Application Cover Page for MMPP Seed Grant
Project Director: Xia Shao, Assistant Research Scientist, Department of Radiology.
Eamil: xshao@umich.edu
Co-principal Investigator: Xueding Wang, Department of Radiology.
Eamil: xdwang@umich.edu
Students involved: Dylan Fink, Undergraduate student (UROP)
Jacqueline Ito, Undergraduate student (UROP)
Title of Project: Development of multi-modality theranostic nanoparticles
Statement of relevance to MMPP:
The mission of the Michigan Memorial Phoenix Project is "devoted to the peaceful, useful and beneficial
applications and implications of nuclear science and technology to the welfare of the human race." The
innovative radiolabeled gold nanoparticle conjugates we have designed allow for dual-modality functional and
molecular imaging of cancer, and they also enable dual-modality therapy including concurrently radiation and
thermotherapy of solid tumors. These will have a major impact and benefit on the management of cancer. The
approach we propose here is an example of the novel use of nuclear science and technology to significantly
improve human health.
Amount of funding requested: $25000
General chemicals
[125I] Sodium iodide ($122 each order, 4 orders)
Peptide syntheses ($1000 each peptide)
Gold nanoparticles
Gamma imaging ($150 each, 80 mice)
Photoacoustic imaging ($40 each)
Animals (40 mice)
Animal housing
Cells and culture supplies
Thermal therapy ($100 each, 16 mice)
Total
500
488
2000
3000
12000
1600
1320
2000
492
1600
25000
Agency of future proposal will be submitted: National Institutes of Health
External proposal deadline: February, 2015
Abstract of Proposed Research:
Plasmonic gold nanostructures, due to their small sizes and associated unique chemical, physical and
biological properties, have been widely used in drug delivery, cellular imaging, and biomedical diagnostics and
therapeutics. Near-infrared-absorbing gold nanoparticles can be used as optical contrast agents for a number of
imaging modalities, and are also highly efficient transducers for tuning the light energy into heat for the
purposes of not only imaging but also therapy. In our previous work, we have successfully utilized gold nanorods
to enhance the contrast in photoacoustic tomography and also developed a highly efficient method to directly
radiolabel gold nanoparticles with I-125 radioisotope. Using a highly sensitive gamma imaging system, the
longitudinal performance of gold nanoparticles can be examined in vivo. In this research, we propose to develop
radiolabeled gold nanorod-peptide conjugates for targeted cancer imaging and therapy, i.e. theranostics. We
hypothesize that peptides, specifically targeting αvβ3 receptor or VEGF receptors, can act as vehicles to navigate
gold nanorods to tumor cells. The combination of peptide ligands with gold nanorods would be advantageous
over either single probe. We expect that radioisotope labeled gold nanorods can facilitate dual-modality imaging
with the combination of nuclear imaging and optical imaging, as well as dual-modality treatment combining the
powers of radiation therapy (by using I-131 instead of I-125) and photothermal therapy. A multifunctional
platform based on gold nanoparticles, with multiple receptor targeting, multimodality imaging, and multiple
therapeutic entities, holds the promise for a “magic gold bullet” against cancer.
Development of multi-modality theranostic nanoparticles
A. Specific Aims
Cancer nanotechnology is an interdisciplinary area with broad potential applications in fighting cancers.
The continued development of cancer nanotechnology holds the promise for personalized oncology in which
biomarkers can be used to diagnose and treat cancer based on the molecular profile of each individual patient.
Targeting ligands, imaging labels, therapeutic drugs, and other functionalities can all be integrated with
nanoparticles to allow for targeted molecular imaging and molecular therapy of cancer. In particular, gold
nanorods (AuRds) are attracting intensive scientific interest for their unique properties and potential
applications. Their remarkable capacity to absorb and scatter light at visible and near-infrared (NIR) regions is
essential for optical imaging. In addition, gold nanoparticles can convert optical energy into heat via
nonradiative electron relaxation dynamics which endows them with intense photothermal properties for
thermal therapy.
Radiolabeled peptides, specifically targeting αvβ3 receptor or VEGF receptors, have been used as
radiopharmaceuticals for diagnosis and therapy in nuclear medicine. Our hypothesis is that a combination of
peptide ligands with gold nanorods would be advantageous over either single probe. Thus we propose
developing 125I/131I-labeled gold nanorod-peptide conjugates for tumor imaging and therapy. Facilitated by the
newly developed conjugates, dual-modality imaging including both high sensitive nuclear imaging and high
resolution optical imaging, as well as dual-modality therapy including both radiotherapy and thermotherapy of a
target tumor can be achieved for the first time.
The specific aims of this project are the following:
1. Preparation of synthetic precursor for radiolabeling experiments.
2. Preparation of radiolabeled conjugates and biodistribution studies.
3. Perform both Gamma imaging and optical imaging of tumor-bearing mice.
4. Development and efficacy testing of thermal therapy of tumor-bearing mice.
B. Background and Significance
Properties of gold nanoparticles
Plasmonic gold nanostructures, due to their small sizes and associated unique chemical, physical and
biological properties, have been widely used in drug delivery, cellular imaging, and biomedical diagnostics and
therapeutics. Gold nanostructures possess very fascinating and unique optical properties as well as related
photothermal properties.4 These optical properties depend on nanoparticle size and shape. One can manipulate
the shape of gold nanostructures to control their electronic and associated optical properties for different
desired applications.5 In particular, gold nanorods (AuRd) have attracted much interest because of their small
sizes, ease of preparation and bioconjugation, strong optical absorbing and scattering properties, as well as their
well-known biocompatibility.6 AuRds with well-defined shapes and sizes are readily synthesized by seeded
growth methods, and their longitudinal plasmon resonances (LPRs) can be finely tuned as a function of aspect
ratio. Near-infrared-absorbing AuRds can be used as optical contrast agents for a number of imaging modalities,
and are also highly efficient transducers for tuning the light energy into heat for the purposes of therapy.7 The in
vitro photothermal effects of AuRds have been reported by a number of groups on cultured tumor cells8-11,
parasitic protozoans12, macrophage13 and bacterial pathogens.14 Furthermore, the surface chemistry of AuRd
allows multiple functionalizations. Target specificity of AuRds can be imparted by tagging with certain
biovectors, which can navigate them to desired organs or sites. Recent studies have successfully demonstrated
that AuRds can be conjugated to molecules to facilitate delivery to tumors for subsequent efficient cancer cell
diagnosis and selective photothermal therapy simultaneously. 6,7
Peptides specifically targeting αvβ3 receptor or VEGF receptors
Both αvβ3 integrin and vascular endothelial growth factor (VEGF) are key players involved in the
mechanisms of tumor angiogenesis. In the past decade, many radiolabeled small peptide containing arginineglycine-aspartic (RGD) amino acid sequence have been evaluated for their potential as the αvβ3 targeted
radiotracer.15-18 18F-galacto-RGD has been under clinical investigations for noninvasive visualization of the
activated αvβ3 integrin in cancer patients.19,20
Another specific and important factor involved in tumor angiogenesis is vascular endothelial growth
factor-165 (VEGF165).21,22 VEGF165 signal is transduced preferentially via the tyrosine kinase receptor KDR (VEGF
receptor-2) and significantly enhanced by association of KDR with co-receptor neuropilin-1 (NRP-1) on
endothelial cells. 23 In patients, over-expression of NRP-1 has been correlated with tumor aggressiveness. 24 Thus,
the molecules that interfere with VEGF165 binding to NRP-1 may be considered for antiangiogenic and antitumor
therapy. A heptapeptide, ATWLPPR (A7R), has been identified as one candidate. This peptide displays in vivo and
in vitro antiangiogenic properties.25,26
Iodonated gold nanorod-peptide conjugates
Multifunctionality is the key feature of nanoparticle-based agents. A multifunctional platform based on
gold nanoparticles, with multiple receptor targeting, multimodality imaging, and multiple therapeutic entities,
holds the promise for a “magic gold bullet” against cancer. Therefore, we have designed 125I-labeled gold
nanorod-peptide conjugates for tumor imaging and therapy. We hypothesize that peptides, specifically targeting
αvβ3 receptor or VEGF receptors, can act as vehicles to navigate gold nanorods to tumor cells. We have utilized
gold nanorods to enhance the contrast in photoacoustic tomography (PAT)21 and have synthesized 18F-labeled
peptides for positron emission tomography (PET) imaging. We expect that radioisotope labeled gold nanorods
can facilitate dual-modality imaging with the combination of nuclear imaging and optical imaging, as well as
dual-modality treatment combining the powers of radiation therapy and photothermal therapy.
C. Preliminary Results
Radiolabeling of AuRds with I-125 and γ-imaging
We have developed the radiolabeling procedures, facilitating reproducible and reliable production of
injectable AuRds for animal studies. AuRds were successfully visualized by iodine-125 tag allowing highly
sensitive detection. Long-term biodistribution in rats for up to 6 days using γ-imaging has been performed. The
typical images are shown in Figure 1.
Radiolabeling of peptides with F-18 and PET imaging
In previous studies using 18F-A7R, we were able to demonstrate tumor localization suitable for PET
imaging (Figure 2) in EMT6 tumor bearing mice as well as stable tumor to background ratios around 5:1 between
30 – 90 min. post injection (Figure 3). These preliminary data show the utility of A7R for imaging of angiogenesis.
D. Approach and Study Design
Prepare the needed synthetic precursor for radiolabeling experiments
Both cyclic RGD and A7R will be prepared at the University of Michigan Peptide Center. The conjugates
of AuRds with peptides will be prepared at the Department of Chemical Engineering, University of Michigan.27,28
Radiolabeling of AuRds with I-125
The conjugates of AuRds with peptides will be radiolabeled by mixing with diluted [125I]NaI based on
developed method. The method developed can be adopted to radiolabeling with I-131.
Perform Gamma imaging studies of tumor-bearing mice to evaluate tumor uptake and treatment
The well characterized mouse breast cancer cell line EMT6 will be used. 31 Tumor targeting conjugates
will be injected into mice through the tail-vein with ~ 100 µCi each of 125I- AuRd -peptide. In vivo imaging will be
acquired using the Gamma Imager (Biospace) and radioactivity will be quantified by drawing regions of interest
using Gamma Vision+ software (Version 3.0).
Specificity of uptake is assessed by blocking experiments of the targeted receptors using “cold”
(unlabeled) peptide (either RGD or A7R). Other than tumor targeting conjugates including 125I-AuRd-RGD and
125
I-AuRd-A7R, systemic injection of 125I-AuRd as a control will also be conducted, as shown in the table below.
Gamma imaging and photoacoustic imaging will be acquired after injection and performed again 2 days postinjection.
Conjugates
125
I-AuRd-RGD
125
I-AuRd-A7R
125
I-AuRd (control)
# of Controls (blocked receptors)
4
4
4
# of tumor-bearing mice
4
4
4
Develop method of thermal therapy of tumor-bearing mice.
16 tumor-bearing mice will be used in this experiment. For each mouse, two tumors will be induced with
one on each flank. 7-14 days after generation, tumors with diameters in the range of 5-10 mm will be ready for
treatment and imaging. Using a caliper, the size of each tumor will be quantified. The 16 mice will be divided
into four groups with four mice in each group. Three radiolabeled nanorods, 125I-AuRd (Control 1), 125I-AuRd-RGD
(Tumor targeting 1) and 125I-AuRd-A7R (Tumor targeting 2), will be introduced to three groups respectively. To
be used as another control, no conjugates will be introduced to the mice in the fourth group (Control 2). Gamma
imaging of each tumor-bearing mouse will be conducted first before therapy. Then the tumor on the right flank
of each mouse will be treated with thermal therapy by illuminating the whole tumor with pulsed laser (ND6000,
Continuum) for 10 min (800 nm of wavelength, 0.2 W/cm2 of energy)29. The tumor on the left flank of each
mouse will be left untreated as a control. 5 days after treatment, the second Gamma imaging of each mouse
will be conducted. The data should manifest the changes of tumor size as well as activation of angiogenesis. The
size of each tumor will be measured again with caliper. With the two measurements before and 5 days after
treatment respectively, the ratio between them will be computed and used to indicate the relative changes in
tumor volume (or growth rate). Moreover, the outcomes from the two tumor targeting groups (i.e. mice
injected with 125I-AuRd-RGD and mice injected with 125I-AuRd-A7R) will also be compared with the outcomes
from the two control groups (mice injected with 125I-AuRd and mice with no injection) to examine the
enhancement in photothermal therapy by introducing the AuRds targeting tumors.
E. Impact
Once validated, the proposed innovative radiolabeled AuRd conjugates could, for the first time, facilitate
high sensitive nuclear imaging and high resolution optical imaging at the same time, with the option of targeted
treatment using both radionuclide therapy and photothermal therapy. This novel approach could be further
expanded as a platform for the development of other bioconjugates targeting different receptors. Such a
multifunctional platform based on the idea of “mix-and-match” with suitably selected components for each
individual application may provide a “magic gold bullet” for cancer intervention and might bring us closer to
personalized therapy.
References:
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)
(27)
(28)
(29)
(30)
(31)
(32)
Chavanpatil, M. D.; Khdair, A.; Panyam, J. J. Nanosci. Nanotechnol. 2006, 6, 2651-2663
Sanstra, S.; Dutta, D.; Walter, G. A.; Moudgil, B. M. Technol. Cancer Res. Treat. 2005, 4, 593-602.
Moghimi, S. M.; Hunter, A. C.; Murray, J. C.; FASEB J. 2005, 19, 311-330.
Zhang, J. Z, The J. of Phys. Chem. Lett. 2010, 1, 686-695.
Noguez, C. J. Phys. Chem. B 2007, 111, 3806-3819.
Oyeler, A. K.; Chen, P. C.; Huang, X.; El-Sayed, I. H.; El-Sayed, M. A. Bioconjugate 2007, 18, 1490-1497.
Chou, C.-H., C.-D. Chen and C. R. C. Wang. J. Phys. Chem. B. 2005, 109, 11135–11138.
Huang, X., I. H. El-Sayed, W. Qian and M. A. El-Sayed. J. Am. Chem. Soc. 2006, 128, 2115–2120.
Huff, T. B., L. Tong, Y. Zhao, M. N. Hansen, J.-X. Cheng ., A. Wei. Nanomedicine 2007, 2, 125–132.
Takahashi, H., T. Niidome, A. Nariai, Y. Niidome, S. Yamada. Chem. Lett. 2006, 35, 500–501.
Black, K. C., N. D. Kirkpatrick, T. S. Troutman, L. Xu, J. Vagner, R. J. Gillies, J. K. Barton, U. Utzinger, M.
Romanowski. Mol. Imaging 2008, 7, 50–57.
Pissuwan, D., S. M. Valenzuela, C. M. Miller, M. B. Cortie. Nano Lett. 2007, 7, 3808–3812.
Pissuwan, D., S. M. Valenzuela, M. C. Killingsworth, X. Xu, M. B. Cortie. J. Nanoparticle Res. 2007, 9, 1109–
1124.
Norman, R. S., J. W. Stone, A. Gole, C. J. Murphy, T. L. Sabo-Attwood. Nano Lett. 2008, 8, 302–306.
Haubner, R.; Wester, H.J.; Reuning, U. J Nucl Med. 1999; 40, 1061-1071.
Haubner, R.; Wester, H.J.; Weber, W.A.; Schwaiger, M. J Nucl Med. 2003; 47, 189-199.
Beer AJ, Haubner R, Goebel M. J Nucl Med. 2005; 46, 1333-1341.
Haubner R, Wester HJ, Burkhart F. J Nucl Med. 2001; 42, 326-336.
Beer AJ, Lorenzen S, Metz S. J Nucl Med. 2008; 49, 22-29.
Beer AJ, Grosu AL, Carlsen J. Clin Cancer Res. 2007; 13:6610-6616.
Ferrara N, Gerber HP, LeCouter J. Nat Med. 2003, 9:669-676.
Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D. Cancer Cell. 2002, 1:193-202.
Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Cell. 1998, 92:735-745.
Starzec A, Vassy R, Martin A. Life Sci. 2006, 79:2370-2381.
Binetruy-Tournaire R, Demangel C, Malavaud B, et al. Embo J. 2000;19:1525-1533.
Perret GY, Starzec A, Hauet N, et al. Nucl Med Biol. 2004, 31:575-581.
Chamberland, DL; Agarwal, A; Kotov, N; Fowlkes, JB; Carson, PL. Wang, X. Nanotechnology 2008, 19,
095101.
Wang, Y.; Xie, X.; Wang, X.; Ku, G.; Bill, K.L.; O’Neal, O.P.; Stoica, G.; Wang, L.V. Nano Letters 2004, 4, 16891692.
Shao, X.; Agarwal, A.; Kotov. N.; Wang, X. Nanotechnology. 2010, in press.
Agarwal, A.; Shao, X.; Kotov, N.; Chamberland, DL; Wang, X. Advanced Material. 2010, in press.
Piert M, Machulla H-J, Picchio M, et al. J Nucl Med. 2005, 46:106-113.
Huang, X.; Jain, P.K.; El-Sayed, I.H.; El-Sayed, M.A. Lasers in Medical Science 2008, 23:217-228.
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
Shao, Xia
Assistant Research Scientist
eRA COMMONS USER NAME
xshao
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
INSTITUTION AND LOCATION
DEGREE
(if applicable)
YEAR(s)
China University of Pharmacy, China
Michigan Technological University, Houghton, MI
University of Michigan, Ann Arbor, MI
B.S.
Ph.D.
Postdoctoral
1984
2000
2000-2003
A.
FIELD OF STUDY
Medicinal Chemistry
Organic Chemistry
Nuclear Medicine
Personal Statement
I have been working as a radiochemist in PET facility, at Division of Nuclear Medicine for fourteen
years, and been involved and leading many research projects related to radiopharmaceuticals. My
experiences in designing, synthesis and bio-evaluation of novel radiotracers would provide strong
support for this project, which involves radiolabeling and animal experiments. In addition, our
radiochemistry laboratories are equipped with advanced radiosynthetic modules and quality control
instruments, as well as licensed for all the radioisotopes we will use in this project.
B.
Positions and Employment
1994-2000
2000-2003
2003-2011
2011-
Graduate teaching assistant for undergraduate Organic Chemistry Laboratory, Michigan
Technological University, Houghton, MI
Post-doctoral Fellow, University of Michigan, Department of Radiology, Division of
Nuclear Medicine, Ann Arbor, MI
Research Investigator, University of Michigan, Department of Radiology, Division of
Nuclear Medicine, Ann Arbor, MI
Assistant Research Scientist, University of Michigan, Department of Radiology, Division
of Nuclear Medicine, Ann Arbor, MI
C. Selected Peer-Reviewed Publications.
1. Shao X, and Kilbourn MR. A simple modification of GE Tracerlab FX C Pro for preparation of
[11C]carfentanil and [11C]raclopride. Appl. Radiat. Isot. 67:602-605, 2009.
4. Scott PJH, and Shao X. Fully automated, high yielding production of N-succinimidyl-4[18F]fluorobenzoate ([18F]SFB), and its use in microwave enhanced radiochemical coupling
reactions. J Label Compd Radiopharm. 53:586-591, 2010.
5. Shao X, Hockley BG, Hoareau R, Schnau P, Scott PJH. High efficiency, fully automated
preparation and quality control of [ 11C]choline and [18F]fluoromethylcholine for routine clinical
application. Appl Radiat Isot. 69:403-409, 2010.
6. Shao X, Hoareau R, Hockley BG, Tluczek L, Park JY, Lee JD, Padgett HC, Walsh JC, Kolb HC,
Scott PJH. Highlighting the Versatility of the Tracerlab-FXFN Synthesis Module through Fully
Automated Production of [18F]FLT; [18F]MPPF; [18F]NaF; [18F]SFB; [18F]Fluorocholine and [18F]RGDK5. J Label Compd Radiopharm. 54:292-307, 2011.
7. Shao X, Agarwal A, Rajian JR, Kotov NA, Wang XD. 125I-Labeled gold nanorods and biodistribution.
Nanotechnology. 22:135102, 2011.
8. Shao X, Zhang HN, Rajian JR, Chamberland DL, Sherman P, Quesada C, Koch A, Kotov NA,
Wang XD. 125I-Labeled gold nanorods for targeted imaging of inflammation. ACS Nano. 5:89678973, 2011.
9. Shao X, Hoareau R, Runkle A, Tluczek LJM, Hockley BG, Henderson BD, Scott PJH. Highlighting
the Versatility of the Tracerlab Synthesis Modules. Part 2: Fully Automated Production of
[11C]Labeled Radiopharmaceuticals using a Tracerlab FXC-Pro. J Label Compd Radiopharm.
54:319-338. 2011.
10. Shao X, Carpenter GM, Desmond TJ, Sherman PS, Quesada CA, Fawaz M, Brooks AF, Kilbourn
MR, Albin RL, Frey KA, Scott PJH.
Evaluation of [ 11C]N-Methyl Lansoprazole as a
Radiopharmaceutical for PET Imaging of Tau Neurofibrillary Tangles. ACS Med Lett. 3:936-941,
2012.
11. Shao X, Schnau P, Scott PJH. Enhanced Radiosyntheses of [11C]Raclopride and
[11C]DASB using Ethanolic Loop Chemistry. Nucl Med Biol. 40:109-116, 2013.
12. Shao X, Wang XD, English SJ, Desmond T, Sherman PS, Quesada CA, Piert M. Imaging of
Carrageenan-Induced Local Inflammation and Adjuvant-Induced Systemic Arthritis with 11C-PBR28
PET. Nucl Med Biol. Accepted. 2013.
13. Shao X, Schnau P, Qian W, Wang XD. Quantitative optimization of 125I-labeled RGD-PEGylated
gold nanoparticles. J Nanosci. Nanotech. Accepted. 2013.
14. Shao X, Fawaz MV, Jang KS, Scott PJH. Ethanolic C-11 Chemistry: The Introduction of Green
Radiochemistry. J Labeled Comp Radiopharm. Accepted. 2014.
15. Rajian JR, Shao X, Chamberland DL, Wang X, “Characterization and treatment monitoring of
inflammatory arthritis by photoacoustic imaging: a study on adjuvant-induced arthritis rat model,”
Biomedical Optics Express 4:900-908, 2013.
D. Research Projects
F032155
Piert (PI)
04/01/2013 – 03/31/2017
DOD
Choline PET and MRI in primary prostate cancer
Investigation of the magnitude of uptake, retention, and spatial distribution pattern of
comparison with MRI and histology obtained from prostate cancer biopsies.
Role: Co-Investigator
18
F-choline in
5-PO1-NS15655
Frey (PI)
09/15/2010 – 06/30/2015
NIH NINDS
"PET Study of Biochemistry and Metabolism of the CNS"
Synthesis and evaluation of PET radioligands for neurological diseases. Emphasis on GABA and
dopamine systems.
Role: Co-Investigator
RO1-AR055179
Wang (PI)
04/01/2008 – 03/31/2013
NIH
Imaging of Inflammation and Treatment: Basic and Translational Potential
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
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
Xueding Wang
Associate Professor
eRA COMMONS USER NAME
xdwang
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
INSTITUTION AND LOCATION
DEGREE
(if applicable)
YEAR(s)
FIELD OF STUDY
Nanjing University, Nanjing, China
Nanjing University, Nanjing, China
B.S.
1997
Electronic Engineering
M.S.
2000
Acoustics
Texas A&M University, College Station, TX, USA
Ph.D.
2004
Biomedical Engineering
A.
Personal Statement
After working on optics and ultrasound for more than 15 years, I have extensive experience in imaging
system development, laser-tissue interactions, and adaptation of novel imaging technologies to
laboratory research and clinical managements, especially those based on photoacoustic imaging (PAI)
technology. As the principal investigator or co-Investigator on numerous NIH, NSF and DoD grants, I
have successfully administered the projects, collaborated with other researchers, and produced high
quality peer-reviewed publications. My contribution to biophotonics and medical ultrasound societies up
to now including 100+ peer-reviewed papers is solid evidence of my creativity and ability to surmount
challenges in the field. My article published in 2003 in Nature Biotechnology has received a number of
citations close to 1000, and is the most cited paper focused on biomedical PAI. For the first time, the
idea of “tomography” has been adapted to PAI successfully, which drastically improved the image
quality and made this novel technique ready for many preclinical and clinical applications. At University
of Michigan Hospital, our research on functional and molecular imaging of inflammatory arthritis has
been supported by two NIH grants, and is now leading to a study on patients affected by rheumatoid
arthritis. I have received the Sontag Foundation Fellow of the Arthritis National Research Foundation in
2005, and the Distinguished Investigator Award of the Academy of Radiology Research in 2013.
B. Positions and Employment
1997-2000 Research Assistant, National Key Lab of Modern Acoustics, Nanjing University, China
2000-2004 Research Assistant, Department of Biomedical Engineering, Texas A&M University
2004-2005 Postdoctoral Research Associate, Department of Radiology, University of Michigan Medical
School
2005-2007 Research Investigator, Department of Radiology, University of Michigan Medical School
2007-2008 Research Assistant Professor, Department of Radiology, University of Michigan Medical
School
2008-2012 Assistant Professor, Department of Radiology, University of Michigan Medical School
2010-2012 Adjunct Assistant Professor, Department of Biomedical Engineering, University of Michigan
2012Associate Professor (tenured), Department of Radiology, University of Michigan
2012Adjunct Associate Professor, Department of Biomedical Engineering, University of
Michigan
C.
Selected peer-reviewed publications
Most relevant to the current application
1. X. Wang, Y. Pang, G. Ku, X. Xie, G. Stoica, and L. V. Wang, “Non-invasive laser-induced
photoacoustic tomography for structural and functional in vivo imaging of the brain,” Nature
Biotechnology 21, 803–806 (2003).
2. X. Wang, X. Xie, G. Ku, G. Stoica, and L. V. Wang, “Noninvasive imaging of hemoglobin
concentration and oxygenation in the rat brain using high-resolution photoacoustic tomography,”
Journal of Biomedical Optics 11(2), 024015 (2006).
3. X. Wang, D. L. Chamberland, P. L. Carson, J. B. Fowlkes, R. O. Bude, D. A. Jamadar, and B. J.
Roessler, “Imaging of joints with laser-based photoacoustic tomography: an animal study,” Medical
Physics 33(8), 2691–2697 (2006).
4. X. Wang, D. L. Chamberland, and D. A. Jamadar, “Noninvasive photoacoustic tomography of
human peripheral joints toward diagnosis of inflammatory arthritis,” Optics Letters 32(20), 3002–
3004 (2007).
5. Z. Xie, W. Roberts, P. Carson, X. Liu, C. Tao, and X. Wang, “Evaluation of bladder
microvasculature with high-resolution photoacoustic imaging,” Optics Letters 36(24), 4815-4817
(2011).
6. Y. Yang, S. Wang, C. Tao, X. Wang, and X. Liu, “Photoacoustic tomography of tissue
subwavelength microstructure with a narrowband and low frequency system,” Applied Physics
Letters 101, 034105 (2012).
7. A. Ray, H. K. Yoon, Y. E. Koo Lee, R. Kopelman, and X. Wang, “Sonophoric nanoprobe aided pH
measurement in vivo using photoacoustic spectroscopy,” Analyst 138(11), 3126-3130 (2013).
8. J. R. Rajian, G. Girish, and X. Wang, “Photoacoustic tomography to identify inflammatory arthritis,”
Journal of Biomedical Optics 17(9), 096013 (2012).
9. J. R. Rajian, X. Shao, D. L. Chamberland, and X. Wang, “Characterization and treatment monitoring
of inflammatory arthritis by photoacoustic imaging: a study on adjuvant-induced arthritis rat model,”
Biomedical Optics Express 4(6), 900-908 (2013).
10. Y.-S. Hsiao, X. Wang, and C. X. Deng, “A dual-wavelength photoacoustic technique for monitoring
tissue status during thermal treatments,” Journal of Biomedical Optics 18(6): 67003 (2013).
11. S.-L. Chen, J. Burnett, D. Sun, X. Wei, Z. Xie, and X. Wang, “Photoacoustic microcopy: a potential
new tool for evaluation of angiogenesis inhibitor, ” Biomedical Optics Express 4(11), 2657-2666
(2013)
D.
Research Support
NIH, 1R01AR060350
9/6/2011-6/30/2016
Title: Physiology of Inflammatory Arthritis in High Resolution
Objective: Development and application of new photoacoustic imaging technologies for the discovery of
biomarkers of inflammatory arthritic disease onset, progression, and response to therapy.
Role: PI
NSF, 1256001
2/1/2013-1/31/2016
Title: IDBR: Spectroscopic photoacoustic microscopy for advanced histopathology on living cells and
tissues
Goals: This project will develop innovative spectroscopic photoacoustic microscopy (SPAM), by
imaging 3D tissue features and functions without need of fixation, sectioning and staining, which may
lead to a revolutionary new tool of biology and medicine, and provide an alternative to the current
methods in histopathology.
Role: Co-investigator; PI: Jay Guo, Ph.D.