Thesis (M.Sc.Eng.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Nanoparticle-based drug delivery has been explored to circumvent the often-toxic chemotherapy treatments used today by providing a more efficient and specific delivery to diseased tissues. Recently we have developed polymeric pH-responsive expansile nanoparticles (eNPs) for intracellular delivery of paclitaxel (Pax) as an improvement upon the traditional methods of delivery of Pax with using Cremophor/ethanol. As eNPs are internalized by the cell, the hydrophobic protecting groups found on side chains along the polymer backbone are hydrolyzed, leaving behind hydrophilic moieties that cause the eNPs to slowly swell with water. In this manner, the encapsulation and controlled release of a hydrophobic drug can be achieved. By altering the surface characteristics of the eNPs, one can change the behavior of the delivery vehicle as well as the biological response. To explore this approach, two surfactant strategies were employed. Specifically, the original sodium dodecyl sulfate (SDS) surfactant has been substituted with PEGylated surfactants (either lipids or poloxamer) to improve circulation and in vivo stability. In addition, these surfactants were functionalized to target the folate receptor (FR), which is overexpressed in several cancers, in order to increase cancer cell-specific localization and uptake. The resulting eNPs retained their swelling characteristics while demonstrating improved cellular uptake in folate receptor-expressing KB and MDA-MB-231 carcinoma cells with no change in uptake in A549 cells, which do not express the folate receptor. / 2999-01-01

Cigarette smoking is prevalent worldwide and has consistently been the top preventable cause of many serious diseases., which result in huge mortality, morbidity, and economic loss, in recent decades. In recent years, nicotine vaccines that can induce production of nicotine specific antibodies in human have emerged as a promising medicine to treat tobacco addiction. In the past decade, there have been numerous nicotine vaccine candidates evaluated in human clinical trials, including NicVaxNicVAX®, TA-NICTA-NIC®, Nic002NIC002®, NiccineNiccine®, and SEL-068SEL-068®. . However, traditional nicotine vaccine designs haves many disadvantages, including low immunogenicity, low specificity, difficulty in integration of molecular adjuvants, and short immune response persistence. To overcome the above limitations, in this study, various nanoparticle-based vaccine delivery systemsvaccine componentss have been developed and evaluated as potential delivery vehicles for vaccines against nicotine addiction. Firstly, a nicotine vaccine was synthesized by conjugating bovine serum albumin (BSA)-nicotine complex to the surface of nano-sized cationic liposome. Significantly higher anti-nicotine antibody titer was achieved in mice by liposome delivered nicotine vaccine compared with nicotine-BSA vaccine. Secondly, a novel nanoparticle (NP)-based delivery platform was constructed by incorporating a negatively charged nanohorn into cationic liposome to improve the stability of liposome and reduce nanoparticle flocculation. Subsequently, nicotine vaccine was constructed by conjugating nicotine-BSA complex to the surface of the nanohorn supported liposome (NsL). Marked improvement in stability in vitro and significant increase in titer of anti-nicotine antibodies were detected in nanohorn supported liposome ( NsL) delivered vaccine than liposome delivered vaccine. In addition, NsL nicotine vaccine exhibited good safety in mice after multiple injections. Thirdly, lipid- poly(lactic-co-glycolic acid) (PLGA) hybrid NPs were constructed as vaccine delivery system. due to the fact that nanohorn is not currently approved for clinical use, we substituted the nanohorn with poly(lactic-co-glycolic acid) (PLGA) nanoparticles and constructed PLGA-lipid hybrid nanoparticles. Preliminary results showed that PLGA-lipid hybrid NPs nanoparticles exhibited improved stability, better controlled release of antigens, as well as enhanced uptake by dendritic cell (DC). A lipid-PLGA hybrid NPnanoparticle was also developed that was structurally responsive to low pH challenge. The lipid shell of the hybrid nanoparticle was rapidly disintegrated under a low pH challenge, which resembles the acidic environment of endosomes in DCsdendritic cells. The hybrid NPs exhibited minimal antigen release in human serum at physiological pH, but a faster release of antigen from this NP compared to non-pH sensitive NPs was observed in DC. In the final study, hybrid NPnanoparticles with various cholesterol concentrations were constructed. Slower and more controlled release of antigens in both human serum and phosphate buffered saline were detected in nanoparticles with higher cholesterol content. However, nanoparticles containing higher cholesterol showed poorer stability due to increase fusion among NPnanoparticles. It was later found that PEGylation of NPs can effectively minimize fusion caused size increase after long term storage, leading to improved cellular uptake. The findings from this study on the nanohorn-lipids based nicotine vaccine as well as lipid-PLGA hybrid NPs may provide solid basis for future development of lipid-PLGA based nicotine vaccine. / Ph. D.

Throughout the United States, there are a large number of groundwater systems contaminated by chlorinated organic compounds. Of these compounds, carbon tetrachloride (CT) is one of the most frequently encountered due to its past, widespread industrial use. In anaerobic groundwater environments, CT has been shown to be susceptible to degradation by both biotic and abiotic processes. One abiotic process that has been researched extensively is the reduction of CT by iron metal and associated iron oxides and hydroxides. Magnetite, an iron oxide, is a ubiquitous component of many subsurface environments and has been investigated as a potential groundwater remediation technology. One beneficial characteristic of magnetite is the capability to be synthetically produced in various sizes and shapes - including particles within the nanoscale range. Nanoscale particles have been shown to be more reactive towards contaminants than larger sized particles due to their large surface areas and high surface reactivity. This project was designed to characterize the behavior of synthetic magnetite in the presence of carbon tetrachloride under anaerobic conditions. / Master of Science

The ability of uniquely functional thermoelectric materials to convert waste heat directly into electricity is critical considering the global energy economy. Profitable, energy-efficient thermoelectrics possess thermoelectric figures of merit ZT ≥ 1. We examined the effect of metal nanoparticle – oxide film interfaces on the thermal conductivity κ and Seebeck coefficient α in bilayer and multilayer thin film oxide thermoelectrics in an effort to improve the dimensionless figure of merit ZT. Since a thermoelectric's figure of merit ZT is inversely proportional to κ and directly proportional to α, reducing κ and increasing α are key strategies to optimize ZT. We aim to reduce κ by phonon scattering due to the inclusion of metal nanoparticles in the bulk of thermoelectric thin films deposited by Pulsed Laser Deposition. XRD, AFM, XPS, and TEM analyses were carried out for structural and compositional characterization. The electrical conductivities of the samples were measured by a four-point probe apparatus. The Seebeck coefficients were measured in-plane, varying the temperature from 100K to 310K. The thermal conductivities were measured at room temperature using Time Domain Thermoreflectance. / Master of Science

This thesis is on molecular dynamics studies of drying suspensions of bidisperse nanoparticle mixtures. I first use an explicit solvent model to investigate how the structure of the dry film depends on the evaporation rate of the solvent and the initial volume fractions of the nanoparticles. My simulation results show that the particle mixtures stratify according to their sizes when the suspensions are quickly dried, consistent with the prediction of recent theories. I further show that stratification can be controlled using thermophoresis induced by a thermal gradient imposed on the drying suspension. To model larger systems on longer time scales, I explore implicit solvent models of drying particle suspensions in which the solvent is treated as a uniform viscous background and the liquid-vapor interface is replaced by a potential barrier that confines all the solutes in the solution. Drying is then modeled as a process in which the location of the confining potential is moved. In order to clarify the physical foundation of this moving interface method, I analyze the meniscus on the outside of a circular cylinder and apply the results to understand the capillary force experienced by a spherical particle at a liquid-vapor interface. My analyses show that the capillary force is approximately linear with the displacement of the particle from its equilibrium location at the interface. An analytical expression is derived for the corresponding spring constant that depends on the surface tension and lateral span of the interface and the particle radius. I further show that with a careful mapping, both explicit and implicit solvent models yield similar stratification behavior for drying suspensions of bidisperse particles. Finally, I apply the moving interface method based on an implicit solvent to study the drying of various soft matter solutions, including a solution film of a mixture of polymers and nanoparticles, a suspension droplet of bidisperse nanoparticles, a solution droplet of a polymer blend, and a solution droplet of diblock copolymers. / PHD / Drying is a ubiquitous phenomenon. In this thesis, I use molecular dynamics methods to simulate the drying of a suspension of a bidisperse mixture of nanoparticles that have two different radii. First, I use a model in which the solvent is included explicitly as point particles and the nanoparticles are modeled as spheres with finite radii. Their trajectories are generated by numerically solving the Newtonian equations of motion for all the particles in the system. My simulations show that the bidisperse nanoparticle mixtures stratify according to their sizes after drying. For example, a “small-on-top” stratified film can be produced in which the smaller nanoparticles are distributed on top of the larger particles in the drying film. I further use a similar model to demonstrate that stratification can be controlled by imposing a thermal gradient on the drying suspension. I then map an explicit solvent system to an implicit one in which the solvent is treated as a uniform viscous background and only the nanoparticles are kept. The physical foundation of this mapping is clarified. I compare simulations using the explicit and implicit solvent models and show that similar stratification behavior emerge in both models. Therefore, the implicit solvent model can be applied to study much larger systems on longer time scales. Finally, I apply the implicit solvent model to study the drying of various soft matter solutions, including a solution film of a mixture of polymers and nanoparticles, a droplet of a bidisperse nanoparticle suspension, a solution droplet of a polymer blend, and a droplet of a diblock copolymer solution.

With the development of controlled and predictable nanoparticle fabrication, assembling multiple nano-objects into larger functional nanostructure has attracted increasing attention. As the most basic structure, assembly of one-dimensional (1D) structures is a good model for investigating the assembly mechanism of a nanostructure's formation from individual particles. In this dissertation, the dynamics and the growth mechanism of anisotropic 1D nanostructures is investigated. In our first study, we demonstrate a simple method for assembling superparamagnetic nanoparticles (SPIONs) into structure-controlled 1D chains in a rotating magnetic field. The length of the SPION chains can be well described by an exponential distribution, as is also seen in SPION chains in a static field. In addition, the maximum chain length is limited by the field's rotational speed, as is seen in micro-sized beads forming chains in a rotating field. However, due to a combination of thermal fluctuations and hydrodynamic forces, the chain length in our case is shorter than either limit. In addition to chain length, the disorder of chains was also studied. Because of the friction between particles, kinetic potential traps prevent relaxation to the global free energy minimum. The traps are too deep to be overcome through thermal fluctuations, and assemblies captured by the kinetic traps therefore form disordered chains. We demonstrate that this disorder gradually heals over a timescale of tens of minutes and that the healing process can be promoted by increasing particle concentration or solution ionic strength, suggesting that the chain growth process provides the energy required to overcome the kinetic trapping. Next, we introduce a novel optical technique we term Quantitative Optical Anisotropy Imaging (QOAI). A fast and precise single-particle characterizing technique for anisotropic nanostructures, QOAI allows real-time tracking of particle orientation as well as the spectroscopic characterization of polarizabilities of nanoparticles on a microsecond timescale. The abilities of QOAI are demonstrated by the detection and the characterization of single gold nanorods. We also show that single particle diffusions and the process of particle binding to a wall can be tracked through QOAI. The rotational diffusivities of gold nanorods near the wall were determined by autocorrelation analysis, which shows that the diffusivity in the polar direction is slightly smaller than in the azimuthal direction. This result demonstrates that a detailed correlation analysis with QOAI may provide the opportunity to analyze both the translational and rotational motion of particles simultaneously, enabling true 3-dimensional orientation tracking. Finally, optical methods including QOAI are applied to the investigation of magnetic assembly, demonstrating that optical anisotropy is generated during particle binding, which can be used as a probe of the magnetic assembly process. QOAI is employed to track the dynamics of magnetic clusters in real time, attempting to capture insights on the self-assembly of the magnetic nanoparticles. By turning the external magnetic field on and off, the processes of combining superparamagnetic colloidal nanoparticle clusters into chain assemblies are monitored along with the chain growth. This fast and orientation-sensitive single-particle measurement opens the door to detailed studies of self-assembly away from equilibrium. / Doctor of Philosophy / Nanotechnology is the study and application of phenomena at the nanoscale, which is between 1 and 100 nm. Due to quantum effects, nanomaterials exhibit many interesting properties that cannot be found in bulk materials and are highly influenced by the shape of the nanostructures. One of the most promising strategies for forming complex nanostructures is to use smaller nanoparticles as building blocks. Therefore, significant efforts have been spent on the studies of the fabrication and modeling of the assembly of nanostructures. As a good starting point for analyzing the mechanism of self-assembly, we focus on the most basic structure, one-dimensional (1D) nanowires and chains. First, we demonstrate a simple method to fabricate one-dimensional magnetic chains from spherical magnetic nanoparticles in a rotating magnetic field. The growth mechanism of the nanochains is investigated, indicating the theory developed for chains formed with larger beads is not applicable at the nanoscale, and additional factors, such as the effect of temperature, need to be considered. Second, we introduce a fast, sensitive optical technique for characterizing anisotropic nanostructures. Because of their unique optical properties, gold nanorods are used to demonstrate the capabilities of the optical system. Not only static properties (orientation, aspect ratio), but also dynamics properties (rotational motion), of single gold nanorods are characterized quantitatively. Finally, this optical technique is extended to preliminary work on characterizing magnetic chain assembly. The processes of magnetic cluster binding and dissociation in a magnetic field are monitored and analyzed.

This dissertation describes the development of the fiberoptic microneedle device (FMD), a microneedle technology platform for fluid and light delivery, from general engineering characterization to specific applications in treating bladder and brain cancers. The central concept of the FMD is physical modification of silica fiberoptics and capillary tubes into sharp microneedles capable of penetrating a tissue's surface, enabling light and fluid delivery into the interstitial spaces. Initial studies sought to characterize the mechanical penetration and optical delivery of multimode fiberoptics and capillary tubes modified through a custom, CO2 laser melt-drawing technique. Additional work with multimode fibers investigated using an elastomeric lateral support medium to ensure robust penetration of small diameter fibers. These early experiments laid an engineering foundation for understanding the FMD technology. Subsequent studies focused on developing the FMD to treat specific diseases. The first such investigation sought to leverage the high aspect ratio nature of FMDs made from long capillary tubes as a therapy delivery device deployable through the instrument channel of a urological cystoscope. The therapeutic strategy was to infuse single-walled carbon nanohorns (SWNHs), a carbon-based nanoparticle allowing surface modification and drug encapsulation, into the infiltrating front of later stage bladder tumors. The SWNHs primarily serve as exogenous chromophores, enabling a fluid-based control of photothermal heat generation created when the SWNHs interacted with laser energy from an interstitial FMD or a light-emitting fiber in the bladder's interior. The study described here primarily sought to characterize the dispersal of the infused SWNHs and the photothermal response of the particles when heated with a 1064 nm laser. The FMD was also developed as a platform capable of conducting convection-enhanced delivery (CED), a therapeutic approach to treat invasive tumors of the central nervous system such as malignant glioma (MG). Intracranial CED involves the placement of small catheters local to the tumor site and slow infusion of a chemotherapeutic over long timeframes (12-72 hours). A primary challenge of this treatment approach is infused chemotherapeutics not dispersing sufficiently to reach the infiltrating cells in the tumor's margins. The hypothetical improvement provided by the FMD technology is using sub-lethal photothermal heating to sufficiently increase the diffusive and convective transport of an infusate to reach infiltrative cells in the tumor's periphery. Initial experiments sought to demonstrate and characterize a heat-mediated increase of volumetric dispersal in Agarose tissue phantoms and ex vivo tissue. Subsequent studies with in vivo rodent models determined the best laser parameters to achieve the desired levels of diffuse, sub-lethal heat generation and then demonstrated the hypothesis of increasing the rate of volumetric dispersal though concurrent local hyperthermia. This research was the first demonstration of photothermal augmentation of an interstitially infused fluid's dispersal rate, which may have uses outside of the CED approach to brain cancer exhibited here. Taken in sum, this manuscript describes the potency and versatility of the FMD technology platform through its development in various biomedical applications. / Ph. D.

This work created a manufacturing process and material system based on binder jetting Additive Manufacturing to process pure copper. In order to reduce the sintered part porosity and shape distortion during sintering, the powder bed voids were filled with smaller particles to improve the powder packing density. Through the investigation of a bimodal particle size powder bed and nanoparticle binders, this work aims to develop an understanding of (i) the relationship between printed part properties and powder bed particle size distribution, and (ii) the binder-powder interaction and printed primitive formation in binder jetting of metals. Bimodal powder mixtures created by mixing a coarse powder with a finer powder were investigated. Compared to the parts printed with the monosized fine powder constituent, the use of a bimodal powder mixture improved the powder flowability and packing density, and therefore increased the green part density (8.2%), reduced the sintering shrinkage (6.4%), and increased the sintered density (4.0%). The deposition of nanoparticles to the powder bed voids was achieved by three different metal binders: (i) a nanoparticles suspension in an existing organic binder, (ii) an inorganic nanosuspension, and (iii) a Metal-Organic-Decomposition ink. The use of nanoparticle binders improved the green part density and reduced the sintering shrinkage, which has led to an improved sintered density when high binder saturation ratios were used. A new binding mechanism based on sintering the jetted metal nanoparticles was demonstrated to be capable of (i) providing a permanent bonding for powders to improve the printed part structural integrity, and (ii) eliminating the need for organic adhesives to improve the printed part purity. Finally, the binder-powder interaction was studied by an experimental approach based on sessile drop goniometry on a powder bed. The dynamic contact angle of binder wetting capillary pores was calculated based on the binder penetration time, and used to describe the powder permeability and understand the binder penetration depth. This gained understanding was then used to study how the nanoparticle solid loading in a binder affect the binder-powder interactions and the printed primitive size, which provided an understanding for determining material compatibility and printing parameters in binder jetting. / PHD / The binder jetting Additive Manufacturing (AM) process can be used to fabricate net-shape metal parts with complex geometries by selectively inkjet printing a liquid binding agent into a powder bed, followed by post-process sintering of the printed green parts. Motivated by the need to create highly efficient thermal management systems, this work has established a binder jetting manufacturing process chain for fabricating components made of pure copper, a conductive and optically reflective material that is challenging to be processed by laser-based AM systems. In order to improve the performance metrics (e.g., mechanical strength, electrical and thermal conductivity) of the printed copper parts, an overall strategy to improve powder bed packing density by filling the powder bed voids with fine particles was investigated. Through the use of a bimodal powder mixture and a nanoparticle binder, the sintered density and structural integrity of the printed parts were improved. Via the investigation of these novel material systems created for binder jetting of copper, (i) the gaps in understanding the relationship between printed part properties and powder bed particle size distribution were filled, and (ii) an experimental approach to characterize and understand the binder-powder interaction and printed primitive formation was created to guide the selection of printing parameters in binder jetting.

New synthetic advances in the control of nanoparticle size and shape along with the development of new surface modifications facilitates the growing use of nanomaterials in biomedical applications. Of particular interest are functional and biocompatible nanomaterials for sensing, imaging, and drug delivery. The goal of this research is to tailor the function of nanomaterials for biomedical applications by improving the biocompatibility of the systems. Our work demonstrates both a bottom up and a post synthetic approach for incorporating stability, stealth, and biocompatibility to metal based nanoparticle systems. Two main nanomaterial projects are the focus of this dissertation. We first investigated the development of a green synthetic procedure to produce gold nanoparticles for biological imaging and sensing. The size and morphology of gold nanoparticles directly impact their optical properties, which are important for their function as imaging agents or their use in sensor systems. In this project, a synthetic route based on the natural process of biomineralization was developed, where a designed protein scaffold initiates the nucleation and subsequent growth of gold ions. To gain insight into controlling the size and morphology of the synthesized nanoparticles, interactions between the gold ions and the protein surface were studied along with the effect of ionic strength on interactions and then subsequent crystal growth. We are able to control the size and morphology of the gold nanoparticles by altering the concentration or identity of protein scaffold, salt, or reducing agent. The second project involves the design and optimization of metal organic framework nanoparticles for an external stimulus triggered drug delivery system. This work demonstrates the advantages of using surface coatings for improved stability and functionalization. We show that the addition of a polyethylene glycol surface coating improved the colloidal stability and biocompatibility of the system. The nanoparticle was shown to successfully encapsulate a variety of small molecule cargo. This is the first report of photo-triggered degradation and subsequent release of the loaded cargo as a mechanism of stimuli-controlled drug delivery. Each of the aforementioned projects demonstrates the design, synthesis, and optimization of metal-based systems for use in biomedical applications. / Ph. D. / Nanomaterials offer a wide range of physical and chemical properties making them good candidates for biomedical applications. Of particular interest are functional and biocompatible nanomaterials for sensing, imaging, and drug delivery. The goal of this research is to tailor the function of nanomaterials for biomedical applications by improving the biocompatibility of the systems. Our work demonstrates both a bottom up and a post synthetic approach for incorporating stability, stealth, and biocompatibility to metal based nanoparticle systems. Two main nanomaterial projects are the focus of this dissertation. We first investigated a synthetic route based on the natural process of biomineralization, where a designed protein scaffold initiates the nucleation and subsequent growth of gold ions. To gain insight into controlling the size and morphology of the synthesized nanoparticles, interactions between the gold ions and the protein surface were studied along with the effect of ionic strength on interactions and then subsequent crystal growth. We are able to control the size and morphology of the gold nanoparticles by altering the concentration or identity of protein scaffold, salt, or reducing agent. The second project involves the design and optimization of metal organic framework nanoparticles for an external stimulus triggered drug delivery system. This is the first report of photo-triggered degradation and subsequent release of the loaded cargo as a mechanism of stimuli-controlled drug delivery. Each of the aforementioned projects demonstrates the design, synthesis, and optimization of metal-based systems for use in biomedical applications.

Yes / Magnetic nanoparticles and surface-enhanced Raman scattering (SERS) active nanoparticles were coated with short chain DNA tags. These were then used to identify a target bacterial DNA sequence. The tags function as primers in a standard PCR with the reverse primers and forward primers on the SERS nanoparticles and magnetic nanoparticles, respectively. During the PCR cycles, a composite nanostructure is formed that is both magnetically responsive and SERS active. After magnetic trapping, the intensity of the SERS signal can be related back to the concentration of the target DNA. A test assay was performed that showed a detection limit (based on the signal to noise ratio) of less than 3 zeptomole (41 pg/L). For comparison, a PCR assay based on the standard SYBR Green method was performed. This used the same primers and target DNA and had a detection limit of 10 attomoles (138 ng/L), 3,000 times less sensitive. The work documents the proof of principle study and shows for the first time the use of SERS-NP labels in the quantification of nucleic acid amplification tests and PCR.