Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2009. / Committee Chair: Murthy, Niren; Committee Member: Bellamkonda, Ravi; Committee Member: Davis, Michael; Committee Member: May, Sheldon; Committee Member: Milam, Valeria. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Chronic respiratory diseases such as asthma, COPD, pulmonary fibrosis are more prevalent throughout the world. For some of these diseases there is no cure, the current treatment options manages the symptoms and acute exacerbation. The new approach to find a curative therapy for respiratory diseases is by targeting the cellular / molecular pathways that either cause the disease or has the potential cure the disease. It becomes important to target the respiratory system in treating these diseases to increase the delivered dose and reduce the unwarranted adverse effects. Dry powder inhaler (DPI) is a targeted drug delivery dosage form commonly used to target the airways to treat respiratory diseases. There are two components to dry powder inhaler product – powdered drug formulation and inhaler device; a unified performance of the two is essential for a successful product. In this study, dry powder aerosol of novel drug compounds that targets the underlying cellular and molecular mechanism are developed for the first time. Advanced organic closed mode spray drying technique was used to the produce microparticulate/ nanoparticulate formulations. The formulation of the novel compounds involved utilizing sugar based excipients. Each formulation that was produced was comprehensively characterized in the solid state. The safety of these formulations were tested in in vitro human pulmonary cell lines. The in vitro aerosol dispersion of the spray dried drugs were tested using three FDA approved human inhaler devices. The influence of the inhaler device resistance and spray drying process conditions on the aerosol dispersion was evaluated. Preliminary testing of the formulations in in vivo animal models shows promising results in treating chronic respiratory diseases with these superior aerosol formulations.

Les nano-objets ou nanoparticules sont des systèmes de taille nanométrique. Dans le domaine de l’oncologie, ils sont capables de transporter des agents anticancéreux et/ou des macromolécules comme des gènes ou des protéines, de sorte qu’ils s’accumulent préférentiellement dans le tissu tumoral. Ainsi, les nanoparticules ont pour but de diminuer la quantité de principe actif libre dans l’organisme, responsable de toxicités. Elles permettent en clinique d’améliorer la balance bénéfice/risque des agents de chimiothérapies conventionnels. Ce sont de véritables plateformes qui permettent de s’affranchir de certains excipients toxiques contenus dans la formulation du paclitaxel (Cremophor El). Ainsi, au cours de ce travail nous nous sommes intéressés dans un premier temps aux nanoparticules d’or (Au-NP) produites par ablation laser femtoseconde. Nous avons ainsi caractérisé ces Au-NP sur le plan physico-chimique et biologique, et mis en évidence leur internalisation et leur innocuité. Dans un deuxième temps, nous avons évalué l’efficacité pharmacologique de conjugués dendron-paclitaxel sur des cultures cellulaires 2D et 3D et mis en avant la libération prolongée intracellulaire du paclitaxel et son effet retard. Compte-tenu des propriétés observées, ces nanoparticules sont de bons candidats pour un futur développement. En effet, la liaison de ces deux nanostructures entre elles permettra l’obtention d’un nano-objet aux propriétés de théranostiques. / Nano-objects or nanoparticles can be readily fabricated with their size being controlled typically in the range of 1–100 nm. In the field of oncology, they can be used for drug delivery, as their composition/structure may be engineered to load anticancer drugs, macromolecules or proteins. Indeed, the delivery of anticancer drugs through a nanoparticle-based platform offers many attractive features. Nanoparticle-based drugs are synthetized to significantly improve the benefit/risk ratio of conventional chemotherapeutics. They allow overcoming some toxic excipients in the formulation of paclitaxel (Cremophor El). In this work, we first studied the physico-chemical and biological properties of Au-NPs synthetized by femtosecond laser ablation and we investigated their safety and cellular uptake. Second, we evaluated the anticancer activity of dendron-paclitaxel conjugates in 2D and 3D cell cultures and showed a delayed effect of this new formulation. Based on these results, the studied nanoparticles are good candidates for future development. By combining the two nano-objects, we will obtain nanoparticles with theranostic properties.

The performance of regenerated cellulose (RC) films and capsules was investigated for their applications in oral controlled drug delivery. Regenerated cellulose films were prepared by non-solvent-mediated, phase inversion of native and depolymerized cotton linter solutions (methylolcellulose; cellulose dissolved in dimethyl sulfoxide/ paraformaldehyde solvent system) in water as well as by phase inversion of native cotton linter solutions in organic non-solvents followed by thermal annealing. These films were monolithic in dry state and formed porous structures when hydrated. Irrespective of the degree of polymerization of the starting cellulose source or the use of organic non-solvents, the cellulose chain length was not significantly altered and cellulose was in an amorphous state. Flux analysis in diffusion cells, using ethanol-water mixtures as the solvent medium, indicated that the films take up solvent to form porous routes for transport of solute. The amount of solvent uptake required to form these routes was greater for films prepared from depolymerized cotton linter. Ionic and hydrophobic solutes traverse the films using the porous pathways following hydration of the film. Blended RC films were prepared by combining native and depolymerized cotton linter solutions in varying ratios and phase-inverting in water, followed by thermal annealing. Porosity, pore size and water uptake of the hydrated films decreased, while the length of the transport pathway (tortuosity) increased, as the fraction of depolymerized cellulose increased in the blended films. Differences in methylene blue dye adsorption on phase-inverted vs. phase-inverted and thermally annealed RC films indicated that the type of non-solvent utilized for phase-inversion does not affect the internal RC film structure during the phase-inversion process. However, as the boiling point of the non-solvent increased, the amount of irreversible polymer consolidation and formation non-swelling domains (hornification) increased during the thermal annealing process. This, in turn, led to reduced porosity and solute flux through these RC films. Two-piece cellulose capsules were fabricated by phase-inversion of methylolcellulose solutions in water using a dip-coating approach. Zero-order release rates for a number of drugs increased as their water solubility increased. The release of water soluble drugs occurred by osmotically-driven convection and diffusion through the pores in the capsule wall, while the release of moderate to poorly soluble drugs predominantly occurred by diffusion. Moreover, as the drug solubility increased, the apparent permeability of the drugs through the capsule wall decreased, which indicated that the inward osmotic flux of water reduced the diffusivity of the drug through the pores. The hydraulic permeability of the cellulose capsules was determined to be higher than for conventional ethylcellulose and cellulose acetate coated osmotic drug delivery systems, indicating that the cellulose-based capsules may be better suited for osmotic drug delivery.

A major drawback of chemotherapy is the lack of selectively leading to damage in healthy tissue, which results in severe acute side effects to cancer patients. The use of nanoparticles as a drug delivery system has emerged as novel strategy to overcome the barriers of immunogenic response, controlled release of therapeutic, and targeting the toxicity only to cancerous cells. In this study, polymeric nanoparticles composed of transition metals and particles derived from natural biopolymers have been generated via self-assembly. For example, nanoparticles composed of cobalt crosslinked with albumin (Co-alb NPs) via Co-amine coordination chemistry of lysine residue were syntheisized in various sizes. The method to generate Co-alb NPs involves no thermal heat, organic solvent or any surfactants, which is ideal for the production of large amounts in a timely manner. The Co-alb NPs displayed exceptional stability under physiological conditions (pH 7.4) for several days with minor changes in size; however degradation could be triggered by reductant (reduced glutathione (GSH), 10 mM) with complete disappearance of particles in less than 2 hour. Numerous therapeutics that are highly effective toward cancer cells have been developed; however, many cannot be administered to patients due to poor solubility in water and pH dependent properties. We have successfully encapsulated 7-ethyl-10-hydroxycampothecin (SN-38) into Co-alb NPs with encapsulation efficiency as high as 94% and loading capacities greater than 30%. We employed an emulsion-solvent evaporation method to incorporate SN-38 into Co-alb (SN38 Co-Alb NPs). Release of the drug from SN38 Co-Alb NPs was determined for particles incubated in PBS or PBS-GSH. SN38 Co-Alb NPs were exceptionally stable under physiological condition (PBS pH 7.4), but exhibited sustained release of SN-38 over time in the presence of GSH. Uptake and toxicity of the particles were also investigated in a gastric carcinoma cell line (SNU-5) where high degrees of macropinocytic uptake were observed. The particles displayed significant toxicity making them a prime candidate for further testing in animal models.

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Biomaterials serve as interventional tools in medicine to treat, improve or replace diseased tissues, organs or function of the body. Although several polymeric biomaterials already exist, they often present challenges, at material level, such as non-biodegradability, degradation into acidic by-products or tissue incompatibility, or at functional level such as failure to sustain prolonged release of therapeutic payload for a desired period. Research has been focused on investigating new polymeric candidates to address these problems of current systems. The use of renewable resources to generate smart polymers for biomedical and pharmaceutical purposes presents a new and exciting avenue for biomaterials. As part of these efforts, a new set of biomaterials were developed from plant-derived high molecular weight (~3.0 kDa) compounds. The advantages of biobased materials include availability for large-scale synthesis, facile post-synthetic modification, biocompatibility, improvement of functional properties and affordability. In this project we used sucrose soyates, i.e. octa-esters obtained from conjugation of sucrose molecules and multiple soybean oil fatty acid chains, to prepare three groups of functional biomaterials namely: a). self-assembled soy-based nano-constructs, b). blended soy-based free-standing films and c). three-dimensional cross-linked soy-based soft matrices. Here, we will discuss the fabrication and physical, chemical and mechanical characterization of these biomaterials prepared from soy-based compounds, as well as, the assessment of their functional performance in biological environment. / National Science Foundation ND EPSCoR Grant No. IIA1355466 through Center of Sustainable Materials Science

Many attempts have been made to make cancer therapy more selective and less detrimental to the health of the patients. Nanoparticles have emerged as a way to solve some of the problems of traditional chemotherapy. Nanoparticles can provide protection for the therapeutic from degradation or clearance, as well as protection to healthy tissue from the damaging effects of chemotherapy drugs. Researchers are pursuing different strategies but all have the same goals of improving the outcomes of cancer patients. The field of controlled release of drugs has increased significantly in hopes of better treating diseases like cancer. Improved control of drug release has great potential for improving patient outcomes. Still there exist certain barriers such as circulation time, cell specificity, and endosomal escape.In this study a novel drug delivery vehicle was studied in vitro. The novel construct consisted of a liposome containing perfluorocarbon emulsions—an eLiposome—that was activated by ultrasound to break open on demand. Two targeting moieties were attached to the eLiposome to increase cell specificity and induce endocytosis. These studies determined the localization of eLiposomes in vitro using flow cytometry and confocal microscopy. Results indicated that eLiposomes modified with a targeting moiety attached to HeLa cells to a greater extent than non-targeting eLiposomes. Confocal images indicated localization of eLiposomes around the membrane of cells. Flow cytometer results indicated that ultrasound does in fact disrupt the eLiposomes but evidence of significant delivery to the cytoplasm was not obtained. However cells that were incubated with eLiposomes for 24 hours showed over 60% of the cells had green color association indicating eLiposome uptake.

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No description available.