Project Director Name/ Academic Rank/Department/e-mail:
Morand R. Piert, M.D. / Associate Professor / Radiology / mpiert@umich.edu
Co-Principal Investigator Names/Departments/e-mails:
Mario L. Fabiilli, Ph.D. / Radiology / mfabiill@umich.edu
Oliver D. Kripfgans, Ph.D. / Radiology / greentom@umich.edu
Other faculty involved (and Department): None
Number of students involved (specify as undergraduate or graduate): None
Is project part of a UROP, REU or PhD project? No
Title of Project: Targeted beta-particle (Iodine-131) treatment using sonosensitive emulsions
Statement of relevance to MMPP: Due to its uptake mechanism, the use of Iodine-131 (131I) is largely restricted to thyroid cancer. We propose to expand the therapeutic utility of 131I to other soft tissue tumors using
a targeted, ultrasound-based delivery mechanism for 131I. Localized delivery could minimize iatrogenic effects
and improve therapeutic efficacy by increasing the radiation dose within targeted tumors and at the same time
decrease side effects to non-target tissues. The proposed work adheres to the principles of the MMPP by improving the life of men and women by developing radiation-based therapies that could reduce patient morbidity, mortality, and pain.
Amount of funding requested in this proposal; itemized budget should be attached (not counted in
page limit): $25,000
Facilities/ space available: The investigators (located in Medical Science Building I) have all of the resources
necessary to complete the project specific aims, including formulation laboratory, iodination laboratory, housing
for radioactive animals, microPET, autoradiography, cryostat, gamma camera imaging equipment, and a GE
cyclotron for production of 18F-FDG.
Agency/agencies to which future proposal would likely be submitted:
National Institutes of Health
Timeline of Work/ External proposal submission deadline:
April 2014 – April 2015. External R21/R01 proposal submission anticipated June 2015
Department Chair (or designate) Signature: ___________________
1 Abstract of Proposed Research: 300 words or less attach as separate page (not counted in page limit):
Iodine is specifically taken up in the thyroid, which allows the use of Iodine-131 (131I) as a well-established betaemitter radionuclide treatment for differentiated thyroid cancers. Its uptake mechanism largely restricts the use of 131I
for thyroid diseases, with very few exceptions (e.g., 131I labeled antibodies against CD-20). We hypothesize that 131I
could be used for targeted tumor treatment almost anywhere in the human body using a non-invasive ultrasoundbased drug release technique called acoustic droplet vaporization (ADV).
Upon ADV, sonosensitive emulsions (i.e., liquid droplets) are converted into gas bubbles when exposed to ultrasound above a specific acoustic threshold. A therapeutic payload (e.g., 131I), encapsulated in the emulsion, can be
released locally with ADV. Thus, using focused ultrasound, ADV can generate “on-demand” drug release in a spatially and temporally-controlled manner with sub-millimeter precision in deeply located sites in the body.
Here, we propose a proof of concept study to a) generate sonosensitive emulsions loaded with 131I using established methods, and b) evaluate the safety and distribution of 131I after ADV-triggered release in a rat tumor model.
In biodistribution studies, we will measure the delivered radiation dose to the tumor compared to non-target tissues
and the whole body. Overlays of histology and autoradiography will be used to determine the spatial deposition of
131
I relative to the location of tumor cells with high precision. Additionally, limited repeated ADV treatment studies will
determine initial effectiveness of this new therapeutic approach.
These pilot data are key to the subsequent development of targeted medical tumor treatment based on the betadecay energy of 131I. If successful, this treatment could become widely available within a relatively short period of
time. The formulation of 131I into an emulsion opens the door for patent applications to secure intellectual property
rights. The project therefore conforms to the core of the MMPP mission.
2 Research Proposal: Targeted beta-particle (Iodine-131,131I) treatment using sonosensitive emulsions
Hypothesis: Focused ultrasound can be used to localize the release and therapeutic effects of 131I from sonosensitive emulsions.
Specific Aim 1: Synthesis and stability testing of micron- and nano-sized 131I loaded emulsions suitable for ultrasonic release.
Specific Aim 2: In vivo evaluation of the safety, biodistribution and initial performance of ultrasonically released 131I
within a rat breast cancer tumor model.
Study rationale: 131I is a powerful beta-emitter treatment for differentiated thyroid cancers. Translation of 131I to
cancers lacking the sodium-iodine symporter (NIS) and iodine organification requires a targeted method of delivery plus suitable local retention of 131I. Here, we propose a delivery mechanism using ultrasound, termed acoustic droplet vaporization (ADV). Ultrasound is ideally suited for targeted drug delivery since ultrasound can be applied non-invasively, focused with sub-millimeter precision to deeply located sites in the body, and delivered in an
“on-demand” manner in a spatially- and temporally-controlled manner. After intravenous injection, a sonosensitive
emulsion (i.e., liquid droplets) is converted into harmless microbubbles when exposed to ultrasound above a specific acoustic threshold 1. ADV is a mechanical process, not thermal, and therefore occurs essentially instantaneously
2
. The sonosensitive phase within the emulsion – a perfluorocarbon (PFC) – has been used clinically in diagnostic/therapeutic applications since it is inert and biocompatible 3. Therapeutic agents, encapsulated within the emulsion using a double emulsion technique, are released locally after ADV only within the focus of the ultrasound beam
4
. There are no pre-focal effects as seen in thermal therapies. We have previously demonstrated the release of
chemotherapeutic agents 5, enzymes 6, and growth factors 7 using ADV. Additionally, we have characterized the
biodistribution of sonosensitive emulsions in rats using 18F-Fluorodeoxyglucose as payload and demonstrated the
stability of such emulsions under presence of access high energy beta+ (positron) and gamma radiation resulting
from the decay of Fluoride-18 8. Furthermore, ADV can temporarily occlude the capillary bed of targeted tissues,
thereby limiting the washout of the payload for an extended and controllable time 9.
Sonosensitive emulsions are typically formulated in two size ranges: micron and submicron. Micron-sized emulsions are vascular agents small enough to pass unhindered through capillaries 10, 11. The drug loading per droplet is
up to 90% (v/v) and during ADV, tissue uptake of drug can be enhanced by ultrasound. Submicron-sized emulsions
are extravascular agents and can passively accumulate within tumors due to large inter-endothelial gaps 12, 13.
Figure 1. A) Focused ultrasound
can be applied non-invasively to
target organs. B) Schematic representation of drug release by
ADV in a blood vessel. The sonosensitive emulsion is administered
intravenously and focused ultrasound is used to release the drug
locally within the tumor. C) Consecutive images (I-III) show ADV
of a single droplet (diameter = 10
μm), captured with an ultra-high
speed imaging system (18.5 x 106
frames/sec) 14. A confocal micrograph (IV) of a PFC double emulsion globule containing fluorescently labeled W1 droplets 7. Scale
bar = 10 μm. A larger droplet is
shown for the sake of clarity. The
mean diameter of the micron-sized
emulsions is 2 μm with more than
99.9% smaller than 8 μm. Water-soluble agents, including 131I, are incorporated into sonosensitive emulsions via a double emulsion technique of the form water-in-PFC-in-water (W1/PFC/W2, panel IV). D) Coronal micro-positron emission
tomography (micro-PET) image of a rat that received an injection of a sonosensitive emulsion containing 18FFluorodeoxyglucose (18F-FDG) as a radiotracer 8. E) Time-activity curves of intravenously injected 18F-FDG solution and
18
F-FDG emulsion in brain tissue of Fisher 344 rats with 9L tumors (n=6). In highly metabolic tissue such as brain, standard uptake values (SUVs) are lower with the 18F-FDG emulsion, thus indicating that 18F-FDG, here used as a drug surrogate, is stably retained within the sonosensitive emulsion 8.
3 Approach
Formulation of 131I-loaded sonosensitive emulsions: Sonosensitive emulsions of the form water-in-PFC-in-water
(W1/PFC/W2), containing 131I in the W1 phase, will be prepared using similar methods as previously described by
our group 6-8, 15 with the following modification. A Poloxamer with a higher polyethylene glycol content will be used to
stabilize the PFC/W2 interface to reduce the rate at which the emulsion is cleared by the mononuclear phagocyte
system. The double emulsion will be further processed using a sonicator or microfluidizer to generate 131I microemulsion and 131I nanoemulsion, respectively. Both emulsions will be washed to remove any unincorporated (i.e.,
free) 131I. Radiochemical yield and purity will be confirmed during quality control testing, while particle size will be
determined with a Coulter counter. In vitro stability of the emulsions will be tested as in our prior study using 18Ffluorodeoxyglucose (18F-FDG) emulsion 8. For biodistribution studies (see below), 131I will be replaced by the chemically identical isotope 125I.
Tumor model: All animal procedures are performed under isoflurane anesthesia. Rat breast cancer will be induced
in female Sprague–Dawley rats (200–230 g, 8 weeks of age) by injecting 1 x 105 Walker 256 cells (ATCC CCL-38,
Manassas, Virginia, USA) into the left abdominal mammary fat pad. Successful tumor inoculation will be monitored
visually and via palpation. Tumors will be allowed to grow until a volume of approximately 0.5 cm3 is reached, as
measured by ultrasound, before treatment is initiated. All animals receiving radioiodine (123I/131I) will receive potassium-iodide (SSKI) drops in drinking water to block radioiodine uptake in the thyroid. Regulatory approval has already been obtained for the use of radioiodine (125I/131I) in our laboratories, housing of radioactive animals,
and for ADV in rats (RSS 101-05-080, UCUCA protocol #PRO00005212).
ADV treatment: Animals will be placed on a restraint platform, positioned, and continuously monitored. A therapeutic ultrasound transducer with a custom-built coupling cone will allow transcutaneous ADV using gel coupling. A diagnostic ultrasound imaging array (operating at an acoustic output below the ADV threshold) will be positioned cofocally with the therapeutic transducer, enabling real-time visualization of blood flow within the tumor as well as assessment of immediate ADV efficacy by imaging the microbubbles generated during ADV.
Biodistribution studies: The purpose is to assess which of the 2 vehicles (micro- or nanoemulsion) provide the highest cumulative radiation dose to the tumor in relation to that of critical organs (thyroid, liver and bone marrow). 125I
(physical T1/2 = 59 days) and 131I (physical T1/2 = 8.02 days) are chemically identical. 125I is used for biodistribution
studies to allow for high quality autoradiography imaging. The biodistribution of intravenously administered 125I micro- and nanoemulsion (0.15 mL/kg) will be determined after a single ADV application. Radioactivity distribution is
determined at 5 time points as follows: 5 min (before ADV), immediately after ADV, 180 min, 24 h, and 72 h. For
the microemulsion, ultrasound to generate ADV will be applied within 10 min after administration. For the
nanoemulsion, ultrasound to generate ADV will be applied within 60 min after administration to allow for extravasation and passive accumulation of the nanoemulsion within the tumor. The ADV procedure is completed after 10 min.
Animals are sacrificed at above time points to obtain tissue and fluids for dosimetry as follows: tumor, brain, thyroid,
muscle, heart, lungs, spleen, liver, kidney, small and large bowel, large bowel content, adrenal, bone, bone marrow,
gallbladder, bladder wall, ovaries, urine, bile and blood. The radioactivity concentrations (in % of the injected
dose/gram (%ID/g)) will be determined using a gamma counter. These data will be used to calculate the radiation
absorbed doses of each organ and the effective dose of radiation to the whole body (using MIRD formalism). Assuming an intragroup variability of 30% and that the maximum difference between tumor and critical organ dose
(%ID/g) of emulsion A is double of emulsion B, 3 rats per group yields a statistical power of 86% using α = 0.05.
Thus, a total of 30 rats will be used for the biodistribution: 2 groups (125I micro- vs. nanoemulsion), 5 time points, 3
animals per sample = 30 animals.
Immediately after gamma counting (10 min duration), a subset of the specimens treated with micro- or nanoemulsion (from time points at 3, 24, 72 h) will undergo autoradiography (GE Typhoon). After calibration for 125I, quantitative uptake measurements (in Bq/cm3) are obtained. Tumors (with muscle and blood for comparison) will be rapidly
frozen and sectioned (Leica Cryostat CM3050S). Multiple autoradiography sections (cut at 20 µm) at defined intervals are compared with immediate subsequent 8 µm cuts for HE histology. Using mutual information image analysis
software, overlays of autoradiography and histology are generated and the spatial (3-dimensional) distribution of
radioactivity in tumors is compared with histology. Our method (described in 16) will be modified to assess the effectiveness of 131I delivery (including absorbed doses) relative to the spatial location of tumor cells in 3D.
In vivo treatment studies: To obtain initial evidence for treatment effectiveness, limited in vivo treatment studies with
repeated administrations will be performed using the optimal vehicle (131I microemulsion or 131I nanoemulsion) as
identified above. A total of 16 rats will be equally divided into 4 groups: (a) sham, (b) intravenous 131I injection, (c)
injection of 131I emulsion without ADV, and (d) injection of 131I emulsion with ADV in tumor. Each group of animals
4 will be treated a total of 3 times within 7 days. Based on an intragroup variability of 10% and a 25% difference between groups, 4 rats per group yields a statistical power of 89% using α = 0.05.
Imaging: The metabolic effectiveness of treatment response is measured by 18F-FDG microPET (Siemens/CTI P4
scanner) comparing the tumor 18F-FDG uptake (visually and quantitatively using SUV values) immediately before
start of the treatment and immediately after the third ADV treatment in 7 animals (2 in groups b and c, 3 in group d).
Approximately 1 mCi of 18F-FDG will be injected intravenously into fasted animals and a 30 min static acquisition of
the thorax and abdomen is performed starting 60 min post injection. These animals will also undergo gamma camera imaging on the same day to obtain estimates for 131I retention in tumors relative to background.
Effectiveness of the overall tumor treatment will be determined by the tumor growth rate (growth delay) in comparison to sham. Tumor growth delay will be determined as the time in days for tumors to grow from 0.5 to 1.5 cm3
(volume) minus the average time in days for sham treated tumors to reach the same size 17. If tumor treatment results in progressive tumor shrinkage, the absolute tumor volume will be used instead. Any tumor shrinkage compared to the pretreatment level observed for 7 days or more is considered a response. Otherwise the treatment result is considered a non-response. During the observation period (4 weeks), mortality, clinical signs, body weight,
and food consumption are determined daily.
Expected findings: In the biodistribution studies, the highest uptake of 131I is anticipated in the tumor. In the treatment studies, the largest delay in tumor growth should be in group (d).
Potential problems / Alternative approaches: If 131I is not sufficiently retained within the W1 phase of either the
micro- or nanoemulsion using our previously published method 6-8, 15, then the following approach will be taken: The
length of the polyethylene glycol block of the triblock fluorosurfactant stabilizing the primary emulsion (W1/PFC) will
be increased to enhance the PEG brush stabilizing the W1/PFC interface.
Timeline:
Months 1 – 2: Synthesis and stability testing of 131I microemulsion and 131I nanoemulsion
Months 3 – 5: Biodistribution studies and autoradiography
Months 6 – 12: In vivo (repetitive) treatment studies, conference presentations, and manuscript publication.
Outlook for future development and clinical translation: A. Applicable for many cancers: If effective, targeted
ADV-triggered tumor treatment with 131I emulsions could revolutionize radionuclide treatments of many cancers. B.
Alternative radionuclides: Alternative radioactive payloads (Yttrium-90, Radium-223 and others) could be used
depending on the location, the individual tumor microenvironment, and radiation sensitivity of particular malignancies. C. Rapid translation: Translation of targeted ADV-triggered tumor treatment based on 131I emulsions into the
clinic is possible within a short time frame as suitable ultrasound equipment (Philips, Sonalleve) for human use preexists at our institution. D. Patents: Furthermore, the formulation of 131I into an emulsion opens the door for patent
applications to secure intellectual property rights for this novel drug product.
Literature
1. O. D. Kripfgans et al., Ultrasound Med Biol 26, 1177 (2000). 2. O. D. Kripfgans et al., J Acoust Soc Am 116, 272 (Jul, 2004). 3. J. G. Riess, Chemical Reviews 101, 2797 (2001). 4. O. Couture et al., Medical Physics 39, 5229 (Aug, 2012). 5. M. L. Fabiilli et al., Ultrasound in Medicine and Biology 36, 1364 (Aug, 2010). 6. M. L. Fabiilli et al., Pharm Res 27, 2753 (Dec, 2010). 7. M. L. Fabiilli et al., Acta Biomater, (Mar 25, 2013). 8. M. L. Fabiilli et al., Contrast Media Mol Imaging 8, 366 (Jul, 2013). 9. O. D. Kripfgans et al., IEEE Trans Ultrason Ferroelectr Freq Control 52, 1101 (Jul, 2005). 10. O. D. Kripfgans et al., Ieee T Ultrason Ferr 49, 726 (Jun, 2002). 11. M. Zhang et al., Ultrasound in Medicine and Biology 36, 1691 (Oct, 2010). 12. N. Rapoport, Progress in Polymer Science 32, 962 (2007). 13. N. Y. Rapoport et al., Journal of Controlled Release 138, 268 (2009). 14. O. Shpak et al., The Journal of the Acoustical Society of America 134, 1610 (Aug, 2013). 15. J. R. Rajian et al., Opt Express 19, 14335 (Jul 18, 2011). 16. C. Meyer et al., Eur J Nucl Med Mol Imaging 40 Suppl 1, 72 (Jul, 2013). 17. R. Beck et al., J Nucl Med 48, 973 (Jun, 2007). 5 Itemized Budget and Justification
We request support for animals, animal housing, imaging (PET, gamma camera,
autoradiography) as well as consumables as follows:
Description
Materials/chemicals for emulsions
CCL‐38 cells (Walker breast carcinom
Unit
Cost per unit
Supplier
Number Required
1 vial
$ 459.17
ATCC
2
Biodistribution studies (I‐125)
Sprague–Dawley (female, 200–230 g)
1 rat
Rat housing
per cage per day
Rat shipping
per shipment
Biodistribution study
per rat
Autoradiography
per rat
In‐vivo studies treatment studies (I‐131)
Sprague–Dawley (female, 200–230 g)
1 rat
Rat housing
per cage per day
Rat shipping
per shipment
[18F]FDG
per dose
MicroPET imaging
per hour
Gamma camera imaging
per hour
Consumables Isoflurane
250 mL
Cell culture media, SSKI, syringes etc.
Trim and cassette tissue
per casette
Parfilm H&E slide
per slide
Iodine‐131 ($366 plus $50 shipping)
Iodine‐125 ($378 plus $50 shipping)
per 2 mCi
per 2 mCi
$ 35.25
Harlan
$ 1.37
ULAM
$ 122.00
Harlan
$ 150.00 ImagingCore
$ 150.00 ImagingCore
30
$ 35.25
Harlan
$ 1.37
ULAM
$ 122.00
Harlan
$ 150.00 ImagingCore
$ 150.00 ImagingCore
$ 150.00 ImagingCore
21
$ 35.00
5
30
20
14
14
14
Total Cost
$ 961.31
$ 918.34
$ 1,057.50
$ 411.00
$ 1,220.00
$ 4,500.00
$ 3,000.00
$ 740.25
$ 575.40
$ 854.00
$ 2,100.00
$ 2,100.00
$ 2,100.00
$ 2.46
$ 3.62
ULAM PCAR
ULAM PCAR
40
240
$ 175.00
$ 800.00
$ 98.40
$ 868.80
$ 416.00
$ 428.00
PerkinElmer
PerkinElmer
4
2
$ 1,664.00
$ 856.00
Grand Total
$ 25,000.00
Radioiodine is needed for syntheses of 125/131I micro- and nanoemulsions at a total of $2,520.
Materials and chemicals for emulsions are requested (@ $961.31).
Tumor cells are obtained from ATCC at a total of $ 918.34. Cell culture media, SSKI, syringes
and other consumables are requested @ $800.
30 animals are needed for biodistribution studies (30 animals @ $35.25, 3 animals per shipment
@ $122). Housing is needed for 30 days in order to allow for sufficient tumor growth.
Subsequent biodistribution and autoradiography studies are performed by the Nuclear Medicine
Imaging Core. A total of 30 biodistribution studies (@ $150) are requested. Only animals from 3
time points will receive autoradiography studies (20 animals @ $150).
In vivo treatment studies will require 21 animals (16 for 4 groups with 4 animals each, plus 5
animals for model development). 21 animals @ $35.25, 3 animals per shipment @ $122 with
60 days of housing are requested (to allow for tumor growth, treatments and follow-up time).
Animal PET and gamma camera imaging (at 2 time points, before and after treatments) is
requested for a subset of animals (7 animals) as detailed in the grant. Thus, 14 PET and 14
gamma camera scintigraphies are requested (@$150 per hour). FDG is charged by dose (@
$150). Imaging studies are performed by the Nuclear Medicine Imaging Core.
Histology will be performed (by ULAM) from tumor (and control) tissues and are charged per
cassette (@ $2.46) and slide (@ $3.62). 40 cassettes and 240 slides are estimated ($416 +
$428, total of @ $967.20).
Principal Investigator/Program Director (Last, First, Middle):
Piert, Morand R.
BIOGRAPHICAL SKETCH
Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Piert, Morand R.
Associate Professor of Radiology
eRA COMMONS USER NAME
mpiert
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
DEGREE
(if applicable)
INSTITUTION AND LOCATION
Medical School University of Cologne , Germany
University of Tuebingen, Germany
M.D.
YEAR(s)
Medical School University of Tuebingen, Germany
Habilitation
1999
Medicine
General Surgery
Residency
Nuclear Medicine
Residency
Surgery
Medical School Technical University of Munich,
Germany
Habilitation
2002
Nuclear Medicine
Technical University of Munich, Germany
1977-1984
07/1996
FIELD OF STUDY
04/2003
PERSONAL STATEMENT
As a Nuclear Medicine physician interested in oncology, the combination of radionuclides and targeted drug
delivery is a very attractive concept with the potential to revolutionize the treatment of many cancers. The
utilization of ultrasound for targeted drug delivery opens the door to overcome physiological restrictions for
radionuclide therapies determined by the chemical structure of radioisotopes and related compounds. This pilot
study could be the basis for groundbreaking discoveries and could lead to an efficient translation into clinical
practice.
POSITIONS
10/1985 – 06/1987
07/1987 - 06/1989
07/1989 - 06/1996
07/1996 -10/1999
11/1999-03/2003
12/1999-11/2002
11/1999 - 11/2002
12/2002-07/2004
04/2003-07/2004
09/2004-present
PHS 398/2590 (Rev. 09/04)
Resident in General Surgery, Kreiskrankenhaus Bergheim/Erft (General Hospital of
Bergheim/Erft) Germany
Resident in Plastic and Reconstructive Surgery, Rheinisch-Westfälische Technische
Hochschule Aachen (RWTH Aachen), Germany
Clinical Instructor and Senior Resident in General Surgery, University of Tübingen
(Universität Tübingen), Germany
Senior Instructor and Specialist Registrar with Consultant Duties in General Surgery,
University of Tübingen (Universität Tübingen) Germany
Senior Resident in Nuclear Medicine, Technical University of Munich (Technische
Universität München), Germany
Privat Dozent (private lecturer; position comparable to Assistant Professor) in General
Surgery, University of Tübingen (Universität Tübingen), Germany
Clinical Instructor in Nuclear Medicine, Technical University of Munich (Technische
Universität München), Germany
Privat Dozent (private lecturer; position comparable to Assistant Professor) in Nuclear
Medicine, Technical University of Munich (Technische Universität München), Germany
Senior Physician and Consultant in Nuclear Medicine at the Clinic of Nuclear Medicine,
Technical University of Munich (Technische Universität München), Germany
Associate Professor of Radiology, Division of Nuclear Medicine (University of Michigan),
USA
Page
Biographical Sketch Format Page
SELECTED HONORS
 Winner, Best Scientific Paper, ”Oxygenation-dependant Uptake of Fluor-18 labelled Fluoroazomycin
Arabinosid (FAZA) using Small Animal PET“ Deutsche Gesellschaft fuer Nuklearmedizin (DGN) 2003,
Essen, Germany.
 Winner, European Association of Nuclear Medicine (EANM) Springer Prize 2008, Best Basic Science Paper,
“Positron detection for the intraoperative localisation of cancer deposits”
SELECTED PEER-REVIEWED PUBLICATIONS (IN CHRONOLOGICAL ORDER)
1. Piert M, Zittel TT, Machulla H-J, Becker GA, Jahn M, Maier G, Bares R, Becker HD. Blood Flow
Measurements with [15O]H2O and [18F]Fluoride Ion PET in Porcine Vertebrae. J Bone Mineral Res 13
(1998):1328-1336.
2. Piert M, Machulla H-J, Becker G, Stahlschmidt A, Aldinger P, Dißmann P, Fischer H, Bares R, Becker HD,
Lauchart W. Introducing [18F]Misonidazole positron emission tomography for the localization and
quantification of pig liver hypoxia. Eur J Nucl Med 26 (1999):95-109.
3. Piert M, Winter E, Becker GA, Bilger K, Machulla H-J, Müller-Schauenburg W, Bares R, Becker HD.
Allogenic Bone Graft Viability after Revision Hip Arthroplasty. Eur J Nucl Med 26 (1999):615-624.
4. Machulla H-J, Blocher A, Kuntzsch M, Wei R, Piert M, Grierson JR. Simplified labeling approach for
synthesizing 3‘-Deoxy-3‘-[18F]Fluorothymidine ([18F]FLT). J Radioanalytical Nucl Chem 243 (2000):843-846.
5. Piert M, Machulla H-J, Becker G, Aldinger P, Winter E, Bares R. Dependency of the [18F]fluoromisonidazole
uptake on oxygen delivery and tissue oxygenation in the porcine liver. Nucl Med Biol 27 (2000):693-700.
6. Winter E, Piert M, Volkmann R, Maurer F, Eingartner C, Weise K, Weller S. Allogenic cancellous bone graft
and a burch-schneider ring for acetabular reconstruction in revision hip arthroplasty. J Bone Joint Surg Am
83 (2001):862-867.
7. Piert M, Zittel TT, Becker GA, Jahn M, Stahlschmidt A, Maier G, Machulla H-J, Bares R. Assessment of
Porcine Bone Metabolism by Dynamic [18F]Fluoride Ion Positron Emission Tomography: Correlation with
Bone Histomorphometry. J Nucl Med 42 (2001):1091-1100.
8. Piert M, Machulla H-J, Becker GA, Jahn M, Stahlschmidt A, Maier G, Zittel TT. Coupling of Porcine Bone
Blood Flow and Metabolism in High-Turnover Bone Disease Measured by 15OH2O and 18FFluoride Ion
Positron Emission Tomography. Eur J Nucl Med 29 (2002):907-914.
9. Piert M, Zittel TT, Jahn M, Stahlschmidt A, Becker GA, Machulla H-J. Increased Sensitivity in the Detection
of a Porcine High-turnover Osteopenia After Total Gastrectomy by Dynamic [18F]Fluoride Ion PET and
Quantitative CT. J Nucl Med 44 (2003):117–124.
10. Stahl A, Wieder H, Wester H-J, Piert M, Lordick F, Ott K, Rummeny E, Schwaiger M, Weber WA. PET/CT
molecular imaging for abdominal oncology. Abdominal Imaging 29 (2004):388-97.
11. Stahl A, Wieder H, Piert M, Wester H-J, Senekowitsch-Schmidtke R, Schwaiger M. Nuclear Medicine
Imaging and Translational Research in Oncology. Mol Imag Biol 6 (2004):214-24.
12. Daldrup-Link HE, Meier R, Rudelius M, Piontek G, Piert M, Metz S, Settles M, Uherek C, Wels W, Schlegel
J, Rummeny EJ. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to
HER2/neu positive mammary tumors with magnetic resonance imaging. Eur Radiol. 15 (2005): 4-13.
13. Piert M, Machulla H-J, Picchio M, Ziegler S, Kumar P, Wiebe LI, Eu P, Schwaiger M. Hypoxia-specific
Tumor Imaging with Fluorine-18 Labelled Fluoroazomycin Arabinoside (FAZA). J Nucl Med. 46 (2005):
106-113.
14. Becker GA, Müller-Schauenburg W, Spilker M, Machulla H-J, Piert M. A Priori Identifiability of a OneCompartment Model with Two Input-Functions usable for Liver Blood Flow Measurements with PET. Phys
Med Biol. 50 (2005):1393-1404.
15. Glatzle J, Piert M, Meile T, Besenthal I, Schafer JF, Zittel TT. Prevalence of vertebral alterations and the
effects of calcium and vitamin D supplementation on calcium metabolism and bone mineral density after
gastrectomy. Br J Surg. 92 (2005):579-585.
16. Grosu AL, Piert M, Weber WA, Jeremic B, Zimmermann FB, Picchio M, Schratzenstaller U, Schwaiger M,
Molls M. PET in Radiation Treatment Planning: Facts and Fiction. Strahlenth Onkol. 181 (2005): 483-499.
17. Grosu AL, Weber W, Franz M, Stark S, Piert M, Thamm R, Gumprecht H, Schwaiger M, Molls M , Nieder
C. Reirradiation of recurrent high-grade gliomas using amino acid PET (SPECT)/CT/MRI image fusion to
determine gross tumor volume for stereotactic fractionated radiotherapy. Int J Radiat Oncol Biol Phys 63
(2005):511-519.
18. Grosu AL, Piert M, Molls M. Experience of PET for target localisation in radiation oncology. British Journal
of Radiology. Suppl 28 (2005):18-32.
19. Krause BJ, Beck R, Souvatzoglou M, Piert M. PET and PET/CT studies of tumor tissue oxygenation.Q J
Nucl Med Mol Imaging. 50 (2006): 28-43.
20. Picchio M, Treiber U, Beer AJ, Metz S, Bossner P, van Randenborgh H, Paul R, Weirich G, Souvatzoglou
M, Hartung R, Schwaiger M, Piert M. Value of 11C-choline PET and contrast-enhanced CT for staging of
bladder cancer: correlation with histopathologic findings. J Nucl Med. 47 (2006):938-44.
21. Piert M, Burian M, Meisetschläger G, Stein H.J, Ziegler S, Nährig J, Picchio M, Buck A, Siewert JR,
Schwaiger M. Positron detection for the intraoperative localisation of cancer deposits. Eur J Nucl Med 34
(2007):1534-1544. PMC2562440
22. Alvarez R., Diehl KM, Avram A, Brown R., Piert M. Localisation of splenosis using Tc99m-damaged red
blood cell SPECT/CT and intraoperative gamma probe measurements. Eur J Nucl Med 34 (2007):969.
23. Beck R, Röper B, Carlsen JM, Huisman MC, Lebschi JA, Andratschke N, Picchio M, Souvatzoglou M,
Machulla H-J, Piert M. Pretreatment 18F-FAZA PET predicts success of hypoxia-directed
radiochemotherapy using tirapazamine. J Nucl Med. 48 (2007):973-980.
24. Grosu A, Souvatzoglou M, Röper B, Dobritz M, Wiedenmann N, Jacob V, Wester H-J, Reischl G, Machulla
HJ, Schwaiger M, Molls M, Piert M. Hypoxia Imaging with FAZA-PET and Theoretical Considerations with
Regard to Dose Painting for Individualization of Radiotherapy in Patients with Head and Neck Cancer. Int J
Radiat Oncol Biol Phys 69 (2007): 541-551.
25. Souvatzoglou M, Grosu AL, Roper B, Krause BJ, Beck R, Reischl G, Picchio M, Machulla HJ, Wester HJ,
Piert M. Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study. Eur
J Nucl Med Mol Imaging 34 (2007):1566–1575.
26. Piert M, Carey J, Clinthorne N. Probe-Guided Localisation of Cancer Deposits Using [18F]FDG. Q J Nucl
Med Mol Imaging. 52 (2008): 37-49.
27. Picchio M, Beck R, Haubner R, Seidl S, Machulla H-J, Johnson TD, Wester H-J, Reischl G, Schwaiger M,
Piert M. Intratumoral spatial distribution of hypoxia and angiogenesis assessed by 18F-FAZA and 125IGluco-RGD autoradiography. J Nucl Med. 49 (2008): 597-605.
28. Wong KK, Foster E, Piert M. Potential false-positive F18-FDG PET/CT study resulting from cervical
extension of thymic tissue. Clinical Nucl Med. 33 (2008):547-548.
29. Meier R, Piert M, Piontek G, Rudelius M, Oostendorp RA, Senekowitsch-Schmidtke R, Metz S, Wels WS,
Uherek C, Daldrup-Link HE. Tracking of 18F-FDG labeled Natural Killer cells to HER2/neu positive tumors.
Nucl Med Biol 35 (2008): 579-88.
30. Soto DE, Kessler ML, Piert M, Eisbruch A. Correlation between pretreatment FDG-PET biological target
volume and anatomical location of failure after radiation therapy for head and neck cancers. Radiother
Oncol, 89:13-18, 2008. PMC2684445.
31. Park H, Piert M, Khan A, Shah R, Hussain H, Siddiqui J, Meyer CR. Registration methodology for
histological sections and in-vivo imaging of human prostate. Academic Rad, 15:1027-1039, 2008.
PMC 2646010.
32. Lee IH, Piert M, Gomez-Hassan D, Junck L, Rogers L, Lawrence T, Hayman J, Ten Haken R K, Cao Y,
Tsien C. Association of 11C-methionine PET uptake with site of failure after concurrent temozolomide and
radiation for primary glioblastoma multiforme. Int J Radiat Oncol Biol Phys, 73:479-485, 2009.
33. Komissarova M, Wong K, Piert M, Mukherji SK, Fig LM. Spectrum of F18-FDG PET/CT findings in
oncology-related recurrent laryngeal nerve palsy. Am J Roentgenol, 192:288-294, 2009.
34. Piert M. Letter to the Editor, authors reply to “Intratumoral spatial distribution of hypoxia and angiogenesis
assessed by 18F-FAZA and 125I-Gluco-RGD autoradiography”. J Nucl Med; 49:1732-1733, 2008.
35. Piert M, Park H, Khan A, Siddiqui J, Hussain H, Chenevert T, Wood D, Johnson T, Shah RB, Meyer C.
Detection of aggressive primary prostate cancer with 11C-choline PET/CT utilizing multi-modality fusion
techniques. J Nucl Med; 50:1585-1593, 2009. PMC 2837847.
36. Johnson TD, Piert M. A Bayesian Analysis of Dual Autoradiographic Images. Computational Statistics and
Data Analysis; 53:4570-4583, 2009.
37. Park H, Meyer C, Wood D, Khan A, Shah R, Hussain H, Siddiqui J, Seo J, Chenevert T, Piert M. Validation
of automatic target volume definition as demonstrated for 11C-Choline PET/CT of human prostate cancer
using multi-modality fusion techniques. Academic Rad; 17:614-623, 2010. PMC 2854219.
38. Arabi M, Piert M. Hypoxia PET/CT imaging: Implications for Radiation Oncology. Q J Nucl Med Mol
Imaging 54(5):500-9, 2010.
39. Djekidel M, Brown R, Piert M. Benefits of SPECT/CT For 111In-Oxine- and 99mTc-HMPAO-Labeled
Leukocyte Imaging. Clinical Nucl Med 36 (7):e50-6.
40. Garcia-Parra R, Clinthorne N, Wang L , Picchio M, Piert M. Performance of beta- and high-energy gamma
probes for the detection of cancer tissue in experimental surgical resection beds. Ann Nucl Med. Elec.
Publication 2011/05/17, 2011.
41. Garcia-Parra R, Wood D, Shah R, Siddiqui J, Hussain H, Park H, Desmond T, Meyer C, Piert, M.
Investigation on tumor hypoxia in resectable primary prostate cancer as demonstrated by 18F-FAZA
PET/CT utilizing multimodality fusion techniques. European Journal of Nuclear Medicine and Molecular
Imaging, 38(10):1816-1823, 2011. PMID 21833840.
42. Tsien, CI, Brown D, Normolle D, Schipper M, Piert M, Junck L, Heth J, Gomez-Hassan D, Ten Haken RK,
Chenevert T, Cao Y, Lawrence T. Concurrent temozolomide and dose-escalated intensity-modulated
radiation therapy in newly diagnosed glioblastoma. Clinical Cancer Research, 18(1):273-279, 2012. PMID
22065084.
43. Park H, Wood D, Hussain H, Meyer CR, Shah RB, Johnson TD, Chenevert T, Piert M. Introducing
Parametric PET/MR Fusion Imaging of Primary Prostate Cancer. J Nucl Med; 53:546-551, 2012. PMID
22419751.
44. Meyer C, Ma B, Kunju LP, Davenport M, Piert M. Challenges in accurate registration of 3D medical imaging
and histopathology in primary prostate cancer. European Journal of Nuclear Medicine and Molecular
Imaging (2013). Published online: 16 March, 2013. PM23503575.
45. Wong KK, Piert M. Dynamic Bone Imaging with 99mTc-labelled Diphosphonates and 18F-NaF:
Mechanisms and Applications. Journal of Nuclear Medicine (2013) 54: 590-9.
46. Fabiilli ML, Piert MR, Koeppe RA, Sherman PS, Quesada CA, Kripfgans OD: Assessment of the
biodistribution of an [(18) F]FDG-loaded perfluorocarbon double emulsion using dynamic micro-PET in
rats. Contrast Media Mol Imaging 8(4): 366-74, 2013. PM23613440.
47. Picchio M, Piert M: Prostate cancer imaging. Eur J Nucl Med Mol Imaging 40 Suppl 1: S1-4, 2013.
PM23775347.
48. Shao X, Wang X, English SJ, Desmond T, Sherman PS, Quesada CA, Piert MR: Imaging of
carrageenan-induced local inflammation and adjuvant-induced systemic arthritis with [11C]PBR28 PET.
Nucl Med Biol 40(7): 906-911, 2013. PM23891203.
49. Arabi M, Brown R, Dwamena B, Jakubowski E, Kim K, Alvarez R, Piert M, Frey K: SPECT/CT as a
problem-solving tool in patients with suspected acute cholecystitis. J Comput Assist Tomo 37 (6): 844-848,
2013.
50. Wong KK, Piert M: Reply to letter to editor. Re: Dynamic Bone Imaging with 99mTc-Labeled
Diphosphonates and 18F-NaF: Mechanisms and Applications J Nucl Med 54: 2190-1, 2013.
51. English SJ, Piert MR, Diaz JA, Gordon D, Ghosh A, D'Alecy LG, Whitesall SE, Sharma AK, DeRoo EP,
Watt T, Su G, McEvoy BS, Henke PK, Eliason JL, Ailawadi G, Upchurch GR: Increased 18F-FDG Uptake
Is Predictive of Rupture in a Novel Rat Abdominal Aortic Aneurysm Rupture Model. Ann Surg 259:
accepted, 2014.
BOOK CHAPTERS
1. Piert M, Kistler D, Eren S, Hettich R: Computer-assisted infusion and nutrition planning in an intensive
care burns unit. In: Progress in burn-injury treatment. Progress in burn-injury treatment, Boeckx W,
Moserova J, Eds. Acco, Leuven, Belgium, 1990. 44-49
2. Piert M, Machulla HJ: Detection of liver hypoxia by [18F]Fluoromisonidazole and application in liver
transplant disorders. Imaging of Hypoxia. Tracer Development, P.H. Cox, Ed. Kluwer Academic Publisher,
Dodrecht, Boston, London, 1999. 119-27
3. Piert M: Hypoxia imaging. Principles and Practice of PET and PET/CT, Richard Wahl, Ed.
Lippincott Williams & Wilkins, Philadelphia, PA, 2009. 2, 464-71
4. Piert M: PET Imaging: Advances in the Detection of Locally Advanced and Nodal Disease. Bladder Cancer:
Diagnosis, Therapeutics, and Management, Lee C, Wood D, Eds. The Humana Press Inc, New York, NY,
2010. 49-53
RESEARCH SUPPORT
Ongoing and/or Completed Research Support within the last 3 years
Piert (PI)
09/30/2012 – 09/29/2016
Department of Defense
Title: Parametric PET/MR Fusion Imaging to Differentiate Aggressive from Indolent Primary Prostate Cancer
with Application for Image-Guided Prostate Cancer Biopsies
Goal: The study will investigate the effectiveness of novel parametric fusion PET/MRI based on metabolic
information obtained from 18F-Choline PET as well as diffusion-weighted MRI to identify significant primary
prostate cancer in an active surveillance population, and use imaging results for targeted prostate cancer
biopsies.
Role: PI
025840 Piert (PI)
02/18/2013 – 07/31/2014
Bayer Healthcare
Title: Radium-223 Chloride (Alpharadin) in Castration-Resistant (Hormone-Refractory) Prostate Cancer
Patients with Bone Metastasis
Goal: Early excess program to provide Alpharadin treatment prior to FDA approval.
Role: PI
P30 CA046592 Max Wicha (PI)
09/2012 – 05/2017
NIH
Title: University of Michigan Comprehensive Cancer Center Support Grant
Goal: The major goal of this CORE is to provide human and animal imaging (MRI/S) capabilities to member of
the University of Michigan Comprehensive Cancer Center.
Role: Co-Investigator
W81XWH-09-1-0146 Hussain, M (PI)
04/2009-03/2014.
Prostate Cancer Clinical Trials Group – University of Michigan Site
Role: Co-Investigator
025840 Piert (PI)
10/11/2010 - 05/11/2013
World Molecular Imaging Society
Title: 18F-Fluoride PET/CT versus 99mTc-MDP Scanning for Detecting Bone Metastases: A Randomized,
Multi-Center Trial to Compare Two Bone Imaging Techniques
Goal: The primary objective is to compare the diagnostic performance (as reflected in differences in the areas
under the ROC curves) of 18F- Fluoride PET/CT scanning to that of conventional bone scanning for detecting
cancer that has spread to the bone (bone metastasis). The hypothesis is that 18F-PET/CT scanning will prove
superior to conventional bone scanning for the detection of bone metastases.
Role: PI
1 R01 CA142840 Kong (PI)
07/01/2010 – 04/30/2015
NIH
Title: Functional Image and Molecular Marker to Individualize Adaptive radiation Dose Escalation in Patients
with Non-Small Cell Lung Cancer
Goal: To identify functional image and molecular predictors during the course of RT to predict the outcome of a
completed course of treatment which provides an opportunity to adapt the radiation dose escalation for
maximized therapeutic gain.
Role: Co-Investigator
R01 AR055179 Xueding Wang (PI)
04/10/2008 – 03/31/2012
NIH
Imaging of Inflammation and Treatment: Basic and Translational Potential
Goals: To develop a novel noninvasive nonionizing light based imaging technology for molecular imaging an
drug delivery research with both excellent sensitivity and high spatial resolution.
Role: Co-Investigator
15117 Piert (PI)
07/01/2011 – 06/30/2012
Bayer Healthcare
Title: PET/CT imaging for safety and tolerability, biodistribution, radiation dosimetry, plasma
pharmacokinetics and diagnostic performance of BAY 1075553 in patients with prostate
cancer and healthy volunteers.
Goal: First in human testing of a radiotracer for prostate cancer binding to PMSA.
P01 CA59827 Fraass (PI)
07/01/2006 - 06/30/2011
NIH
Optimization of High Dose Conformal Therapy
Goals: The overall objective of this program project is to continue the study and improvement of high dose
conformal radiation therapy treatments for cancer
BIOGRAPHICAL SKETCH
NAME
POSITION TITLE
Fabiilli, Mario
Research Investigator, Radiology
eRA COMMONS USER NAME
MFABIILL
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
INSTITUTION AND LOCATION
University of Michigan, Ann Arbor, Michigan
University of Michigan, Ann Arbor, Michigan
University of Michigan, Ann Arbor, Michigan
University of Michigan, Ann Arbor, Michigan
DEGREE
(if applicable)
YEAR(s)
B.S.E.
M.S.E.
Ph.D.
Postdoc
2003
2004
2010
2011-12
FIELD OF STUDY
Chemical Engineering
Biomedical Engineering
Biomedical Engineering
Radiology
A. Personal Statement
The overall goal of this project is to develop a sonosensitive emulsion formulation for the targeted delivery
of iodine-131. The emulsion can be loaded with iodine-131 and ultrasound can be used to locally release the
drug within a tumor.
I have been active in the fields of drug delivery and ultrasound-mediated therapies for over ten years. Prior
to obtaining my doctorate in biomedical engineering, I worked in the pharmaceutical sciences division of Pfizer
Global Research and Development for three years. My work focused on the development of different drug
formulation types and the analytical techniques to evaluate formulation performance. During my doctoral
studies, I investigated the use of ultrasound to spatially and temporally control the release of therapeutic
agents, including chemotherapy drugs, from acoustically-sensitive emulsions. Currently, my research is
focused on the integration of ultrasound-responsive systems into tissue engineering scaffolds, the
physiochemical mechanisms and interactions of sonosensitive drug vehicles, and the pharmacokinetics of
targeted fluorocarbon colloids. Recently, I, along with Dr. Morand Piert and Dr. Oliver Kripfgans , coinvestigators on this application, published a paper investigating the in vivo biodistribution of sonosensitive
emulsions. The proposed work builds upon my previous research background and I am confident that the
assembled team can successfully perform the planned experiments.
B. Positions and Honors
Positions and Employment
2003-2007 Scientist, Pfizer Global Research and Development, Ann Arbor, MI
2007-2010 Graduate Student Research Assistant, Radiology Dept, University of Michigan, Ann Arbor, MI
2011-2012 Post-Doctoral Fellow, University of Michigan, Radiology Dept, Ann Arbor, MI
8/2012Research Investigator, Radiology, University of Michigan, Ann Arbor MI
Honors and Awards
2001
Tau Beta Pi Engineering Honor Society
2002
Norman H. Horowitz Award for best student presentation at the Young Investigator’s Symposium of
the Great Lakes Chapter of the American Association of Physicists in Medicine (GLC-AAPM)
2002
James B. Angell Scholar, University of Michigan, Ann Arbor, MI
2003
Graduated with honors (magna cum laude)
Professional Society Membership
American Association for the Advancement of Science
Biomedical Engineering Society
IEEE/Ultrasound Ferroelectrics and Frequency Control
International Contrast Ultrasound Society
C. Selected peer-reviewed publications (in chronological order)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Kripfgans OD, Fabiilli ML, Carson PL, Fowlkes JB. On the acoustic vaporization of micrometer-sized
droplets. J Acoust Soc Am 116(1):272-281, 2004.
Pelletier MJ, Fabiilli ML. Rapid, non-destructive near-infrared assay for water in sealed dimethyl sulfoxide
compound repository containers. Appl Spectrosc 61(9):935-939, 2007.
Pelletier MJ, Fabiilli ML, Moon B. On-line analysis of flow-through ozonolysis reaction using Raman
spectroscopy. Appl Spectrosc 61(10):1107-1115, 2007.
Fabiilli ML, Haworth KJ, Fakhri NH, Kripfgans OD, Carson PL, Fowlkes JB. The role of inertial cavitation
in acoustic droplet vaporization. IEEE Trans Ultrason Ferroelectr Freq Control 56(5):1006-17, 2009.
PMCID: PMC3085427.
Zhang M, Fabiilli ML, Haworth KJ, Fowlkes JB, Kripfgans OD, Roberts WW, Ives KA, Carson PL. Initial
investigation of acoustic droplet vaporization for occlusion in canine kidney, Ultrasound Med Biol, 36(10):
1691-703, 2010. PMCID: PMC2951622.
Fabiilli ML, Haworth KJ, Sebastian IE, Kripfgans OD, Carson PL, Fowlkes JB. Delivery of chlorambucil
using an acoustically-triggered, perfluoropentane emulsion. Ultrasound Med Biol, 36(8):1364-1375, 2010.
PMCID: PMC2933659.
Fabiilli ML, Lee JA, Kripfgans OD, Carson PL, Fowlkes JB. Delivery of water-soluble drugs using
acoustically-triggered, perfluorocarbon double emulsions. Pharm Res, 27(12):2753-2765, 2011. PMCID:
PMC3085450.
Zhang M, Fabiilli ML, Haworth KJ, Padilla FR, Swanson SD, Kripfgans OD, Carson PL, Fowlkes JB.
Acoustic droplet vaporization for enhancement of thermal ablation by high intensity focused ultrasound.
Acad Radiol, 18(9):1123-32, 2011. PMCID: PMC3152672.
Rajian JR, Fabiilli ML, Fowlkes JB, Carson PL, Wang X. Drug delivery monitoring by photoacoustic
tomography with an ICG encapsulated double emulsion, Opt Express, 19(15):14335-14347, 2011.
PMCID: PMC3324934.
Samuel S, Duprey A, Fabiilli ML, Bull JL, Fowlkes JB. In vivo microscopy of targeted vessel occlusion
employing acoustic droplet vaporization, Microcirculation, 19(6):501-9, 2012. PMCID: PMC3414215.
M.L. Fabiilli, M.R. Piert, R.A. Koeppe, P.S. Sherman, C.A. Quesada, O.D. Kripfgans. Assessment of the
biodistribution of an [18F]FDG-loaded perfluorocarbon double emulsion using dynamic micro-PET in rats.
Contrast Media Mol I, 8(4): 366-374, 2013. PMID: PMC3677228.
M.L. Fabiilli, C.G. Wilson, F.R. Padilla, F.M. Martin-Saavedra, J. B. Fowlkes, R.T. Franceschi. Acoustic
droplet-hydrogel composites for on-demand delivery of growth factors and control of scaffold properties.
Acta Biomater, 9(7): 7399-7409, 2013. PMID: 23535233.
O. Shpak, T. Kokhuis, Y. Luan, D. Lohse, N. de Jong, J.B. Fowlkes, M.L. Fabiilli, M. Versluis. Ultrafast
dynamics of the acoustic vaporization of superheated microdroplets. J Acoust Soc Am, 134(2): 16101621, 2013.
M. Zhu, L. Jiang, M.L. Fabiilli, A. Zhang, J.B. Fowlkes, L.X. Xu. Treatment of murine tumors using
acoustic droplet vaporization-enhanced high intensity focused ultrasound. Phys Med Biol, 58(17): 61796191, 2013.
Z. Xie, S. Chen, M.L. Fabiilli, J.B. Fowlkes, K.K. Shung, Q. Zhou, P.L. Carson, X. Wang. Simultaneous
viewing of individual cells and local microvasculature using optical absorption and fluorescence contrasts.
Mol Imaging, accepted August 2013
D. Research Support (Ongoing or Completed in Last 3 Years)
R01 EB006476 (PI: J.L. Bull)
NIH
05/01/2013 – 04/30/2018
Title: Dynamics of Vascular Microbubbles and Microdroplets in Gas Embolotherapy
Goals: Determine the ability of bubbles produced by acoustic droplet vaporization to generate hypoxia, induce
tumor cell apoptosis, and slow tumor growth.
Role: Co-investigator
R03 AI096029 (PI: K. Cook)
05/01/2012 – 04/30/2014
NIH
Title: Antibacterial Perfluorocarbon Ventilation to Treat Severe Respiratory Infections
Goals: To accelerate standard antibiotic therapy by actively removing infected mucus from airway walls due to
fluid shear and reduced mucus surface tension, in order for antibiotic to be delivered directly to the source of
infection, allowing for higher concentrations in the lung and lower systemic concentrations and toxicity.
Role: Co-investigator
University of Michigan Department of Radiology Seed (multi PI: Fabiilli/Dillman)
11/01/2013-10/30/2014
Sonosensitive Theranostic Emulsions for Crohn’s Disease
The overall objective of this project is to improve the imaging assessment and management of Crohn’s disease
via the development of receptor-targeted emulsions loaded with inhibitors of tumor necrosis factor alpha.
Role: PI
W81XWH-10-0992 (PI: R.T. Franceschi)
09/30/2010 – 02/29/2012
DOD
This project involves integrating two emerging therapeutic technologies – high intensity focused ultrasound
(HIFU) and synthetic gene expression circuits – to achieve temporal and spatial control over the expression of
regenerative molecules.
Role: Postdoctoral Research Fellow
W81XWH-10-1-00730 (PI: M. Moghaddam)
09/01/2010-09/30/2012
BCRP / DOD-USAMRMC
Novel Electromagnetic-Ultrasound Synergistic Technique for Treatment of Cancer
Goals: To optimize and build a dual modality (ultrasound and electromagnetic energy) thermal therapy
treatment system for breast cancer.
Role: Postdoctoral Research Fellow
OVPR-Univ of Michigan and Shanghai Jiao Tong Univ (SJTU)
08/01/2010 – 07/31/2012
Collaboration on Biomedical Technologies
Development of Acoustic Droplet Vaporization (ADV) for the Enhancement of High Intensity Focused
Ultrasound (HIFU) Therapy
Goals: Determine the impact of bubbles produced by ADV in controlled phantom studies. Validate the ADV
enhancement effects in animal models.
Role: Postdoctoral Research Fellow
BIOGRAPHICAL SKETCH
Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Kripfgans, Oliver Daniel
Research Assistant Professor
eRA COMMONS USER NAME
greentom
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
DEGREE
(if applicable)
YEAR(s)
Universität des Saarlandes/Germany
University of Michigan, Ann Arbor, Michigan
Diploma
Ph.D.
1996
2002
University of Michigan, Ann Arbor, Michigan
Post. Doc.
2002-2003
INSTITUTION AND LOCATION
FIELD OF STUDY
Physics
Applied physics and med.
ultrasound
Imaging and therapeutic
ultrasound
A. Personal Statement
Dr. Kripfgans will contribute with expertise in physical acoustics and medical ultrasound. He obtained his PhD
for the investigation of droplets and gas bubbles with acoustic waves in medical applications and currently
holds a R01 for the use of ultrasound contrast agents in treading hypertrophic cardiomyopathy. Additionally
Dr. Kripfgans has investigated drug delivery with perfluorocarbon emulsions and developed a silicon-based
microfluidic device for the controlled production of sono-sensitive emulsions as well as drug encapsulated
emulsions. In this device, uniform size emulsions can be manufactured at a rate of up to 10 million particles per
second, yielding typical in vivo doses of 109 particles per milliliter within an acceptable time range for preclinical
studies. Dr. Kripfgans’ laboratory has state of the art equipment for acoustic exposure dosimetry, therapeutic
sonography and ultrasonic imaging.
B. Positions and Honors
Positions and Employment
1991-1996 Research Assistant, Fraunhofer Institute f. Bio.Med.Engin., Dept. Ultrasound, St. Ingbert,
Germany
1996-2002 Graduate Student Research Assistant, University of Michigan, Dept. Radiology, Ann Arbor, MI
2002-2003 Post Doctoral Research Fellow at the University of Michigan, Dept. Radiology, Ann Arbor, MI
2003-2006 Research Investigator at the University of Michigan, Dept. Radiology, Ann Arbor, MI
2006Research Assistant Professor at the University of Michigan, Dept. Radiology, Ann Arbor, MI
Other Experience and Professional Membership
1992
Member, Deutsche Physikalische Gesellschaft (DPG)
1992
Member, Deutsche Arbeitsgemeinschaft Akustik (DAGA)
1998
Member, The Acoustical Society of America (ASA)
1999
Member, IEEE/Ultrasound Ferroelectrics and Frequency Control
2003
Member, The American Institute of Ultrasound in Medicine (AIUM)
Honors
2000
Norman H. Horowitz Award for best student presentation at the Young Investi. Spring Symp., Ann
Arbor
2001
Best Student Paper Award of The Acoustical Society of America at the 141st meeting in Chicago, IL
2003
Research Mentor Award of The College of Engineering Graduate Student Advisory Committee and
the office of the Associate Dean for Graduate Education
C. Selected peer-reviewed publications (pertaining to this application, in chronological order)
1.
Kripfgans OD, Fowlkes JB, Miller DL, Eldevik OP, Carson PL. Acoustic droplet vaporization for
therapeutic and diagnostic applications. Ultrasound in Med & Biol 26(7): 1177-1189, 2000.
2.
Kripfgans OD, Fowlkes JB, Woydt M, Eldevik OP, and Carson PL. In Vivo Droplet Vaporization for
Occlusion Therapy and Phase Aberration Correction. IEEE Transactions UFFC 49(6):726-38, 2002.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Kripfgans OD, Fabiilli ML, Carson PL, and Fowlkes JB. On the acoustic vaporization of micrometer-sized
Droplets. J. Acoust. Soc. Am. 116(1), 272-81, 2004.
Lo AH, Kripfgans OD, Carson PL and Fowlkes JB. “Spatial Control of Gas Bubbles and Their Effects on
Acoustic Fields.” Ultrasound in Med & Bio 32(1), 95-106, 2006.
Haworth KJ, Kripfgans OD, Fowlkes JB, and Carson PL. Towards Aberration Correction of Transcranial
Ultrasound. Ultrasound Med Biol 34(3): 435-45, 2008. PMCID: PMC2323442.
Zhang M, Fabiilli ML, Haworth KJ, Fowlkes JB, Kripfgans OD, Roberts WW, Ives KA, Carson PL. Initial
investigation of acoustic droplet vaporization for occlusion in canine kidney, Ultrasound Med Biol, 36(10):
1691-703, 2010. PMCID: PMC2951622.
Fabiilli ML, Haworth KJ, Sebastian IE, Kripfgans OD, Carson PL, Fowlkes JB. Delivery of chlorambucil
using an acoustically-triggered, perfluoropentane emulsion. Ultrasound Med Biol, 36(8):1364-1375, 2010.
PMCID: PMC2933659.
Fabilli ML, Lee JA, Kripfgans OD, Carson PL, and Fowlkes JB. Delivery of water-soluble drugs using
acoustically triggered perfluorocarbon double emulsions. Pharmaceutical Research, 27(12):2753–2765,
2010. PMCID: PMC3085450.
Zhang M, Fabiilli ML, Haworth KJ, Padilla FR, Swanson SD, Kripfgans OD, Carson PL, Fowlkes JB.
Acoustic droplet vaporization for enhancement of thermal ablation by high intensity focused ultrasound.
Acad Radiol, 18(9):1123-32, 2011. PMCID: PMC3152672.
Carneal CM, Kripfgans OD, Kruecker J, Carson PL, Fowlkes JB, A tissue-mimicking ultrasound test
object using droplet vaporization to create point targets, IEEE Trans Ultrason Ferroelectr Freq Control,
58(9): 2013-25, 2011. PMCID: PMC3440948.
Lemmerhirt DF, Cheng X, White RD, Rich CA, Zhang M, Fowlkes JB and Kripfgans OD, A 32 x 32
Capacitive Micromachined Ultrasonic Transducer Array Manufactured In Standard CMOS, IEEE Trans
Ultrason Ferroelectr Freq Control, 59(7):1521-36, 2012. PMID 22828847
Pinter SZ, Rubin JM, Kripfgans OD, Treadwell MC, Romero VC, Richards MS, Zhang M, Hall AL,
Fowlkes JB. Three-dimensional sonographic measurement of blood volume flow in the umbilical cord, J
Ultrasound Med, 31(12):1927-34, 2012. PMCID: PMC3654397.
Fabiilli ML, Piert MR, Koeppe RA, Sherman PS, Quesada CA, Kripfgans OD. Assessment of the
biodistribution of an [(18 F]FDG-loaded perfluorocarbon double emulsion using dynamic micro-PET in
rates, 8(4):366-74, 2013. PMCID: PMC3677228.
Kripfgans OD, Zhang M, Fabiilli ML, Carson PL, Padilla F, Swanson SD, Mougenot C, Fowlkes JB.
Acceleration of Ultrasound Thermal Therapy by Patterned Acoustic Droplet Vaporization. J. Acoust. Soc.
Am. 135(1):537-545, 2014.
Miller DL, Dou C, Owens GE, Kripfgans OD. Optimization of Parameters for Therapeutic Applications of
High Intensity Myocardial Contrast Echocardiography. Ultrasound Med Biol 134(5):4181, 2013.
D. Research Support (Ongoing or Completed in Last 3 Years)
1R01HL114595-01 (Kripfgans, O.D.)
07/17/2012 – 06/30/2017
NIH
Therapeutic Microlesioning by Contrast Echocardiography for Myocardial Reduction
The objective of this project is to create a safer, gentler method of myocardial reduction for HCM. Myocardial
contrast echocardiography (MCE) has enabled visualization of myocardial perfusion by imaging strong echos
from contrast-agent microbubbles. For high amplitude MCE, intermittent destruction of contrast microbubbles
has been shown to lethally injure cardiomyocytes by the cavitation mechanism, which leads to randomly
scattered microlesions seen in histology.
Role: PI
R43 HD069250 (Fowlkes, J.B.)
07/01/2011 – 06/30/2013
Sonetics/NIH
Development of a Neonatal Monitoring System with Arrays
This project will investigate the development of a neonatal monitoring device using ultrasound arrays from
Sonetics, Inc., which use Capacitive Micromachined Ultrasonic Transducers (CMUT) technology.
Role: Co-Investigator
EB006476-01A2 (Bull, Joseph)
09/12/2007 – 05/31/2012
NIH
Dynamics of Vascular Microbubbles and Microdroplets in Gas Embolotherapy FED
Goals: Characterize the process of acoustic droplet vaporization (ADV), including the mechanisms involved
and the effects of droplet and flow parameters. Evaluate the processes by which by the resulting bubbles are
transported through the vasculature prior to reaching the where they lodge, and evaluate the effects of bubble
and flow parameters the ability to target specific locations for bubble delivery. Assess the dynamics of bubble
lodging and the ability of lodged bubbles to occlude blood flow.
Role: Co-Investigator
R01 CA091713 07S1 (Carson, P.L.)
08/01/2009 – 05/31/2012
NIH/BRP
Combined Digital X-Ray, Optical, and Ultrasound Breast Imaging
Goals: To develop a multimodality breast screening system that combines x-ray, ultrasound, and
optical/ultrasound imaging, each in 3D for improved detection and characterization of breast lesions. While
working on parent project, new opportunities have become apparent for further development and fundamental
improvement in technology. We will be creating and retaining jobs and making fundamental advances that
could significantly impact breast imaging and other fields.
Role: Co-Investigator
W81XWH-10-1-0514 (Moghaddam, M.)
09/1/2010 - 9/30/2012
BCRP / DOD-USAMRMC
Novel Electromagnetic-Ultrasound Synergistic Technique for Treatment of Cancer
Goals: To optimize and build a dual modality (ultrasound and electromagnetic energy) thermal therapy
treatment system for breast cancer.
Role: Co-Investigator
R01 HL067921 (Fowlkes, J.B.)
07/01/2009 – 06/30/2011
NIH
Quantification of Blood Volume Flow Using Ultrasound
The proposed work will verify these results over a range of flow conditions anticipated in vivo, make direct
comparisons to a standard flow measurement technique in animal studies and perform a pilot study
quantifying flow grafts of human subjects undergoing dialysis. The successful conclusion of these studies will
be the verification of a system suitable for clinical use in measurement of volume blood flow.
Role: Co-Investigator
R01 CA115267 (PI of subcontract: Carson, P.L.)
09/04/2007 – 06/30/2011
GE/NIH - Subcontract #700174652
GE 2D Silicon Transducer Compression Plates for Breast US
Ultrasound transducer array plates on both sides would image the entire breast. We will develop many of the
imaging techniques on a current commercial system and test preliminary and proposed system and its
potential for clinical trials. In vitro studies will be performed but emphasis will be on preclinical trials of normal
volunteers, those with probably benign lesions and modest number with lesions going to biopsy.
Role: Co-Investigator
R01 EB000281 (Carson, P.L.)
08/01/1999 - 12/31/2010
NIH
Vascular Bubble Generation for Diagnosis and Therapy
It is proposed to develop the recently-demonstrated, controlled generation of arterial microbubbles using
intense, focused ultrasound pulses to delineate the technique's potential for medical use and for understanding
of ultrasound effects in vivo
Role: Co-Investigator