Trimetallic nitride endohedral fullerenes (TNT-EMF) have been recognized for their multifunctional capabilities in biomedical applications. Functionalized gadolinium-loaded fullerenes attracted much attention as a potential new nanoplatform for next-generation magnetic resonance imaging (MRI) contrast agents, given their inherent higher 1H relaxivity than most commercial contrast agents. The fullerene cage is an extraordinarily stable species which makes it extremely unlikely to break and release the toxic Gd metal ions into the bioenvironment. In addition, radiolabeled metals could be encapsulated in this robust carbon cage to deliver therapeutic irradiation. In this dissertation, we aim to develop a series of functionalized TNT-EMFs for MRI detection of various pathological conditions, such as brain cancer, chronic osteomyelitis, and gastrointestinal (GI) tract. As a general introduction, Chapter 1 briefly introduces recent progress in developing metallofullerenes for next-generation biomedical applications. Of special interest are MRI contrast agents. Other potential biomedical applications, toxicity, stability and biodistribution of metallofullerenes are also discussed. Finally, the challenges and future outlook of using fullerene in biomedical and diagnosis applications are summarized at the end of this chapter. The large carbon surface area is ideally suited for multiple exo-functionalization approaches to modify the hydrophobic fullerene cage for a more hydrophilic bio-environment. Additionally, peptides and other agents are readily covalently attached to this nanoprobe for targeting applications. Chapter 2 presents the functionalized metallofullerenes conjugated with interleukin-13 peptide exhibits enhanced targeting of U-251 glioblastoma multiforme (GBM) cell lines and can be effectively delivered intravenously in an orthotopic GBM mouse model. Chapter 3 shows, with the specific targeting moiety, the functionalized metallofullerenes can be applied as a non-invasive imaging approach to detect and differentiate chronic post-traumatic osteomyelitis from aseptic inflammation. Fullerene is a powerful antioxidant due to delocalization of the π-electrons over the carbon cage, which can readily react with free radicals and subsequently delivers a cascade of downstream possessions in numerous biomedical applications. Chapter 4 investigates the antioxidative and anti-inflammatory properties of functionalized Gd3N@C80. This nanoplatform would hold great promise as a novel class of theranostic agent in combating oxidative stress and resolving inflammation, given their inherent MRI applications. In chapter 5, Gd3N@C80 is modified with polyethylene glycol (PEG) for working as MRI contrast agents for GI tract. The high molecular weight can prevent any appreciable absorption through the skin or mucosal tissue, and offer considerable advantages for localized agents in the GI tract. Besides the excellent contrast capability, the PEGylated-Gd3N@C80 exhibits outstanding radical scavenging ability, which can potentially eliminate the reactive oxygen species in GI tract. The biodistribution result suggests this nanoplatform can be worked as the potential contrast agent for GI tract at least for 6 hours. A novel amphiphilic Gd3N@C80 derivative is discussed in Chapter 6. It has been noticed for a long time the functionalization Gd3N@C80 contrast agents have higher relaxivity at lower concentrations. The explanation for the concentration dependency is not fully understood. In this work, the amphiphilic Gd3N@C80 derivative is used as the model to investigate the relationship between the relaxivity and concentration of the Gd-based fullerenes. Click chemistry has been extensively used in functionalization due to the high efficiency and technical simplicity of the reaction. Appendix A describes a new type of Sc3N@C80 derivative conducted by employing the click reaction. The structure of Sc3N@C80-alkynyl and Sc3N@C80- alkynyl-benzyl azide are characterized by NMR, MALDI-TOF, UV-Vis, and HPLC. The high yield of the click reaction can provide access to various derivatives which have great potential for application in medical and materials science. The functionalization and characterizations of Ho3N@C80 derivatives are reported in Appendix B. The contrast ability of Ho3N@C80 is directly compared with Gd3N@C80. The Ho-based fullerenes can be performed as the radiotherapeutic agents; the leaching study is performed to test the stability of carbon cage after irradiation. Appendix C briefly shows a new method to develop Gd3N@C80 based targeting platform, which can be used as the probe for chronic post-traumatic osteomyelitis. / PHD / Since the discovery of fullerene in 1985, fullerenes and metallofullerene in medical and diagnostics applications is rapidly increasing. Functionalized gadolinium-loaded fullerenes attracted much attention as a potential new nanoplatform for magnetic resonance imaging (MRI) contrast agents, given their inherent better contrast ability than most commercial contrast agents. The fullerene cage is an extraordinarily stable species which makes it extremely unlikely to break and release the toxic metal ions into the bioenvironment. In this dissertation, we report the development of a series of functionalized fullerenes for MRI detection of various pathological conditions, such as brain cancer and chronic osteomyelitis, and working as the agent for gastrointestinal (GI) tract. As a general introduction, Chapter 1 briefly introduces recent progress in developing fullerenes for next-generation biomedical applications. Of special interest are MRI contrast agents. Other potential biomedical applications, toxicity, stability and biodistribution of fullerenes are also discussed. Finally, the challenges and future outlook of using fullerene in biomedical and diagnosis applications are summarized at the end of this chapter. The large carbon surface area is ideally suited for multiple chemical reactions approaches to make the fullerene soluble in bio-environment. Additionally, peptides and other agents are readily attached to this nanoprobe for targeting applications. Chapter 2 presents the functionalized fullerenes conjugated with interleukin-13 peptide exhibits enhanced targeting of glioblastoma multiforme (GBM) cell lines and can be delivered efficiently intravenously in a GBM mouse model. Chapter 3 shows, with the specific targeting moiety, the functionalized fullerenes can be applied as a non-invasive imaging approach to detect and differentiate chronic post-traumatic osteomyelitis from aseptic inflammation. The nature of fullerene aromaticity makes it a powerful antioxidant. Fullerene can readily react with free radicals and subsequently delivers a cascade of downstream possessions in numerous biomedical applications.Chapter 4 investigates the antioxidative and anti-inflammatory properties of functionalized Gd₃N@C₈₀. This nanoplatform would hold great promise as a novel class of theranostic agent in combating oxidative stress and resolving inflammation, given their inherent MRI applications. In chapter 5, Gd₃N@C₈₀ is modified with polymer polyethylene glycol (PEG) for working as MRI contrast agents for GI tract. The high molecular weight can prevent any appreciable absorption through the skin or mucosal tissue, and offer considerable advantages for localized agents in the GI tract. Besides the excellent contrast capability, the PEGylated-Gd₃N@C₈₀ exhibits outstanding radical scavenging ability, which can potentially eliminate the reactive oxygen species in GI tract. The biodistribution result suggests this nanoplatform can be worked as the potential contrast agent for GI tract at least for 6 hours. A novel amphiphilic Gd₃N@C₈₀ derivative is discussed in Chapter 6. It has been noticed for a long time the functionalization Gd₃N@C₈₀ contrast agents have better contrast ability at lower concentrations. The explanation for the concentration dependency is not fully understood. In this work, the amphiphilic Gd₃N@C₈₀ derivative is used as the model to investigate the relationship between the contrast ability and concentration of the Gd-based fullerenes. Click chemistry has been extensively used in functionalization due to the high efficiency and technical simplicity of the reaction. Appendix A describes a new type of Sc₃N@C₈₀ derivative conducted by employing the click reaction. The high yield of the click reaction can provide access to various derivatives. It makes this kind of fullerene has excellent potential for application in medical and materials science. The functionalization and characterizations of Ho₃N@C₈₀ derivatives are reported in Appendix B. The contrast ability of Ho₃N@C₈₀ is directly compared with Gd₃N@C₈₀. The Ho-based fullerenes can be performed as the radiotherapeutic agents; the leaching study is conducted to test the stability of carbon cage after irradiation. Appendix C briefly shows a new method to develop Gd₃N@C₈₀ based targeting platform, which can be used as the probe for chronic post-traumatic osteomyelitis.

Made available in DSpace on 2017-07-24T19:38:13Z (GMT). No. of bitstreams: 1 Daniele Seremeta.pdf: 2814746 bytes, checksum: d8432852db6f29a1454166368a3deda5 (MD5) Previous issue date: 2014-03-12 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The linseed oil, obtained from the flax´s seed (Linum usitatissimum L.) contains high levels of polyunsaturated fatty acids as oleic, linoleic and linolenic acid, which makes it susceptible to oxidation. As oxidation is a critical factor inherent to vegetable oils, this study intends to contribute with data from thermal and oxidative stability of linseed oil, with and without the antioxidant quercetin subject photo-oxidation for a period of 15 days. The oxidative process was evaluated by chemical parameters acidity index (AI), peroxide índex (IP) and spectroscopic UV-Vis, IR and 1H NMR. The results showed that the methodology adopted for the photo-oxidation in light box (at room temperature; 115.2 Lux and 15 days) was effective because there was oil degradation. The statistical analyzes confirmed that the greater the exposure time, and this coupled with the presence of light, the more easily occurs the degradation process. Was also evaluated the effect of adding quercetin and TBHQ antioxidant in the oil during photo-oxidation. The results showed that they did not prevent the formation of free fatty acid, peroxides and conjugated dienes, but prevented the formation of secondary oxidation compounds as volatile generating the rancidity, and the polymerization characterized by crosslinking. / O óleo extraído da linhaça, a semente do linho (Linum usitatissimumL.), contém elevado teor de ácidos graxos poliinsaturados (ácido oleico, linoleico e linolênico) os quais o torna susceptível à oxidação. Como a oxidação é um fator crítico inerente aos óleos vegetais, este trabalho visou contribuir com dados de estabilidade térmica e oxidativa do óleo de linhaça, aditivado ou não como antioxidante quercetina, submetido à foto-oxidação por um período de 15 dias. O processo oxidativo foi avaliado pelos parâmetros químicos índice de acidez e índice de peróxidos, assim como por espectroscopia UV-Vis, IV e RMN de 1H. Os resultados mostraram que a metodologia adotada para a foto-oxidação em câmara clara (temperatura ambiente; 115,2 Lux; 15 dias) foi eficiente, pois o óleo apresentou sinais típicos de degradação, como a formação de ácidos graxos livres, peróxidos e dienos conjugados. A presença de compostos secundários de oxidação como os voláteis que geram o denominado de ranço e o processo de polimerização por formação de ligações cruzadas também foram observados. As análises estatísticas confirmaram que quanto maior o tempo de exposição, aliado à presença de luz, maior a facilidade de ocorrer degradação. Avaliou-se também o efeito protetor da adição de agentes antioxidantes (TBHQ e quercetina) no óleo durante a foto-oxidação. Os resultados indicaram que os mesmos não evitaram a formação de ácidos graxos livres, peróxidos e dienos conjugados, mas impediram a formação dos compostos secundários do ranço e o processo de polimerização.