US-12623094-B2 - Incoherent field sonodynamic therapy for treating cancer

US12623094B2US 12623094 B2US12623094 B2US 12623094B2US-12623094-B2

Abstract

Ultrasound transducer element arrays using acoustic ensonification drive patterns via a patient interface for sonosensitizer activation in sonodynamic therapy. Incoherent acoustic field generation varying phase, frequencies, and/or amplitude via controlled delivery of low intensity planar acoustic waves. Method includes generating a first and a second signal to generate respective acoustic ensonification drive patterns with phase, frequency, and amplitude and generating at least one relative phase, frequency or amplitude difference to generate a third incoherent acoustic ensonification pattern to activate a sonosensitizer. Calibration and complementary therapy procedures to improve cell susceptibility of cells to sonodynamic therapy are disclosed.

Inventors

Vijay Agarwal
Braden Eliason
Jeremy Ling
John Ballard
Gregg Miller

Assignees

Alpheus Medical, Inc.

Dates

Publication Date: 20260512
Application Date: 20240823

Claims (20)

1 . An ultrasound transducer system that generates a diffuse incoherent acoustic pressure field for activating a sonosensitizer in conjunction with providing sonodynamic therapy, the ultrasound transducer system comprising: an ultrasound transducer array comprising a plurality of ultrasonic piezoelectric transducer elements, wherein the plurality of ultrasonic piezoelectric transducer elements is configured to generate the diffuse incoherent acoustic pressure field with an energy profile to saturate a treatment volume to ensure treatment of a lesion of cancer cells located within a tissue of a patient by activating the sonosensitizer located within the tissue of the patient, wherein the plurality of ultrasonic piezoelectric transducer elements is driven by a signal to generate the diffuse incoherent acoustic pressure field, wherein the signal comprises one or more of the group consisting of: a modulated phase across the plurality of ultrasonic piezoelectric transducer elements, a modulated frequency across the plurality of ultrasonic piezoelectric transducer elements, and a modulated amplitude across the plurality of ultrasonic piezoelectric transducer elements; wherein each ultrasonic piezoelectric transducer element in the plurality of ultrasonic piezoelectric transducer elements comprises an emitting surface configured to emit planar acoustic waves or defocused acoustic waves, wherein the signal is configured to minimize a spatial variation of an acoustic wave intensity to activate the sonosensitizer at the lesion of cancer cells with the planar acoustic waves or the defocused acoustic waves, and wherein the signal is configured with a duty cycle to drive each ultrasonic piezoelectric transducer element in the plurality of ultrasonic piezoelectric transducer elements to generate (i) a high temporal peak acoustic intensity sufficient to activate the sonosensitizer at the lesion of cancer cells with the planar acoustic waves or the defocused acoustic waves and (ii) a low temporal average acoustic intensity to preserve tissue.
2 . The ultrasound transducer system of claim 1 , wherein the signal comprises the modulated phase across the plurality of ultrasonic piezoelectric transducer elements, and wherein the modulated phase comprises a randomized phase difference.
3 . The ultrasound transducer system of claim 1 , wherein the plurality of ultrasonic piezoelectric transducer elements comprises over 128 ultrasonic piezoelectric transducer elements.
4 . The ultrasound transducer system of claim 1 , further comprising a cooling system configured to remove excess heat from the patient, wherein the cooling system comprises a flexible cavity configured for circulation of a degassed fluid.
5 . The ultrasound transducer system of claim 1 , wherein the energy profile is driven at ultrasonic frequencies in a range of 20 kHz to 2 MHz.
6 . The ultrasound transducer system of claim 1 , wherein the sonosensitizer is selected from the group consisting of: aminolevulinic acid (ALA), hematoporphyrin, Rose Bengal, curcumin, titanium nanoparticles, and chlorine e6.
7 . The ultrasound transducer system of claim 1 , wherein the ultrasound transducer system is configured for treating cancerous tissue in a brain, lung, breast, liver, stomach, prostate, vagina, testes, pancreas, or intestines.
8 . The ultrasound transducer system of claim 1 , wherein the plurality of ultrasonic piezoelectric transducer elements are disposed on a patient interface comprising a detachable flexible membrane configured to couple to a head of the patient.
9 . The ultrasound transducer system of claim 1 , wherein the plurality of ultrasonic piezoelectric transducer elements are disposed on a helmet configured to couple to a head of the patient via a replaceable flexible membrane.
10 . The ultrasound transducer system of claim 1 , wherein the plurality of ultrasonic piezoelectric transducer elements comprises between 128 to 1024 ultrasonic piezoelectric transducer elements.
11 . An ultrasound transducer system that generates a diffuse incoherent acoustic pressure field for activating a sonosensitizer in conjunction with providing sonodynamic therapy, the ultrasound transducer system comprising: an ultrasound transducer array comprising a plurality of ultrasonic piezoelectric transducer elements, wherein the plurality of ultrasonic piezoelectric transducer elements is configured to generate the diffuse incoherent acoustic pressure field with an energy profile to saturate a large treatment volume to ensure treatment of a lesion of cancer cells located within a tissue of a patient by activating the sonosensitizer located within the tissue of the patient, wherein each ultrasonic piezoelectric transducer element in the plurality of ultrasonic piezoelectric transducer elements comprises an emitting surface configured to emit planar acoustic waves or defocused acoustic waves, wherein the plurality of ultrasonic piezoelectric transducer elements is driven by a signal to generate the diffuse incoherent acoustic pressure field, wherein the signal comprises a modulated phase across the plurality of ultrasonic piezoelectric transducer elements, wherein the signal is configured to minimize a spatial variation of an acoustic wave intensity to activate the sonosensitizer at the lesion of cancer cells with the planar acoustic waves or the defocused acoustic waves, wherein the signal is configured with a duty cycle to drive each ultrasonic piezoelectric transducer element in the plurality of ultrasonic piezoelectric transducer elements to generate (i) a high temporal peak acoustic intensity sufficient to activate the sonosensitizer at the lesion of cancer cells with the planar acoustic waves or the defocused acoustic waves and (ii) a low temporal average acoustic intensity to preserve tissue.
12 . The ultrasound transducer system of claim 11 , wherein the plurality of ultrasonic piezoelectric transducer elements are arranged in a hemispherical arrangement disposed on a patient interface comprising a detachable flexible membrane configured to couple to a head of the patient.
13 . The ultrasound transducer system of claim 11 , further comprising a therapy selected from radiation, chemotherapy, immunotherapy, radiotherapy, and hyperthermia.
14 . The ultrasound transducer system of claim 11 , wherein the plurality of ultrasonic piezoelectric transducer elements is acoustically coupled to the patient via a degassed fluid.
15 . The ultrasound transducer system of claim 11 , wherein the ultrasound transducer system is configured for treating cancerous tissue in a brain, lung, breast, liver, stomach, prostate, vagina, testes, pancreas, or intestines.
16 . The ultrasound transducer system of claim 11 , wherein the sonosensitizer is selected from the group consisting of: aminolevulinic acid (ALA), hematoporphyrin, Rose Bengal, curcumin, titanium nanoparticles, and chlorine e6.
17 . The ultrasound transducer system of claim 11 , wherein the plurality of ultrasonic piezoelectric transducer elements comprises between 128 to 1024 ultrasonic piezoelectric transducer elements.
18 . The ultrasound transducer system of claim 11 , wherein the modulated phase comprises a randomized phase difference.
19 . The ultrasound transducer system of claim 11 , further comprising a cooling system configured to remove excess heat from the patient, wherein the cooling system comprises a flexible cavity configured for circulation of a degassed fluid.
20 . The ultrasound transducer system of claim 11 , wherein the energy profile is driven at ultrasonic frequencies in a range of 20 kHz to 12 MHz.

Description

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 18/215,497 filed Jun. 28, 2023 and entitled Incoherent Field Sonodynamic Therapy For Treating Cancer, which is a continuation of U.S. patent application Ser. No. 18/040,610 filed Feb. 3, 2023 and entitled Blood Brain Barrier Penetration To Treat Glioblastoma, which is a U.S. national phase application of International Application No. PCT/US2021/071101 filed Aug. 4, 2021 and entitled Ultrasound Arrays For Enhanced Sonodynamic Therapy For Treating Cancer, which claims priority from U.S. Provisional Patent Application 63/062,879 filed Aug. 7, 2020 and entitled Ensonification Drive Patterns For Sonodynamic Therapy; U.S. Provisional Patent Application 63/062,895 filed Aug. 7, 2020 and entitled Sonodynamic Therapy Methods and Systems For Treating Cancer; U.S. Provisional Patent Application 63/062,915 filed Aug. 7, 2020 and entitled Sonodynamic Therapy Methods and Systems For Treating Cancer; U.S. Provisional Patent Application filed 63/062,926 Aug. 7, 2020 and entitled Sonodynamic Therapy System for Treating Brain Cancer; and U.S. Provisional Patent Application filed 63/062,937 Aug. 7, 2020 and entitled Enhanced Sonodynamic Therapy, each of which is hereby incorporated by reference in its entirety, herein. BACKGROUND Field of the Invention This document relates to methods and apparatuses for generating ensonification drive patterns using ultrasound transducer arrays for initiating and enhancing treatment of cancer with sonodynamic therapy. Description of the Related Art Sonodynamic therapy is a proposed form of cancer treatment that uses ultrasound energy to activate a drug, prodrug, and/or sonosensitizer that selectively accumulates in cancer cells. In one embodiment, a sonosensitizing agent (e.g., drug, prodrug, sonosensitizer) preferentially accumulates in the cells of the lesions. In one embodiment, the sonosensitizing agent increases a quantity, accumulation, or concentration of a sonosensitizer in the cancer cells. Sonosensitizers initiate a cytotoxic response in target tissues when exposed to ultrasonic energy. Upon activation by the ultrasonic energy, sonodynamic therapy drugs or “sonosensitizers” produce reactive oxygen species (ROS) that generate the cytotoxic effect. They can be used alone or in concert with other sonosensitizers, many of which are approved by the Food and Drug Administration (FDA) for use in neurosurgical diagnostic imaging or treatment of tumors throughout the body. Many types of ultrasound devices (e.g., transducer arrays) and therapies have been developed over the years. However, none of these devices (e.g., arrays) and their respective ensonification patterns have been developed for the specific purpose of activating a sonosensitizer. For example, sonodynamic therapy research to date has largely repurposed ultrasound machines designed for high intensity focused ultrasound (HIFU). These machines coordinate the ensonification pattern to coherently focus energy in a particular region or regions. The fundamental principle is analogous to using a magnifying glass to focus beams of sunlight on a single point to burn a hole in a leaf. With focused ultrasound, an acoustic lens or electronic focusing is used to concentrate multiple intersecting beams of ultrasound on one target deep in the body with extreme precision and accuracy. Where each of the individual beams passes through the tissue, there is no effect. But, at the focal point, the convergence of the multiple beams of focused ultrasound energy results in indiscriminate tissue death in the region of interest through thermal ablation. SUMMARY The following summary is provided to facilitate an understanding of some of the innovative features unique to the aspects (e.g., embodiments) disclosed herein, and is not intended to be a full description. A full appreciation of the various aspects can be gained by taking the entire specification, claims, and abstract as a whole. As described herein, in several embodiments, tumors are treated using sonosensitizers and ultrasound, wherein the ultrasound activates the sonosensitizer with cavitational, thermal energy to produce reactive oxygen species that interact with other molecules to intentionally damage cancer cells by via oxidation and associated thermal, chemical, and/or luminescent phenomena for enhancing a cytotoxic effect, stressing and/or inhibiting repair mechanisms of cancer cells, such as by affecting cancer cell production of Heme, removing iron ions, and/or inhibiting the action of ferrochelatase. Advantageously, in one embodiment, a sonodynamic therapy system delivers a signal that is attenuated and enhanced to reduce the amount of energy needed to destroy cancer cells, therapy limiting damage to surrounding healthy cells. In various embodiments, the sonodynamic therapy system generates electric drive signals to form modulated, incoherent acoustic wave par