Can focused ultrasound be used as a tool to allow therapeutic agents to reach deadly brain tumors? Is it possible to stop the progression and spread of breast cancer? If Parkinson’s disease is diagnosed early, could its effect on the brain be reversed? These questions and more are being tackled by scientists in the Price Laboratory at the University of Virginia’s Biomedical Engineering Department.
Rich Price, PhD, Professor of Biomedical Engineering, Radiology, and Radiation Oncology is the inaugural winner of the Lockhart Prize, awarded for outstanding contributions to the advancement of cancer treatment using focused ultrasound and demonstrating great potential for further achievements in the field.
Q & A with Rich Price, PhD
Focused Ultrasound Work
Q. When and how did you get interested in focused ultrasound?
In the late 1990s, I joined a collaborative project as a post-doctoral fellow at UVA. I had been studying microcirculation, and in the experiment, we were interested to see how contrast agent microbubbles interact with the microcirculation when exposed to ultrasound. At that time we observed that high pressure ultrasound would excite the microbubbles and open up pores in the blood vessels, creating sonoporation. Those results were published in Circulation and the Journal of the American College of Cardiology, and they are still well-cited articles. Fifteen to twenty years later, this effect is related to the one that we use for focused ultrasound opening of the blood-brain barrier (BBB) and for targeted drug delivery.
Q. How did you make the jump from ultrasound to focused ultrasound?
It took me a long time to switch; I studied the cardiovascular system for many years. After the Focused Ultrasound Foundation was started, I realized that other scientists were using focused ultrasound for BBB opening. I had a track record in nanoparticle delivery to muscle but saw an opportunity to move toward the BBB. The Foundation funded my study, and I used that early data to write grant applications to the Hartwell Foundation and then the NIH.
Q. What are your areas of interest in focused ultrasound?
- Chemotherapy Delivery to Brain Tumors with Focused Ultrasound
- Focused Ultrasound Brain Tumor Immunotherapy
- Focused Ultrasound for Breast Cancer Drug Delivery and Immunotherapy
- Gene Therapy for Parkinson’s Disease via Focused Ultrasound-Targeted Nanoparticle Delivery
- Therapeutic Gene Delivery with Ultrasound for Peripheral Arterial Disease
- Ultrasound-Induced Cavitation for Melanoma Immunotherapy
Q. What mechanisms and clinical indications do you study?
The focused ultrasound mechanisms that we study are BBB disruption, immunomodulation, sonoporation, drug delivery vehicles, and thermal ablation. Some of the new preclinical work that we are doing entails comparing ablation, hyperthermia, and mechanical tissue destruction for treating breast tumors. We are interested in moving nanoparticles across both the BBB and the blood-tumor barrier (BTB) to treat brain tumors and Parkinson’s disease. For the other mechanisms, we are working with gene therapy, immunotherapeutic nanoparticles, controlled drug release nanoparticles, and immunotherapeutic drugs. For glioblastoma multiforme (GBM), we are using focused ultrasound to deliver nanoparticles with microRNA to determine how they affect the growth of the GBM.
Q. What is the goal of your work?
I would say that 75 percent of our work is in oncology, but we also study Parkinson’s disease and cardiovascular disease.
Q. What are your funding sources?
We have received research grants from the Focused Ultrasound Foundation, NIH, the Melanoma Research Alliance, the Cancer Research Institute (with Tim Bullock), and the Hartwell Foundation. We are currently applying for Department of Defense funding.
Q. Who are your team members?
My laboratory, the Price Lab, has six Biomedical Engineering graduate students who are working toward earning a PhD. We currently have no post-doctoral fellows, but are seeking to fill these roles. The lab has one full time technician and four undergraduate students who are doing formal research for credit, internships, or volunteering.
The Foundation’s Scientific Programs Manager, Kelsie Timbie, PhD, is an alumni of the Price Lab.
Q. Who are your internal and external collaborators?
Internally, at UVA we collaborate with:
- Tim Bullock, PhD, in Pathology/Immunology
- Victor Engelhard, PhD, in Microbiology, Immunology, and Cancer Biology
- Roger Abounader, MD, PhD, in Microbiology, Immunology, and Cancer Biology
- Benjamin Purow, MD, in Neurology/Neuro-oncology
- Wilson Miller, PhD, in Radiology and Medical Imaging
- James Mandell, MD, PhD, in Pathology/Neuropathology
- Craig Slingluff, Jr., MD, in Surgical Oncology
- Patrick Dillon, MD, in Hematology/Oncology
- David Brenin, MD, in Surgical Oncology
- Brian Annex, MD, in Cardiovascular Medicine and Biomedical Engineering
- Sasha Klibanov, PhD, in Cardiovascular Medicine and Biomedical Engineering
Outside of UVA, we work with Justin Hanes, PhD, and Jung Soo Suk, PhD, at Johns Hopkins University. Their laboratories design and fabricate the nanoparticles for many of our current projects. It is a natural collaboration because their particles are designed to penetrate, but they do not have a specific molecular target.
Q. What are your greatest professional achievements?
Our work using focused ultrasound to safely open the BBB and permit the delivery of brain-penetrating nanoparticles in sufficient concentrations to be therapeutically efficacious has been highly rewarding. The paper that we recently published in Nano Letters is likely my best work to date, but time will tell. We did not know that we could obtain enough transfection to reverse neurodegeneration.
Q. Any major professional disappointments?
For a long time, we studied how microbubble activation with ultrasound in skeletal muscle directly affects blood vessel growth through monocyte recruitment. I learned a lot in those studies, but it was disappointing that the effect itself was neither sustained nor of high magnitude and, therefore, unlikely to be too useful clinically.
Q. What do you see as impediments to your success?
At this moment, we have good funding and we have good people, but I need more good/experienced people. I need post-doctoral fellows. My ideal post-doc is someone who can take ownership of a project. It could be someone who has been productive in another type of experience, in immunotherapy for example.
Q. What is your research wish list?
Besides more people, it would be nice to identify more support for translational studies. I would like our work to transfer to the clinical setting. There is often a gap between preclinical laboratory work and the clinic, but we have momentum and we have our foot in the door. The Cancer Moonshot project is also helping for faster translation.
Q. Did the Foundation play a role in your work?
Yes – with both funding and guidance for the field in general. The meetings and workshops are terrific. They are extremely well organized and present myriad opportunities to talk with others in the field. I have learned a lot this way.
Q. What comes next?
There is a lot coming up right now, including studies on delivering chemotherapy drugs to brain tumors and gene therapy for Parkinson’s disease.
These and all of our projects are described on our website.
Q. What are your key FUS publications?
Mead BP, Kim N, Miller GW, Hodges D, Mastorakos P, Klibanov AL, Mandell JW, Hirsh H, Suk HS, Hanes H, Price RJ. Novel Focused Ultrasound Gene Therapy Approach Non-Invasively Restores Dopaminergic Neuron Function in a Rat Parkinson’s Disease Model. Nano Lett 2017;17:3533-42.
Dallapiazza RF, Timbie KF, Holmberg S, Gatesman J, Lopes MB, Price RJ, Miller GW, Elias WJ. Noninvasive Neuromodulation and Thalamic Mapping with Low-Intensity Focused Ultrasound. J Neurosurg 2017 Apr 21;1-10.
Timbie KF, Afzal U, Date A, Zhang C, Song H, Miller GW, Suk JS, Hanes J, Price RJ. MR Image-Guided Delivery of Cisplatin-Loaded Brain-Penetrating Nanoparticles to Invasive Glioma with Focused Ultrasound. J Control Release 2017;263:120-31.
Curley CT, Sheybani ND, Bullock TN, Price RJ. Focused Ultrasound Immunotherapy for Central Nervous System Pathologies: Challenges and Opportunities. Theranostics 2017;7:3608-23.
Mead BP, Mastorakos P, Suk JS, Klibanov AL, Hanes J, Price RJ. Targeted Gene Transfer to the Brain via the Delivery of Brain-Penetrating DNA Nanoparticles with Focused Ultrasound. J Control Release 2016;223:109-17.
Timbie KF, Mead BP, Price RJ. Drug and Gene Delivery across the Blood-Brain Barrier with Focused Ultrasound. J Control Release 2015;219:61-75.
Moyer LC, Timbie KF, Sheeran PS, Price RJ, Miller GW, Dayton PA. High Intensity Focused Ultrasound Ablation Enhancement In Vivo via Phase-shift Nanodroplets Compared to Microbubbles. J Ther Ultrasound May 2015;3(1):7.
Nance E, Timbie K, Miller GW, Song J, Louttit C, Klibanov AL, Shih TY, Swaminathan G, Tamargo RJ, Woodworth GF, Hanes J, Price RJ. Noninvasive Delivery of Stealth Brain Penetrating Nanoparticles Across the Blood-Brain Barrier with MR Image-Guided Focused Ultrasound. J Control Release 2014;189:123-132.
Burke CW, Alexander E 4th, Timbie K, Kilbanov AL, Price RJ. Ultrasound-Activated Agents Comprised of 5FU-Bearing Nanoparticles Bonded to Microbubbles Inhibit Solid Tumor Growth and Improve Survival. Mol Ther 2014 Feb;22(2):321-8.
Burke CW, Suk JS, Kim AJ, Hsiang YH, Klibanov AL, Hanes J, Price RJ. Markedly Enhanced Skeletal Muscle Transfection Achieved by the Ultrasound-Targeted Delivery of Non-Viral Gene Nanocarriers with Microbubbles. J Control Release 2012 Sep 10;162(2):414-21.
Burke CW, Hsiang YH, Alexander E 4th, Kilbanov AL, Price RJ. Covalently Linking Poly (Lactic-co-Glycolic Acid) Nanoparticles to Microbubbles Before Intravenous Injection Improves Their Ultrasound-Targeted Delivery to Skeletal Muscle. Small 2011 May 9;7(9):1227-35.
Burke CW, Klibanov AL, Sheehan JP, Price RJ. Inhibition of Glioma Growth by Microbubble Activation in a Subcutaneous Model Using Low Duty Cycle Ultrasound without Significant Heating. J Neurosurg 2011;114(6):1654-61.
Chappell JC, Song J, Burke CW, Klibanov AL, Price RJ. Targeted Delivery of Nanoparticles Bearing FGF-2 by Ultrasonic Microbubble Destruction for Therapeutic Arteriogenesis. Small 2008;4:1769-77.
Song J, Chappell JC, Qi M, Van Gieson EJ, Kaul S, Price RJ. Influence of Injection Site, Microvascular Pressure, and Ultrasound Variables on Microbubble Mediated Delivery of Microspheres to Muscle. J Am Coll Cardiol 2002;39:726-31.
Price RJ, Skyba DM, Kaul S, Skalak TC. Delivery of Colloidal Particles and Red Blood Cells to Tissue Through Microvessel Ruptures Created by Targeted Microbubble Destruction with Ultrasound. Circulation 1998;98:1264-67.