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Victor Frenkel, PhD

Laboratories

Victor Frenkel
Victor Frenkel, PhD

Victor Frenkel, PhD

Associate Professor, Department of Diagnostic Radiology and Nuclear Medicine
Director of Translational Focused Ultrasound Research
Phone: 410-706-7783
Email: vfrenkel@som.umaryland.edu

Biosketch

Dr. Frenkel received his PhD in Agricultural Engineering at the Technion, Israel Institute of Technology in Haifa, Israel in 1999. He then spent four years as a post-doctoral fellow at the University of Maryland Biotechnology Institute in Baltimore, MD and two years as an Imaging Sciences Training Program fellow at the Clinical Center, National Institutes of Health. For the next six years he was a staff scientist at the Department of Radiology and Imaging Sciences at the NIH Clinical Center, and headed the focused ultrasound program.

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Focused Ultrasound Lab

Dr. Frenkel is the Director of Translational Focused Ultrasound Research and Associate Professor in the Department of Diagnostic Radiology and Nuclear Medicine at the University of Maryland School of Medicine (UMSOM). In these roles, he leads efforts related to the pre-clinical and translational study of focused ultrasound (FUS) within the FUS Foundation-designated Center of Excellence at UMSOM.


Research Projects

Select a project below to learn more.

Mechanistic Investigations of Therapeutic Ultrasound

All our ultrasound applications are rooted in the understanding of how ultrasound energy interacts with biological tissues and using this knowledge for developing clinically important interventional procedures. These investigations include understanding how low intensity nonfocused ultrasound can alter the permeability of skin to enhance transdermal delivery [1, 2]. And the mechanisms involved in employing FUS for improving the bioavailability and delivery and therapeutics in various disease models including solid tumors and acute and chronic blood clots [3]. Examples of these studies appear below (Fig. 1).

Examples of mechanistic studies on ultrasound bioeffects.

Figure 1. Examples of mechanistic studies on ultrasound bioeffects. (Upper left) Expansion of the extracellular space in the upper layers of skin in fish exposed to low intensity nonfocused ultrasound [1]. (Lower left) Modeling of focused ultrasound-induced displacements in skeletal muscle, indicating localized strains generated in the tissue. This type of bioeffect has been associated with structural effects for altering tissue permeability and mechanotransduction for eliciting molecular effects [3]. (Right) Theoretical model of ultrasound-induced ‘bilayer sonophores’, where local disparities in pressure amplitudes can overcome attractional forces within the lipid bilayers of membranes, causing expansion and contractions that cycle with the ultrasound exposures [2].

  1. Frenkel V, Kimmel E, Iger Y. Ultrasound-induced intercellular space widening in fish epidermis. Ultrasound in Medicine and Biology 2000;26(3):473-480. [PMID10773379]
  2. Krasovitski B, Frenkel V, Shoham S, Kimmel E. Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. Proceedings of the National Academy of Sciences 2011;108(8):3258-63. [PMC3044354]
  3. Hancock HA, Smith LH, Cuesta J, Durrani AK, Angstadt M, Palmeri M, Kimmel E, Frenkel V. Investigations into pulsed-high intensity focused ultrasound enhanced delivery: Preliminary evidence for a novel mechanism. Ultrasound in Medicine and Biology 2009;35(10:1722-36. [PMC2752481] 

Focused Ultrasound Mediated Drug and Gene Delivery in Solid Tumors

As described above, a large part of our research projects involves investigating the potential of using FUS for noninvasively enhancing the delivery of therapeutics in various disease models. For these applications, we use pulsed FUS (pFUS) exposures where the bioeffects generated for enabling these procedures are primarily, if not exclusively, nonthermal. In solid tumor models, for example, we have shown that in addition to the reversible structural alterations generated by pFUS for increasing the average pore size of the tissue, we may also be affecting factors in the tumor microenvironment (e.g. high interstitial fluid pressure), which would also contribute to improving the delivery of agents. One example of these studies appears below (Fig. 2). We are currently working on a project using pFUS to enhance the delivery of targeted nanocarriers for chemotherapy in a head and neck squamous cell carcinoma xenograft tumor model.

pFUS-enhanced delivery of a monoclonal (mAb) antibody in a solid tumor model.

Figure 2. pFUS-enhanced delivery of a monoclonal (mAb) antibody in a solid tumor model. (Left) Fluorescence microscopy images showing improved distribution of fluorescently tagged mAbs (green) in the tumor that was pretreated with pFUS. (Blue and red color indicate cell nuclei and blood vessels, respectively). (Middle) Image processing results of the fluorescent images indicating improved penetration of the mAbs from the tumor edge (A) as well was improved penetration from the closest blood vessel where extravasation occurred (B) when pretreating with pFUS. (Right) pFUS-enhanced tumor growth inhibition (A) and, consequently, improved survival (B) when the fluorescent tag on the mAbs was substituted with the beta emitter 90Y [2].

  1. Dromi S, Frenkel V, Traughber B, Angstadt M, Bur M, Poff J, Luk A, Xie J, Li KCP, Wood BJ. Pulsed-high intensity focused ultrasound and low temperature sensitive liposomes for enhanced targeted drug delivery and anti-tumor effect. Clinical Cancer Research 2007;13(9):2722-7. [PMC2555974]
  2. Wang S, Shin IS, Hancock H, Jang BS, Kim HS, Lee SM, Zderic V, Frenkel V, Pastan I, Paik CH, Dreher MR. Pulsed high intensity focused ultrasound increases penetration and therapeutic efficacy of monoclonal antibodies in murine xenograft tumors. J Control Release 2012 Aug 20;162(1):218-24. [PMC4219504]
  3. Poff J, Traughber BJ, Allen C, Colunga A, Chen Z, Wood BJ, van Waes C, Li CKP, Frenkel V. Pulsed-high intensity focused ultrasound enhances apoptosis and growth inhibition of squamous cell carcinoma xenografts by proteasome inhibitor bortezomib. Radiology 2008;248(2):485-91. [PMC2621259]
  4. Ziadloo A, Xie J, Frenkel V. Pulsed focused exposures enhance locally administered gene therapy in a murine solid tumor model. Journal of the Acoustical Society of America 2013;133:1827-34. [PMC3606298]

Focused Ultrasound Mediated Delivery in the Brain

We have recently begun pursuing applications of pFUS in brain using a state-of-the-art MRI guided FUS (MRgFUS) system. Using this system, we’ve shown we can improve the dispersion of nanoparticles (NPs) administered locally by convection-enhanced delivery. In a previous ex vivo study, we found that enhanced dispersion of locally administered NPs was associated with expansion of the extracellular (ECS) and perivascular (PVS) spaces. We have also demonstrated the ability to deliver neural progenitor cells to the brain that were administered systemically following MRgFUS (Fig. 3). We are currently pursuing both treatment approaches for enhancing the delivery of cells and therapeutics for the treatment of invasive brain tumors.

MRgFUS mediated delivery of neural progenitor cells (NPCs) in the brain.

Figure 3. MRgFUS mediated delivery of neural progenitor cells (NPCs) in the brain. (A) Schematic of the MRgFUS system, including the transducer, the water bolus (to couple between the head and transducer) and the position of the coil. (B) Screen capture of the graphic user interface of the MRgFUS system, showing overlay of the position of the FUS transducer focal zone (arrow) on an axial T2 weighted MR image of the rat brain. (C) T1 weighted axial MR image taken post-treatment and administration of MR contrast. Hyperintense signal (arrow) shows location where BBB was opened. (D) Whole brain section showing Evans blue dye (arrows), further validating opening of the BBB. (E, F) Fluorescence micrographs of brain section, showing location of NPCs, labeled with a fluorophore. (G - I) Bright field micrographs of brain section showing NPCs stained with Perl’s Prussian blue (arrow heads). The NPCs were also labeled with super paragmagnetic iron oxide (SPIO) nanoparticles, which are stained blue with the Perl’s Prussian blue reagent. Scale bars: 10 mm (B, C); 2 mm (D); 400 mm; (E) 200 mm (F); 1 mm (G); 50 mm (H); 5 mm (I) [2].

  1. Hersh DS, Nguyen BA, Dancy JG, Adapa AR, Winkles JA, Woodworth GF, Kim AJ, Frenkel V. Pulsed ultrasound expands the extracellular and perivascular spaces of the brain. Brain Research 2016;1646:543-50. [PMID: 27369449]
  2. Shen, WB, Anastasiadis PA, Nguyen BA, Yarnell D, Yarowsky PJ, Frenkel V, Fishman PS. Magnetic enhancement of stem cell-targeted delivery into the brain following MR-guided focused ultrasound for opening the blood-brain barrier. Cell Transplantation 2017;26(7):1235-46. [PMID: 28933214]
  3. Hersh, DS, Anastasiadis PA, Mohammadabadi A, Nugyen BA, Guo S, Winkles JA, Keller A, Kim AJ, Gullapalli R, Frenkel, V, Woodworth, GF. Transcranial pulsed ultrasound mediates neuromodulatory and expansile interstitial effects in vivo, PLoS One 2018;13(2): e0192240 [PMID: 29415084].

Focused Ultrasound Mediated Stem Cell Delivery

In addition to employing the structural effects of pFUS for improving the delivery of therapeutics, we have also been studying the molecular effects generated by these exposures and their potential applications. We have shown that pFUS can enhance the levels of cytokines, chemokines, trophic factors and integrins in a controlled manner, both spatially and temporally. Employing these effects, we found that we can enhance both homing and retention of various types of stem cells (e.g. MSCs) in different anatomical and disease models including kidneys [1] (Fig. 4A, B), skeletal muscle [2], as well as a model of critical limb ischemia [3]. In the latter, we showed we could significantly increase revascularization for improved reperfusion in the affected limb (Fig. 4C). We continue to investigate the mechanisms underlying this procedure, so that we may optimize it and demonstrate its potential for clinical translation.

FUS for enhanced homing and retention of stem cells.

Figure 4. FUS for enhanced homing and retention of stem cells. (A) Representative T2*-weighted MRI scans and Prussian blue-stained brightfield microscopy sections of an FUS-treated kidney and untreated (contralateral control). Enhanced presence of super paragmagnetic iron oxide (SPIO)-labeled bone marrow stromal cells (BMSC) is seen (hypo-intense signal in MRI; blue labeled cells in histology). Scale bar = 50 mm. (B) Quantification of the experimental results of ‘A’, showing significant increases in cell counts in the FUS treated kidneys on day 1 & 3 post-FUS treatment compared to controls. (C) In a model of critical limb ischemia, significant increases in normalized perfusion were observed with laser doppler perfusion imaging (LDPI) in response to three consecutive days of FUS followed each time by the administration of MSCs, compared to MSCs alone, FUS alone and saline (vehicle) control. (D) Representative LDPI images of all experimental groups taken at the termination of the study (week 7).

  1. Ziadloo A, Burks SR, Gold EM, Lewis BK, Chaudry A, Merino MJ, Frenkel V, Frank JA. Enhanced homing permeability and retention of bone marrow stromal cells by noninvasive pulsed focused ultrasound. Stem Cells 2012;30(6):1216-27. [PMC3356926]
  2. Tebebi PA, Burks SR, Kim SJ, Williams RA, Nguyen BA, Venkatesh P, Frenkel V, Frank JA. Cyclooxygenase-2 or tumor necrosis factor-α inhibitors attenuate the mechanotransductive effects of pulsed focused ultrasound to suppress mesenchymal stem cell homing to healthy and dystrophic muscle. Stem Cells 2014;33:1173-86. [PMID25534849]
  3. Tebebi PA, Kim SJ, Williams RA, Milo B, Frenkel V, Burks SR, Frank JA. Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound. Scientific Reports 2017;7:41550. [PMC5294408]

New FUS Applications

Immunomodulation
We are looking at pFUS induced molecular effects to elicit immune responses against invasive brain tumors (glioblastomas). These studies are currently ongoing.

Neuromodulation
We are also looking at low energy pFUS for both stimulating and inhibiting neuronal activity as an improved modality over trans-magnetic stimulation. This project is also currently underway.

Traumatic Brain Injury
We have started investigating the potential of pFUS mediated neurogenesis as a method for enhance treatment of TBI in a controlled cortical impact model.


Lab Members

Victor Frenkel

Victor Frenkel, PhD
Associate Professor
Department of Diagnostic Radiology and Nuclear Medicine
Director of Translational Focused Ultrasound Research
Tel: 410-706-7783
Email: vfrenkel@som.umaryland.edu

Head shot of Ali Mohammadabadi, MSc

Ali Mohammadabadi, MSc
Email: ali.mohammadabadi@som.umaryland.edu
Ali received a Bachelor’s degree in 1999 in Mechanical Engineering from Ferdowsi University, in Mashhad, Iran. In 2014, he received his Master’s, also in Mechanical Engineering, from the University of Michigan - Shanghai Jiao Tong University Joint Institute, in Shanghai, China. His thesis research involved the development of a novel technique for nondestructive testing of materials with low acoustic impedance ultrasound. He is currently a Ph.D. candidate in Mechanical Engineering at the University of Maryland, Baltimore County (UMBC) and doing his dissertation research in the Focused Ultrasound Lab in the Department of Diagnostic Radiology & Nuclear Medicine, UMSOM. His dissertation project involves investigations on the use of pulsed focused ultrasound for enhancing the delivery and therapy of antineoplastic agents for the treatment of Head and Neck tumors.

Publications

Click here to view Dr. Frenkel's publications on Pubmed

Please refer Dr. Frenkel's faculty profile for highlighted publications