This thesis is centered on the Gadonanotubes (GNTs), an ultra-high-performance magnetic resonance imaging (MRI) contrast agent material discovered in our laboratories in 2005. The GNTs are a new paradigm in MRI contrast agent design with small clusters of Gd3+ ions within ultra-short carbon nanocapsules (ca. 50 nm) cut from full-length single-walled carbon nanotubes. Here, the factors underlying the performance efficacy of the GNTs have been investigated for the first time by variable-field (-50,000 Oe to 50,000 Oe at 2K) and variable-temperature (2K to RT at 100 Oe) magnetic susceptibility measurements using a Magnetic Property Measurement System (MPMS, based on a SQUID magnetometer). Additionally, experiments focused on the effects of hydroxylation of the GNTs’ exterior surface regarding water-solubility are examined. Finally, the use of the GNTs as potential replacements for traditional metal-chelating/sequestering agents is explored. More specifically, the internal Gd3+-ion clusters of the GNTs have been radiolabeled: (1) with 153Gd3+ ions to test Gd3+-ion stability to simulated biological challenge, (2) with 225Ac3+ ions to generate a new concept for a GNT-based agent for α-radiotherapy, and finally (3) with 64Cu2+ ions to produce the first bimodal MRI/PET (PET = positron emission tomography) imaging agent derived from the GNTs.

Thesis (M.S.)--University of Akron, Dept. of Biomedical Engineering, 2008. / "August, 2008." Title from electronic thesis title page (viewed 12/9/2009) Advisor, Stephanie T. Lopina; Committee members, Amy Milsted, Daniel B. Sheffer, Daniel Ely; Department Chair, Daniel B. Sheffer; Dean of the College, George K. Haritos; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.

Thesis (Ph.D.)--University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on May 6, 2009) Vita. Includes bibliographical references.

Thesis (Ph.D.)--University of Alberta, 2009. / Title from pdf file main screen (viewed on August 13, 2009). "A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Medical Sciences - Biomedical Engineering, University of Alberta." Includes bibliographical references.

El cáncer es, a día de hoy, una de las principales causas de muerte, lo que lo convierte en uno de los objetivos más importantes de la medicina moderna. Las terapias convencionales son, o bien altamente invasivas (cirugía), o bien poseen una baja selectividad (quimio- y radioterapia), lo cual disminuye la eficacia de estos tratamientos e induce la aparición de efectos secundarios. Los nanomateriales, debido a su tamaño nanométrico, poseen una serie de características especiales que pueden aportar grandes ventajas en cuanto al diagnóstico y tratamiento de esta serie de dolencias. Estos nuevos sistemas tienen un gran potencial para conducir a la detección del cáncer en estadíos más tempranos, y al diseño de terapias personalizadas que actúen únicamente en las zonas afectadas, consiguiendo mejores resultados. / Nowadays, cancer is one of the main causes of death worldwide, the cure of which makes it one of the most important targets of modern medicine. Conventional therapies are, either highly invasive (surgery) or little selective (chemo- and radiotherapy), which diminishes the effectiveness of these treatments leading to undesired secondary effects. Nanomaterials, due to its nano size, possess new special features that may provide several advantages for the diagnosis and treatment of this disease in all of its forms. These new systems, have great potential for leading to an early detection of cancer and the design of personalized therapies working only at target zones, improving the results obtained.

Os nanomateriais, nanopartículas e nanocompósitos apresentam novas propriedades físicas e químicas, que combinam as do mundo clássico com as do mundo quântico, e despontam de maneira surpreendente na ciência e na vida cotidiana impulsionando a era da nanotecnologia. Os avanços tecnológicos nessa nova ciência estão atrelados à descoberta de materiais com características inovadoras e as moléculas atualmente são peças chaves de sistemas mais elaborados e projetados para maior desempenho. A presente dissertação teve como principal proposta levantar o estado da arte da utilização da nanotecnologia em diagnóstico e terapia no panorama nacional. O trabalho abordou pesquisa bibliográfica em bases de dados e pesquisa de campo com entrevistas semi estruturadas a profissionais locais atuantes na área biomédica. A coleta de dados evidenciou o progresso da nanotecnologia em função do tempo de acordo ao crescimento do número de publicações desde os primeiros artigos publicados até o presente e mostrou que ainda é incipiente o número de referências da nanotecnologia dentro da área nuclear: IAEA/INIS 25.948, frente a MEDLINE 90.627, PubMed 102.738 e Scopus 268.299 em maio 2015. A revisão bibliográfica contextualizou e embasou os conceitos, como interação da nanotecnologia nos sistemas biológicos e também a utilização e problemática da fiscalização e regulamentação nacional. Chegou-se à conclusão que a nanomedicina no Brasil está em processo de evolução e desenvolvimento tecnológico. O País se encontra atualmente em fase de testes pré clínicos de nanomedicamentos e ainda não possui produção em escala industrial, e está na criação e implantação legislativa. O conhecimento e a tecnologia estão sediados em pólos já desenvolvidos, fundamentalmente na região sudeste, e que mesmo nesta, a nanotecnologia encontram-se numa etapa muito inicial de aplicação no setor terapêutico e diagnóstico. / Nanomaterials, nanoparticles and nanocomposites exhibit new physical and chemical properties, matching those from the classic world with the ones from the quantum world: they emerge, surprisingly, in science and everyday life, boosting the era of nanotechnology. Technological advances in this new science are linked to the discovery of materials with innovative characteristics and molecules are, nowadays, key pieces of more complex systems designed for higher performance. This work was, mainly, proposed to improve the state of the art nanotechnology use for both diagnosis and therapy, in the national scene. This work covered bibliographic research in databases and field survey with semi-structured interviews with local professionals working in the biomedical field. Data collection showed the progress of nanotechnology, as a function of time, in agreement with the growing number of publications since the first articles published to date, demonstrating that the number of nanotechnology references is still deficient, within the nuclear area: IAEA / INIS 25 948 , compared to 90,627 MEDLINE, PubMed and Scopus 268 299 102 738, in May 2015. The literature review contextualized and comprised some concepts, such as the nanotechnology interaction with biological systems and, also, its use and problems concerning supervision and national regulation. We came to the conclusion that nanomedicine, in Brazil, is under an evolution process and technological development. The country is, currently, in a preclinical testing phase of nanodrugs, which are not produced in industrial scale yet. Also, we are working for creating and establishing a legislative policy. Our knowledge and technology are based on a geographical distribution already developed, mainly, in the southeastern region. Nevertheless, even there, nanotechnology is at an early stage as to its application for therapeutic and diagnostic purposes.

De nombreux traitements anti-cancéreux ont été découverts au cours des dernières années. Cependant, ces derniers sont souvent responsables d'effets secondaires du fait de leur manque de spécificité.Le but de cette étude est de développer des formulations nanométriques de micelles pour améliorer le ciblage des cellules malades par ciblage passif et/ou actif. Les micelles peuvent être utilisées en tant que transporteurs de médicaments afin de les amener aux cellules cibles sans atteindre les organes sains.Des micelles polymérisées ont été développées pour cibler de manière passive les tissus tumoraux.Des micelles sensibles à certains stimuli comme la lumière ou le pH ont également été préparées pour assurer une libération contrôlée de principes actifs.Afin de conférer aux micelles des propriétés de ciblage actif, elles ont été fonctionnalisées par des ligands de ciblage. Les ligands présents à la surface du transporteur permettent un ciblage actif des cellules qui sur-expriment certains récepteurs.Enfin des micelles ont été développées pour pouvoir les utiliser comme agents de contraste en IRM. / Many drugs directed against cancer have been discovered over the past few years. However, the latter often induce severe side effects due to their lack of specificity.The aim of this study is to develop nanometric micellar formulations in order to improve the passive and/or active targeting of diseased cells. The micelles can be used as drug carriers to deliver drugs without affecting healthy organs.Polymerized micelles have been developed in order to passively target tumor tissues.Micelles sensitive to some stimuli such as light or pH have been prepared in order to ensure a controlled release of active compounds.In order to achieve active targeting, micelles were functionnalized with targeting ligands. These ligands at the carrier’s surface are responsible for active targeting of cells overexpressing some receptors.Some micelles have also been developed in order to be used as contrast agents in RMI.

The use of nanoparticles in biomedical applications has greatly increased in recent years due to their unique properties, which allow them to supplement or even surpass the effectiveness of traditional treatments. Multiple types of nanoparticles are currently utilized or proposed for use in medicine, including gold, silver, and iron oxide. Each of these substances confer a unique set of benefits; gold has anti-inflammatory properties, silver is antibacterial, and iron oxide, in addition to being relatively inert, is useful is treating those with anemia. Unfortunately, many of the properties which make nanoparticles potentially useful for medical applications frequently contribute to their toxicity. While studies have been performed which examine the toxicity of nanoparticle therapeutics, virtually all have taken place in healthy conditions. This is not representative of the conditions in which these nanoparticles will be used, as treatments are, by definition, given to individuals who are somehow unhealthy. Additionally, a large and growing proportion of the population in the United States and worldwide suffer from a chronic disease, with some of the most common being obesity, high cholesterol, and metabolic syndrome. It is therefore important to consider these individuals in the development and testing of nanoparticle therapeutics. Specifically, these diseases alter the content of the circulation beyond the differences which exist solely due to individual variability. This may in turn may alter the biocorona, the term given to the coating of biomolecules which forms on the nanoparticle surface following exposure to a physiological environment. We hypothesized that individual variability and disease, specifically the common diseases obesity, high cholesterol, and metabolic syndrome, would alter the content of the biocorona, and that this would translate to differential nanoparticle toxicity.It was determined that both disease and individual variability caused distinct alterations in the biomolecular content of the biocorona. Further, these alterations were found to elicit distinct inflammatory responses when comparing between individuals or healthy to diseased conditions. These results have implications for the use of nanoparticles in biomedicine, as the variability observed within the biocoronain disease and between individuals may have a significant impact on the efficacy of the treatment,as well as any toxicological effects. It is therefore in the interest of public health to modify the process of developing, testing, and utilizing nanoparticle therapeutics such that the biocorona may work in conjunction with or regardless of differences in the biological milieu which exist as a result of individual variability or disease. By this, researchers 18ABSTRACTThe use of nanoparticles in biomedical applicationshas greatly increased in recent years due to their unique properties, which allow them to supplement or even surpass the effectiveness of traditional treatments. Multiple types of nanoparticles are currently utilized or proposed for use in medicine, including gold, silver, and iron oxide. Each of these substances confer a unique set of benefits; gold has anti-inflammatory properties, silver is antibacterial, and iron oxide, in addition to being relatively inert, is useful is treating those with anemia. Unfortunately, many of the properties which make nanoparticles potentially useful for medical applications frequently contribute to their toxicity. While studies have been performed which examine the toxicity of nanoparticle therapeutics, virtually all have taken place in healthy conditions. This is not representative of the conditions in which these nanoparticles will be used, as treatments are, by definition, given to individuals who are somehow unhealthy. Additionally, a large and growing proportion of the population in the United States and worldwide suffer from achronic disease, with some of the most common being obesity, high cholesterol, and metabolic syndrome. It is therefore important to consider these individuals in the development and testing of nanoparticletherapeutics. Specifically, these diseases alter the content of the circulationbeyond the differences which exist solely due to individual variability. This mayin turn may alter the biocorona, the term given to the coating of biomolecules whichforms on the nanoparticle surface following exposure toa physiologicalenvironment. We hypothesized that individual variability and disease, specifically the common diseases obesity, high cholesterol, and metabolic syndrome, would alter the content of the biocorona, and that this would translateto differential nanoparticle toxicity.It was determined that both disease and individual variability caused distinct alterations in the biomolecular content of the biocorona. Further, these alterations were foundto elicit distinct inflammatory responses when comparing between individuals or healthy to diseased conditions. These results have implications for the use of nanoparticles in biomedicine, as the variability observed within the biocoronain disease and between individuals may have a significant impact on the efficacy of the treatment,as well as any toxicological effects. It is therefore in the interest of public health to modify the process of developing, testing, and utilizing nanoparticle therapeutics such that the biocorona may work in conjunction with or regardless of differences in the biological milieu which exist as a result of individual variability or disease. By this, researchers.

Les oligonucléotides sont de courtes séquences d’acide nucléique qui ont la capacité d’inhiber ou de moduler l’expression d’un gène cible par différents mécanismes. Cependant, leur potentiel thérapeutique est limité par leur faible internalisation. Pour pallier ce problème de vectorisation, il a été envisagé de conjuguer les oligonucléotides à des molécules biocompatibles. Ce travail de thèse porte sur des bioconjugués composés d’un nucléolipide à l’extrémité 5’ ou 3’ des oligonucléotides. Tout d’abord, les propriétés physico-chimique et d’hybridation de ces nouveaux composés ont été évaluées. Des études biologiques ont ensuite été réalisées in vitro et in vivo. Les résultats obtenus ont permis de mettre en évidence le mécanisme d’internalisation cellulaire mais aussi de prouver l’efficacité de transfection et d’inhibition de ces conjugués. En outre, le caractère amphiphile de ce type de composé rend possible leur auto-assemblage pour la formulation de substances actives. Dans ce cadre, différentes formulations ont été investiguées. Ainsi, dans ce travail de thèse une nouvelle technologie d’oligonucléotides conjugués a été développée. La séquence de ces molécules peut être modulée et maitrisée de manière à l’adapter à la cible thérapeutique visée. Actuellement, ce système est appliqué sur treize projets différents à l’échelle nationale. L’effet thérapeutique est ainsi évalué dans différentes pathologies telles que des cancers hormono-dépendants, des leucémies, des maladies neurologiques chroniques ou encore la résistance aux antibiotiques. / Oligonucleotides are short nucleic acid molecules able to modulate or inhibit gene expression. However the main drawback of oligonucleotides lies in their poor cellular internalization, which limit their therapeutic applications. Herein, to overcome this limitation, oligonucleotides were conjugated to biocompatible molecules as a nucleolipid to either the 5'- or the 3'-end. First, physico-chemical properties and binding behaviour of this newly compound were investigated. Then in vitro and in vivo biological assays were performed to characterize but also understand the cellular internalization pathways and their biological activities. Finally, the amphiphilic nature of the oligonucleotide-nucleolipid confers spontaneously self-assembling properties for drugs loading and vectorization purposes. This Ph.D. thesis focuses on new oligonucleotide bioconjugates for various biological applications. Sequences of nucleotides can also be modulated to specifically bind to the therapeutic target. This tuneable technology is actually used in 13 different projects, including hormone-dependent cancers, leukemia, chronic neurological disorders and antibiotic resistance, for example.

Master thesis deals with the use of bacteriophage as a theranostic drug nanocarrier. The term theranostics is used in recent years for systems that allow connecting of diagnostics, targeted drug delivery and monitoring of patient’s response to administered treatment in a single modality. These systems are very suitable especially with heterogeneous diseases, such as cancer. Nowadays, the treatment of cancer has often severe side effects to the patient’s body, which lowers his capability to fight the disease. Theoretical part of this work is focused on the properties of viral capsids, proteins and inorganic materials as drug nanocarriers. In practical part of this work, different methods for cultivation of bacteriophage are compared, both in liquid and solid medium and with different concentrations of the maltose, trough whose receptors bacteriophage is able to enter the host cell. Optimal was cultivation with 0.2% maltose in solid medium. Practical part is focused mainly on the use of bacteriophage as a nanocarrier for cytotoxic drug doxorubicin. Bacteriophage was able to encapsulate all applied concentrations of doxorubicin (0; 12.5; 25; 50; 100 and 200 g/ml), which was proved using fluorescent detection. Different times of encapsulation (2; 4; 8 and 12 hours) were studied. Optimal time was 2 hours. Encapsulation properties of bacteriophage were compared to apoferritin. Bacteriophage was able to encapsulate 4× higher concentrations of doxorubicin and its release during rinsing with water was 10× lower compared to apoferritin. This work concludes that bacteriophage is a very suitable platform for targeted drug delivery in theranostics.