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Insonation of ultrasound microbubbles at low frequency to enhance image-guided therapy

Award Number: R01CA112356
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2005
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Insonation of ultrasound microbubbles at low frequency to enhance image-guided therapy - Contrast ultrasound imaging and therapy is a compelling technology, as it is inexpensive, widely used, portable, and permits real-time anatomical and molecular imaging. Targeted agents are now in human molecular imaging trials in the US and Europe and therapeutic uses of microbubbles are also expanding into clinical trials. MB oscillation can enhance vascular and cell membrane permeability and can accomplish local therapeutic transfection. Here, we will apply US-guided transfection to enhance suicide gene therapy. In suicide gene therapy, cell suicide-inducing transgenes (e.g. cytosine deaminase/5-fluorocytosine and the herpes simplex virus/ganciclovir) are introduced into cancer cells. The therapeutic transgenes locally convert a non-toxic small molecule pro-drug into a cytotoxic drug or create a toxic gene expression product. Recent game-changers that make our work feasible include: programmable US systems combining imaging and therapy, commercially-available (human quality) ionizable lipids, immunotherapy reagents, and new adeno- associated viruses (AAV) with organ-specific serotypes, and all are used here. Both viral and non-viral approaches are feasible and will be compared. We have recently explored the use of image-guided microbubble oscillation to transfect cells in vivo and achieve a therapeutic response. We find that ultrasound- mediated transfection can be highly effective and endeavor to extend this technique to delivery and transfection in cancer. Translational delivery protocols for human medicine involve transducers with center frequencies between 1 MHz and 220 kHz. The use of such low frequencies is highly desirable to facilitate 3D beam steering both for applications in the brain and for image-guided transfection. Practical therapeutic ultrasound systems and transducers use 1000 or less transducer elements and random element geometries result in grating lobes at higher frequencies. The highly nonlinear effect of frequency on microbubble oscillation has not yet been carefully evaluated in this frequency range. Here, we will compare in vivo delivery, transfection and suicide gene therapy achieved with MHz and hundreds of kHz transducers. Our overall goal in the renewal is to safely enhance delivery and transfection in vitro and in vivo in a clinically relevant manner. We will specifically assess suicide gene therapy with viral and non-viral vectors and will combine the local ultrasound therapy with immunotherapy in breast cancer. Our specific aims are to: develop and validate models for contrast agent oscillation and received echoes with driving frequencies in the hundreds of kHz; maximize the delivery of unique AAVs and non-viral vectors in liver and breast cancer by insonation with a frequency selected within the hundreds of kHz to MHz, and assess safety and efficacy of a) suicide gene therapy in mice with and without immunotherapy and b) transfection in canines.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$1 )
2024	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Detection and Diagnosis Research	000	15	9/10/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2022 ( Subtotal = $431,977 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Detection and Diagnosis Research	000	15	6/28/2022	NON-COMPETING CONTINUATION	$431,977
														Subtotal = $431,977

Issue Date FY: 2021 ( Subtotal = $451,407 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Detection and Diagnosis Research	000	14	6/22/2021	NON-COMPETING CONTINUATION	$451,407
														Subtotal = $451,407

Issue Date FY: 2020 ( Subtotal = $409,448 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Detection and Diagnosis Research	000	13	6/2/2020	NON-COMPETING CONTINUATION	$409,448
														Subtotal = $409,448

Issue Date FY: 2019 ( Subtotal = $404,494 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Detection and Diagnosis Research	002	12	6/13/2019	NON-COMPETING CONTINUATION	$404,494
2019	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Detection and Diagnosis Research	001	11	10/23/2018	COMPETING CONTINUATION	$2
2019	2015	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	000	10	10/23/2018	NON-COMPETING CONTINUATION	-$2
														Subtotal = $404,494

Issue Date FY: 2018 ( Subtotal = $402,443 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Detection and Diagnosis Research	001	11	7/25/2018	COMPETING CONTINUATION	-$3,242
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Detection and Diagnosis Research	000	11	7/3/2018	COMPETING CONTINUATION	$405,685
2018	2015	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	002	10	8/23/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,443

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	000	10	4/5/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $396,873 )
2015	2015	UNIVERSITY OF CALIFORNIA	1850 RESEARCH PARK DRIVE	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	000	10	5/19/2015	NON-COMPETING CONTINUATION	$396,873
														Subtotal = $396,873

Issue Date FY: 2014 ( Subtotal = $385,942 )
2014	2014	UNIVERSITY OF CALIFORNIA	1850 RESEARCH PARK DRIVE	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	000	9	5/30/2014	NON-COMPETING CONTINUATION	$385,942
														Subtotal = $385,942

Issue Date FY: 2013 ( Subtotal = $374,966 )
2013	2013	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cancer Detection and Diagnosis Research	000	8	6/7/2013	NON-COMPETING CONTINUATION	$374,966
														Subtotal = $374,966

Issue Date FY: 2012 ( Subtotal = $435,365 )
2012	2012	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cancer Detection and Diagnosis Research	000	7	6/20/2012	NON-COMPETING CONTINUATION	$435,365
														Subtotal = $435,365

Issue Date FY: 2011 ( Subtotal = $399,100 )
2011	2011	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cancer Detection and Diagnosis Research	000	6	7/26/2011	COMPETING CONTINUATION	$399,100
														Subtotal = $399,100

Issue Date FY: 2009 ( Subtotal = $370,514 )
2009	2009	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cancer Detection and Diagnosis Research	000	5	4/20/2009	NON-COMPETING CONTINUATION	$370,514
														Subtotal = $370,514

Issue Date FY: 2008 ( Subtotal = $409,108 )
2008	2008	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cancer Detection and Diagnosis Research	000	4	4/22/2008	NON-COMPETING CONTINUATION	$409,108
														Subtotal = $409,108

Issue Date FY: 2007 ( Subtotal = $389,952 )
2007	2007	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cancer Detection and Diagnosis Research	000	3	5/24/2007	NON-COMPETING CONTINUATION	$389,952
														Subtotal = $389,952

Issue Date FY: 2006 ( Subtotal = $422,919 )
2006	2006	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cancer Detection and Diagnosis Research	000	2	6/30/2006	NON-COMPETING CONTINUATION	$422,919
														Subtotal = $422,919

Issue Date FY: 2005 ( Subtotal = $406,702 )
2005	2005	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cancer Detection and Diagnosis Research	000	1	7/7/2005	NEW	$406,702
														Subtotal = $406,702

Grand Total All Awards = $6,091,209

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Insonation of ultrasound microbubbles at low frequency to enhance image-guided therapy

Award Number: R01CA112356

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/07/2005

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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