Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1994. / Includes bibliographical references. / by Ulrich Bernd Holeschovsky. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 108-112). / Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor. Treatment of GBM is a daunting task with median survival just at 21 months. Methods of localized delivery have achieved moderate success in treating GBM. Depot devices have been limited due to the relatively narrow drug distribution profile they achieve. Convection enhanced delivery has demonstrated that broad distribution is key, but is limited due to uncertain spatial distribution and serious side effects. Miniaturized depot devices, implanted into the tissue surrounding the tumor resection site, could achieve a broad aggregate distribution profile. The capabilities of localized delivery can be enhanced by utilizing microelectromechanical systems (MEMS) technology to deliver drugs with precise temporal control over release kinetics. An intracranial MEMS based device was developed to deliver the clinically utilized chemotherapeutic temozolomide (TMZ) in a 9L rodent glioma model. An activation mechanism based on thermally induced membrane failure was developed and incorporated. The kinetics of TMZ release were validated and quantified in vitro. The safety of implanting the device intracranially was confirmed. The impact of TMZ release kinetics on survival was investigated by comparing the effects of drug release rates and timing. TMZ delivered from the device prolonged animal survival. The results from the in vivo efficacy studies indicate that early, rapid delivery of TMZ from the device results in the most prolonged animal survival. This miniaturized MEMS device holds tremendous potential for the treatment of GBM and related diseases. Circuit diseases are neurological disorders that arise from the dynamic miscommunication within a neural circuit. Anxiety, mood disorders, and the chronic effects of traumatic brain injury (e.g. Parkinsonism) are prevalent, and are circuit diseases. Circuit diseases could be clinically addressed by a technology capable of electrical, and chemical neuro-modulation. A catheter based device capable of simultaneous infusion of multiple fluids and electrical stimulation was designed and fabricated. Preliminary in vitro infusion studies indicate that the reliable and reproducible infusion of multiple fluids is possible. Future work will focus on improving the biocompatibility of the device and studying the performance of the device in non-human primate models of neurological disorders. / by Byron C. Masi. / Ph.D.

Massachusetts Institute of Technology. Dept. of Chemical Engineering. Thesis. 1965. Mat.Eng. / Mat.Eng.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2002. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (leaves 172-183). / This thesis constitutes the development and application of a theory for the lumped parameter, convective-diffusive-reactive transport of individual, non-interacting Brownian solute particles ("macromolecules") moving within spatially periodic, solvent-filled networks - the latter representing models of chip-based microfluidic devices, as well as porous media. The use of a lumped parameter transport model and network geometrical description affords the development of a discrete calculation scheme for computing the relevant network-scale (macrotransport) parameters, namely the mean velocity vector U*, dispersivity dyadic D* and, if necessary, the mean volumetric solute depletion rate K*. The ease with which these discrete calculations can be performed for complex networks renders feasible parametric studies of potential microfluidic chip designs, particularly those pertinent to biomolecular separation schemes. To demonstrate the computational and conceptual advantages of this discrete scheme, we consider: (i) a pair of straightforward examples, dispersion analysis of (non-reactive) pressure-driven flow in spatially periodic serpentine microchannels and reactive transport in an elementary geometric model of a porous medium; and (ii) a pair of case studies based upon the microfluidic separation techniques of vector chromatography and entropic trapping. / (cont.) The straightforward examples furnish explicit proof that the present theory produces realistic results within the context of a simple computational scheme, at least when compared with the prevailing continuous generalized Taylor-Aris dispersion theory. In the case study on vector chromatography, we identify those factors which break the symmetry of the chip-scale particle mobility tensor, most importantly the hydrodynamic wall effects between the particles and the obstacle surfaces. In the entropic trapping case study, analytical expressions derived for the solute dispersiviy, number of theoretical plates, and separation resolution are shown to furnish results that accord, at least qualitatively, with experimental trends and data reported in the literature. / by Kevin David Dorfman. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 163-170). / Cancer is routinely treated with surgery, chemotherapy, and radiotherapy, but in recent decades, two new modes of treatment have emerged, targeted therapy and immunotherapy. Targeted therapies exploit differences between cancerous and healthy cells, targeting the proteins and pathways that exclusively drive cancer cell growth, while immunotherapies harness the body's immune system to destroy cancer cells. With these new treatment strategies, tumor regression and complete remission of disease have become attainable for a larger subset of patients. Nevertheless, the fight against cancer continues to be met with significant challenges, including development of resistance to targeted therapies and immunosuppressive factors that cripple anti-tumor immune responses. Broadly, the work presented in this thesis focuses on the development of novel therapeutic cancer agents using protein engineering. First, we explore combination immunotherapies designed to simultaneously activate an anti-tumor immune response, using a tumor-targeting antibody and a serum-persistent form of the immunostimulatory cytokine interleukin-2 (IL-2), and reduce immunosuppression in the tumor microenvironment, via blockade of either transforming growth factor-p (TGF-[beta]) or phosphatidylserine. We performed in vitro characterization and extensive preclinical evaluation of our constructs in syngeneic murine tumor models but failed to show therapeutic efficacy. Our studies nevertheless contribute to the field and demonstrate the complex and interdependent nature of the immune system, something that must be considered in future endeavors in combination immunotherapies. In the field of targeted therapy, mutant K-Ras continues to be the holy grail of oncogenic targets, but remains undruggable due to its high affinity for activating nucleotide GTP and a lack of welldefined drug-binding pockets. We engineered a protein binder RI 1.1.6 that binds mutant K-Ras with nanomolar affinity and exhibits specificity over the wildtype protein. The work in this thesis further characterizes RI 1.1.6 and shows inhibition of K-Ras-driven signaling in a model system. Translation to human cancer cell lines, however, failed to recapitulate this RI 1.1.6-mediated signaling disruption. Mathematical modeling of Raf-competitive Ras antagonism by R11.1.6 revealed that insufficient inhibition of Ras-Raf complexes is attained, offering an explanation of the lack of biological effects we observed. / by Monique Jacqueline Kauke. / Ph. D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1989. / Includes bibliographical references (leaves 184-193). / by Peter John Ludovice. / Ph.D.

Thesis (Sc. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1962. / Vita. / Includes bibliographical references (leaves 313-317). / by Robert Kaiser. / Sc.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references. / Cancer is the collective group of diseases distinguished by uninhibited growth and spread of abnormal cells. It often results in death if the spread is not controlled. Most cancers are treated by surgery, radiation, chemotherapy, hormones, or immunotherapy. However, currently there are many issues with these forms of treatment, namely the lack of ability to consistently remove the entire tumor and the side effect of killing normal cells during the treatment process. Therefore there has been an increased interest in targeted drug delivery to tumors to specifically kill cancer cells. We have developed a highly adaptable amphiphilic alternating copolymer system that self-assembles into micelles for therapeutic delivery applications in cancer. The synthetic scheme includes the enzymatic polymerization of multifunctional linker molecules (dimethyl 5-hydroxyisopthalate) with poly(ethylene glycol). This chemoenzymatic synthesis is much faster and more convenient than an entirely chemical synthesis. Subsequent synthetic steps have been developed to attach ligands (for targeting), perfluorocarbons (19F MR imaging), fluorescent dyes (NIRF imaging), and radioiodine (nuclear imaging and radioimmunotherapy) to the backbone. Attachment of hydrocarbon or perfluorocarbon sidechains provides amphiphilicity to produce the multimodal self-assembling micelles. Additionally, encapsulation procedures for chemotherapeutic agents, doxorubicin and paclitaxel, have been established. / (cont.) These unique alternating copolymer micelle nanoparticles were designed as delivery vehicles targeted to human cancer cells expressing the underglycosylated mucin-1 antigen, which is found on almost all epithelial cell adenocarcinomas, by use of the peptide EPPT or the folate receptor (FR) by use of folate. Development of the synthetic schemes has been coupled with in vitro toxicity experiments using various cell viability assays to minimize the toxic effect of these copolymer structures. Overall the polymers used in this study were largely non-toxic when studied in vitro. The non -toxic polymers were brought forward into drug delivery and uptake experiments. Cell death due to doxorubicin increased with encapsulation in these alternating copolymers and increased slightly more with the addition of targeting ligand to the encapsulating polymer. Encapsulating paclitaxel in polymer also increased cell death as compared to free drug. These results demonstrate that these alternating copolymers have had some success as drug delivery vehicles. Other in vitro studies included the investigation of cellular uptake by 125I or 3H radioactive analysis and fluorescence confocal microscopy. Microscopy images of the fluorescently labeled polymer alone demonstrated that the polymer was likely confined to vesicles within the cytoplasm and it was not found in the nucleus, but encapsulated doxorubicin was shown to be largely confined to the nucleus. / (cont.) Theoretical models of polyvalent binding were employed to guide the design of the targeting polymers, however, the polymers used in this study appeared largely non-specific for the targeted cells when studied in vitro. The cellular uptake of polymer targeted with EPPT was twice that of untargeted polymer, although the difference was not statistically significant. For polymers containing folate, regardless of the amount of folate attached, the length of the spacer used, or the type of radioactive label used, the uptake did not decrease in the presence of an excess of folate, indicating a high amount of non-specific uptake for all folate-containing polymers. When all of the folate-containing polymers were used to competitively inhibit 3Hfolate, almost all inhibited the uptake by 1 or 2 orders of magnitude, suggesting that the targeted polymers bind to the FR. An in-depth study of the cell-association of these polymers clarified that polymer was taken up non -specifically in high amounts. An excess of unlabeled folate, up- or down-regulation of the FR, and cleaving the FR did not measurably affect polymer uptake, but did alter folate uptake. It was also determined that a low level of polymer does bind to the FR. The amount of surface bound polymer was much lower than the total uptake of polymer in folate-free media for each polymer concentration investigated. In addition, the amount of surface bound folate and polymer decreased when the FR was cleaved, confirming the attachment of polymer to the FR. Light scattering measurements showed that polymers that contain folate form aggregates of multiple polymers chains. / (cont.) It is possible that this aggregation was allowing a portion of the folate ligands to be hidden in the aggregate and unavailable for binding to the FR, the most likely mechanistic cause of the failure of the folate-containing polymers to demonstrate targeting. The versatility of these polymer constructs allows for continued optimization of a targeting delivery system for drugs and imaging agents as lessons discovered from passed studies are incorporated into the design. Initial in vivo biodistribution studies were begun to explore the behavior of these polymers in mouse models of human cancers. The alternating copolymers used in this study do accumulate in tumors in vivo, comparable to the levels of accumulation observed in the literature. It is desirable to minimize the accumulation in other organs, while maximizing the accumulation in the tumor tissue. Therefore, this preliminary study warrants continued investigation of our polymer platform as a delivery vehicle in vitro and in vivo. / by Michelle Teresa Miller. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Stimuli-responsive polymers provide a method to control system behavior through the use of an external stimulus, such as temperature, pH, or electric fields among others. Temperature-responsive polymers, especially those based on N-isopropylacryalmide (NIPAAm), are of particular research interest due the ease of implementation of temperature changes to systems as well as the large accessible range of hydrophilic / hydrophobic switching. Initiated chemical vapor deposition (iCVD) is shown to be a useful technique for surface modification with NIPAAm-based polymers due to its ability to provide complete functional retention and applicability to "real world" substrates, which many times have varying compositions and / or micro- or nano-structured surfaces. The novel copolymer thin film of iCVD poly(NIPAAm-co-di(ethylene glycol) divinyl ether) (p(NIPAAm-co-DEGDVE)) is shown to exhibit a sharp lower critical solution temperature (LCST) transition, better-than or equivalent to other surface modification techniques, while also being able to achieve a wider range of thicknesses from the nano- to micro-scale, which is especially useful for flow control, actuator or sensor applications. The bottom-up film growth of iCVD allows for compositional gradients throughout the thickness of a polymer film. A novel NIPAAm-based copolymer with a NIPAAm-rich surface layer is developed which exhibits both fast swelling and deswelling kinetics. Quartz crystal microbalance with dissipation monitoring (QCM-D) is used to study the transition behavior of these films. These data provide valuable information relating to the polymer conformational changes throughout the transition region and help elucidate thermodynamic and mesh characteristics of the films. Finally, an application is developed which utilizes both iCVD and a complementary technique, oxidative CVD (oCVD), to create self-heating membranes with responsive permeability characteristics. / by Mahriah E. Alf. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2007. / Includes bibliographical references (p. 184-204). / Surface engineering of a variety of materials including colloidal particles and porous membranes has been achieved by using layer-by-layer assembly of pH-sensitive polymers and nanoparticles. In the first part of this thesis, hydrogen-bonded multilayer coatings comprising poly(acrylic acid) and polyacrylamide were used to functionalize spherical colloidal particles. Multilayer-modified colloids showed an excellent resistance to cell adhesion. Hydrogen-bonded multilayer coatings on microspheres also could be utilized as templates for in situ nanoparticle synthesis enabling the formation of nanoparticle-loaded hollow microcapsules. Silver nanoparticle-loaded multilayer coatings were created on magnetic microspheres to create antibacterial agents that can be manipulated using a magnetic field. In the second part, the surfaces of track-etched polycarbonate membranes were functionalized with multilayer coatings that undergo discontinuous swelling transition. Multilayers comprising poly(allylamine hydrochloride) and poly(styrene sulfonate) were deposited at a high pH condition (pH > 9.0). These multilayer-modified membranes exhibited hysteretic gating behavior that could be useful for the separation of pH-sensitive materials such as proteins. / (cont.) The growth and swelling behavior of the multilayers in the cylindrical pores of TEPC membranes were also investigated. Heterostructured magnetic nanotubes could be created by further modifying the multilayer-coated TEPC membranes. These magnetic nanotubes were utilized for the separation and controlled release of anionic molecules including active pharmaceutical ingredients. In the last part of this thesis, all-nanoparticle thin film coatings were created by sequentially depositing oppositely charged nanoparticles. The fundamental investigation of all-nanoparticle multilayers revealed that a narrow processing window exists in which multilayers of oppositely charged nanoparticles can be assembled in a true layer-by-layer manner. It was also demonstrated that structure and properties of all-nanoparticle thin films could be varied by controlling the assembly conditions. All-nanoparticle thin film coatings consisting of titanium oxide and silica nanoparticles exhibited potentially useful antifogging, antireflection and self-cleaning properties. / by Daeyeon Lee. / Ph.D.