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Vascular Medicine Institute
University of Pittsburgh
BST E1240
200 Lothrop Street
Pittsburgh, PA 15261
Phone: 412-383-5853
Fax: 412-648-5980

Flordeliza S. Villanueva, MD

 

liza villanueva

 

Liza Villanueva, MD

Vice Chair for Pre-Clinical Research,
Department of Medicine

Professor of Medicine,
Division of Cardiology

Director, Non-Invasive Cardiovascular Imaging

Director, Center for Ultrasound Molecular Imaging and Therapeutics

Heart and Vascular Institute
UPMC Presbyterian, Suite A-351
200 Lothrop Street
Pittsburgh, PA 15213

Phone: 412-647-5840
Email: villanuevafs@upmc.edu

Assistant: April Youschak
Email: youschakal@upmc.edu

UPMC Profile


Center for Ultrasound Molecular Imaging and Therapeutics

   

Bio

Dr. Villanueva is the Director of the Center for Ultrasound Molecular Imaging and Therapeutics, a multidisciplinary translational research facility espousing the philosophy that moving technologies from pre-clinical status to the bedside requires strong traditional science and engineering, married to strong entrepreneurship. Her laboratory was the first to demonstrate that molecularly targeted microbubbles bind to biological surfaces overexpressing the molecular target, ultimately allowing ultrasonic imaging of disease/function-specific epitopes in vivo. Her group has led the study of how unique acoustic behaviors of microbubbles can be harnessed to therapeutic effect, such as drug/gene delivery or sonothrombolysis.


Education

MD, Boston University School of Medicine, 1984


Training

Internship, Internal Medicine, Duke University Medical Center, 1985

Residency, Internal Medicine, Duke University Medical Center, 1987

Research Fellowship, Cardiology, University of Pittsburgh School of Medicine, 1988

Clinical Fellowship, Cardiology, University of Virginia Health Sciences Center, 1990


Lab

Center for Ultrasound Molecular Imaging and Therapeutics

Vascular endothelial leukocyte adhesion molecules, such as E-selectin, are acutely upregulated in myocardial ischemia/reperfusion and are thus ‘‘ischemic memory’’ biomarkers for recent cardiac ischemia. Contrast enhanced ultrasound imaging using microbubbles targeted to E-selectin, can be used  for ischemic memory imaging (Villanueva FS, Lu E, Bowry S, Kilic S, Tom E Wang J, Gretton J, Pacella JJ, Wagner WR.  Myocardial ischemic memory imaging using molecular echocardiography. Circulation 2007;115:345-352; Leng X, Wang J, Carson A, Chen X, Fu H, Ottoboni S, Wagner WR, Villanueva FS.  Ultrasound detection of myocardial ischemic memory using an E-selectin targeting peptide amenable to human application.  J Molecular Imaging 2014;16:1-9).


Villanueva Fig 1

Background-subtracted, color coded ultrasound contrast images from a rat undergoing LAD occlusion/reperfusion. (A) During coronary occlusion, there was a risk area (region between the arrows), corresponding to the LAD territory. (B) During reperfusion and injection of non-targeted microbubbles, there was homogeneous contrast enhancement of the myocardium. (C) There was no infarction by triphenyl tetrazolium chloride staining. (D) After injection of MBESEL, there was persistent contrast enhancement of the previously ischemic LAD territory, not seen after injection of either of the MBCTL (E) or MBIgG (F). Adapted from Leng X, …, Villanueva FS,J Molecular Imaging 2014.


UPMC Cam, the ultrafast multiframe imaging system developed at the Center of Molelcualr Imaging and Therapeutics is well suited for the study of dynamic behaviors of microbubbles and other microscopic objects (Chen X, Wang J, Versluis M, de Jong N, and Villanueva FS, Ultra-fast bright field and fluorescence imaging of the dynamics of micrometer-sized objects. Rev Sci Instrum, 2013. 84(6): p. 063701).


Villanueva Fig 2

Overview of UPMC Cam, the ultra-fast imaging system for studying the dynamic behavior of microbubbles. This system is capable of imaging microscopic bright field and fluorescence movies at 25 million frames per second for 128 frames, with a frame size of 920×616 pixels.

 

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This is a bright field movie of lipid microbubbles under ultrasound excitation (f=2.25 MHz, Pa=1.0 MPa), demonstrating ultrasound-induced microbubble vibration and breaking. Imaging is at 25 million fps, and playback is at 16 fps. Frame size is 27 µm × 27 µm. Adapted from Chen X,…Villanueva FS, Rev Sci Instrum, 2013. 84(6).

 

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This is a brightfield movie of a microbubble oscillating adjacent to a thrombus (left) under the influence of ultrasound (1 MHz, 1.5 MPa), causing intermittent thrombus deformation.  After the microbubble has disappeared from the microscopic field, a “pit” remains in the thrombus at the previous site of microbubble oscillation.  Imaging is at 5 million fps, and playback is at 8 fps.  Frame size is 55 µm x 55 µm. Adapted from Chen X, …Villanueva FS, Ultrasound Med Biol 2014;40).


Ultrasound in conjunction with microbubbles can deliver genes and drugs for therapeutic purposes (Carson AE, McTiernan CF, Lavery L, Hodnick A, Grata M, Leng X, Wang J, Chen X, Modzelewski RA, Villanueva FS.  Gene therapy of carcinoma using ultrasound-targeted microbubble destruction. Ultrasound in Med Biol 2011;37:393-402. PMID: 21256666; PMC4111473; Carson AR, McTiernan CF, Lavery L, Grata M, Leng X, Wang J, Chen X, Villanueva FS.  Therapy of carcinoma using small inhibitory RNA against epidermal growth factor receptor and ultrasound targeted microbubble destruction.  Cancer Res 2012; 72:1-9. PMID: 23010078; PMCID: PMC3654825).


Villanueva Fig 3

Postmortem histology of tumors in mice after intravenous delivery of either pCMV-TK (a, c, d) or pEGFP-C1 (b)-loaded microbubbles and treatment with ultrasound and ganciclovir. (a, b) Acellular zones (arrows) visible under H&E stain. (c) Merged image of two sister slides, one stained by Heoscht 33342 (blue overlay) and one stained by H&E. (d) Variable vWF staining in acellular zones (arrows). Adapted from Carson AE, …, Villanueva FS.  Ultrasound in Med Biol 2011;37.

 
Villanueva Fig 4

Growth of murine tumors after intravenous injection of either pCMV-TK (□) or pEGFP-C1 (▲)-loaded microbubbles and treated with ultrasound. Daily GCV injections began on day 3. Best-fit lines were calculated from all data points in each group assuming an exponential growth curve (TK R2 = 0.94; GFP R2 = 0.91). Adapted from Carson AE, …, Villanueva FS.  Ultrasound in Med Biol 2011;37.


Media


Dr. Villanueva discusses using microbubbles as ultrasound contrast agents for myocardial perfusion testing.


Grants

1RO1EB016516-01A1
National Institutes of Health (NIBIB)             
“Ultrasound Activated Microbubbles for Targeted siRNA Delivery to Tumor”
Principal Investigator
7/1/12-5/31/16

R21 CA167373-01
National Institutes of Health (NCI)
“Targeted Theranostic Microbubble Vectors for Transcription Factor Decoy Delivery”
Principal Investigator
8/1/12-7/31/14

National Institutes of Health, NIA/AGS RO3
“Effects of Aging on Aortic Wall Behavior and Aneurysm Growth”
Co-investigator:  Villanueva
Principal Investigator:  Rabih Chaer, MD
2012-2014

RO1 CA140215-01A1
National Institutes of Health
“Enhancing Delivery and Regulating Gene Expression in Oncolytic Vaccinia Vectors.”
Co-Investigator: Villanueva
Principal Investigator:  Stephen Thorne, PhD
2010-2015

RO1HL098230
National Institutes of Health, NHLBI
“Ultrasound-induced Thermal Strain Imaging for Arterial Plaque Characterization”
Co-Investigator: Villanueva
Principal Investigator:  Kang Kim, PhD
2010-2015

Fonds de la recherché en santé Quebec  FRSQ:PF1Yu, 23629
“Controlled Release of Liposomal Chemotherapeutic Agents Using Nanobubbles”
Fellowship grant for Francois Yu, PhD (post-doctoral fellow)
Research sponsor:  Villanueva
2011-2014

Fonds de recherché du Quebec – Nature et technologies File number 181968
Fellowship grant for Brandon Helfield, PhD (post-doctoral fellow)
Research sponsor:  Villanueva
2014-2016

1F32HL126421
National Institutes of Health NRSA Fellowship Training Grant
“Ultrasound-mediated modulation of microRNAs for treatment of cardiac hypertrophy”
Training Grant for Jonathan Kopechek, PhD
Research Sponsor:  Villanueva
2014-2017


Publications

Helfield B, Chen X, Watkins S, Villanueva FS. Biophysical insight into mechanisms of sonoporation. PNAS 2016;(in press). EPub 2016 August 22. doi: 10.1073/pnas.1606915113.

Kopechek JA, Carson AR, McTiernan CF, Chen X, Klein EC, Villanueva FS. Cardiac gene expression knockdown using small inhibitory RNA-loaded microbubbles and ultrasound. PLoS ONE 2016; 11(7):e0159751. doi: 10.1371/journal.pone.0159751. PMID: 27471848.

Helfield B, Chen X, Qin B, Villanueva FS. Individual lipid encapsulated microbubble radial oscillations: Effects of fluid viscosity. J Acoust Soc Am 2016;139(1):204-214. Epub 2016 January 11. doi: 10.1121/1.4939123. PMID: 26827018.

Helfield B, Black JJ, Qin B, Pacella J, Chen X, Villanueva FS. Fluid viscosity affects the fragmentation and inertial cavitation threshold of lipid encapsulated microbubbles. Ultrasound Med Biol 2016;42(3):782-794. Epub 2015 Dec 7. doi: 10.1016/j.ultrasmedbio.2015.10.023. PMID: 26674676.

Yu FTH, Chen X, Wang J, Qin B, Panday R, Villanueva FS. Low intensity ultrasound mediated liposomal doxorubicin delivery using polymer microbubbles. Mol Pharmaceutics 2016;13(1):55-64. Epub 2015 Nov 15. doi: 10.1021/acs.molpharmaceut.5b00421. PMID: 26567985.

Chen X, Wang J, Pacella JJ, Villanueva FS. Dynamic behavior of microbubbles during long ultrasound tone-burst excitation: mechanistic insights into ultrasound-microbubble mediated therapeutics using high-speed imaging and cavitation detection. Ultrasound Med Biol 2016;42(2):528-538. Epub 2015 Nov 18. doi: 10.1016/j.ultrasmedbio.2015.09.017. PMID: 26603628.

Kopechek JA, Carson AR, McTiernan CF, Chen X, Villanueva FS. Transcription factor decoy-mediated knockdown of STAT3 signaling to inhibit tumor growth using ultrasound targeted microbubble destruction. Theranostics 2015;5(12):1378-1387. doi: 10.7150/thno.12822. PMID: 25542487.

Pacella JJ, Brands J, Schnatz F, Black JJ, Chen X, Villanueva FS. Treatment of microvascular micro-embolization using microbubbles and long-tone-burst ultrasound: an in vivo study. Ultrasound Med Biol 2015;41:456-464.

Chen X, Leeman JE, Wang J, Pacella JJ, Villanueva FS.  New insights into mechanisms of sonothrombolysis using ultra-high speed imagingUltrasound Med Biol 2014;40:258-262.

Leng X, Wang J, Carson A, Chen X, Fu H, Ottoboni S, Wagner WR, Villanueva FS.  Ultrasound detection of myocardial ischemic memory using an E-selectin targeting peptide amenable to human applicationJ Molecular Imaging 2014;16:1-9.

Yu FT, Villanueva FS, Chen X.  Radial modulation contrast imaging using a 20MHz single element intravascular ultrasound catheterIEEE Trans Ultrason Ferroelect Freq Control 2014;61:779-791.

Brands J, Kliner D, Kameneva MV, Villanueva FS, Pacella JJ.  New insights into the microvascular mechanisms of drag reducing polymers:  effect on the cell free layerPLoS ONE 2013;8(10):e77252.

Mahmoud AM, Dutta D, Lavery L, Stephens DN, Villanueva FS, Kim K.  Noninvasive detection of lipids in atherosclerotic plaque using ultrasound thermal strain imaging:  in vivo animal studyJ Am Coll Cardiol 2013;62:1804-1809.

Chen X, Wang J, Versluis M, de Jong N, Villanueva FS.    Ultra-fast brightfield and fluorescence imaging of the dynamics of micrometer-sized objectsRev Sci Instrum 2013;84:063701;1-13.

Weiss RJ, Ahmad M, Villanueva FS, Schmitz S, Bhat G, Hibberd MG, Main ML; CaRES Investigators.  CaRES (Contrast Echocardiography Registry for Safety Surveillance):  A prospective multicenter study to evaluate the safety of the ultrasound contrast agent Definity in clinical practice.  J Am Soc Echo 2012;25:790-705.

Kaya M, Toma C, Wang J, Grata M, Fu H, Villanueva FS, Chen X.  Acoustic radiation force for vascular cell therapy:  Theory and in vitro validationUltrasound Med Biol 2012;38:1989-2012.

Kim  JS, Leeman JE, Kagemann MS, Yu F, Chen X, Pacella JJ, Schuman JS, Villanueva FS, Kim K.  Volumetric quantification of in vitro sonothrombolysis with microbubbles using high resolution optical coherence tomographyJ Biomed Optics 2012;17:070502 1-3.

Pacella JJ, Kameneva MV, Brands J, Lopowsky HH, Vink H, Lavery L, Villanueva FSModulation of pre-capillary arteriolar pressure with drag reducing polymers:  A novel method for enhancing microvascular perfusionMicrocirculation 2012; 19:580-585.

Leeman JE, Kim JS, Yu F, Chen X, Kim K, Villanueva FS, Pacella JJ.  Effect of acoustic conditions on  microbubble-mediated microvascular sonothrombolysisUltrasound Med Biol 2012; 38:1589-1598.

Carson AR, McTiernan CF, Lavery L, Grata M, Leng X, Wang J, Chen X, Villanueva FSTherapy of carcinoma using small inhibitory RNA against epidermal growth factor receptor and ultrasound targeted microbubble destructionCancer Res 2012; 72:1-9.

Deglau T, Villanueva FS, Wagner WR.  In vivo peg-modification of vascular surfaces for targeted deliveryJ Vasc Surg 2012;55:1087-1095.

Toma C, Fisher A, Wang J, Chen X, Grata M, Leeman J, Winston B, Kaya M, Fu H, Lavery L, Fischer D, Wagner WR, Villanueva FS.  Vascular endoluminal delivery of mesenchymal stem cells using acoustic radiation force. Tissue Eng J, Part A 2011;17(9-10):1457-1464.

Carson AE, McTiernan CF, Lavery L, Hodnick A, Grata M, Leng X, Wang J, Chen X, Modzelewski RA, Villanueva FS.  Gene therapy of carcinoma using ultrasound-targeted microbubble destruction. Ultrasound in Med Biol 2011;37:393-402.

Maul TM, Dudgeon DD, Beste MT, Hammer DA, Lazo JS, Villanueva FS, Wagner WR.  Optimization of contrast ultrasound agents with computational models to improve selection of ligands and binding strengthBiotechnol Bioeng 2010;107;854-864.

Moguillansky D, Leng X, Carson A, Lavery L, Schwartz A, Chen X, Villanueva FSQuantification of plaque neovascularization using contrast ultrasound:  A histologic validationEur Heart J 2011;32:646-653.

For more of Dr. Villanueva's publications, please visit PubMed.