Thesis: S.M., Massachusetts Institute of Technology, Department of Chemical Engineering, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 31-40). / Optical biosensors based on fluorescent single-walled carbon nanotubes (SWNT) are a promising alternative to conventional biosensors due to the exceptional photophysical properties of SWNT. Such sensors can enable highly-sensitive, selective, and real-time detection of biological analytes. However, important questions regarding sensor fabrication and reproducibility must be addressed for these sensors to be of practical value. Herein we describe the use of highly-purified, single-chirality SWNT which are functionalized for antibody detection, and demonstrate that reproducibility is drastically improved with these SWNT. Further, we observe a concentration dependence of the effective equilibrium dissociation constant, KD,eff, which is in good agreement with previous reports, yet has eluded mechanistic description due to complexities associated with multivalent interactions. We show that a bivalent binding mechanism is able to describe this concentration dependence of KD,eff which varies from 100 pM to 1 uM for IgG concentrations from 1 ng/ml to 100 ug/ml, respectively. The mechanism is shown to describe the unusual concentration-dependent scaling demonstrated by other sensor platforms in the literature, and a comparison is made between resulting parameters. The platform is then extended to the detection of human growth hormone (hGH) using SWNT functionalized with a native hGH receptor (hGH-R), with potential use as a real-time and label-free measurement of protein activity. Native hGH is detected in the micromolar range, and an invariant equilibrium dissociation constant of 9 uM is revealed upon fitting the calibration curve to a single-site adsorption model. Selective detection of native hGH over thermally denatured hGH is shown at a concentration which is 1% of a clinical dose. Lastly, a multichannel detector was built to demonstrate real-time characterization of multiple protein properties. This work could find broad impact in biomanufacturing as real-time analysis of complex biologics is a long-standing goal in this field. / by Justin T. Nelson. / S.M.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1997. / Includes bibliographical references. / by Jane Farrol Ciebien. / Ph.D.

Massachusetts Institute of Technology. Dept. of Chemical Engineering. Thesis. 1966. Ph.D. / Bibliography: leaves 188-190. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, September 2005. / "August 2005." / Includes bibliographical references. / A Multi-Scale Analysis methodology was developed and carried out for gaining fundamental understanding of the pharmaceutical powder blending process. Through experiment, analysis and computer simulations, microscopic particle properties were successfully linked to their macroscopic process performance. This work established this micro-to-macro approach as a valid way to study unit operations in the pharmaceutical manufacturing of solid dosage forms. The pharmaceutical materials investigated were anhydrous caffeine, lactose monohydrate and micro- crystalline cellulose (MCC). At the macroscopic level, blending experiments were conducted in mini-scale lab blenders using the Light-Induced Fluorescence (LIF) technique. Effects of operating parameters on blending kinetics were systematically evaluated. It was found that the time required to reach a homogeneous mixture (thg) increased with blender fill volume (FV) and decreased with blender rotation rate (RPM). It was also found that MCC, as an excipient, always took longer time to mix with caffeine than lactose. At the microscopic level, force interactions - cohesion/adhesion and friction - were measured directly at the single particle level with Atomic Force Microscopy (AFM). / (cont.) It was found that cohesion/adhesion and friction fell into lognormal distributions. Based on AFM force maps, these distributions were attributed to the particle surface morphology. Chemically modified AFM cantilever tips were used to probe the hygroscopicity on the particle surfaces. In addition, the cohesive/adhesive forces were found to be size- dependent and thus, were converted to JKR surface energies to eliminate this dependence. Amongst the materials tested, MCC showed the strongest cohesive/adhesive and friction interactions. The AFM-measured microscopic force interactions were used to explain the blending kinetics profiles observed in the blending experiments. The longer blending time (thg) required by MCC was linked to its strong cohesive nature. In addition to these multi-scale relations, the AFM force interactions were used in Discrete Element Method (DEM) models for simulating blending processes. A two-dimensional model was used to simulate blending in a circular blender. With respect to the effect of operating parameters on blending kinetics, the simulations showed that thg increased as FV increased, RPM decreased, or when MCC as opposed to lactose was chosen as the excipient. / (cont.) These trends were identical to experimental observation. A three dimensional DEM code was developed. Blending in a V-shaped blender was simulated and results were consistent with experiments, namely the flow behavior correlated well with the differences in cohesion/adhesion and friction intensities of the excipients. Through a fundamental understanding at a microscopic level, one can identify opportunities for process improvement. In this way, Multi-Scale Analysis will facilitate the ability of pharmaceutical companies in pursuing the desired quality-by-design state in manufacturing. / Samuel SH Ngai. / Ph.D.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2002. / Includes bibliographical references. / In order to predict the quality of the fabricated devices as a function of growth conditions in chemical vapor deposition (CVD) reactors, a model should describe multiple time and length scales. These scales include the reactor scale ([approx]0.1-1 m), the feature scale ([approx.]0.1-100 [mu]m), and the atomistic morphology evolution scale ([approx.]10 nm). At present, good reactor and feature scale models are available. However, the linking between them has been done only for low pressure CVD. Also, the atomistic Kinetic Monte Carlo models have been developed only for deposition on unpatterned substrates or over V-grooves. In this work the linking between reactor and feature scale models for both low and high pressure CVD is achieved by matching concentrations and fluxes across the interface. For low-pressure systems, we improve the convergence of the previously developed linking schemes by applying a flux-split algorithm. We analyze the assumptions underlying the linking, and demonstrate that the size of the feature domain is constrained by these assumptions and not simply by the assumption of collisionless gas phase transport. At high-pressure, mass transport between features complicates solution of the entire feature field. To capture the diffusive inter-feature transport, we develop the overlapping computational domains method. The simulation results obtained with the multiscale method are in excellent agreement with experimental data for selective epitaxy of AlGaAs in the presence of HC1. A KMC model is developed for AlGaAs surface morphology evolution during selective epitaxy. The model takes into account zincblende structure of AlGaAs, and reproduces the c(4x4) reconstruction on (100) surfaces. / (cont.) In order to model selective epitaxy, the mask is represented as a hard wall boundary condition, and overgrowth on (111)A facets is included. With this model, we investigate the effects of the unknown parameters and the growth conditions on film morphology evolution. The observed trends are in agreement with the experimental data. Since KMC simulations are limited to small surfaces and short deposition times we propose algorithms for linking the KMC and mesoscale feature shape evolution models. Finally, the feasibility of linking the coupled KMC-mesoscale model and the reactor or reactor-feature scale models is assessed. / by Maria A. Nemirovskaya. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2007. / Includes bibliographical references. / Polymeric drug delivery systems have been widely used in the pharmaceutical industry. Such systems can solubilize and sequester hydrophobic drugs from degradation, thereby increasing circulation half-life and efficacy. However, there are still challenges in the design of drug delivery vehicles to achieve efficient drug delivery in a site-specific manner. In this thesis, an amphiphilic linear-dendritic block copolymer was designed, synthesized, and applied as a new polymeric drug delivery platform. First, to develop the drug delivery vehicle, an ABA dendritic-linear-dendritic block copolymer consisting of poly(amidoamine) (PAMAM) and poly(propylene oxide) (PPO) was synthesized. In order to determine the viability of the linear-dendritic block copolymer as a drug delivery vehicle, the solution-phase self-assembly behavior and the self-assembled structures were characterized experimentally and through molecular dynamics simulations. The triblock self-assembles in aqueous media to form stable micelles with low CMC values. Dynamic light scattering results and TEM indicate the formation of particles ranging from 9 to 18 nm in diameter, with smaller diameters exhibited at higher generations. Static light scattering also confirmed the trend where the aggregation number decreased with higher generations. The experimental characterization results indicated that the physical characteristics of the PPO-PAMAM micelles were desirable and within the design specifications necessary for drug delivery. The experimental results were utilized to set up simulations where further knowledge of the microstructure of the micelles formed could be gained. It was found that the block copolymers simulated formed micelles in the same size range that was seen experimentally. However, the simulations indicated that the micelles displayed greater asphericity than dendrimers. / (cont) Backfolding of the terminal amine ends was encountered, which would have implications for the configuration and spacing of any additional targeting ligand attached to the dendritic ends. Further analysis revealed that with increasing generation, the porosity of the micelles increased, which could affect the diffusion rate of drugs released out of the system. Another important finding detailed the preferential localization of a model hydrophobid drug, triclosan, in an equilibrated micelle structure. Additional experiments were performed to assess the feasibility of the nanoparticles for drug delivery applications. Drug loading studies were performed with a model hydrophobic drug, triclosan, resulting in high loading efficiencies. In comparison, linear block copolymers were half as efficient in loading triclosan. It was determined that the dendritic block synergistically increased the drug loading due to either acting as an additional block capable of encapsulating drug or sterically favoring the seclusion of the drug in the core. The linear-dendritic block copolymer synthesized was found to be a promising candidate for drug delivery due to its relative stability in aqueous solution and its drug encapsulation and release properties. Overall, the linear-dendritic block copolymer displayed physical characteristics and self-assembly behavior that satisfied the design criteria for a viable drug delivery vehicle. As a further step, the potential benefits of the novel linear-dendritic architecture were explored in two different drug delivery applications. First, PPO-PAMAM was explored as a circulating nanoparticle with the capability of multivalently targeting to specific cells, due to the presence of the dense functional groups on the dendritic block forming the corona of the micelles. PPO-PAMAM was functionalized with galactose and targeted to hepatocellular carcinoma cells. It was found that the polymer was not cytotoxic and could bind to the asialoglycoprotein receptor. / (cont) The galactose-functionalized micelles were loaded with a chemotherapeutic, doxorubicin, and delivered to the carcinoma cells more efficiently than non-functionalized micelles and bare doxorubicin. The results from in vitro testing showed that PPO-PAMAM micelles with targeting capability are promising circulating drug delivery vehicles. In order to ensure success of subsequent testing in vivo of the targeted linear-dendritic block copolymer system, some improvements to the system were explored. First, PPO-PAMAM micelles were stabilized by physical entrapment of the hydrophobic core. An emulsion polymerization of hydrophobic methacrylate monomers created an interpenetrating polymer keeping the micelles intact at concentrations below the CMC and in a solubilizing solvent, methanol. This improvement would ensure that once injected into the bloodstream, the micelles would not destabilize and release high concentrations of drug. Another improvement that was explored was the synthesis of a new linear-dendritic block copolymer composed of a hydrophobic poly(amino acid) and a polyester dendron. Additionally, poly(ethyleneglycol) (PEG) groups were attached to the outer surface of the polyester dendron. The new system synthesized has a low CMC and is thermodynamically slow to break apart in the bloodstream. Furthermore, the micelles formed would be able to circulate for longer times with PEG aiding in evading the reticuloendothelial system. The second drug delivery application explored, which advantageously utilized the dendritic blocks on the outer surface of the block copolymer micelles was as a localized drug delivery coating created by the layer-by-layer (LbL) assembly approach. The electrostatic LbL assembly approach offers large potential in the area of drug delivery from thin films and surfaces; however, because the processing technique is aqueous-based, there have been few strategies proposed to incorporate hydrophobic molecules into these films. / (cont) Here we created an LbL film that is capable of incorporating hydrophobic drug at high loadings via encapsulation with linear-dendritic block copolymer micelles and demonstrate for the first time release times of a hydrophobic antibacterial agent over a period of several weeks--a significant improvement over reports of other micelle-encapsulated thin films with release times of several minutes. The PAMAM block, which is polycationic, enabled LbL deposition with negatively charged poly(acrylic acid) (PAA). The stable PPO-PAMAM micelles incorporated into the LbL films encapsulated a hydrophobic bactericide, triclosan. Film thickness and UV-vis measurements confirm the formation of the LbL film and incorporation of triclosan into the film. Fluorescence measurements of PPO-PAMAM/PAA films with pyrene indicated the presence of hydrophobic domains in the film. GISAXS revealed regular spacing of approximately 10.5 nm in the direction parallel to the film substrate, which is approximately the same size as the PPO-PAMAM micelles in aqueous solution. Volume fraction measurements based on elemental analysis and TGA confirm the GISAXS data. An in vitro release study revealed long release times of triclosan on the order of weeks, and a Kirby Bauer test was performed on Staphylococcus Aureus demonstrating that the drug released was still active to inhibit the growth of bacteria. Linear-dendritic block copolymer micelles were successfully used in two different drug delivery applications where the dendritic block could be fully utilized. It is hoped that with the research and results presented in this thesis further development of this drug delivery platform can result in a product successfully treating a serious disease. / by Phuong Nguyen. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2016. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Vita. Cataloged from PDF version of thesis. / Includes bibliographical references (pages 108-115). / Antibody-Drug Conjugates (ADCs) are a promising therapeutic class which combines the potency of chemotherapeutic drugs with the specificity of a tumor targeting antibody. ADCs aim to reduce systemic toxicity and maintain or improve therapeutic efficacy. Once an ADC reaches a tumor and binds its target antigen, it is internalized via receptor-mediated endocytosis. The ADC is internalized into an endosomal/lysosomal compartment, where the ADC is degraded, releasing the drug component from the antibody. The drug component can then leave the endosomal/lysosomal compartment and bind its intracellular target; hopefully, resulting in tumor cell killing. In this thesis, we focus on how ADCs get processed at a cellular level. First, we developed a flow cytometric clonogenic assay and used this assay to study the single-cell potency of the chemotherapeutic drug doxorubicin. Across a number of cancer cell lines, we found that a cell's ability to proliferate was only dependent on the amount of doxorubicin inside the cell and independent of varying drug media concentration, length of treatment time, or treatment with verapamil. We established a single-cell IC50 of 4 - 12 million doxorubicin molecules per cell. Next, we developed a model for ADC cellular processing and parameterized this model using a clinically approved ADC, T-DM1. Sensitivity analysis suggests that the amount of drug that is delivered to cells is a function of the amount of drug that comes in via internalization and the amount the leaves via drug efflux. This work also demonstrates how it is important to consider ADC processing as a complete system rather than isolating individual steps when designing ADCs. We also incorporated this cellular level processing model into a larger pharmacokinetic/pharmacodynamic model. Finally, we used fluorescence microscopy with a Trastuzumab-Doxorubicin ADC to track where within a cell the drug component traffics once released from the antibody. We find that the ADC does not deliver a significant number of doxorubicin molecules to the nucleus, suggesting that escape from the lysosome limits the amount of drug that can be delivered to its target via an ADC. The ability to escape the lysosome should be considered when designing an ADC. / by Katie F. Maass. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1985. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Bibliography: leaves 176-186. / by John Abraham Tsamopoulos. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references. / In the past decades, many new and interesting modalities for therapeutics have been discovered, including nucleic acid therapeutics such as siRNA and mRNA. However, one of the limiting challenges in developing these technologies into medicines is delivering the therapeutics to the correct location in the body or in the cell. Furthermore, many older modalities for therapeutics, such as vaccines and chemotherapeutics, could become more efficacious with optimization of delivery. By using chemical engineering principles, we can develop better delivery methods, materials, and formulations to improve the treatment of a wide range of diseases. In this thesis, I report on applications to vaccines and cancer. Vaccines are currently the vanguard of public health efforts; unfortunately, a wide range of diseases have no effective vaccine. This includes devastating diseases such as HIV, malaria, and others. One area of vaccination that few people have considered optimizing is the kinetics by which the vaccine is delivered. We found that using an exponential increasing dosing profile, we could produce over 7 times more antibodies compared to the current prime-boost profile using the same amount and type of vaccine. The antibodies generated were also of higher affinity. By improving antibody affinity and titer, this work may make existing vaccines for diseases such as HIV sufficiently efficacious to use in humans. Cancer is one of the leading causes of death in both developed and developing countries, and is extremely difficult to cure due to its high variability. Furthermore, current cancer therapeutics cause severe toxicity. By delivering more of the cancer therapeutics to the tumor, we can reduce the side effects. Some tumors, because of their location, are even harder to access: brain tumors, such as glioblastoma, are protected from most drugs by the blood-brain barrier or blood-brain-tumor barrier. Circumventing these challenges allow us to develop safer and more efficacious therapies. We found that conjugates of siRNA with chlorotoxin could knock down levels of a housekeeping gene in vitro and in vivo in a mouse brain tumor model. Furthermore, we developed prostate-cancer targeting ligands that demonstrate in vitro efficacy and tested them in vivo. / by Hok Hei Tam. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 94-107). / The immense chemical complexity of atmospheric organic particulate matter ("aerosol") has left the general field of condensed-phase atmospheric organic chemistry relatively under-developed when compared with either gas-phase chemistry or the formation of inorganic compounds. In this work, we endeavor to improve the general understanding of the narrow class of oxidation reactions that occur at the interface between the particle surface and the gas-phase. The heterogeneous oxidation of pure erythritol (C4H1 00 4 ) and levoglucosan (C6H1 00 5) particles by hydroxyl radical (OH) was studied first in order to evaluate the effects of atmospheric aging on the mass and chemical composition of atmospheric organic aerosol, particularly that resembling fresh secondary organic aerosol (SOA) and biomass-burning organic aerosol (BBOA). In contrast to what is generally observed for the heterogeneous oxidation of reduced organics, substantial volatilization is observed in both systems. As a continuation of the heterogeneous oxidation experiments, we also measure the kinetics and products of the aging of highly oxidized organic aerosol, in which submicron particles composed of model oxidized organics -- 1,2,3,4-butanetetracarboxylic acid (C8H100 8), citric acid (C6 H8 0 7), tartaric acid (C4H6 0 6 ), and Suwannee River fulvic acid -- were oxidized by gas-phase OH in the same flow reactor, and the masses and elemental composition of the particles were monitored as a function of OH exposure. In contrast to studies of the less-oxidized model systems, particle mass did not decrease significantly with heterogeneous oxidation, although substantial chemical transformations were observed and characterized. Lastly, the immense complexity inherent in the formation of SOA -- due primarily to the large number of oxidation steps and reaction pathways involved -- has limited the detailed understanding of its underlying chemistry. In order to simplify this inherent complexity, we give over the last portion of this thesis to a novel technique for the formation of SOA through the photolysis of gas-phase alkyl iodides, which generates organic peroxy radicals of known structure. In contrast to standard OH-initiated oxidation experiments, photolytically initiated oxidation forms a limited number of products via a single reactive step. The system in which the photolytic SOA is formed is also repurposed as a generator of organic aerosol for input into a secondary reaction chamber, where the organic particles undergo additional aging by the heterogeneous oxidation mechanism already discussed. Particles exiting this reactor are observed to have become more dramatically oxidized than comparable systems containing SOA formed by gas-phase alkanes undergoing "normal" photo-oxidation by OH, suggesting simultaneously the utility of gas-phase precursor photolysis as an effective experimental platform for studying directly the chemistry involved in atmospheric aerosol formation and also the possibility that heterogeneous processes may play a more significant role in the atmosphere than what is predicted from chamber experiments. Consideration is given for the application of these results to larger-scale experiments, models, and conceptual frameworks. / by Sean Herbert Kessler. / Ph.D.