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Triptolide (TPL), a diterpenoid triepoxide that is extracted from a traditional Chinese herb called Tripterygium Wilfordii (also known as ‘Thunder God Vine’) has recently drawn increasing interests from pharmaceutical and biomedical researchers, especially in the aspect of its potential efficacy on multiple cancer treatment. TPL has shown significant growth and proliferation inhibition activities in a broad range of cancer cell types. Moreover, it has shown the inhibition of osteoclastogenesis by breast cancer bone metastasis. However, due to its limitation in toxicity, solubility and non-specific biodistribution, it is challenging for the application of TPL in clinical study. Besides, TPL can rapidly distribute in most vital organs and no evidences shown tissue accumulation of drug. It is indispensable to overcome those barriers and optimize the properties and performance of the promising drug molecule. Lipid-based nanocarriers such as nanostructured lipid carriers (NLC) have been extensively studied for delivery of poorly-water soluble drug compounds. They also have the potential to optimize the physicochemical properties of the drug and may enhance a targeted delivery of the drug to specific therapeutic site. Alendronate (Fosamax®), an FDA approved bisphosphonate drug for osteoporosis, osteogenesis imperfecta and several other bone diseases, has been used as a bone targeting decoration agent. Breast cancer cell line MDA-MB-231 and other type of cancer cell lines have been used to study the in vitro cytotoxicity of TPL and the carriers while MC3T3-E1 cell line was used for toxicity assessment. Rats have also been used to study the in vivo performance of the drug. After modifying and optimizing the formulation of the particle, the formulation had the ability to remain structurally and functionally stable when being in the bio-simulated media at 37 °C and in water at room temperature with high encapsulation efficiency. In vitro study illustrated that both TPL free drug (stock solution 10mg/mL dissolved in DMSO) and TPL nanoparticle without alendronate (TPL-NP) had similar cytotoxicity on MDA-MB-231 and some other type of cancer cell lines. The ALE decoration on the particle (ALE-NP-TPL) has enhanced the anti-cancer effect especially with breast cancer cell line. The in vivo study shows that after 24 hours of the dose injection at local bone site, the formulation and TPL can remained at the location without random distribution to other organs. TPL-NP has not only successfully optimized the physicochemical properties of the drug, but also shows great enhancement of therapeutic effect both in vitro and in vivo study. / Pharmaceutical Sciences

Polycyclic aromatic hydrocarbons (PAHs) are highly hydrophobic and lipophilic and are readily retained by soil surfaces and organic matter. Hence, several techniques have been developed in an effort to economically and effectively remove them from soil solids. Their strong affinity to soil organic matter limits their biodegradation processes by microorganisms, making them persistent in the soil environment. Recently, the use of “small unilamellar vesicles” (SUVs), nano-scale lipid aggregates, has been proposed as a means to enhance these microbial degradations, by effectively solubilizing lipophilic PAHs from the soil solids. In this thesis, laboratory-scale batch experiments were performed to examine this potential by measuring the uptake of benzo[a]pyrene (BaP), a model PAH compound, by SUVs from a simulated soil organic matter. This environmental surface was created by coating silica (SiO2) nanospheres with a layer of poly-L-lysine, followed by humic acid, and characterized by dynamic light scattering for particle size and zeta potential values. Then, these humic acid-bound SiO2 particles were saturated with BaP and then equilibrated with SUVs. The uptake of BaP by SUVs was measured through fluorescence spectroscopy, and the average amount of BaP concentrated in the 1 mg/L humic acid-bound SiO2 particles was found to be 1.77 µg/L. After one week of equilibration with SUVs, 94.4% and 83.6% of the added BaP was solubilized by SUVs (in solutions containing 50 mg/L and 100 mg/L of vesicles, respectively), indicating an excellent ability to extract BaP from the soil organic particles. SUVs can therefore be an effective vehicle to enhance the biodegradability of PAHs in soils, with potential as an environmentally sustainable and affordable method. / Geology

Lateral flow biosensors are analytical devices that detect biomaterials with physicochemical signals, such as optical signals. Unlike other biosensors, lateral flow biosensors are based on porous membranes, which use capillary force to transport biomaterials spontaneously. However, lateral flow biosensors are fabricated in batch mode, which means that membranes need to be cut from the rolls, pretreated, and assembled using a step-by-step process. Thus, there is a need for a more efficient manufacturing process. This thesis aims to accelerate the fabrication process by developing a method wherein the whole device is printed directly, including the printable substrates, as well as by developing a clog-free process for depositing expensive reagents. These novel printable porous media were developed using printing inks that contained various pigments and polymer binders. To this end, candidate formulations were screened from nine hundred inks formulations via wicking experiments. The results of these tests showed that the most promising formulations were based on calcium carbonates and latex polymers. This formulation was then used to develop printable porous media that can easily be printed into complex patterns, with changeable wicking speeds within each pattern. In addition, a bio- colorimetric assay of alkaline phosphates conducted on these porous media showed strong color signals that were comparable to the traditional membrane-based lateral flow strips. Clog-free printing processes were investigated by using a piezoelectric inkjet printer to print silica sols and six nanoparticle inks. The results of these tests showed that the vibration of the piezoelectric layer and the deposition of particles on the printhead surfaces induced clogging issues. Over time, the silica sols formed multilayer deposits on the print head surface, which subsequently detached due to the vibration of the piezoelectric layer. Consequently, these large sheets of silica clogged the nozzles during printing. This clogging issue was eliminated by adjusting the pH value of the silica sol inks to 3.1. The hydrophobic cationic polystyrene nanoparticles form a sub-monolayer on the printhead surface, which causes air entrainment and promotes air bubble adhesion into the interior of the print head surface when the piezoelectric layer deforms. Thus, alternate surface chemistries for the print head and ink particle surfaces may be required in order to print hydrophobic ink materials. Overall, this enhanced understanding of these clogging mechanisms helps to explain why printer performance varies when different particles are used. / Thesis / Doctor of Philosophy (PhD) / Many devices in our day-to-day lives incorporate lateral flow biosensors, for example, home pregnancy test kits. These tests allow users to obtain results within 30 minutes by simply applying a few droplets of urine onto a test strip. However, these biosensors are largely manufactured using manual processes: workers cut strips (also called substrates) from sheets, deposit reagents onto the strips, and then assemble the pretreated strips into devices. As such, these processes are time consuming and less productive. To accelerate the manufacturing process, we developed printable porous substrates and a clog-free printing process for depositing expensive reagents onto the substrates. Novel porous media can be flexibly printed into complex patterns using pigment- based inks. Moreover, the use of different pigments within the designed patterns enables these porous media to control wicking velocity. In addition to printable porous substrates, the research in this thesis shows that the manufacturing process can be improved by using piezoelectric inkjet printers. The use of these printers not only allows the expensive reagents to be precisely deposited onto the substrates, but it also offers a more cost-effective method of doing so. Finally, in order to ensure the printing process remained clog-free, we systematically investigated clogging mechanisms by printing with different polymers and nanoparticles.

Superparamagnetic Magnetite (Fe3O4) nanoparticles were synthesized and complexed with carboxylate-functionalized block copolymers, and aqueous dispersions of the complexes were investigated as functions of their chemical and morphological structures. The block copolymer dispersants possessed either poly(ethylene oxide), poly(ethylene oxide-co-propylene oxide), or poly(ethylene oxide-b-propylene oxide) outer blocks, and all contained a polyurethane center block with pendant carboxylate functional groups. The complexes were formed through interactions of the carboxylates with the surfaces of the magnetite nanoparticles. Initial efforts utilized an aqueous coprecipitation method for the synthesis of magnetite nanoparticles, which yielded polydisperse magnetite nanoparticles. The nanoparticle complexes were characterized with a range of solution- and solid-state techniques including TGA, XPS, TEM, VSM, DLS and zeta potential measurements. DLVO calculation methods, which sum the contributions from van der Waals, steric, electrostatic and magnetic forces were utilized to examine the interparticle potentials in the presence and absence of external magnetic fields. Compositions were identified wherein a shallow, attractive interparticle potential minimum appears once the magnetic term is applied. This suggested the possibility of tuning the structures of superparamagnetic nanoparticle shells to allow discrete dispersions without a field, yet permit weak flocculation upon exposure to a field. This property has important implications for biomedical applications where movement of particles with an external magnetic field is desirable. In a second study, well-defined, narrow size dispersity magnetite nanoparticles were synthesized via the thermolysis of an iron (III) acetylacetonate (Fe(acac)3) precursor in the presence of benzyl alcohol. The magnetite nanoparticles were coated with triblock and pentablock copolymers possessing poly(ethylene oxide) and poly(propylene oxide-b-ethylene oxide) tailblocks and the carboxylate-functional anchor block. DLVO calculations were applied to the new magnetite particles and diagrams of potential energy versus interparticle distance indicated the predominant effect of steric and magnetic interactions on the particle stability. Exposure of the pentablock copolymer-magnetite complexes in phosphate buffered saline to a 1500 Oe magnetic field with concomitant DLS measurements indicated flocculation of the magnetic nanoparticles. DLS measurements showed increased hydrodynamic radii and scattering intensities with time. / Ph. D.

Luminescent quantum dots (QDs) or rods are semiconductor nano-particles that may be used for a wide array of applications such as in electro-optical devices, spectral bar coding, tagging and light filtering. In the case under investigation, the nano-particles are cadmium-selenide (CdSe), though they can be made from cadmium-sulfide, cadmium-telluride or a number of other II-VI and III-V material combinations. The CdSe quantum dots emit visible light at a repeatable wavelength when excited by an ultraviolet source. The synthesis of colloidal quantum dot nanoparticles is usually an organo-metallic precursor, high temperature, solvent based, airless chemical procedure that begins with the raw materials CdO, a high boiling point ligand, and a Se-trioctylphosphine conjugate. This investigation explores the means to produce quantum dots by this method and to activate the surface or modify the reaction chemistry with such molecules as trioctylphosphine oxide, stearic acid, dodecylamine, phenyl sulfone, aminophenyl sulfone, 4,4'dichlorodiphenyl sulfone, 4,4'difluorodiphenyl sulfone, sulfanilamide and zinc sulfide during the production to allow for further applications of quantum dots involving new chemistries of the outer surface. Overall, the project has been an interesting and successful one, producing a piece of equipment, a lot of ideas, and many dots with varied capping structures that have been purified, characterized, and stored in such a way that they are ready for immediate use in future projects. / Master of Science

Drinking water supplies contaminated with arsenic (As), a toxin and carcinogen, adversely impact the health of millions of people worldwide. Previous work has documented that different inorganic and organic As species vary with respect to their toxicities. It is, however, currently not well understood how As speciation affects bioavailability, defined as the capacity of a contaminant to cross an organism's cellular membrane, or how arsenic's form (dissolved vs. non-dissolved) can affect bioavailability. This dissertation addresses the effect of speciation and form on As bioavailability through a combination of field and laboratory studies. In the first project, a poultry litter application experiment was conducted to determine if trace elements (As, Cu, and Zn) are released from litter to underlying soil water, and if so, whether the trace elements are present in dissolved form or complexed to nanoparticles, colloids, or particles. Results showed that Cu and Zn released from the litter were dominantly complexed to organic matter or to iron oxides/clay particles, while As was dominantly dissolved or complexed to organic matter. In the second project, a luminescent E. coli bioreporter was created and exposed to different As species, including As(III), As(V), MSMA, and roxarsone. Results showed variable response, with As(III) producing the strongest response, followed by As(V) and MSMA; roxarsone showed no response. The bioreporter was exposed to As solutions with varying cation concentrations to examine the impact of sample geochemistry on performance. Increased monovalent (Na,K) concentrations enhanced luminescent response, while increased divalent (Ca) concentrations inhibited response. These altered responses reflect different As uptake pathways into the cell. The third study addressed bioavailability of As species to Corbicula fluminea, a clam commonly used for biomonitoring. Results demonstrate that As(III) is most bioavailable to Corbicula, followed by As(V), MSMA, and roxarsone. Corbicula also displayed the ability to change As speciation through internal processing and via their shell, demonstrating that Corbicula can affect As speciation in solution. Results of these studies enhance the scientific knowledge of how speciation and form affect As bioavailability, and can also inform regulators who use bioavailability to set remediation goals for As-contaminated systems. / Ph. D.

Silver nanoparticles (nanosilver) are gaining significant attention from the academic and regulatory communities, not only because of their antimicrobial effects and subsequent product applications, but also because of their potential health and environmental impacts. Although some human health effects of silver nanoparticles have been reported, realistic exposure levels from the use of consumer products are still largely unknown. The objective of this work was to characterize the release of silver and silver- containing particles during the normal use of silver nanotechnology consumer products. Specific objectives were to review the environmental and human health risks of airborne, engineered nanoparticles, to characterize aerosol emissions from nanosilver spray products, and to characterize nanosilver that may be released from childrenʼs consumer products under conditions of normal use. We identified possible routes of aerosolization of nanosilver from the production, use, and disposal of consumer products and estimated that about 14% of silver nanotechnology products that have been inventoried could potentially release silver particles into the air during use. The spray products investigated emitted 0.24 – 56 ng of silver in aerosols per spray action, and the plurality of aerosols were 1 – 2.5 μm in diameter, easily inhaled, for two products. Both the products' liquid characteristics and the bottles' spraying mechanisms played roles in determining the aerosol size distributions, but the size of silver-containing aerosols was largely independent of the liquid phase size distributions. We compiled an inventory of 82 children's consumer products that claim to contain nanosilver, of which 13 products were examined for presence of silver and tested for release of silver into liquid media and air, and onto skin. All products contained some form of silver, but silver-containing particles were observed in only four products, with sizes ranging from nanoscale up to 10 μm in size. Silver leached preferably into synthetic biological media with higher chloride concentrations, such as sweat and urine. We determined that levels of silver to which children would be exposed during normal use of these products are likely to be low, and bioavailable silver is expected to be in ionic rather than particulate form. / Ph. D.

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.