The present work is divided into two sections. The first section deals with the synthesis of regenerable adsorbents for the removal of arsenic from contaminated waters. An adsorbent based on carboxymethylated polyethylenimine grafted agarose gels was synthesized and characterized as a regenerable synthetic ferric oxide adsorbent with high capacity for arsenate ions at pH 3.0. Similarly, four metal ion chelating adsorbents based on dipicolylamine were synthesized and characterized with respect to their Cu(II), Fe(III) and As(V) adsorption capacities. The most efficient adsorbents were Nov-PEI-DPA and Nov-TREN-DPA. Additionally, a commercial ion exchange resin was modified with permanganate to oxidize arsenite into arsenate. A complete oxidation-adsorption system was proposed in which a column packed with the oxidation resin was connected in series with an adsorbent column composed of the polyethylenimine grafted agarose gels.The second section involved work with magnetic nanoparticles. First, composite adsorbents consisting of magnetic particles encapsulated within agarose beads with and without grafted iminodiacetic acid (IDA) chelating groups were synthesized. The adsorption capacity of the adsorbents for Cu(II), Fe(III) and As(V) at different concentrations was investigated. Batch experiments were carried out to determine the Fe(III) and As(V) adsorption isotherms for the magnetic Novarose-IDA. Regenerability of the adsorbent was achieved with a pH change of the inlet solution, without affecting its magnetic or adsorption properties.Magnetic composite particles were synthesized for biomedical applications. First, magnetic nanoparticles were coated with silica and then used for gold nanoshell production. These nanoshells were functionalized with a Brij S10 derivative, containing carboxylic groups, using dodecanethiol as a bridging agent to incorporate a fluorescent biomolecule.Finally, magnetic and gold particles were encapsulated in PLGA nanoparticles. Docetaxel was loaded on these multifunctional nanoparticles and released studies were performed at 37°C. The presence of magnetite, colloidal gold and gold nanoshells in the PLGA nanoparticles was revealed by the coloration acquired by the polymeric nanoparticles. The release of drug from the polymeric nanoparticles showed a biphasic behavior with an initial burst followed by a prolonged slow release. There was no effect of the presence of magnetic or metallic particles on docetaxel release.

Elastin-like peptides (ELPs) are stimulus-responsive protein-based polymers which are attractive material for biomedical research due to their biocompatibility and unique properties. The physical properties of ELPs are dependent on the chain length and the chosen amino acid at the guest residue position. This imparts unlimited flexibility in designing ELP based biomaterials with the desired physical properties. We have shown that in addition to their physical properties, ELPs have biological activities that are conducive to tissue regeneration. Specifically, we found that ELPs induce fibroblast proliferation via cell surface heparan sulfate proteoglycans (HSPG). Furthermore, our data suggests that ELP based materials with differential proliferative potential can be designed by controlling the interaction of ELPs with HSPGs by incorporating either hydrophobic or positively charged residues within the ELP sequence. Fibroblast proliferation is important for granulation tissue formation which is important in chronic wounds as well as in healing of other tissues. The customizable biological activity of ELPs coupled with their unique physical properties will enable us to design novel, sustainable and cost effective therapies for different tissue regeneration applications. ELPs can be genetically fused to biologically active peptides or proteins. These fusions can be expressed and readily purified since they maintain the phase transitioning property of the fused ELP domain. Moreover, depending on the ELP sequence chosen the chimeric fusion sequences can self-assemble into unique structures such as nanoparticles. These structures can then be applied to the injury site where they not only provide unique topographical cues or structural support but also act as delivery vehicles for the fused bioactive protein. We developed a multifunctional nanoparticle that is comprised of PMP-D2-ELP fusion protein and different functional peptide ELP fusion proteins to preserve the bioactivity of the functional group with the existence of elastase. These heterogeneous particles will be beneficial for the delivery of combination therapies to solve multiple problems that often existed in chronic wound healing or other tissue regeneration process. In summary, this study adds to our understanding of the biological activity of ELP and the interaction mechanism that allow the regulation of cellular behavior. Furthermore this work also investigated the potential therapeutic application of ELP as a delivery platform for chronic wound healing.

No description available.

A utilização de nanopartículas magnéticas em biomedicina e biotecnologia vem recebendo elevado destaque nos últimos anos, graças à versatilidade de aplicações como reparo de tecidos, diagnósticos, ressonância magnética por imagem, tratamento contra o câncer, separação celular, transporte controlado de drogas, entre outras. Atualmente, as nanopartículas com potencialidade de aplicação em biomedicina se restringem aos óxidos magnéticos de ferro, os quais apresentam comportamento superparamagnético a temperatura ambiente e magnetização da ordem de 300 emu/cm3. Entretanto, há necessidade inerente da funcionalização da superfície para possibilitar aplicações biomédicas tornando as nanopartículas biocompatíveis e/ou biosseletivas. Essa funcionalização adicional é obtida geralmente introduzindo camadas de materiais diamagnético e/ou paramagnéticos na superfície das NP, as quais baixam a eficiência das propriedades magnéticas exigindo o desenvolvimento de núcleos com elevado valor de magnetização de saturação. Desta forma, nesse trabalho foram sintetizadas nanopartículas magnéticas metálicas de FePt recobertas com óxido de ferro obtidas via processo poliol modificado combinado com a metodologia de crescimento mediado por sementes. Os núcleos magnéticos como-sintetizados foram recobertos com uma camada de sílica, seguido pelo recozimento em atmosfera redutora para elevar o valor da magnetização de saturação. Em seguida, sobre a superfície de sílica foram ancoradas moléculas luminescentes de rodamina B com o auxílio de moléculas de APTES atuando como grupo sililante e as NP resultantes foram novamente recobertas com uma fina camada de sílica. Os resultados permitem concluir que foi obtido um sistema bifuncional combinando em uma única nanopartícula a possibilidade de sensoriamento óptico e magnético, além de possuir sua magnetização de saturação intensificada cerca de 10 vezes em relação aos óxidos metálicos (64 emu/g), manter o caráter superparamagnético e possuir superfície biocompatível com possibilidades de funcionalizações adicionais, com grande potencial para aplicações em biomedicina. / In recent years, the magnetic nanoparticles uses in many biomedical and biotechnological areas have received great attention due to their several applications possibilities such as: tissue repair, diagnostics, magnetic resonance imaging, cancer treatment, cell separation, and controlled drug delivery, among others. Today, the potential magnetic nanoparticles applications are limited to magnetic iron oxides uses, which exhibit superparamagnetic behavior at room temperature and low saturation magnetization around 300 emu/cm3. However, for biomedical applications, the nanoparticle surface must be properly functionalized in order to confer biocompatibility and biosselectivity. These additional functionalizations are generally obtained by paramagnetic and/or diamagnetic materials incorporations onto the nanoparticle surface leading a dramatic decreasing in the already low saturation magnetization. In this context, the development of new magnetic nuclei with high magnetizations values is required. Thus, in this work iron oxide-coated metallic FePt magnetic nanoparticles were synthesized by using the modified polyol process combined with the seed mediated growth method. The magnetic as-synthesized nuclei were coated with a thin silica shell followed by thermal annealing under reducing atmosphere in order to increase the saturations magnetization of this material. After that, onto the silica-coated magnetic nanoparticles surface luminescent dye Rhodamine B molecules were supported using the APTES as intermediate sililant molecules. Then, the functionalized nanoparticles were coated again with an outer layer. In conclusion, according to the obtained results, a bifunctional system combining the optical and magnetic sensing in the same nanoparticle was reported. The obtained nanoparticles present superparamagnetic behavior and high saturation magnetization around 10 times higher (~64 emu/g) compared with the iron oxide nanoparticles synthesized at the same conditions. In addition, the luminomagnetic nanoparticle surface is biocompatible allowing additional future functionalizations with high potential to biomedical applications.

Lanthanide phosphate (LnPO4) and lanthanide vanadate (LnVO4) nanoparticles (NPs) are promising platforms for theranostic applications because of their chemical stability, low solubility, low toxicity, and unique luminescence and magnetic properties. Motivated by the high radiation resistance and ability to host actinides of naturally occurring lanthanide-based compounds, LnPO4 and LnVO4 NPs were studied as radionuclide carriers for targeted radionuclide therapy using in vivoα-generators, 223Ra, 225Ac, and 227Th. The implementation of these radionuclides has shown potential for the treatment of micrometastases and solid tumors as well as challenges in the retention of decay daughters at the target site to minimize unwanted radiotoxicity. LnPO4 and LnVO4 core-shell NPs doped with either 156Eu, a “cocktail” of 85, 89Sr and 156Eu, or in vivo α-generators 223Ra, 225Ac, and 227Th were synthesized in aqueous media. In vitro retention of radionuclides was investigated by dialyzing the radionuclide-doped NPs suspensions against deionized water and quantifying the activity in dialysate aliquots over time. The crystal structure, morphology, physical stability, luminescence and magnetic properties were evaluated. Partial retention of 156Eu (~70–95%) and 85, 89Sr (>80%) was evidenced in LnPO4 core NPs, while 227Th and decay daughters were quantitatively retained in LaPO4 core + 2 shells NPs (>99%). Gd0.8Eu0.2VO4 and GdVO4 core-shell NPs showed partial retention of 223Ra (~75%), 225Ac (75–95%), 227Th (>96%), and decay daughters. Radionuclide retention was influenced by the lanthanide concentration, crystal structure, and number of shells. The partial retention of radionuclides in both LnPO4 and LnVO4 core-shell NPs may enhance the treatment efficacy while minimizing unwanted toxicity. LnVO4 core and core-shell NPs have potential as carriers of short-lived radionuclides for both diagnostic and therapeutic applications. Emission intensities were higher for LnVO4 with respect to LnPO4 NPs, whereas no significant difference was observed in the magnetic susceptibilities. GdVO4 core NPs displayed enhancement of the signal intensity in T1-weighted images. This work evidences the promising application of both LnPO4 and LnVO4 NPs as platforms for targeted radionuclide therapy and multimodal molecular imaging.

A utilização de nanopartículas magnéticas em biomedicina e biotecnologia vem recebendo elevado destaque nos últimos anos, graças à versatilidade de aplicações como reparo de tecidos, diagnósticos, ressonância magnética por imagem, tratamento contra o câncer, separação celular, transporte controlado de drogas, entre outras. Atualmente, as nanopartículas com potencialidade de aplicação em biomedicina se restringem aos óxidos magnéticos de ferro, os quais apresentam comportamento superparamagnético a temperatura ambiente e magnetização da ordem de 300 emu/cm3. Entretanto, há necessidade inerente da funcionalização da superfície para possibilitar aplicações biomédicas tornando as nanopartículas biocompatíveis e/ou biosseletivas. Essa funcionalização adicional é obtida geralmente introduzindo camadas de materiais diamagnético e/ou paramagnéticos na superfície das NP, as quais baixam a eficiência das propriedades magnéticas exigindo o desenvolvimento de núcleos com elevado valor de magnetização de saturação. Desta forma, nesse trabalho foram sintetizadas nanopartículas magnéticas metálicas de FePt recobertas com óxido de ferro obtidas via processo poliol modificado combinado com a metodologia de crescimento mediado por sementes. Os núcleos magnéticos como-sintetizados foram recobertos com uma camada de sílica, seguido pelo recozimento em atmosfera redutora para elevar o valor da magnetização de saturação. Em seguida, sobre a superfície de sílica foram ancoradas moléculas luminescentes de rodamina B com o auxílio de moléculas de APTES atuando como grupo sililante e as NP resultantes foram novamente recobertas com uma fina camada de sílica. Os resultados permitem concluir que foi obtido um sistema bifuncional combinando em uma única nanopartícula a possibilidade de sensoriamento óptico e magnético, além de possuir sua magnetização de saturação intensificada cerca de 10 vezes em relação aos óxidos metálicos (64 emu/g), manter o caráter superparamagnético e possuir superfície biocompatível com possibilidades de funcionalizações adicionais, com grande potencial para aplicações em biomedicina. / In recent years, the magnetic nanoparticles uses in many biomedical and biotechnological areas have received great attention due to their several applications possibilities such as: tissue repair, diagnostics, magnetic resonance imaging, cancer treatment, cell separation, and controlled drug delivery, among others. Today, the potential magnetic nanoparticles applications are limited to magnetic iron oxides uses, which exhibit superparamagnetic behavior at room temperature and low saturation magnetization around 300 emu/cm3. However, for biomedical applications, the nanoparticle surface must be properly functionalized in order to confer biocompatibility and biosselectivity. These additional functionalizations are generally obtained by paramagnetic and/or diamagnetic materials incorporations onto the nanoparticle surface leading a dramatic decreasing in the already low saturation magnetization. In this context, the development of new magnetic nuclei with high magnetizations values is required. Thus, in this work iron oxide-coated metallic FePt magnetic nanoparticles were synthesized by using the modified polyol process combined with the seed mediated growth method. The magnetic as-synthesized nuclei were coated with a thin silica shell followed by thermal annealing under reducing atmosphere in order to increase the saturations magnetization of this material. After that, onto the silica-coated magnetic nanoparticles surface luminescent dye Rhodamine B molecules were supported using the APTES as intermediate sililant molecules. Then, the functionalized nanoparticles were coated again with an outer layer. In conclusion, according to the obtained results, a bifunctional system combining the optical and magnetic sensing in the same nanoparticle was reported. The obtained nanoparticles present superparamagnetic behavior and high saturation magnetization around 10 times higher (~64 emu/g) compared with the iron oxide nanoparticles synthesized at the same conditions. In addition, the luminomagnetic nanoparticle surface is biocompatible allowing additional future functionalizations with high potential to biomedical applications.

Les limitations rencontrées aujourd'hui dans le traitement du glioblastome (GBM) concernent notamment la qualité de l'exérèse dont dépend le pronostic et le manque de contrôle local de la croissance tumorale, sachant que les récidives apparaissent dans plus de 80% des cas dans le volume cible de radiothérapie. Dans ce contexte, la thérapie photodynamique interstitielle (iPDT) se présente comme un outil complémentaire prometteur qui permettrait d'améliorer le contrôle local de la tumeur. La première partie de ce travail de thèse a porté sur le suivi longitudinal par Imagerie par Résonance Magnétique (IRM) de la réponse tumorale post-iPDT sur un modèle de rat nude xenogreffé en orthotopique par un modèle de GBM humain. Le suivi par IRM et Spectroscopie par Résonance Magnétique (SRM) a fourni des indicateurs précoces de l'efficacité du traitement, permettant de discriminer dès un jour post-iPDT les animaux répondeurs des non-répondeurs. Cependant, une des limitations de la PDT, demeure la faible profondeur de pénétration de la lumière visible utilisée pour activer le photosensibilisateur et induire les réactions de photo-oxydations. La seconde partie de ce travail a porté sur l'évaluation d'un nouveau concept appelé "PDTX" permettant de coupler l'effet photodynamique à celui de la radiothérapie pour une radiothérapie photodynamique, en jouant notamment sur la complémentarité des espèces réactives de l'oxygène générées et des effets RX-induits. Pour cela, nous avons validé l'intérêt d'une nanoparticule hybride de type AGuIX® composée de terbium et de porphyrine, le terbium étant le scintillateur capable d'être excité par les rayons X et d'émettre des photons à une longueur d'onde appropriée pour activer le photosensibilisateur. Le transfert d'énergie par FRET (Förster Resonance Energy Transfer) entre le terbium et la porphyrine a été mis en exergue. Les résultats in vitro démontrent le potentiel thérapeutique de ce nouveau nano-objet à basse énergie / The limitations encountered today in the treatment of glioblastoma (GBM) involve the quality of the resection on which depends prognosis and the lack of local control of the tumor, knowing that relapses occur in 80% of cases in the radiotherapy target tumor volume. In this context, interstitial photodynamic therapy (iPDT) is a promising additional tool that would allow to improve local control of the tumor. The first part of this thesis focused on the longitudinal follow-up by Magnetic Resonance Imaging (MRI) of the post-iPDT tumor response in a nude rat model of orthotopic xenograft of human GBM cell line. MRI and Magnetic Resonance Spectroscopy (MRS) monitoring provided early indicators of the effectiveness of treatment, for discriminate from one day post-IPDT non-responders from responders animals. However, one of the limitations of PDT remains the low penetration of visible light used to activate the photosensitizer and induce reactions of photo-oxidation. This is why the second part of this research focused on the evaluation of a new concept called "PDTX" for coupling the photodynamic effect with radiotherapy effect for a photodynamic radiotherapy, playing especially on the complementarity of reactive species of oxygen generated and RX-induced effects. For this, we validated the interest of an AGuIX®-type hybrid nanoparticle composed of terbium and porphyrin, terbium being the scintillator capable of being excited by X-rays and emits photons at an appropriate wavelength in order to activate the photosensitizer. The energy transfer FRET (Förster Resonance Energy Transfer) between terbium and porphyrin was highlighted. In vitro results demonstrate the therapeutic potential of this new nano-object at low-energy

Lanthanide-based nanoparticles are of interest for optical displays, catalysis, telecommunication, bio-imaging, magnetic resonance imaging, multimodal imaging, etc. These applications are possible partly because the preparation of lanthanide-based nanoparticles has made tremendous progress. Now, nanoparticles are routinely being made with a good control over size, crystal phase and even shape. Despite the achievements, little attention is given to the fundamental physical chemistry aspects, such as crystal structure, architecture, cation exchange, etc. The results of the study on the crystal structures of LnF3 nanoparticles show that the middle GdF3 and EuF3 nanoparticles have two crystal phases, which has then been tuned by doping with La3+ ions. However, the required doping level is very different from the bulk. While the results for the bulk are well explained by thermodynamic calculations, kinetics is actually responsible for the results of the undoped and doped GdF3 and EuF3 nanoparticles. The attempt to make LnF3 core-shell nanoparticles led to the finding of cation exchange, a phenomenon that upon exposure of LnF3 nanoparticles to an aqueous solution containing Ln3+ ions, the Ln3+ ions in the nanoparticles are replaced by the Ln3+ ions in the solution. The consequence of the cation exchange is that LnF3 core-shell nanoparticles are unlikely to form in aqueous media using a core-shell synthesis procedure. It has also been verified that nanoparticles synthesized using an alloy procedure do not always have an alloy structure. This means that the core-shell and alloy structure of nanoparticles in the literature may not be true. The investigation of the architecture of nanoparticles synthesized in aqueous media is extended to those synthesized in organic media. The dopant ion distribution in NaGdF4 nanoparticles has been examined. It has been found that they don’t have the generally assumed statistical dopant distribution. Instead, they have a gradient structure with one type of Ln3+ ions more concentrated towards the center and the other type more concentrated towards the surface of the nanoparticles. With the understanding of these physical insights, lanthanide-based core-shell nanoparticles are prepared using the cation exchange. These core-shell nanoparticles containing a photoluminscent core and a paramagnetic shell are promising candidates for multimodal imaging. / Graduate

Cette étude concerne le développement de nanoparticules hybrides offrant de nouvelles stratégies pour la thérapie et le diagnostic médical. Elles sont constituées d’un cœur magnétique jouant le rôle d’agent de contraste pour l’IRM et d’inducteur de chaleur par hyperthermie, d’une couronne de polymère thermosensible permettant d’encapsuler des principes actifs et de peptides de reconnaissance biologique. Une grande partie de l’étude a consisté à étudier les processus d'adsorption de copolymères poly(éther)-b-poly(L-lysine) de composition variable sur les particules magnétiques et à comprendre le rôle de la conformation des chaînes polymère à la surface des particules sur la stabilité des colloïdes en milieu physiologique. Un agent antitumoral a été encapsulé puis libéré de façon contrôlée sous l’effet d’un champ magnétique alternatif en exploitant le caractère thermosensible des blocs polyéthers. Des séquences peptidiques ciblant les zones d’inflammation de la barrière hémato-encéphalique ont été greffées sur les copolymères. L’efficacité du ciblage a été validée par IRM et fluorescence sur un modèle animal démontrant ainsi la multifonctionnalité des nanoparticules. / This work deals with the development of hybrid nanoparticles that could offer new strategies for therapy and diagnostic. These are based on a magnetic core which can play the role of contrast agent for MRI as well as heat inductor in AC magnetic field. This inorganic core is surrounded by a thermo-responsive polymeric brush that controls the loading and the release of drugs, and can be functionalized by specific ligands ensuring the targeting specificity. A large part of this work consists in studying the adsorption mechanism of poly(ether)-b-poly(L-lysine) based block copolymers onto magnetic particle and to better understand the influence of the polymer chain conformation at particles surface on the colloidal stability under physiological conditions. An anticancer drug has been loaded and released in a controlled manner under alternative magnetic field by taking advantage from the thermosensitivity of the polyether block. Targeting peptides specific of inflammation sites at the blood brain barrier have been grafted onto copolymers. The targeting specificity has been demonstrated by MRI and fluorescence imaging in rats attesting the multifunctionality of such nanoparticles.

Cette thèse décrit une stratégie de synthèse de nouvelles générations des nanoparticules (NPs) pour applications biomédicales, visant à une amélioration de leurs performances pour l’imagerie, le diagnostic thérapeutique. Ces NPs présentent plusieurs fonctionnalités leur permettant de réaliser des tâches multiples. Deux types de sondes bimodales ont été développés et étudiés afin d'évaluer leur potentiel comme agents (1) de contraste en IRM et (2) luminescents. Ces objetscombinent les propriétés des complexes de lanthanide (Ln3+) et celles des NPs de silice ou de type coeur-écorce Fe2O3@SiO2 pour une imagerie bimodale. Ces NPs testées sur des cellules vivantes ont permis d’illustrer la preuve du concept aussi bien en IRM avec une augmentation d'intensité des images et un impact significatif sur les relaxivities r1, r2 et r2* qu’en photoluminescence. L’étude du système coeur-écorce a montré que l’influence du contrôle fin de l’écorce autour du noyau d'oxyde de fer a pu être modélisée. / This thesis describes a strategy of synthesis of new generations of nanoparticles (NPs) for biomedical applications, aiming at an improvement of their performances for the imaging, and the therapeutic diagnosis. These NPs present several functionalities enabling them to carry out multiple tasks. Two types of bimodal probes were developed and studied so as to evaluate their potential as contrast agents (1) in MRI and (2) and luminescence. These objects combine the properties of the lanthanide complexes (Ln3+) and those of NPs of silica or core/shell Fe2O3@SiO2 for a bimodal imaging. These NPs tested on living cells were able to illustrate the proof of the concept not only in MRI with an increase of intensity of the images and a significant impact on the relaxivities r1, r 2 and r2* but also in photoluminescence. The study of the core/shell system showed that the influence of the fine control of the shell around the iron oxide core could be modeled.