped energy beam to the target volume after administration of the therapeutic agent. System as described.
(Item 9)
The tissue permeability map includes a plurality of permeability levels, each permeability level being associated with a tissue region within the target volume and defining a maximum size of a molecule capable of entering the associated tissue region. 8. The system of item 7, wherein:
(Item 10)
10. The system of item 9, wherein the administration device is configured to administer the therapeutic agent based on the permeability level.
(Item 11)
The therapeutic agents include busulfan, thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), temozolomide, methotrexate, topotecan, cisplatin, etoposide, irinotecan/SN-38, carboplatin, doxorubicin, vinblastine, vincristine, procarbazine, At least one of paclitaxel, fotemustine, ifosfamide/4-hydroxyifosfamide/aldoifosfamide, bevacizumab, 5-fluorouracil, bleomycin, hydroxyurea, docetaxel, or cytarabine (cytosine arabinoside, ara-C)/ara-U 3. The system of item 2, comprising one.
(Item 12)
The controller further determines, at least in part, based on at least one of MRI contrast imaging, planning or simulating the at least one ultrasonic vibration, or acoustic response of the target volume during the destruction , the tissue The system of item 1, configured to generate a permeability map.
(Item 13)
The imaging device is further configured to acquire images of the target volume during delivery of the at least one ultrasonic vibration, and the controller is further associated with subsequent ultrasonic vibrations based on the images. The system of item 1, configured to adjust a parameter.
(Item 14)
The controller is further configured to cause the ultrasonic transducer to generate a plurality of ultrasonic vibrations, each ultrasonic vibration directing shaped acoustic energy into one of a plurality of focal zones within the target volume. and wherein the focal zones are collectively coextensive with the target volume.
(Item 15)
2. The system of claim 1, wherein the at least one ultrasonic vibration causes microbubble generation and cavitation within the target volume.
(Item 16)
8. The system of item 7, further comprising an administration device for administering microbubble seeds to said target volume, wherein said at least one ultrasonic vibration and said microbubble seeds cause generation of said microbubbles.
(Item 17)
2. The system of item 1, further comprising an administration device for administering microbubbles to the target volume, wherein the at least one ultrasonic vibration causes cavitation of the microbubbles.
(Item 18)
A method of destroying target tissue for treatment and assessing destruction of said target tissue, said method comprising:
(a) identifying a target volume of said target tissue;
(b) causing disruption of the target tissue within a region corresponding to the target volume so as to increase tissue permeability within the target volume;
(c) computationally generating a tissue permeability map indicating regions of increased tissue permeability and an estimate of said tissue permeability resulting from said disruption ;
(d) computationally assessing destruction of the target tissue within the target volume based, at least in part, on the tissue permeability map and the identified target volume.
(Item 19)
19. The method of item 18, further comprising computationally determining whether tissue within the target volume is capable of receiving a therapeutic agent based on the tissue permeability map.
(Item 20)
20. The method of item 19, wherein step (d) comprises comparing a target volume in the tissue permeability map and the target volume identified in step (a) to determine a match therebetween.
(Item 21)
Item 20, wherein the therapeutic agent is administered only when tissue within the target volume is capable of receiving the therapeutic agent and the target volume substantially matches the target volume identified in step (a). The method described in .
(Item 22)
20. The method of item 19, wherein whether tissue within said target volume is capable of receiving said therapeutic agent is computationally determined based on its molecular size and said estimated tissue permeability.
(Item 23)
20. The method of item 19, further comprising administering the therapeutic agent into the target volume based on the tissue permeability map.
(Item 24)
24. The method of item 23, further comprising generating and delivering at least a second ultrasonic oscillation of a shaped acoustic energy beam to the target volume after administering the therapeutic agent.
(Item 25)
20. The method of item 19, further comprising computationally verifying, based on the tissue permeability map, that tissue outside the target volume is incapable of receiving the therapeutic agent to a clinically significant extent.
(Item 26)
The tissue permeability map includes a plurality of permeability levels, each permeability level being associated with a tissue region within the target volume and defining a maximum size of a molecule capable of entering the associated tissue region. 20. The method of item 19, wherein
(Item 27)
27. The method of item 26, wherein said therapeutic agent is administered based on said permeability level.
(Item 28)
The therapeutic agents include busulfan, thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), temozolomide, methotrexate, topotecan, cisplatin, etoposide, irinotecan/SN-38, carboplatin, doxorubicin, vinblastine, vincristine, procarbazine, At least one of paclitaxel, fotemustine, ifosfamide/4-hydroxyifosfamide/aldoifosfamide, bevacizumab, 5-fluorouracil, bleomycin, hydroxyurea, docetaxel, or cytarabine (cytosine arabinoside, ara-C)/ara-U 20. The method of item 19, comprising one.
(Item 29)
The tissue permeability map is generated based, at least in part, on at least one of MRI contrast imaging, planning or simulating the ultrasonic vibrations, or acoustic response of the target volume during step (b). 19. The method of item 18.
(Item 30)
19. The method of item 18, further comprising generating and delivering at least one ultrasonic vibration of a shaped energy beam to the target volume to increase the tissue penetration rate.
(Item 31)
A plurality of ultrasonic vibrations are generated, each delivering shaped acoustic energy to one of a plurality of focal zones within the target volume, the focal zones collectively being identical to the target volume. 31. The method of item 30, wherein the method is
(Item 32)
Item 31, further comprising imaging the target volume during delivery of a first one of said ultrasonic vibrations and adjusting parameters associated with subsequent ones of said ultrasonic vibrations based thereon. The method described in .
(Item 33)
19. The method of item 18, further comprising causing cavitation of microbubbles within the target volume to increase the tissue permeability within the target volume.
(Item 34)
34. The method of item 33, wherein the microbubbles are injected into the target volume.
(Item 35)
34. The method of item 33, wherein the microbubbles are generated by a shaped acoustic energy beam.
(Item 36)
34. The method of item 33, wherein the microbubbles are generated by microbubble seeds and a shaped acoustic energy beam injected into the target volume.

In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention. In the following description, various embodiments of the invention are described with reference to the following drawings.

FIG. 1A diagrammatically depicts an exemplary ultrasound system, according to various embodiments of the present invention.

FIG. 1B schematically depicts an exemplary MRI system, according to various embodiments of the present invention.

FIG. 2 depicts one or more focal bands of ultrasound waves/pulses generated within a target volume, according to various embodiments.

FIG. 3 depicts the presence of microbubbles within a target tissue region, according to various embodiments.

FIG. 4A depicts a comparison of a permeability map and a 3D voxel set of a target volume, according to various embodiments.

FIG. 4B depicts an exemplary permeability map, according to various embodiments.

FIG. 5 is a flow chart illustrating an approach to computationally generating a permeability map, according to various embodiments.

FIG. 6 illustrates the application of ultrasonic vibrations to achieve targeted drug delivery by temporarily increasing tissue permeability within the target area in a controlled and reversible manner, according to various embodiments of the present invention. 4 is a flow chart illustrating the enrichment approach.

FIG. 1A illustrates an exemplary ultrasound system 100 for generating and delivering a focused acoustic energy beam to a target area to disrupt tissue and thereby increase tissue permeability therein. In various embodiments, the system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 that drives the phased array 102, a controller 108 that communicates with the beamformer 106, and beamforms input electronic signals. and a frequency generator 110 that provides the frequency generator 106 .

Array 102 may have a curved (e.g., spherical or parabolic) shape suitable for placing it on the surface of the patient's body, or may have one or more planar or otherwise shaped sections. may contain. Its dimensions may vary from a few millimeters to tens of centimeters. Transducer elements 104 of array 102 may be piezoceramic elements and may be mounted in silicone rubber or any other material suitable for damping mechanical coupling between elements 104 . Piezoelectric composites, or generally any material capable of converting electrical energy into acoustic energy, may also be used. To ensure maximum power transfer to transducer element 104, element 104 may be configured for electrical resonance at 50Ω, matching the input connector impedance.

Transducer array 102 is coupled to beamformer 106, which drives individual transducer elements 104 such that they collectively produce a focused ultrasound beam or field. For n transducer elements, the beamformer 106 may contain n drive circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120, each drive circuit Drive one of the elements 104; Beamformer 106 receives a radio frequency (RF) input signal, typically in the range of 0.1 MHz to 10 MHz, from frequency generator 110, which is, for example, model DS345 available from Stanford Research Systems. It may be a generator. The input signal may be split into n channels for the n amplifiers 118 and delay circuits 120 of beamformer 106 . In some embodiments, frequency generator 110 is integrated with beamformer 106 . Radio frequency generator 110 and beamformer 106 are configured to drive individual transducer elements 104 of transducer array 102 at the same frequency but with different phases and/or different amplitudes.

The amplification or attenuation coefficients α ₁ -α _n and phase shifts a ₁ -a _n imposed by the beamformer 106 transmit and focus the ultrasonic energy onto the target area, and the distance between the transducer elements 104 and the target area. It serves to account for wave distortions induced in intervening tissues. Amplification factors and phase shifts are calculated using controller 108, which may provide computer functionality through software, hardware, firmware, hard-wiring, or any combination thereof. For example, the controller 108 may use undue experimentation in a conventional manner to determine the phase shift and amplification factors necessary to obtain the desired focusing or any other desired spatial field pattern in the target region. Alternatively, a software programmed general purpose or special purpose digital data processor may be utilized. In some embodiments, the computer is based on detailed information about the properties (eg, structure, thickness, density, etc.) of the tissue located between the transducer elements 104 and their effects on the propagation of acoustic energy. Such information may be obtained from imager 122 . Imager 122 may be, for example, a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, a positron emission tomography (PET) device, a single photon emission tomography (SPECT) device, or an ultrasound device. There may be. Image acquisition may be three-dimensional (3D), or alternatively, imager 122 captures two-dimensional (2D) images suitable for reconstructing a three-dimensional image of the target area and/or its surrounding areas. may provide a set of Additionally, ultrasound system 100 and/or imager 122 may be utilized to detect the presence, type, and/or location associated with microbubble cavitation, as further described below. Additionally or alternatively, the system includes a cavitation detection device (such as a hydrophone or suitable alternative) 124 for detecting information associated with microbubble cavitation, and a therapeutic agent, as further described below. and/or a delivery system 126 for parenterally introducing the microbubbles into the patient's body. Imager 122, cavitation detection device 124, and/or administration system 126 may be operated using the same controller 108 that facilitates transducer operation. Alternatively, they may be separately controlled by one or more separate controllers that intercommunicate with each other.

FIG. 1B illustrates an exemplary imager or MRI machine 122 . Apparatus 122 may include cylindrical electromagnet 134 , which generates the required static magnetic field within bore 136 of electromagnet 134 . During a medical procedure, a patient is placed inside bore 136 on movable support 138 . A region of interest 140 within the patient (eg, the patient's head) may be positioned within the imaging region 142 and the electromagnet 134 generates a substantially homogeneous field. A set of cylindrical magnetic field gradient coils 144 may also be provided within bore 136 to surround the patient. Gradient coils 144 generate magnetic field gradients of predetermined magnitude in three mutually orthogonal directions at predetermined times. Using field gradients, different spatial locations can be associated with different precession frequencies, thereby giving the MR image its spatial resolution. Surrounding the imaging region 142, an RF transmitter coil 146 emits RF pulses into the imaging region 142, causing the patient's tissue to emit magnetic resonance (MR) response signals. Raw MR response signals are sensed by RF coil 146 and passed to MR controller 148, which then computes the MR image, which may be displayed to the user. Alternatively, separate MR transmitter and receiver coils may be used. The images acquired using the MRI machine 122 provide radiologists and physicians with visual contrast between different tissues and detailed interiors of the patient's anatomy that cannot be visualized using conventional X-ray techniques. can provide a view.

The MRI controller 148 may control the pulse sequence, ie the relative timing and strength of the magnetic field gradient and RF excitation pulses and the response detection period. The MR response signals are amplified, conditioned and digitized into raw data using conventional image processing systems, and converted into an array of image data by methods known to those skilled in the art. Based on the image data, target regions (eg, tumors) can be identified.

In order to perform targeted drug delivery, it is necessary to determine the location of the target area with high accuracy prior to drug administration. Thus, in various embodiments, the imager 122 is first activated, and the target area and/or non-target area (e.g., healthy tissue surrounding the target area and/or the relationship between the transducer array 102 and the target area). An image of the intervening tissue (intervening tissue) is obtained, based on which anatomical properties (eg, location, size, density, structure, and/or shape) associated therewith are determined. For example, a tissue volume may be represented as a 3D set of voxels (ie, volumetric pixels) based on a 3D image or a series of 2D image slices, and may include target and/or non-target regions.

Referring to FIG. 2, in various embodiments, after a 3D voxel set corresponding to target volume 202 has been identified using imager 122, transducer array 102 is activated, causing focal zone 204 to extend into the target volume. 202. Generally, the size of target volume 202 is larger than that of focal zone 204 . Accordingly, transducer array 102 is sequentially activated to create multiple focal zones 204 within target volume 202 to disrupt tissue therein, thereby temporarily increasing tissue permeability. may occur. Additionally, each focal zone 204 may be shaped (eg, to a focal point or volume such as a sphere or toroid) to conform to the local shape of the target region 202 . Approaches for configuring ultrasound transducer elements to generate focal zones with desired sizes and shapes are described, for example, in U.S. Pat. No. 7,611,462, the contents of which are incorporated herein by reference. provided).

In general, the degree of permeability and/or the size of the tissue region with increased permeability depends on the intensity and/or duration of the ultrasound application. Thus, by adjusting the ultrasound intensity and/or duration, the tissue penetration of the target area can be increased to a desired extent, allowing the therapeutic agent to penetrate and/or diffuse therein. can. In some embodiments, the ultrasonic procedure is such that the focused bands generated from a series of ultrasonic vibrations collectively occupy the target volume 202, disrupt tissue within the target volume 202, and increase tissue permeability. is monitored in real time by controller 108 based on image information from imager 122 until is temporarily increased. Additionally, the controller 108 adjusts the ultrasonic parameters (e.g., frequency, power, duration of application, etc.) of subsequent series of ultrasonic vibrations based on the image information acquired in the previous series of ultrasonic vibrations. may

Referring to FIG. 3, in various embodiments, the ultrasonic energy emitted by the transducer elements 104 exceeds a threshold, thereby causing the generation of small gas bubble clouds (or “microbubbles”) 302 within the target area 202. It can occur in contained liquids. Microbubbles 302 were produced by propagating ultrasound waves or pulses when a heated liquid bursts and fills with gas/vapor, or when a mild acoustic field is applied over tissue containing cavitation nuclei. Due to the negative pressure can be formed. However, at relatively low acoustic power (e.g., 1-2 Watts above the microbubble generation threshold), the generated microbubbles 302 tend to undergo oscillations with equal compression and rarefaction. , and therefore the microbubbles generally remain unruptured (ie, “stable cavitation”). At higher acoustic power (eg, more than 10 watts above the microbubble generation threshold), the generated microbubbles 302 undergo rarefaction over compression, which causes the microbubbles in the liquid to rapidly collapse. , can give rise to inertial (or transient) cavitation of the microbubbles. Microbubble cavitation, in turn, can result in transient disruption of tissue within the target area 202, resulting in increased tissue permeability within the target area. The degree of permeability increase may depend on the microbubble concentration and/or the acoustic power (or power density) delivered and the energy within the target area 202 . Therefore, the desired tissue penetration rate (i.e., to allow therapeutic agent penetration/diffusion) is determined by microbubble properties (e.g., concentration, dosing profile, etc.) and/or ultrasound This may be achieved by adjusting parameters (eg, amplitude, frequency, duration of application, etc.).

In some embodiments, microbubbles are injected into the target area 202 to assist in tissue disruption , thereby increasing its permeability. The microbubbles may be introduced in the form of droplets that subsequently evaporate as gas-filled bubbles or are entrained with another suitable substance such as a conventional ultrasound contrast agent. The injected microbubbles themselves may generate or facilitate the generation of additional microbubbles. For example, administration system 126 may introduce seed microbubbles into target area 202, and controller 108 then focuses ultrasound waves/pulses into an area proximate to the seed microbubbles, thereby Generation of a microbubble cloud to destroy tissue at 202 may be induced. Therefore, the actual destructive effect on the target tissue may result from a combination of injected microbubbles and additionally generated microbubbles within the tissue.

式中、Ｉ_０は、組織の中への進入点における超音波強度（Ｗ／ｃｍ^２単位で測定される）であって、Ｉは、距離ｚにわたる組織を通したビーム伝搬後の強度（ｃｍ単位で測定される）であって、ｆは、超音波の周波数（ＭＨｚ単位で測定される）であって、αは、その周波数における吸収係数（ｃｍ^－１・ＭＨｚ^－１単位で測定される）である。積α・ｆの値が高いほど、標的領域内の吸収の程度がより大きくなるが、また、標的領域に到達する前に吸収される超音波のより大きい割合をもたらす。したがって、組織内のある深度ｚにおいて、印加される波の超音波周波数は、経路ゾーン内の音響出力の吸収と集束帯におけるピーク強度との間のトレードオフを反映し得る。いくつかの実施形態では、最適超音波伝送周波数は、標的領域２０２におけるピーク強度を達成するように、標的および／または介在組織の解剖学的特性（例えば、タイプ、サイズ、場所、性質、構造、厚さ、密度等）に基づいて決定される。それに基づいて、トランスデューサ要素は、次いで、アクティブ化され、マイクロバブルの発生および／またはキャビテーションを生じさせることができる。超音波印加のための最適周波数を決定するためのアプローチは、例えば、米国特許公開第２０１６／０００８６３３号（その内容は、参照することによって本明細書に組み込まれる）に提供される。 In some embodiments, ultrasound-induced microbubble cavitation is utilized to temporarily disrupt (or "open") a target blood-brain barrier (BBB) region. Opening the BBB has been found to reduce amyloid plaque area fraction, thereby providing therapeutic value for Alzheimer's disease. Additionally, disrupting the BBB region may allow therapeutic agents present in the bloodstream to penetrate the "opened" BBB region and effectively deliver therapy to target brain cells. Again, the degree and size of BBB opening may be controlled by adjusting microbubble properties and/or ultrasound parameters. For example, to effectively and efficiently produce microbubble generation and/or cavitation within the target region 202, maximize the amount of acoustic energy transmitted to the target region 202 while providing a healthy introduction to ultrasound. It may be desirable to minimize exposure of non-target tissue (eg, tissue located between the transducer and the target area). Typically, the degree of ultrasound absorption in tissue is a function of frequency given by:

where I ₀ is the ultrasound intensity at the point of entry into tissue (measured in W/cm ² ) and I is the intensity after beam propagation through tissue over distance z (cm is the frequency of the ultrasound (measured in MHz), and α is the absorption coefficient at that frequency (measured in cm ⁻¹ ·MHz ⁻¹ ). Higher values of the product α·f lead to a greater degree of absorption within the target region, but also lead to a greater proportion of the ultrasound waves being absorbed before reaching the target region. Thus, at some depth z in tissue, the ultrasonic frequency of the applied wave may reflect a trade-off between absorption of acoustic power in the path zone and peak intensity in the focal zone. In some embodiments, the optimum ultrasound transmission frequency is determined by anatomical characteristics (e.g., type, size, location, nature, structure, thickness, density, etc.). Based thereon, the transducer elements can then be activated to produce microbubble generation and/or cavitation. Approaches for determining the optimal frequency for ultrasound application are provided, for example, in US Patent Publication No. 2016/0008633, the contents of which are incorporated herein by reference.

Additionally, when microbubbles are pre-formed and introduced into the target volume 202 via the delivery system 106, the microbubble resonance frequency should match the ultrasound transmission frequency to avoid damaging non-targeted areas. It may be desirable to choose the size distribution to be different. In general, the smaller the radius of the microbubble, the higher its resonance frequency will be. Therefore, once the optimum ultrasound frequency is determined, the average radius of microbubbles having a resonant frequency substantially equal to the ultrasound frequency can be determined. In one implementation, the size distribution of the pre-formed microbubbles is such that a significant proportion (e.g., 50%, 90%, 95%, or 99% or more) of the microbubbles are It is chosen to have a radius below that corresponding to the resonant frequency equal to the frequency. Preferably, the microbubble resonance frequency is substantially greater than the ultrasound frequency (eg, ten times), but can be substantially less than the ultrasound frequency if desired. As a result, when the transducer element 104 is activated at low acoustic power, microbubbles in the non-target area are relatively insensitive to the low acoustic field, while the target area (acoustic field is , relatively high) at 202 may oscillate and/or collapse. Thus, the present approach can destroy tissue in the target volume 202 with high spatial accuracy, avoiding unwanted collateral damage to healthy tissue surrounding the target. Approaches for determining and selecting the desired size distribution of microbubbles are described, for example, in the US patent application entitled "Ultrasound Frequency and Microbubble Size Optimization in Microbubble-Enhanced Ultrasound Treatment," filed on even date herewith. The contents of which are incorporated herein by reference).

Referring to FIG. 4A, in various embodiments, after an ultrasound procedure and prior to administration of a therapeutic drug, an image of tissue permeability (or BBB opening) in the target region 202 and/or surrounding healthy non-target tissue is used. Or a "map" 402 is created as described below. This map 402 then shows that the tissue permeability within the target region 202 has been increased sufficiently to allow the therapeutic drug to penetrate and/or diffuse therein, while the tissue within the non-target region Validation that permeability remains sufficiently constant to substantially block therapeutic drug entry (i.e., prevent drug from having clinically significant effects in non-target tissues) To do so, it is compared against a 3D voxel set of target volume 202 acquired prior to the ultrasound procedure (eg, using imager 122). The permeability map 402 includes tissue permeability levels (e.g., permeability of molecules having various sizes) in target and/or non-target regions, and more specifically, openings in the BBB region and/or its surrounding regions. It's okay. For example, referring to FIG. 4B, MRI contrast agents having three molecular weights D ₁ -D ₃ (D ₁ <D ₂ <D ₃ ) can be separately injected into the target area. The permeability map produced thereby may show three regions 412-416. Region 412 allows all MRI contrast agents with _three molecular weights to penetrate and diffuse therein, and region 414 allows _only MRI contrast agents with molecular weights of D1 and D2 to penetrate and diffuse therein. Allowing diffusion, region 216 allows only MRI contrast agents having _a molecular weight of D1 to penetrate and diffuse therein. As a result, permeability map 402 includes various levels 418-422 that indicate the maximum size of a molecule that can enter each region of tissue. The procedure may of course be performed with more or less than three contrast agents.

Mapped region 402, which has high tissue permeability, conforms substantially (e.g., within 1%, 5%, or 10%) volumetrically to 3D target volume 202 (i.e., regions 202, 402 are substantially coextensive in space), the therapeutic drug may be administered. If the mapped region 402 with high permeability is smaller than the defined target volume 202, additional ultrasonic vibration may be performed to increase tissue permeability in the low permeability portion 404 of the target region. good. The ultrasound-mediated permeability augmentation procedure may continue until a substantial match between the mapped region with high permeability and the defined target volume 202 is achieved. In some embodiments, the therapeutic agent to be administered when the high-permeability map region is larger than the defined 3D target volume 202 or when sensitive organs 406 outside the target volume 202 have high-permeability. Depending on the toxicity of the drug, the patient will rest for a day or two until the destroyed tissue is regenerated (thereby reducing tissue permeability to its normal state) and ready to be destroyed again. may be required to

A tissue permeability map 402 may be generated using an MRI contrast agent. For example, an MRI contrast agent may be selected based on the molecular size of the therapeutic agent, as explained above. In various embodiments, a selected MRI contrast agent (preferably substantially the same size as the therapeutic agent) is injected into the target region 202 using, for example, the delivery system 106, and tissue therein is injected. Determine the penetration rate. By monitoring contrast changes in the MRI image (resulting from penetration of the MRI contrast agent into the destroyed tissue), a map is generated that reflects the tissue penetration rate based on the size of the MRI contrast agent. be able to. Additionally, by selecting separately resolvable MRI contrast agents having different sizes and injecting them into the target region 202, the map can show different levels of tissue penetration, each level representing It shows the specific maximum size of a molecule that can enter and diffuse into. In some embodiments, the 3D voxel set of target volume 202 is acquired using a non-MRI imaging system, so image registration between the two imaging systems may be required prior to comparison. . Approaches for registering images acquired using two or more imaging systems are described, for example, in U.S. Pat. No. 9,934,570, the full disclosure of which is incorporated herein by reference. ).

Additionally or alternatively, the penetrance map 402 may, at least in part, represent the local acoustic response (e.g., instantaneous acoustic response level, cumulative acoustic response dose, and/or may be established based on the spectral distribution of the acoustic response). The acoustic response may be detected using cavitation detection device 124 (shown in FIG. 1) and/or ultrasonic transducer array 102 . Generally, the volume of tissue whose permeability is increased and/or the degree of permeability increase correlates with the amount of microbubble cavitation within the target region 202 . Thus, by detecting acoustic responses emanating from microbubbles localized in the target region 202 and/or non-target regions, increased tissue permeability and/or size of tissue with increased permeability can be estimated. can be Approaches for measuring instantaneous acoustic response level and cumulative acoustic response dose are described, for example, in PCT/US18/33815 filed on International Application Date May 22, 2018 (the full disclosure of which is incorporated herein by reference). incorporated herein). Additionally, approaches for constructing transducer arrays for detecting acoustic signals from microbubbles are described, for example, in U.S. Patent Application Serial No. 62/681,282, filed Jun. 6, 2018, the contents of which are incorporated herein by reference. , incorporated herein by reference).

Additionally or alternatively, the permeability map 402 may be created during the planning stage. Generally, the degree of tissue permeability and/or the volume of tissue with increased permeability determines the microbubble properties (e.g., concentration) and/or delivered acoustic power (or power density) and energy within the target region 202. predictably correlates with ultrasound parameters such as . Therefore, by synchronizing the distribution of acoustic power emission and microbubble administration, the degree of tissue permeability can be calculated by computing the cumulative expected cavitation or other acoustic effects during the ultrasonic vibration procedure and/or can be reliably estimated by an actual computer simulation of . For example, referring to FIG. 5, in various embodiments, target and/or non-target tissue information is first obtained prior to implementing computer simulations to predict permeability maps. (at step 502). In one embodiment, tissue information is determined based on images acquired by imager 122, either manually or automatically using conventional tissue analysis software. In a second step 504, a computer simulation creates a tissue model that characterizes the material properties of the target and/or non-target regions based on the information. The tissue model may take the form of a 3D table of cells corresponding to voxels representing target and/or non-target tissue. Cellular values represent tissue properties such as heat resistance associated with tissue destruction . Voxels are acquired tomographically by imager 122, and the type of tissue each voxel represents can again be automatically determined by conventional tissue analysis software. Using a lookup table of determined tissue types and tissue parameters (eg, thermal tolerance by tissue type), cells of the tissue model may be populated. Further details regarding the creation of tissue models that identify the thermal sensitivity and/or thermal energy tolerance of various tissues are found in U.S. Patent Publication No. 2012/0029396, the entire disclosure of which is incorporated herein by reference. can be found in

In addition, the simulations were conducted to determine the characteristics of the microbubbles to be introduced (e.g., dosing profile, size distribution, concentration, etc.) and/or the parameters of the applied ultrasound (e.g., amplitude, frequency, duration of ultrasonic vibration pulses, etc.). etc.), microbubble cavitation in the target/non-target regions may be computationally modeled (at step 506). In some embodiments, based on the modeled microbubble cavitation and the established tissue model, the simulation computationally predicts the effects of microbubble cavitation on target and/or non-target regions (step 508 in). A target/non-target tissue permeability map 402 resulting from the microbubble-enhanced ultrasound procedure is then computationally predicted (at step 510). An approach for computationally simulating the effects of microbubble cavitation on target/non-target regions and generating a permeability map 402 based thereon is described, for example, in Simulation-Based Drug Treatment Planning, the contents of which are incorporated herein by reference.

Penetrance maps generated using MRI contrast agents, local acoustic responses, or computer simulations, alone or in combination with each other, were applied to a 3D voxel set of the target volume 202 acquired prior to the ultrasound procedure. may be compared using Again, based on the comparison, the tissue permeability within the target region 202 may be verified to ensure that the therapeutic drug can effectively penetrate and/or diffuse therein.

In various embodiments, after applying the first series of ultrasonic vibrations and generating the permeability map 402 , the therapeutic agent is administered into the target volume 202 based on the permeability map 402 . This approach advantageously reduces the uptake rate (e.g., penetration rate , release rate, and/or activation rate). Additionally, in this situation, it may not be necessary to acquire and validate a new permeability map for subsequent ultrasonic vibration and/or drug administration.

FIG. 6 illustrates a representative approach 600 that uses ultrasonic vibrations to enhance targeted drug delivery by temporarily increasing tissue permeability within the target area in a controlled and reversible manner. Illustrate. In a first step 602, an imager (eg, an MRI device) 122 acquires information (such as location, size, or shape) of target and/or non-target regions prior to applying ultrasonic vibrations. used to The target information may include a 3D set of voxels corresponding to the target region, and in some cases the voxels include attributes defining tissue properties. Optionally, in a second step 604, microbubbles may be injected and/or generated within the target area to facilitate tissue disruption and thereby increase tissue permeability. For example, microbubbles may be generated by applying an ultrasound pulse with energy above a threshold. Additionally or alternatively, the microbubbles may be injected using dosing system 126 . In a third step 606, based on the defined target information, a focused ultrasound beam is applied to the target area to disrupt tissue and increase tissue permeability therein. Tissue destruction (and the resulting increase in tissue permeability) can also result from microbubble cavitation when microbubbles are present within the target area. In a fourth step 608, tissue permeability maps in target and/or non-target regions are generated utilizing approaches described above (e.g., using MRI contrast agents, local acoustic responses, and/or computer simulations). ) is generated. In a fifth step 610, the tissue permeability map is compared against the target volume obtained in step 602 to verify substantial agreement therebetween. Steps 606-610 may be performed iteratively until the tissue region with appropriately increased permeability substantially matches the defined target volume. In some embodiments, when the disrupted tissue area on the permeability map is greater than the target volume identified in step 602, the patient is advised that tissue in the target/non-target area has regenerated and induced A day or two of rest is required (at step 612) until the permeability is lost (and can therefore be broken down again from baseline levels). Finally, at step 614, a therapeutic agent is administered into the target area for treatment.

Generally, analyzing the imaging data of the target and/or non-target regions acquired, for example, using the imager 122, as described above, generating a 3D voxel set of the target volume based on the imaging data. creating a tissue model that characterizes the material properties of the target/non-target regions based on the imaging data; microbubbles in the target/non-target regions based on the microbubble properties and/or ultrasound parameters; modeling the cavitation; computationally predicting the effect of microbubble cavitation on the target/non-target area; computationally predicting the permeability map of the target/non-target tissue; applying an ultrasound beam to a target area to increase tissue permeability therein; introducing an MRI contrast agent into the target/non-target area and based thereon, permeating generating a permeability map, comparing the generated tissue permeability map against a set of 3D voxels of the target volume identified in the image, and/or administering a therapeutic agent into the target region for treatment. The functionality for increasing tissue permeability within the target region, including the steps of causing the Or may be structured into one or more modules implemented in hardware, software, or a combination of both, whether provided by multiple entities. Ultrasound controller 108 and/or MR controller 148 may include one or more modules implemented in hardware, software, or a combination of both. For embodiments in which the functionality is provided as one or more software programs, the programs may be written in PYTHON, FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and/or HTML, etc. may be written in any of several high-level languages. Additionally, the software can be implemented in assembly language directed to a microprocessor resident on the target computer. For example, the software may be implemented in Intel 80x86 assembly language when configured to run on an IBM PC or PC clone. Software may be embodied on an article of manufacture including, but not limited to, a floppy disk, jump drive, hard disk, optical disk, magnetic tape, PROM, EPROM, EEPROM, field programmable gate array, or CD-ROM. may Embodiments using hardware circuitry may be implemented using, for example, one or more FPGAs, CPLDs, or ASIC processors.

A therapeutic agent may include any drug suitable for treating a tumor. For example, to treat glioblastoma (GBM), drugs include, for example, busulfan, thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), temozolomide, methotrexate, topotecan, cisplatin, etoposide, irinotecan/ SN-38, carboplatin, doxorubicin, vinblastine, vincristine, procarbazine, paclitaxel, fotemustine, ifosfamide/4-hydroxyifosfamide/aldoifosfamide, bevacizumab, 5-fluorouracil, bleomycin, hydroxyurea, docetaxel, cytarabine (cytosine arabinoside , ara-C)/ara-U, etc.

Additionally, to treat GBM, one skilled in the art can select optimized drugs and BBB-opening regimens to enhance drug absorption across the BBB within patient safety constraints. In this regard, the BBB is in fact already disrupted within the core of many tumors and is known to allow partial penetration of anti-tumor drugs. However, the BBB is largely intact around the 'tumor-adjacent brain' (BAT) region where invading/escaping GBM cells can be found, which causes tumor recurrence. Overcoming the BBB can be accomplished using ultrasound as described herein for better drug delivery within the tumor core and BAT. The drugs employed have varying degrees of toxicity and varying percentages of penetration through the BBB. An ideal drug would have high cytotoxicity and no BBB permeability to tumors (so that its absorption and cytotoxic effects can be confined to the area where the BBB is destroyed ), low neurotoxicity (no damage to the nervous system). to avoid) and have acceptable systemic toxicity (eg, below threshold) at pre-specified doses. Drugs may be administered intravenously or, in some cases, by injection proximal to the tumor area. Additionally, the configuration of delivery system 106 for introducing microbubbles and/or therapeutic agents into target area 202 is described in US Patent Application No. 62/597,076, the contents of which are incorporated herein by reference. (incorporated in ).

The terms and expressions employed herein are used as terms of description and not of limitation and any equivalent or one thereof of the features shown and described may be used in the use of such terms and expressions. There is no intention to exclude parts. Additionally, while certain embodiments of the invention have been described, it is to be appreciated that other embodiments incorporating the concepts disclosed herein may also be used without departing from the spirit and scope of the invention. will be clear to the trader. Accordingly, the described embodiments are to be considered in all respects only as illustrative and not restrictive.

Claims (27)

A system for destroying target tissue for treatment and assessing destruction of said target tissue, said system comprising:
An imaging device for obtaining a digital representation of at least a portion of a target volume of said target tissue , said imaging device being a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, a positron emission tomography device. an imaging device, which is one of a (PET) device, a single photon emission tomography (SPECT) device, or an ultrasound examination device ;
generating at least one ultrasonic vibration of a shaped energy beam to cause destruction of the target tissue within a region corresponding to the target volume so as to increase tissue permeability within the target volume; , an ultrasound transducer for delivery to said target volume;
generating, in response to the imaging device, a tissue permeability map indicating regions of increased tissue permeability and an estimate of the tissue permeability resulting from the disruption ; and a controller configured to computationally assess the disruption of the target tissue within a volume , wherein the at least one ultrasonic vibration causes microbubble generation and cavitation within the target volume. . 2. The system of claim 1, wherein the controller is further configured to computationally determine whether tissue within the target volume is capable of receiving a therapeutic agent based on the tissue permeability map. 3. The system of claim 2, wherein the controller is further configured to compare a target volume within the tissue permeability map to the target volume acquired using the imaging device. injecting the therapeutic agent only when tissue within the target volume is capable of receiving the therapeutic agent and the target volume substantially matches the target volume acquired using the imaging device. 4. The system of claim 3, further comprising an administration device for administering. The controller is further configured to computationally determine whether tissue within the target volume is capable of receiving the therapeutic agent based on the molecular size of the therapeutic agent and the estimated tissue permeability. 3. The system of claim 2, wherein: 3. The system of claim 2, further comprising an administration device for administering the therapeutic agent into the target volume by injection based on the tissue permeability map. 7. The controller is further configured to cause the ultrasonic transducer to generate and deliver at least additional ultrasonic vibrations of a shaped energy beam to the target volume after administering the therapeutic agent. The system described in . The tissue permeability map includes a plurality of permeability levels, each permeability level associated with a tissue region within the target volume and a maximum number of molecules capable of entering the tissue region within the target volume. 7. The system of claim 6 , indicating size. 9. The system of Claim 8 , wherein the administration device is configured to administer the therapeutic agent based on the permeability level. The therapeutic agents include busulfan, thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), temozolomide, methotrexate, topotecan, cisplatin, etoposide, irinotecan/SN-38, carboplatin, doxorubicin, vinblastine, vincristine, procarbazine, At least one of paclitaxel, fotemustine, ifosfamide/4-hydroxyifosfamide/aldoifosfamide, bevacizumab, 5-fluorouracil, bleomycin, hydroxyurea, docetaxel, or cytarabine (cytosine arabinoside, ara-C)/ara-U 3. The system of claim 2, comprising one. The controller generates the tissue permeability map based on one or more of MRI contrast imaging, planning or simulating the at least one ultrasonic vibration, or acoustic response of the target volume during the destruction . 2. The system of claim 1, further configured to: The imaging device is further configured to acquire images of the target volume during delivery of the at least one ultrasonic vibration, and the controller controls, based on the images, an ultrasonic vibration associated with subsequent ultrasonic vibrations. 3. The system of claim 1, further configured to adjust acoustic wave parameters. The controller is further configured to cause the ultrasonic transducer to generate a plurality of ultrasonic vibrations, each ultrasonic vibration directing shaped acoustic energy into one of a plurality of focal zones within the target volume. and wherein the focal zones are collectively coextensive with the target volume. 2. The system of claim 1, further comprising an administration device for administering said microbubbles to said target volume. 1. A system for destroying target tissue for treatment and assessing destruction of said target tissue, said system comprising an imaging device, an ultrasound transducer, and a controller;
said imaging device configured to identify a target volume of said target tissue, said imaging device comprising: a magnetic resonance imaging (MRI) device; a computed tomography (CT) device; a positron emission tomography (PET) device; a single photon emission tomography (SPECT) device, or an ultrasound examination device;
The ultrasonic transducer directs at least one of the shaped energy beams to cause destruction of the target tissue within a region corresponding to the target volume so as to increase tissue permeability within the target volume. configured to generate and deliver ultrasonic vibrations to said target volume ;
the controller is configured to computationally generate a tissue permeability map indicating regions of increased tissue permeability and an estimate of the tissue permeability resulting from the disruption ;
The controller is configured to computationally assess the destruction of the target tissue within the target volume based at least in part on the tissue permeability map and the identified target volume; wherein one ultrasonic vibration causes microbubble generation and cavitation within the target volume . 16. The system of Claim 15 , wherein the controller is further configured to computationally determine whether tissue within the target volume is capable of receiving a therapeutic agent based on the tissue permeability map. Computationally assessing the destruction of the target tissue within the target volume includes comparing the target volume within the tissue permeability map to the target volume identified by the imaging device and determining the volume therebetween. 17. The system of claim 16 , comprising determining a match. The therapeutic agent is administered only when tissue within the target volume is capable of receiving the therapeutic agent and the target volume substantially matches the target volume identified by the imaging device. Item 18. The system according to Item 17 . 17. The system of claim 16 , wherein the ability of tissue within said target volume to receive said therapeutic agent is computationally determined based on its molecular size and said estimated tissue permeability. 17. The system of claim 16 , further comprising an administration device for administering the therapeutic agent by injection into the target volume based on the tissue permeability map. 21. The method of Claim 20 , wherein the ultrasonic transducer is further configured to generate and deliver at least additional ultrasonic vibrations of a shaped acoustic energy beam to the target volume after administering the therapeutic agent. system. The tissue permeability map includes a plurality of permeability levels, each permeability level associated with a tissue region within the target volume and a maximum number of molecules capable of entering the tissue region within the target volume. 17. The system of claim 16 , indicating size. 23. The system of claim 22 , wherein said therapeutic agent is administered based on said permeability level. The therapeutic agents include busulfan, thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), temozolomide, methotrexate, topotecan, cisplatin, etoposide, irinotecan/SN-38, carboplatin, doxorubicin, vinblastine, vincristine, procarbazine, At least one of paclitaxel, fotemustine, ifosfamide/4-hydroxyifosfamide/aldoifosfamide, bevacizumab, 5-fluorouracil, bleomycin, hydroxyurea, docetaxel, or cytarabine (cytosine arabinoside, ara-C)/ara-U 17. The system of claim 16 , comprising one. 16. The tissue permeability map of claim 15 , wherein the tissue permeability map is generated based on one or more of MRI contrast imaging, planning or simulating the ultrasonic vibrations, or acoustic response of the target volume during the destruction . system. A plurality of ultrasonic vibrations are generated , each delivering shaped acoustic energy to one of a plurality of focal zones within the target volume, the focal zones collectively defining the target volume 16. The system of claim 15 , coextensive with . The imaging device is further configured to image the target volume during delivery of a first one of the ultrasonic vibrations, and the controller associated subsequent ones of the ultrasonic vibrations accordingly. 27. The system of claim 26 , further configured to adjust ultrasound parameters.