Ultrasound arrays for enhanced sonodynamic therapy for treating cancer

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.

1 .- 216 . (canceled) 
     
     
         217 . A method of using ultrasound to facilitate drug delivery across a blood brain barrier, the method comprising:
 administering a drug to a subject,   applying ultrasound waves that generate an incoherent acoustic pressure field to activate the drug in the subject to induce a temporary disruption that opens a blood brain barrier in a head of the subject, thereby facilitating penetration of the drug to a brain in the head of the subject,   wherein the ultrasound waves comprise planar ultrasound waves or defocused ultrasound waves,   wherein the drug preferentially accumulates in tumor cells in the brain of the subject,   wherein the activated drug causes apoptosis of the tumor cells,   wherein the ultrasound waves are driven by a signal to generate the incoherent acoustic pressure field, wherein the signal comprises one or more of the group consisting of: a modulated phase, a modulated frequency, and a modulated amplitude;   wherein the ultrasound waves are driven at a frequency in a range of 20 kHz to 12 MHz,   wherein the signal is configured to produce the ultrasound waves comprising a temporal-average intensity output in a range of 1-30 W/cm 2 .   
     
     
         218 . The method of  claim 217 , wherein the applying ultrasound waves comprises emission from an ultrasound transducer array comprising a plurality of ultrasonic piezoelectric transducer elements. 
     
     
         219 . The method of  claim 218 , wherein the plurality of ultrasonic piezoelectric transducer elements is configured to generate the incoherent acoustic pressure field via an aperture sized and configured with an energy profile to saturate a large treatment volume to ensure treatment of the tumor cells. 
     
     
         220 . The method of  claim 219 , wherein the aperture size is selected to be larger than a size of the tumor cells, such that an aspect ratio of the aperture size to the size of the tumor cells enables initiation of the incoherent acoustic pressure field to treat the tumor cells and extraneous cancer cells in the brain. 
     
     
         221 . The method of  claim 218 , wherein the ultrasound transducer array comprises an array dimension of at least 150 mm. 
     
     
         222 . The method of  claim 218 , wherein each of the ultrasonic piezoelectric transducer elements in the plurality of ultrasonic piezoelectric transducer elements comprises a dimension in a range of 0.5 mm to 20 mm. 
     
     
         223 . The method of  claim 217 , further comprising administering microbubbles to the subject. 
     
     
         224 . A method of using ultrasound to facilitate drug delivery across a blood brain barrier, the method comprising:
 administering a drug to a subject,   applying ultrasound waves to activate the drug in the subject to induce a temporary disruption that opens a blood brain barrier in a head of the subject, thereby facilitating penetration of the drug to a brain in the head of the subject,   wherein the drug preferentially accumulates in tumor cells in the brain of the subject,   wherein the activated drug causes apoptosis of the tumor cells,   wherein the ultrasound waves are driven at a frequency in a range of 20 kHz to 12 MHz.   
     
     
         225 . The method of  claim 224 , wherein the applying ultrasound waves comprises emission from an ultrasound transducer array comprising a plurality of ultrasonic piezoelectric transducer elements. 
     
     
         226 . The method of  claim 225 , wherein the plurality of ultrasonic piezoelectric transducer elements is configured to generate an incoherent acoustic pressure field via an aperture sized and configured with an energy profile to saturate a large treatment volume to ensure treatment of the tumor cells. 
     
     
         227 . The method of  claim 226 , wherein the aperture size is selected to be larger than a size of the tumor cells, such that an aspect ratio of the aperture size to the size of the tumor cells enables initiation of the incoherent acoustic pressure field to treat the tumor cells and extraneous cancer cells in the brain. 
     
     
         228 . The method of  claim 225 , wherein the ultrasound transducer array comprises an array dimension of at least 150 mm. 
     
     
         229 . The method of  claim 225 , wherein each of the ultrasonic piezoelectric transducer elements in the plurality of ultrasonic piezoelectric transducer elements comprises a dimension in a range of 0.5 mm to 20 mm. 
     
     
         230 . The method of  claim 224 , further comprising cooling the head of the subject. 
     
     
         231 . The method of  claim 224 , wherein the administering the drug comprises an oral administration or an injection. 
     
     
         232 . The method of  claim 224 , wherein the drug comprises aminolevulinic acid (ALA). 
     
     
         233 . The method of  claim 224 , wherein the administering the drug results in increased production of protoporphyrin IX via a heme biosynthesis pathway, and wherein the protoporphyrin IX preferentially accumulates in tumor cells in the brain of the subject. 
     
     
         234 . The method of  claim 224 , further comprising administering microbubbles to the subject. 
     
     
         235 . A method of using ultrasound to treat glioblastoma, the method comprising:
 administering a drug to a subject,
 wherein the drug preferentially accumulates in tumor cells in a brain of the subject, 
   acoustically coupling a patient interface to a skin surface of a head of the subject, the patient interface comprising: an ultrasound transducer array, a patient interface, and a cooling system,
 wherein the ultrasound transducer array comprises at least 16 ultrasound transducer elements, 
 wherein the ultrasound transducer array is configured to emit focused acoustic waves through a skull of the subject, 
 wherein the patient interface is configured to acoustically couple the ultrasound transducer array to the skin surface, 
 wherein the patient interface is configured for conforming to the skin surface; 
   applying focused ultrasound waves to activate the drug resulting in apoptosis of the tumor cells to the brain of the subject; and   circulating a fluid in the cooling system to reduce heat at the head of the subject at the patient interface,   wherein the ultrasound waves are driven at a frequency in a range between 20 kHz to 12 MHz.   
     
     
         236 . The method of  claim 235 , wherein the administering the drug comprises an injection, wherein the drug comprises aminolevulinic acid (ALA).