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.

<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> / Dissertation

Gold nanoshells, a material generally composed of a core of silica surrounded by a thin shell of gold, are of great interest due to their unique and tunable optical properties. By varying the shell thickness and core size, the absorption and scattering properties are greatly enhanced. The nanoshells can be made to absorb or scatter light at various regions across the electromagnetic spectrum, from visible to the near infrared. The ability to tune the optical properties of nanoshells allows for their potential use in many different areas of research such as optical imaging, tumor ablation, drug delivery, and solar energy conversion. The research in this thesis focused on the synthesis and characterization of two novel gold nanoshell materials containing thermally-responsive, organic-inorganic hybrid layers. One type of material was based on a two-layer particle with a thermally responsive hybrid core of N-isopropylacrylamide (NIPAM) copolymerized with 3-(trimethoxysilyl)propyl methacrylate (MPS) that was then coated with a thin layer of gold. The second material was a three-layer particle with a silica core, a thermally responsive copolymer of NIPAM and MPS middle layer and an outer shell of gold. Various techniques were used to characterize both materials. Transmission electron microscopy (TEM) was used to image the particles and dynamic light scattering (DLS) was used to determine particle size and the temperature response. Additionally, UV-Vis spectroscopy was used to characterize the optical properties as a function of temperature.

Polymeric biomaterials have become ubiquitous in modern medical devices. ‘Smart’ materials, materials that respond to external stimuli, have been of particular interest for biomedical applications such as drug delivery. Poly(n-isopropylacrylamide) (pNIPAAm) is the best studied thermally responsive, biocompatible, ‘smart’ polymer and has been integrated into many potential drug delivery devices; however, the architectural design of the polymer in these devices is often overlooked. My research focus was the exploration of pNIPAAm architecture for biological applications. Two new biomaterials were synthesized as a result. Architectural modification of linear pNIPAAm was used to synthesize a well-defined homopolymer pNIPAAm with a sharp transition slightly above normal body temperature under isotonic conditions. This polymer required a combination of polymerization and control techniques including controlled radical polymerization, hydrogen bond induced tacticity, and end-group manipulation. The synthesis of this polymer opened up a variety of biomedical possibilities, one of which is the use of these polymers in a novel hydrogel system. Through the use of the controlled linear pNIPAAm synthesized through chain architectural modification, hydrogels with physiological transition temperatures were also synthesized. These hydrogels showed greater shrinking properties than traditional hydrogels synthesized in the same manner and showed physiological mechanical properties. Highly branched pNIPAAm was also optimized for biological applications. In this case, the branching reduced the efficacy of end-groups in transition temperature modification but increased the efficacy of certain copolymers. The resulting biomaterial was incorporated into a nanoparticle drug delivery system. By combining gold nanoparticles with highly branched pNIPAAm, which was designed to entrap small molecule drugs, a hybrid system was synthesized where heating of the nanoparticle through surface plasmon resonance can trigger drug release from the pNIPAAm. This system proved to be easy to synthesize, effective in loading, and controlled in release. As shown from the applications, architectural control of pNIPAAm can open up new possibilities with this polymer for biomedical applications. Small structural changes can lead to significant changes in the bulk properties of the polymer and should be considered in future pNIPAAm based medical devices.

The rapidly expanding of the global population in the 21st-century forces people facing two serious problems: water scarcity and energy shortage. Enormous continuous studies focus on providing enough fresh water and energy in a sustainable way. This thesis aims at exploring novel membrane processes based on thermally responsive ionic liquids with the upper critical solution temperature (UCST ILs) for water desalination and energy conversion from low-grade heat energy to electricity. A UCST IL protonated betaine bis(trifluoromethylsulfonyl)imide ([Hbet][Tf2N]) was first experimentally studied as a novel draw solute in a thermal forward osmosis (FO). A 3.2 M [Hbet][Tf2N] solution can be obtained via spontaneous phase separation from an IL and water mixture at room temperature. By heating and maintaining the temperature above 56°C, this solution can draw water from high-salinity solution up to 3.0 M, 5 times salty as the sea water. The IL draw solution can be easily regenerated by phase separation. Conducting the FO process at higher temperatures can also increase the water flux. According to the different choices of the freshwater polishing step, the electric energy consumption in this novel process was estimated as 26.3% to 64.2% of conventional one-step sea water reverse osmosis. Two UCST ILs with better performance, [Hbet][Tf2N] and choline bis(trifluoromethylsulfonyl)imide ([Choline][Tf2N]), were selected as the agents in a novel closed-loop thermally responsive IL osmotic heat engine (TRIL-OHE) to convert low-grade thermal energy to electricity. The specific energies of the [Hbet][Tf2N] system and the [Choline][Tf2N] system are 2500 kJ/t and 3700 kJ/t, which are 2.7 and 4.0 times of the seawater and river water system, respectively. The maximum power density measured from a commercial FO membrane is 1.5 W/m2 for the [Hbet][Tf2N] system and 2.3 W/m2 for the [Choline][Tf2N] system, leaving a big room to improve if highly permeable membranes are used. Another notable advantage of the TRIL-OHE is the heat released from the cooling stage can be largely recovered. A rigorous energy balance showed with a 70% heat recovery, the energy efficiency could be increased from around 20% to 70% of the Carnot efficiency in both UCST ILs systems.

Polymer matrices are commonly used as guest-host systems for organic chromophores for use in non-linear optical materials. The chromophores must be aligned or poled in an electric field in order to impart anisotropy and non-linear activity to the material. This poling process raises several issues, the two largest being the eventual relaxation of the chromophores back into random orientations due to brownian motion, and high molecular weight polymer matrices limiting chromophore mobility during poling. The prevention of this relaxation process is an area of significant interest, especially in applications that require long term coating stability and activity. In this study, a polymer matrix is synthesized that seeks to solve both of these problems with one system. The ideal system would be one that allows for chromophore mobility during processing, but once chromophores have reached the desired orientation, limits mobility and relaxation during in-service usage. A copolymer of methyl methacrylate and a Diels-Alder adduct cross-linking monomer was synthesized in order to meet these challenges. This polymer was blended with commercially available acrylic polymer and organic chromophore molecules in order to test the viability of the solution. It was found that at the percent composition of cross-linker being utilized in the study, the Diels-Alder linkages were not reforming in any measurable amount due to the low amount of Diels-Alder active monomer units. This led to the development of a new system based on mixing polyfuran based polymers with polymaleimide based polymers during processing. This method allows for high amounts of cross-linking after processing ceases, which achieves both initial goals of the project, as well as allowing facile synthesis of the desired polymer components. Another attempt to address these issues in polymer matrix formation led to the use of a novel inimer system. The cross-linking agent was also the polymerization initiator, and these functionalities were separated by a Diels-Alder linkage that would fall apart upon exposure to thermal stimulus. These polymers were synthesized and isolated easily, although in some cases gelation occurred. In order to observe the extent of the cross-linking inimer being incorporated into the matrix, cleavage experiments were performed to induce the breaking of the Diels-Alder adduct. Analyzing the Diels-Alder cleaved polymer led to an interesting result: all polymers showed an increase in apparent molecular weight when analyzed by gel permeation chromatography. The increase in molecular weight occurring upon cleavage of main chain bonds has never before been observed in literature. The explanation proposed was that the polymer adopted a "ropeball" like topology consisting of tightly coiled loops and knots. Upon cleavage of the cross-links, the ropeball was able to unwind into a much more linear topology, occupying a much larger hydrodynamic volume. This increase in hydrodynamic volume would cause the gel permeation chromatography results to show an apparent increase in molecular weight.

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