DEVELOPMENT AND APPLICATION OF MODIFIED HYLAURONIC ACID DERIVED NANOPARTICLES FOR IMAGE GUIDED SURGERY AND DRUG DELIVERY BY TANNER KINKADE HILL A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Biomedical Engineering May, 2015 Winston-Salem, North Carolina Approved By: Aaron M. Mohs, PhD, Advisor and Chair Lissett R. Bickford, PhD Nicole H. Levi, PhD Frank C. Marini, PhD, Thaddeus J. Wadas, PhD
Transcript
DEVELOPMENT AND APPLICATION OF MODIFIED HYLAURONIC ACID
DERIVED NANOPARTICLES FOR IMAGE GUIDED SURGERY AND DRUG
DELIVERY
BY
TANNER KINKADE HILL
A Dissertation Submitted to the Graduate Faculty of
WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND
SCIENCES
in Partial Fulfillment of the Requirements
for the Degree of
DOCTOR OF PHILOSOPHY
Biomedical Engineering
May, 2015
Winston-Salem, North Carolina
Approved By:
Aaron M. Mohs, PhD, Advisor and Chair
Lissett R. Bickford, PhD
Nicole H. Levi, PhD
Frank C. Marini, PhD,
Thaddeus J. Wadas, PhD
i
DEDICATION AND ACKNOWLEDGEMENTS
I would first like to thank my advisor Dr. Aaron M. Mohs for the extensive support,
guidance, and encouragement he has provided, without which this work would
not have been possible. Throughout the time spent in his lab, Dr. Mohs has had
an incredibly supportive, innovative, and driving role as my advisor and this has
been critical in terms of learning, productivity, and well-being. I would also like to
thank the other members of my committee, Dr. Frank C. Marini, Dr. Nicole H.
Levi, Dr. Lissett R. Bickford, and Dr. Thaddeus J. Wadas for their thoughtful
critiques and advice how to improve this research. Amanda Davis, Dr. Steve
Kridel, and Dr. Todd Lowther also deserve special thanks for their work on the
Nano-ORL collaboration, as without their contribution the work would not have
come to completion. Dr. Colleen Webb and Dr. Joseph von Fischer both deserve
thanks for their incredible influence on my choice of a scientific career and the
research training they provided me with during my time at Colorado State
University. I would also like to give a very special thanks to Dr. Kenneth
Klopfenstein of the Colorado State University Department of Mathematics, whose
influence on me personally and scientifically cannot be overstated. Dr. K. was a
wonderful mentor to me, his classes and teaching not only taught me calculus
but about the world and myself as well. I would also like to thank the Mike and
Lucy Robbins family for their generous financial support of my graduate career
through their fellowship. Finally, I would like to thank my parents, whose support
has been a significant boon to me during my graduate career.
ii
TABLE OF CONTENTS
DEDICATION AND ACKNOWLEDGEMENTS............................................... i
TABLE OF CONTENTS................................................................................. ii
LIST OF FIGURES AND TABLES................................................................. viii
LIST OF ABBREVIATIONS............................................................................ x
ABSTRACT.................................................................................................... xiii
CHAPTER 1: INTRODUCTION…………………………………………………. 1
1.0 Nanoparticles in Medicine and Biomedical Research…….……………… 1
D = diameter. Theoretical values calculated using Equation 6.1 for the flow rates
in this experiment range from 0.287-2.58 dyne/cm2. Using these values will result
in underestimation of the actual shear stress experience by the NPs as the
peristaltic pump action will result in transiently higher shear values as the fluid
passes the pump head. Thus, a safe approximation for maximum shear stress
experienced in this experiment is on the order of 10 dyne/cm2. However,
physiological shear stress values range from 50 dyne/cm2 in the aorta, 2.8-100
dyne/cm2 in capillaries, and 17-211 dyne/cm2 in arterioles, and even as high as
600 dyne/cm2 in mouse aortas.91-94 Thus, the shear stress experienced in this
system is a gross underestimate of shear stress experienced in humans or the in
vivo model used here, meaning ICG release should actually release more
rapidly. Additionally, we found that dissolution of either ICG or NanoICG in BSA-
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PBS followed by elution through a 100 kDa centrifugal filter kit resulted in similar
elutions of ICG and BSA, indicating that elution was not dependent upon the
initial presence of ICG in the NP formulation (Figure 3-8). These results suggest
that ICG is being released from NanoICG and should thus behave similarly to
free ICG in vivo.
Contrary to the in vitro results, NanoICG appears to behave very much
like a NP in its biodistribution and clearance in mice (Figure 4-1 & 4-4). In vivo
results show that two different NanoICG formulations both result in improved
SNR and CNR compared to free ICG at 24 hours. Kidney signal is higher for ICG
at 4 hours, and similar to NanoICG at 24 hours. These results are consistent with
small molecule clearance for ICG and NP clearance for NanoICG. Additionally,
this work was replicated in two separate animal experiments and with consistent
results. It thus appears that ICG within NPs, while it does release to serum
proteins, still remains within the NPs for some time. This is shown by the gradual
increase in the release profile and likely causes the difference in biodistribution. It
has also been shown that smaller molecules or polymers diffuse more easily
from tumors back into circulation, so that the larger NanoICG particles would be
retained in tumors longer than ICG.97 One possible method to examine this in
vitro would be to use tumors grown in decellularized tissues perfused with
peristaltic pumps. This would allow for the combination of natural-like tumors in
controlled flow conditions, and would afford precise control of solution
composition such as NP and protein concentration. This approach would prevent
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the complications of metabolism and excretion, and could thus focus solely on
release, quenching, flow, and diffusion from tumors.
An additional complicating factor is the total ICG signal in mice at 4 hours,
which shows ICG as being present in higher quantities in all tissues. ICG content
of all contrast agents was measured with absorbance spectrometry prior to
administration, so this is not likely to be a result of higher ICG administration
levels. A possible explanation for this is the quenching phenomenon previously
observed when ICG is closely bound within NanoICG. As the biodistribution
indicates that ICG is retained within NP cores it follows that fluorescence
quenching would also occur, which would reduce the observed signal. A future
pharmacokinetic in vivo study is necessary in which ICG is extracted from tissues
at various timepoints and more rigorously quantified in order to prevent
systematic error due to quenching of NanoICG. The ICG release to serum
proteins should also be further examined to determine to what extent ICG is
released from NanoICG at various timepoints, and what effect solution
composition has on this release.
Though NanoICG shows significantly higher CNR than free ICG, it may be
possible to improve this further by controlling ICG release from the NPs. In order
to prevent the loss of ICG to serum proteins, chemical modifications to NanoICG
will be necessary. The most obvioius potential modification is PEGylation, which
as been clearly demonstrated to reduce interactions with serum proteins in
numerous studies.86 This type of modification could be performed using the same
chemistry required for conjugation of the hydrophobic groups to HLA, namely
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amide bond formation between a primary amine on a PEG molecule and the
carboxylic acid on HLA by EDC/NHS reaction. This method has been used
previously with Cy5.5 labeled HLA, where PEGylation resulted in increased
retention within the tumor and within the entire body, as well as lower relative
uptake by the liver.50 Another strategy to prevent loss of the fluorophore from the
NPs is through direct conjugation to HLA. Previous studies have investigated
direct conjugation of ICG-OSU, an N-hydroxysuccinimide activated form of ICG,
as well as direct conjugation of Cy5.5.50, 228 Furthermore, chemical crosslinking of
the HLA polymers could prevent dissociation and ensure that NPs remain intact
during tumor accumulation. However, direct conjugation of fluorophores to HLA
requires the use of non-FDA approved materials, significantly reducing the ease
and speed of clinical translation. An alternative strategy to avoid this complication
would be to test alternative NP formulations by utilizing different polymers. Other
groups have successfully loaded ICG into PLGA or PLA based NPs, and a
number of polymeric or liposomal formulations may need to be investigated in
order to acquire optimal release kinetics and biodistribution.220, 233, 261-263
An IGS-Specific Animal Model is Needed
Further addressing the in vivo issues in IGS is the choice of animal model.
New tumor models specifically considering the experimental requirements of IGS
are needed. Mice provide high sample sizes but their physical dimensions
prevent adequate separation of metabolic and excretory organs from target
tissues (Figure 4-7). Additionally, for breast cancer models in particular, mice
146
provide little breast tissue with which to examine contrast between tumors and
healthy tissue. Subcutaneous tumor models in which the tumor is placed in the
back hip, as in Figure 4-3, provide the best optical protection of the tumor signal
from the signal of visceral organs such as the liver and kidneys, but this location
does not provide tumor orthotopic growth as would be found by injection into
breast tissue. The studies demonstrated here have demonstrated the superior
tumor distribution of NanoICG, but future in vivo studies will require survival
surgery and direct comparison of contrast between target tissues. Thus, a
different animal model, using a larger animal with orthotopic tumors, is necessary
to gain a complete understanding of expected contrast between tumors and
various tissues in a surgical setting. Some investigations into this have been
performed in spontaneously occurring tumors in canines, which provides
advantages in both animal size as well as natural tumor formation that provides
realistic contrast agent distribution.230 However, this method is not reasonable for
routine work due to limitations on animal patient populations. One appropriate
animal may be rats, which are substantially larger than mice while smaller than
many other research species.
Extension of NanoICG to SLN Mapping
The current gold standard for SLN mapping involves radioisotope probes
or the visual dye Patent blue.177 ICG alone has previously shown success as
both a color and fluorescent dye in SLN mapping, with rates comparable to
radioisotope probes. HLA has also shown success in improving SLN mapping by
147
mixing with Patent blue or SPIO NPs, as free HLA increased the viscosity of the
solution, which prolonged the duration of stain within the SLN.62 NanoICG clearly
shows increased retention within the tumor over free ICG, and would likely serve
equally well or better than free ICG to image SLNs. Additionally, the ratio of ICG
to HLA could easily be tailored to result in a higher viscosity solution and possibly
decrease the quenching effect, which could further improve the retention and
signal present for quick imaging. Using NIR imaging with ICG would serve both
to provide surgeons with visual feedback as opposed to lymphoscintigraphy, and
would decrease the radiation exposure of both patients and operating room staff.
Summary of Nano-ORL Studies
The Nano-ORL work presented here represents the first NP formulation of
ORL. ORL was efficiently loaded into the NP cores (Figure 5-1A), which
demonstrates its highly hydrophobic nature. Nano-ORL was also found to inhibit
FASN and block lipid synthesis in vitro, indicating that the molecular action of
Nano-ORL is the same as that of ORL, and that the NP loading process does not
cause ORL degradation (Figure 5-2A&B). Toxicity against cancer cell lines was
found with both Nano-ORL and ORL, except that Nano-ORL appeared to be
more toxic than free ORL over 48 hours (Figure 5-3). This additional toxicity was
not due to negative effects of the NP material itself, as empty NPs were not
found to be toxic. Thus, the greater cytotoxicity must result from a synergistic
effect of the Nano-ORL formulation. It was hypothesized that the Nano-ORL
formulation provides better aqueous stability of ORL, thus increasing the total
148
exposure to the cells. Pre-incubation of both ORL and Nano-ORL resulted in
greatly reduced cytotoxicity of ORL, while the toxicity of Nano-ORL was not
effected. This indicates that the aqueous stability of ORL is increased when
loaded into the hydrophobic cores of NPs. Further analysis indicated that the
toxic effect of both ORL and Nano-ORL resulted in decreased metabolic activity
of the cells due to perturbed mitochondrial function (Figure 5-7).
Diameter of Nano-ORL
Further work is needed with regard to the average NP size. Figure 5-1B
indicates that the average diameter of Nano-ORL loaded with 20 wt% ORL is
approximately 600 nm, while that of 5 wt% is approximately 400 nm. These
diameters are too large to fit through the vascular fenestrations of many tumors.
Though many complicating and competing factors must be addressed in NP
biodistribution, NPs of 100 nm in diameter have been found to be appropriate in
many situations.82 For delivery to solid tumors, it will thus be preferable to
develop a formulation with signficantly smaller average diameters than what we
have observed with 10 kDa High-PBA-HLA. Alternatives exist in the form of other
polymeric or liposomal formulations, as these have commonly been used in NP
drug delivery as outlined previously, however the exact composition will need to
be determined experimentally.
Despite the non-optimal diameters, the increased solubility of Nano-ORL
will likely increase total bioavailability and thus improve overall delivery to tumors.
Additionally, modification of the HLA molecular weight or hydrophobic ligand
149
content may allow for further decrease of NP diameter. Additionally, the ability to
control NP size based on ORL content will likely prove useful in optimizing
biodistribution, circulation time, and ultimately delivery of ORL to tumors.
In Vivo Testing of Nano-ORL
It is desirable to begin in vivo studies using Nano-ORL. The improved
aqueous stability and prolonged activity observed are sufficient reason for initial
investigations into the anti-tumor activity in living animals. No previous in vivo
experiments have utilized systemic injection of ORL,211-213 and thus both efficacy
and toxicity studies are needed. Possible side effects of ORL administration are
likely to be similar to those observed with C75, including weight loss and
anorexia,195, 201, and ORL is known to be active against pancreatic lipases,
FASN, lipoprotein lipase, and potentially GADPH and β-tubulin as well.253, 264
However, despite these potential complications, the potential beneficial outcomes
of systemic administration of a solubilized form of ORL must be addressed. The
in vitro results presented in this work demonstrate significant and meaningful
improvements in the action of ORL against cancer cells. Additionally, previous
NP formulations of other drugs, such as Doxil®, have resulted in lower off-target
toxicities compared to the free drug, so it is reasonable to expect that a NP
formulation of ORL could exhibit this behavior as well.
150
HLA Remains a Suitable Biopolymer for NP Research
HLA has been, and remains, a useful biopolymer for the synthesis of
nanoscale polymeric micelles. However, HLA has both positive and negative
aspects for use as a NP backbone. Benefits include the biodegradability,
hydrophilic nature, potential for active targeting against CD44, multivalency for
hydrophobic moiety, stealth moiety, drug, or targeting ligand conjugation.
Detriments include the molecular effects of different molecular weight HLA
polymers, as large MW HLA is antiangiogenic and immunosuppressive, while
small (20 kDa) MW HLA is angiogenic and inflammatory.265 The polydispersity of
both natural and commercial HLA, and the multivalency resulting in non-location-
specific conjugation also result in a diversity of similar products formed in the
same reaction. Simply, HLA is difficult to precisly control on a molecular level. As
such, its limitations and variations should be recognized and addressed prior to
utilizing HLA in new formulations. Nonetheless, it remains a highly useful polymer
for NP formulations and the applications will doubtlessly expand.
Conclusion
The field of nanomedicine is expanding rapidly and for good reason.
Nanomedicines have shown numerous advantages over their free drug
counterparts both pre-clinically and clinically, a number of which are evidenced
here in the form of superior tumor contrast from ICG delivery and prolonged
cytotoxic effects with ORL. Though there are significant hurdles in the delivery of
NPs to tumors, in many ways what remains is an optimization problem rather
151
than proof of efficacy. Optimization must occur in the form of NP size, stability,
drug release rate, charge, and targeting. This will require novel contributions in
the form of combinations and modifications of materials. Material choice will
depend on the drugs or contrast agents being delivered, which in turn depend on
the cellular and extracellular biochemical and biophysical environment that is
being targeted. Related to the field of personalized genetic medicine, one can
envision a field of personalized nanomedicine in which optimized NP
formulations may be chosen based on an individual tumor’s expected attributes,
such as vascularity, fenestration size, and predicted susceptibility to various
chemotherapeutics. This could allow better outcomes at every stage of the
cancer treatment process, from improved diagnosis, staging and restaging,
optimized visualization during surgical resection, to improved chemotherapeutic
outcomes.
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TANNER K. HILL CURRICULUM VITAE
Virginia Tech/Wake Forest University School of Biomedical Engineering and Sciences 1440 Brookwood Dr. Winston-Salem, NC. 27106 (336) 831-4301 [email protected][email protected] EDUCATION 2015 Ph.D., Biomedical Engineering, Virginia Tech/Wake Forest University, Winston
Salem, NC. (exp. May 2015) 2009 B.S., Biological Sciences, Magna cum Laude, Colorado State University, Ft.
Synthesis, characterization, in vitro and in vivo testing of polymeric hyaluronic acid nanoparticles for image guided surgery and drug delivery
Virginia Tech/Wake Forest University Principal Investigator: Aaron M. Mohs, Ph.D. 2010-2012 Graduate Student
Synthesis, characterization, in vitro and in vivo testing of electrospun collagen-poly-(caprolactone) tissue engineered vascular scaffolds for treatment of peripheral vascular disease Virginia Tech/Wake Forest University Principal Investigator: Sang Jin Lee, Ph.D.
2008-2009 Undergraduate Research Assistant
Cloning of a recombinant plasmid for the purpose of expressing H4 histone with reversed amino acid sequence in tail domain for protein-protein interaction analysis Colorado State University Principal Investigator: Jeffrey Hansen, Ph.D.
2007-2008 Undergraduate Research Assistant
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Computational modeling of predator/prey interaction in two dimensional space. Computational modeling of Los Gatos Research Methane Analyzer using Matlab Colorado State University Principal Investigator: Colleen Webb, Ph.D., Joseph von Fischer, Ph.D.
Translational Design of experiments, data and statistical analysis, novel assay design
and implementation, image guided surgery, small and large animal surgery, small animal tumor models, stress/strain testing, bioreactor design, detailed record keeping
SCHOLARSHIPS AND AWARDS 2014-2015 Mike and Lucy Robbins Fellowship Award Winner, Wake Forest
University Graduate School of the Arts and Sciences 2010-2014 Graduate Research Assistant, Virginia Tech/Wake Forest University
School for Biomedical Engineering, Summer 2008-2009 FEScUE Undergraduate Computational Modeling Fellowship, Colorado
State University 2007-2008 First Year Undergraduate Physics Scholarship, Colorado State University 2006-2007 Colorado State University Undergraduate Scholarship LEADERSHIP AND SERVICE 2013-2014 Biomedical Engineering Society Student Chapter President, Wake Forest
University 2013-2014 Volunteer, Wake Forest Baptist Health
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2013-2014 Volunteer, Community Care Center of Winston-Salem 2011-2015 Undergraduate and Summer Student Mentor 2010-2015 Biomedical Engineering Society Member AUTHORSHIPS AND PRESENTATIONS Journal Publications Indocyanine Green-Loaded Nanoparticles for Image Guided Tumor Surgery. Tanner K.
Hill, Asem Abdulahad, Sneha S. Kelkar, Frank C. Marini, Timothy E. Long, James M. Provenzale, Aaron M. Mohs. Bioconjugate Chemistry 2015, 26(2), 294-303. http://pubs.acs.org/doi/abs/10.1021/bc5005679
Fabrication and Characterization of Medical Grade Polyurethane Composite Catheters for Near-Infrared Imaging. Andre T. Stevenson Jr., Laura M. Reese, Tanner K. Hill, Jeffrey McGuire, Aaron M. Mohs, Raj Shekhar, Lissett R. Bickford, Abby R. Whittington. Biomaterials 2015, 54, 168-176. http://www.sciencedirect.com/science/article/pii/S0142961215002902 Oral and Poster Presentations Development of a Nanoparticle Formulation of Orlistat: Solubility, Stability, and Cytotoxicity. Tanner K. Hill, Frances B. Wheeler, Amanda L. Davis, Sneha Kelkar, Steven J. Kridel, Aaron M. Mohs. BMES Annual Meeting, poster presentation, 2014/10/24 Synthesis, Characterization, and Pre-Clinical Evaluation of Hyaluronan Based Nanoparticles for Image-Guided Surgery. Tanner K. Hill, Sneha Kelkar, Frank C. Marini, Edward A. Levine, James M. Provenzale, Aaron M. Mohs. Annual SBES Symposium, poster presentation, 2014/5/15 Synthesis, Characterization, and Pre-Clinical Evaluation of Hyaluronan Based Nanoparticles for Image Guided Surgery. Tanner K. Hill, Sneha Kelkar, Frank C. Marini, Edward A. Levine, James M. Provenzale, Aaron M. Mohs. 2014 Duke University Fitzpatrick Institute for Photonics Annual Symposium. Poster presentation, 2014/3/11 Near Infrared Fluorescent Polysaccharide-Based Nanoparticles for Image-Guided Tumor Surgery. Tanner K. Hill, Sneha Kelkar PhD, Frank C. Marini PhD, Aaron M. Mohs, PhD. 2013 NCI Alliance for Nanotechnology in Cancer Annual Principal Investigators Meeting. Podium presentation, 2013/9/19 Development of Hyaluronan-Based Nanoparticles for Intraoperative Breast Cancer Imaging. Tanner K. Hill, Sneha Kelkar, Asem Abdulahad, Timothy Long, Frank C. Marini, Aaron M. Mohs. 2013 Annual SBES Symposium. Poster presentation, 2013/5/16
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Near Infrared Image Guided Tumor Removal: Epidermal Growth Factor as a Target. Tanner K. Hill, Frank C. Marini, Aaron M. Mohs. 2012 BMES Annual Meeting. Podium presentation, 2012/10/27 An Innovative Approach to Building Clinically Relevant sized Tissues and Organs. Tanner K. Hill, Jaehyun Kim, Peter Masso, Sang Jin Lee, Karl-Erik Andersson, Anthony Atala, James J. Yoo. Poster presentation, 15th Annual Hilton Head Workshop: Regnerative Medicine, Innovations for Clinical Applications, hosted by Georgia Tech. March 18, 2011 Book Chapters Electrospun Nanofibers in Tissue Engineering. Mitchell R. Ladd, Tanner K. Hill, James J. Yoo, Sang Jin Lee. Chapter 16 of “Nanofibers – Production, Properties and Functional Applications”. ISBN 978-953-307-420-7, InTech Publishing. 2011
