The favorable interaction between proteins and nanoparticles has sparked potential applications of nanotechnology in medicine, and the unique electronic and chemical properties of nanoparticles also provide novel strategies for protein-related therapeutics. The formation of the biocorona has attracted substantial interest over the past decades. For instance, as a potential drug delivery mechanism, protein-coated nanoparticles can improve biocompatibility and increase targeting ability. However, the mechanistic details of protein-nanoparticle interactions remain poorly understood. For example, it is currently impossible to predict the orientation and structure of proteins on the nanoparticle surface, as well as the fate of the biocorona in vivo. Since the composition of the biocorona determines the biological response, identifying and stabilizing the biocorona seems critical for the further development of applications in biological system. In this study, we investigated the physicochemical properties of protein interactions with gold nanoparticles (AuNPs). Firstly, we developed an NMR-based approach for measuring the stoichiometry of protein adsorption to AuNPs, which can be generally applied to globular proteins of different size. Quantitative analysis enabled us to create a protein binding model that involves an initial association, structure reorientation and irreversible adsorption. Secondly, we measured the protein hydrogen-deuterium exchange rates and found that they were unperturbed in the presence of AuNPs, suggesting that proteins retain their globular structure upon adsorption. Finally, we investigated the electrostatic contribution to binding, and we identified a dynamically changing surface in which the factors of net charge, binding affinity and protein size play distinct roles at different phases.

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Polymer matrices doped with a dispersion of noble metal nanoparticles combine the strong plasmon resonance-based optical signatures of the latter with the flexibility and processability of the former. We have developed a nonlinear lithographic technique to generate large populations of epoxide waveguides containing a uniform dispersion of Au nanoparticles. The method is based on the self-trapping of multiple beams of white light propagating through a catonic polymerizable matrix doped with a gold salt, initiating the polymerization of epoxide moieties and simultaneously the in situ synthesis of elemental Au nanoparticles. Each white light filament inscribes a cylindrical waveguide, leading to an array of metallodielectric waveguides. Field of view (FOV) measurements indicate that the metallodielectric waveguide array has a nearly 59 % increase in FOV relative to its all-dielectric counterparts and can be tuned through the concentration of Au nanoparticles and the optical intensities employed to generate waveguides. / Thesis / Master of Science (MSc)

Gold nanoparticles (GNPs) are currently being intensely investigated for their potential use in biomedical applications. Nanotoxicity studies are urgently needed to validate their safety in clinical practice. The objective of this research was to assess the acute, subacute, and chronic effects of a single intravenous exposure to commercially available GNPs in two in vivo models, mice and rats. Gold nanoparticles were purchased and independently characterized. Animals were exposed to either 1000 mg GNPs/kg body weight (GNP group) or an equivalent volume of phosphate buffered saline (PBS group) intravenously via the tail vein. Subsets of animals were euthanized 1, 7, 14, 21, 28 days (female BALB/c mice and female F344 rats) or 20 weeks (female and male C57BL/6 mice) post-exposure and samples were collected for biochemistry, histopathology, electron microscopy, and atomic absorption spectrometry analysis. Independent characterization demonstrated that the physicochemical properties of the purchased GNPs were in good agreement with the information provided by the supplier. Important differences in GNP-induced immune responses were identified when comparing mice and rats 1 to 28 days post-exposure. Gold nanoparticles stimulated the formation of liver microgranulomas in mice, along with transiently increased serum levels of the proinflammatory cytokine interleukin-18. No such alterations were found in rats. Species differences in GNP biodistribution and excretion were also detected, with higher relative accumulation of GNPs in spleen and longer fecal excretion in rats. In the long-term (20 weeks after dosing), exposure to GNPs incited chronic inflammation in mice, characterized by the persistence of microgranulomas in liver, spleen, and lymph nodes, as well as further increased serum levels of interleukin-18. Impairment of body weight gain was also observed in the GNP-exposed group. No sex differences were detected. In conclusion, GNPs are not innocuous and have the ability to incite a robust macrophage response in mice. However, considering the mildness of the toxic effects identified despite the high dose selected for the study, GNPs continue to have great potential for biomedical uses. Further studies are needed in order to determine specific mechanisms of toxicity and the role of chronic inflammation in the development of adverse effects after co- or post-exposures. / Ph. D.

Emerging technologies in the healthcare industry encompass revolutionary devices or drugs that have the potential to change how healthcare will be practiced in the future. While there are several emerging healthcare technologies in the pipeline, a few key innovations are slated to be implemented clinically sooner based on their mass appeal and potential for healthcare breakthroughs. This thesis will focus on specific topics in the emerging technological fields of nanotechnology for photothermal cancer therapy, 3D printing for irreversible electroporation applications, and imageable biomaterials. While these general areas are receiving significant attention, we highlight the potential opportunities and limitations presented by our select efforts in these fields. First, in the realm of nanomedicine, we discuss the optimization and characterization of sodium thiosulfate facilitated gold nanoparticle synthesis. While many nanoparticles have been examined as agents for photothermal cancer therapy, we closely examine the structure and composition of these specific nanomaterials and discuss key findings that not only impact their future clinical use, but elucidate the importance of characterization prior to preclinical testing. Next, we examine the potential use of 3D printing to generate unprecedented multimodal medical devices for local pancreatic cancer therapy. This additive manufacturing technique offers exquisite design detail control, facilitating tools that would otherwise be difficult to fabricate by any other means. Lastly, in the field of imageable biomaterials, we demonstrate the development of composite catheters that can be visualized with near infrared imaging. This new biomaterial allows visualization with near infrared imaging, offering potentially new medical device opportunities that alleviate the use of ionizing radiation. This collective work emphasizes the need to thoroughly optimize and characterize emerging technologies prior to preclinical testing in order to facilitate rapid translation. / Master of Science

Yes / Peptide-enabled nanoparticle (NP) synthesis routes can create and/or assemble functional nanomaterials under environmentally friendly conditions, with properties dictated by complex interactions at the biotic/abiotic interface. Manipulation of this interface through sequence modification can provide the capability for material properties to be tailored to create enhanced materials for energy, catalysis, and sensing applications. Fully realizing the potential of these materials requires a comprehensive understanding of sequence-dependent structure/function relationships that is presently lacking. In this work, the atomic-scale structures of a series of peptide-capped Au NPs are determined using a combination of atomic pair distribution function analysis of high-energy X-ray diffraction data and advanced molecular dynamics (MD) simulations. The Au NPs produced with different peptide sequences exhibit varying degrees of catalytic activity for the exemplar reaction 4-nitrophenol reduction. The experimentally derived atomic-scale NP configurations reveal sequence-dependent differences in structural order at the NP surface. Replica exchange with solute-tempering MD simulations are then used to predict the morphology of the peptide overlayer on these Au NPs and identify factors determining the structure/catalytic properties relationship. We show that the amount of exposed Au surface, the underlying surface structural disorder, and the interaction strength of the peptide with the Au surface all influence catalytic performance. A simplified computational prediction of catalytic performance is developed that can potentially serve as a screening tool for future studies. Our approach provides a platform for broadening the analysis of catalytic peptide-enabled metallic NP systems, potentially allowing for the development of rational design rules for property enhancemen / Air Force Office for Scientific Research (Grant #FA9550-12-1-0226, RRN; AFOSR LRIR) and DOE-BES grant DE-SC0006877, fellowship support from the National Research Council Research Associateship

Surface modification of colloidal nanoparticles is essential for broadening the scope of nanotechnology. In this dissertation, we discuss novel approaches to functionalize the surface of nanoparticles to tailor their properties for applications including radical polymerization inhibitors, supported heterogeneous catalysts, and building blocks for plasmonic devices. First, we investigate the interaction of hydrogen-terminated silicon nanoparticles (H-SiNPs) with Karstedt's catalyst and report a room‑temperature synthesis of Pt-coated SiNPs with highly tunable Pt loading. Analysis of the Pt on-Si ensemble reveals surface-bound Pt(II) on SiNPs which can undergo ligand exchange. Upon calcination, Pt-loaded SiNPs catalyze the hydrogenation of phenyl acetylene, and the SiNP scaffold enables efficient recovery and reuse of the catalyst. Conditions that favor the reductive elimination of the catalyst and efficient hydrosilylation of olefins are also discussed. Next, we report H-SiNPs as inhibitors for anerobic thermal autopolymerization of methacrylates. Prior to use, these solid-state inhibitors can be easily removed from the methacrylic monomers by low-speed centrifugation, offering great advantage to the traditionally used phenols and quinones. Analysis of SiNPs isolated after heating in methacrylates reveals the grafting of ester groups. As such, thermal hydrosilylation is presented as a powerful yet facile route to attach ester and allyl ester groups onto the surface of SiNPs. Finally, we report a method to rapidly and uniformly assemble gold nanoparticles (AuNPs) and their clusters on cm‑scale unmodified substrates. Cetyltrimethylammonium (CTAC) capped AuNPs were conjugated to a sparse coating of poly(ethylene glycol) and extracted into dichloromethane. The clustered patterns were deposited on hydroxyl terminated surfaces from stable dispersions using centrifugal force. The degree of clustering on substrates was tuned by varying a single parameter, the concentration of CTAC in the deposition dispersion. This approach bridges the gap between methods for depositing isolated AuNPs (typically using electrostatic interactions) and AuNP clusters (using covalent or electrostatic binders) and enables large-scale uniform deposition of isolated AuNPs, as well as clusters with tunable size. The non‑covalent assembly onto the substrate provided a means for depositing AuNPs into nanowells in topographically patterned substrates: after uniform deposition onto these substrates, the AuNPs on the surface were selectively removed using mechanical rubbing. This facile approach enabled large-scale selective deposition of AuNPs into patterned substrates that are attractive as SERS substrates and refractive index sensors.

Yes / We report on the use of non-equillibrium biocatalytic self-assembly and gelation to guide the reductive synthesis of gold nanoparticles. We show that biocatalytic rates simultaneously dictate supramolecular order and presentation of reductive phenols which in turn results in size control of nanoparticles that are formed. / BBSRC funding (BB/K007513/1); European Research Council under the European Union’s Seventh Framework Programme, ERC (Starting Grant EMERgE) grant agreement no. 258775.

Yes / Thermal desolvation of poly(N‐isopropylacrylamide) (PNIPAM) in the presence of a low concentration of gold nanoparticles incorporates the nanoparticles resulting in suspended aggregates. By covalently incorporating <1% acenaphthylene into the polymerization feed this copolymer is enabled to be used as a model to study the segmental mobility of the PNIPAM backbone in response to gold nanoparticles both below and above the desolvation temperature, showing that there is a physical conformational rearrangement of the soluble polymer at ultralow nanoparticle loadings, indicating low affinity interactions with the nanoparticles. Thermal desolvation is capable of extracting >99.9% of the nanoparticles from their solutions and hence demonstrates that poly(N‐isopropylacrylamide) can act as an excellent scrubbing system to remove metallic nanomaterial pollutants from solution. / Science Foundation Ireland's ETS. Grant Number: 11/W.I/12085; MRC. Grant Number: MR/N501888/2