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Doctoral Thesis
DOI
https://doi.org/10.11606/T.76.2016.tde-21102016-155818
Document
Author
Full name
Valeria Spolon Marangoni
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Carlos, 2016
Supervisor
Committee
Zucolotto, Valtencir (President)
Baptista, Mauricio da Silva
Borra, Ricardo Carneiro
Caballero, Nelson Eduardo Duran
Fávaro, Wagner José
Title in English
Theranostic nanomaterials applied to the cancer diagnostic and therapy and nanotoxicity studies
Keywords in English
Magnetic resonance imaging
Photothermal therapy
Plasmonic nanoparticles
Abstract in English
Multifunctional plasmonic nanoparticles have shown extraordinary potential for near infrared photothermal and triggered-therapeutic release treatments of solid tumors. However, the accumulation rate of the nanoparticles in the target tissue, which depends on their capacity to escape the immune system, and the ability to efficiently and accurately track these particles in vivo are still limited. To address these challenges, we have created two different systems. The first one is a multifunctional nanocarrier in which PEG-coated gold nanorods were grouped into natural cell membrane vesicles from lung cancer cell membranes (A549) and loaded with β-lap (CM-β-lap-PEG-AuNRs). Our goal was to develop specific multifunctional systems for cancer treatment by using the antigens and the unique properties of the cancer cell membrane combined with photothermal properties of AuNRs and anticancer activity of β-lap. The results confirmed the assembly of PEG-AuNRs inside the vesicles and the irradiation with NIR laser led to disruption of the vesicles and release of the PEG-AuNRs and β-Lap. In vitro studies revealed an enhanced and synergic cytotoxicity against A549 cancer cells, which can be attributed to the specific cytotoxicity of β-Lap combined with heat generated by laser irradiation of the AuNRs. No cytotoxicity was observed in absence of laser irradiation. In the second system, MRI-active Au nanomatryoshkas were developed. These are Au core-silica layer-Au shell nanoparticles, where Gd(III) ions are encapsulated within the silica layer between the inner core and outer Au layer of the nanoparticle (Gd-NM). This theranostic nanoparticle retains its strong near infrared optical absorption properties, essential for in vivo photothermal cancer therapy, while simultaneously providing increased T1 contrast in MR imaging by concentrating Gd(III) within the nanoparticle. Measurements of Gd-NM revealed a substantially enhanced T1 relaxivity (r1 ~ 17 mM-1 s-1) even at 4.7 T, surpassing conventional Gd(III)-DOTA chelating agents (r1 ~ 4 mM-1 s-1) currently in clinical use. The observed relaxivities are consistent with Solomon-Bloembergen-Morgan (SBM) theory, describing the longer-range interactions between the Gd(III) and protons outside the nanoparticle. These novel multifunctional systems open the door for the development of more efficient nanoplatforms for diagnosis and treatment of cancer.
Title in Portuguese
Nanomateriais Teranósticos Aplicados à Problemática do Câncer e Estudos de Nanotoxicidade.
Keywords in Portuguese
Imagem por ressonância magnética
Nanopartículas plasmônicas
Terapia fototérmica
Abstract in Portuguese
Nanopartículas plasmônicas multifuncionais têm revelado elevado potencial para fototermia na região (NIR) do infravermelho e liberação controlada de fármacos para o tratamento de tumores sólidos. No entanto, a taxa de acumulação das nanoparticulas no tecido alvo, que depende da capacidade delas de escapar do sistema imunológico, e a habilidade de rastrear de maneira efetiva essas partículas in vivo ainda são limitadas. Para superar essas barreiras, dois sistemas diferentes foram desenvolvidos. O primeiro corresponde a um nanocarreador multifunctional, onde nanobastões de ouro funcionalizados com PEG foram agrupados dentro de vesículas de membranas de células naturais originarias de células cancerígenas de pulmão (A549) conjugadas com β-Lap (CM-β-lap-PEG-AuNRs). Nosso principal objetivo foi desenvolver um sistema multifuncional especifico para tratamento de câncer utilizando os antígenos e propriedades únicas da membrana das células cancerígenas combinados com as propriedades fototérmicas dos AuNRs e a atividade anticancerígena da β-Lap. Os resultados confirmaram o agrupamento dos PEG-AuNRs dentro das CM e irradiação com o laser no NIR levou ao rompimento das vesículas e liberação dos AuNRs e β-Lap. Estudos in vitro revelaram uma elevada e sinérgica citotoxicidade contra células A549, que pode ser atribuída a combinação da especifica toxicidade da β-Lap com o calor gerado pelos AuNRs por meio da irradiação com laser. Nenhuma citotoxicidade significativa foi observada na ausência de irradiação com laser. No segundo sistema, nanomatryoshkas de Au ativas em MRI foram desenvolvidas. Elas consistem em um núcleo de Au, uma camada intersticial de sílica, onde os íons de Gd(III) são encapsulados, e uma camada externa de Au (Gd-NM). Esta nanopartícula teranóstica mantém as propriedades de elevada absorção óptica no NIR, enquanto simultaneamente fornece um elevado contraste T1 em imagem por ressonância magnética por meio da concentração dos íons de Gd(III) dentro da nanoparticula. Medidas de Gd-NM revelaram uma relaxividade elevada (r1 ~ 17 mM-1 s-1 ) a 4,7 T, superando os convencionais agentes quelantes de Gd(III)-DOTA (r1 ~ 4 mM-1 s-1) utilizados clinicamente. As relaxividades observadas são consistentes com a teoria Solomon-Bloembergen-Morgan (SBM), descrevendo as interações de longo alcance entre Gd(III) e prótons de H fora da partícula. Os novos sistemas multifuncionais desenvolvidos abrem oportunidades para o desenvolvimento de nanoplataformas mais eficientes para o diagnóstico e tratamento de câncer.
 
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Publishing Date
2016-11-01
 
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