| dc.description.abstract |
<p>Cancer is currently the second leading cause of death in the United States. Although
many treatment options exist, some of the most common, including radiotherapy and
chemotherapy, are restricted by dose-limiting toxicities. In addition, the largest
hurdle for translating novel biological therapies such as siRNA into the clinic is
lack of an efficient delivery mechanism to get the therapeutic into malignant cells.
This work aims to improve this situation by engineering a minimally invasive controlled
release system that specifically delivers therapeutics to the site of malignant tissue.
This platform consists of two novel material components: a thermally responsive poly[N-isopropylacrylamide-co-acrylamide]
(NIPAAm-co-AAm) hydrogel and gold-silica nanoshells. Therapeutic molecules are encapsulated
within a poly(NIPAAm-co-AAm) hydrogel carrier, leading to increased serum stability,
circulation time, and decreased exposure to off-site tissues. Additionally, gold-silica
nanoshells embedded within this hydrogel will be used to optically trigger therapeutic
release from the carrier. This hydrogel-nanoshell composite material was designed
to be swollen under physiologic conditions (37 oC), and expel large amounts of water
and absorbed molecules at higher temperatures (40-45 oC). This phase transition can
be optically triggered by embedded gold-silica nanoshells, which rapidly transfer
near-infrared (NIR) light energy into heat due to the surface plasmon resonance phenomena.
NIR light can deeply penetrate biological tissue with little attenuation or damage
to tissue, and upon exposure to such light a rapid temperature increase, hydrogel
collapse, and drug expulsion will occur. Ultimately, these drug-loaded hydrogel-nanoshell
composite particles would be injected intravenously, passively accumulate in tumor
tissue due to the enhanced permeability and retention (EPR) effect, and then can be
externally triggered to release their therapeutic payload by exposure to an external
NIR laser. This dissertation describes the synthesis, characterization, and validation
of such a controlled therapeutic delivery platform.</p><p>Initial validation of poly(NIPAAm-co-AAm)-gold
nanoshell composites to act as a material in site-specific cancer therapeutic delivery
was accomplished using bulk hydrogel-nanoparticle composite disks. The composite material
underwent a phase transition from a hydrated to a collapsed state following exposure
to NIR light, indicating the ability of the NIR absorption by the nanoshells to sufficiently
drive this transition. The composite material was loaded with either doxorubicin or
a DNA duplex (a model nucleic acid therapeutic), two cancer therapeutics with differing
physical and chemical properties. Release of both therapeutics was dramatically enhanced
by NIR light exposure, causing 2-5 fold increase in drug release. Drug delivery profiles
were influenced by both the molecular size of the drug as well as its chemical properties.
</p><p>Towards translation of this material into in vivo applications, the hydrogel-nanoshell
composite material was synthesized as injectable-sized particles. Such particles retained
the same thermal properties as the bulk material, collapsing in size from ~330 nm
to ~270 nm upon NIR exposure. Furthermore, these particles were loaded with the chemotherapeutic
doxorubicin and NIR exposure triggered a burst release of the drug payload over only
3 min. In vitro, this platform provided increased delivery of doxorubicin to colon
carcinoma cells compared to free-drug controls, indicating the irradiated nanoshells
may increase cell membrane permeability and increase cellular uptake of the drug.
This phenomena was further explored to enhance cellular uptake of siRNA, a large anionic
therapeutic which cannot diffuse into cells easily. </p><p>This work advances the
development of an injectable, optically-triggered delivery platform. With continued
optimization and in vivo validation, this approach may offer an novel treatment option
for cancer management.</p>
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