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Background
Bill received his
B.S.E. in Chemical and Biochemical
Engineering from the University of Iowa
in May 2007. As an undergraduate
researcher, Bill examined
photopolymerization kinetics of
polymer-liquid crystal composites with
Dr. Tim White in the laboratories of Dr.
Allan Guymon. In 2007, he was awarded a
Gates Cambridge Scholarship for graduate
study at Cambridge University and
received an M.Phil in Chemical
Engineering under the supervision of Dr.
Nigel K.H. Slater in 2008. As a
researcher in the Cambridge Unit for
Bioscience Engineering, he examined the
use of biomimietic pH-responsive
polymers for intracellular protein
delivery. Currently, Bill is conducting
his Ph.D. research under the direction
of Dr. Nicholas Peppas as an NSF
Graduate Research Fellow.
Research Summary
The landmark
discovery of RNA mediated interference (RNAi)
in 1998 has sparked a massive research
effort in all fields of biological
science and redefined our understanding
of the mechanisms of gene regulation.
RNAi pathways are guided by the presence
of small interfering RNA (siRNA), short
strands of duplex RNA capable of
selective, potent, and reversible
silencing of target genes.
Theoretically, siRNA could be used as a
powerful and versatile therapeutic to
treat nearly any disease resulting from
aberrant gene expression. Owing to its
remarkable potency and low therapeutic
dosage, siRNA holds extraordinary
promise as a new biological therapeutic.
However, efficient delivery has been
implicated as the major hurdle to its
widespread clinical application.
Although much
effort has been directed toward
synthetic polymer carriers for siRNA,
there remains a paucity of data on the
development of oral delivery systems.
The primary goal of our work is to
develop intelligent,
environmentally-responsive nanoscale
hydrogels for the oral delivery of siRNA.
From a pharmaceutical standpoint, the
oral route of administration is
advantageous because it increases
patient compliance and comfort over
injection, provides a simple, repeatable
administration, and large surface area
for absorption. This represents a
significant departure from current
thrusts in siRNA delivery, which rely on
painful intravenous or impractical
intraperitoneal injections. In an oral
drug delivery system, the carrier should
be used to ensure that the drug does not
cause non-specific toxicity to the
digestive tract lining, does not
localize in unintended tissues prior to
reaching its site of action, or become
inactivated or altered by the
environment in the GI tract.
Additionally, the carrier must provide
therapeutically relevant concentrations
of siRNA to disease targets along the
gastrointestinal tract.
We propose that
polycationic nanogels are well suited to
accomplish these tasks. The
pH-responsive swelling behavior of these
matrices can be exploited to entrap
siRNA and facilitate endosomal release.
These carriers are advantageous over
their self-assembled counterparts
because of their inherent mechanical
integrity and stability in the GI tract.
Through optimization of molecular
architecture and a rigorous
investigation of in vitro properties,
i.e. siRNA binding, hemolytic ability,
cellular toxicity, and silencing
efficiency, we aim to arrive at a system
able to efficiently encapsulate siRNA,
protect it from the environment of the
small intestine, and facilitate
endosomal release following cellular
uptake. Successful development of this
system will pave the way for improved
treatment of gastrointestinal diseases
by providing patients a powerful
therapeutic in a convenient and
accessible form.
Publications
W.B. Liechty and N.A.
Peppas, “Expert
Opinion: Responsive Polymer
Nanoparticles in Cancer Therapy”,
Europ. J. Pharm. Biopharm., 2011
(In Press).
M.E. Caldorera-Moore, W.B.
Liechty and N.A.
Peppas, “Responsive Theranostic
Systems: Integration of Diagnostic
Imaging Modalities into Responsive
Controlled Release Drug Delivery
Systems”, Acc. Chem. Res., 44
(10), 2011,
1061-1070.
W. B. Liechty, M. Caldorera-Moore,
M. A. Phillips, C. Schoener and N. A.
Peppas, “Advanced Molecular Design of
Biopolymers for Transmucosal and
Intracellular Delivery of
Chemotherapeutic Agents and Biological
Therapeutics”, J. Controlled Release,
155(2), 2011, 119-127.
W.B. Liechty,
D.R. Kryscio, B.V. Slaughter, N.A.
Peppas, “Polymers in Drug Delivery,”
Annual Review of Chemical and
Biomolecular Engineering, 1
(1), 2010, 149-173.
W.B. Liechty,
R. Chen, F. Farzaneh, M. Tavassoli, and
N.K.H. Slater, “Synthetic pH-Responsive
Polymers for Protein Transduction,” Advanced
Materials, 21 (38-39),
2009, 3910-3914.
T. J. White, W. B. Liechty,
and C. A. Guymon, “The Influence of
N-Vinyl-Pyrrolidone on Polymerization
Kinetics and Thermo-Mechanical
Properties of Cross Linked Acrylate
Polymers,” Journal of
Polymer Science Part A: Polymer
Chemistry, 45 (17), 2007,
4062-4073.
T. J. White, W. B. Liechty,
L. V. Natarajan, V. P. Tondiglia, T. J.
Bunning, and C. A. Guymon, “The
Influence of N-Vinyl-2-Pyrrolidone in
Polymerization of Holographic Polymer
Dispersed Liquid Crystals (HPDLCs),”
Polymer, 47 (7), 2006,
2289-2298.
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