Cavitation-enhanced targeted drug delivery and dosing
Inventors
Assignees
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Publication Number
US-11938343-B2
Publication Date
2024-03-26
Expiration Date
Abstract
Various approaches for disrupting target tissue for treatment include identifying a target volume of the target tissue; causing disruption of the target tissue in a region corresponding to the target volume so as to increase tissue permeability therein; computationally generating a tissue permeability map of the target volume; and based on the tissue permeability map, computationally evaluating the disruption of the target tissue within the target volume.
Core Innovation
The invention provides a system for causing a disruption of a target tissue for treatment and evaluating the disruption of the target tissue. The system includes a controller that, prior to causing the disruption, causes an imaging device to acquire a digital representation of at least a portion of a target volume. The controller then causes the disruption of the target tissue in a region corresponding to the target volume by causing an ultrasound transducer to generate and deliver at least one sonication of shaped energy beams so as to increase tissue permeability therein.
Subsequent to causing the disruption, the controller generates a tissue permeability map indicating regions of increased tissue permeability and estimates of the tissue permeability due to the disruption. The controller computationally evaluates, based on the tissue permeability map, the disruption of the target tissue within the target volume, and compares a mapped region of the tissue permeability map having increased permeability due to the disruption to the digital representation of the target volume acquired prior to the disruption.
The controller determines that a therapeutic agent should be administered into the target volume only when, based on the comparing, there is a substantial match between the mapped region having increased permeability and the digital representation of the target volume. Additional system aspects described include generating the tissue permeability map using MRI contrast imaging, planning or simulation of the sonication, and/or an acoustic response, as well as using imaging during delivery to adjust a parameter associated with a subsequent sonication.
Claims Coverage
The partial content provides one independent claim. The claim coverage centers on pre-acquisition of a target volume, ultrasound sonication with shaped energy beams to increase tissue permeability, post-disruption tissue permeability mapping with computational evaluation, comparison to the pre-acquired digital representation, and therapeutic agent administration only upon a substantial match.
Pre-acquiring a digital representation of a target volume
The controller causes an imaging device to acquire a digital representation of at least a portion of a target volume of the target tissue prior to causing the disruption of the target tissue.
Ultrasound disruption using shaped energy beams to increase tissue permeability
The controller causes the disruption of the target tissue in a region corresponding to the target volume by causing an ultrasound transducer to generate and deliver at least one sonication of shaped energy beams to the target volume so as to increase tissue permeability therein.
Generating and computationally evaluating a tissue permeability map after disruption
Subsequent to causing the disruption, the controller generates a tissue permeability map indicating regions of increased tissue permeability and estimates of the tissue permeability due to the disruption, and computationally evaluates the disruption of the target tissue within the target volume based on the tissue permeability map.
Comparing mapped increased-permeability region to the pre-acquired digital representation
The controller compares a mapped region of the tissue permeability map having increased permeability due to the disruption to the digital representation of the target volume acquired prior to causing the disruption.
Administering a therapeutic agent only upon substantial match
The controller determines that a therapeutic agent should be administered into the target volume only when, based on the comparing, there is a substantial match between the mapped region of the tissue permeability map having increased permeability due to the disruption and the digital representation of the target volume.
Generating the tissue permeability map using MRI contrast imaging, planning or simulation, or acoustic response
The controller generates the tissue permeability map using at least one of MRI contrast imaging, planning or simulation of the sonication, or an acoustic response of the target volume during disruption.
Imaging during sonication and adjusting a parameter for a subsequent sonication
The controller causes the imaging device to acquire an image of the target volume during delivery of the at least one sonication and adjusts a parameter associated with a subsequent sonication based on the image.
Defining substantial match as substantially coextensive spatially
The mapped region of the tissue permeability map having increased permeability substantially matches the digital representation of the target volume if the mapped region and the digital representation are substantially coextensive spatially.
Microbubble generation and cavitation during sonication
The at least one sonication causes generation and cavitation of microbubbles in the target volume.
Therapeutic agent selected from a specified drug list
The therapeutic agent comprises at least one of 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, or Cytarabine (cytosine arabinoside, ara-C)/ara-U.
The core coverage centers on imaging-based pre-acquisition of a target volume, ultrasound sonication with shaped energy beams to increase tissue permeability, post-disruption tissue permeability mapping with computational evaluation, comparison to the pre-acquired digital representation, and restricting therapeutic agent administration to cases with a substantial spatial match. Dependent claims refine map-generation inputs, real-time imaging during delivery with parameter adjustment, a substantially coextensive spatial match criterion, microbubble cavitation during sonication, and a specified set of candidate therapeutic agents.
Stated Advantages
Increase tissue permeability in the target tissue while avoiding non-target effects.
Verify a substantial volumetric match between increased-permeability regions and the target volume before administering a therapeutic agent.
Documented Applications
Targeted drug delivery by ultrasound-based disruption to increase tissue permeability, including an example context involving blood-brain barrier (BBB) opening and glioblastoma (GBM).
Treatment using a therapeutic agent administered only when substantially matched increased-permeability is determined, with example drug entities including Busulfan, Thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), and others.
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