Poly(NIPAAm-co-AAm)-gold nanoshell composites for optically-triggered cancer therapeutic delivery

摘要

Chemotherapy regimens, one of the most common cancer treatments, are often dictated by dose-limiting toxicities. Also, 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. Both of these situations would benefit from a minimally-invasive controlled release system that only delivers a therapeutic to the site of malignant tissue. This thesis presents work towards the creation of such a delivery platform using two novel material components: a thermally responsive poly[N-isopropylacrylamide-co-acrylamide] (NIPAAm-co-AAm) hydrogel and gold-silica nanoshells. Thermally responsive hydrogels undergo a physical property transition at their lower critical solution temperature (LCST). When transitioning from below to above the LCST, the hydrogel material expels large amounts of water and absorbed molecules. This phase change can be optically triggered by embedded gold-silica nanoshells, which rapidly transfer near-infrared (NIR) light energy into heat energy due to the surface plasmon resonance phenomena. When this material is loaded with absorbed drug molecules, drug release can be externally triggered by exposure to an NIR laser. Initial characterization of this material was accomplished using bulk hydrogel-nanoshell composites. Poly(NIPAAm-co-AAm)-nanoshell composites were synthesized via free radical polymerization. The LCST of the poly(NIPAAm-co-AAm) hydrogels was determined to be from 39-45 deg C, or slightly above physiologic temperature. The material was swollen in a drug solution of either doxorubicin (a common chemotherapeutic) or a 21bp dsDNA olgio (a model molecule for siRNA). Composites were then exposed to an 808 nm laser, which was found to trigger release of the therapeutics from the composite material. Further work has been done in translating this composite material to nano-scale sized particles, such that it could be injected intravenously, passively accumulate in tumor tissue, and be externally triggered to release therapeutics by exposure to an NIR laser. Sub-micron composite particles were synthesized using dissolvable gelatin templates with 500 nm wells. Analysis by transmission electron microscopy (TEM) indicates that these particles consist of gold nanoshells surrounded by a hydrogel coating. Dynamic light scattering (DLS) measurements were used to show that these particles display the same thermal properties as seen in the bulk material: collapsing in response to increased temperatures or NIR light exposure. Ultimately, the work in this thesis advances the development of a minimally-invasive, optically-triggered drug delivery platform.