Development of a theranostic system for central nervous system based on superparamagnetic nanoparticles

• Autor(a) principal: Amaro, Mariana Filipa Mestre Pina
• Data de Publicação: 2016
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/82957
• topic: Nanoparticles; theranostic system; blood-brain-barrier; cell penetrating peptides; antibodies; Beta amyloid inhibition; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

Nanotechnology has revealed its potential in the biomedicine area with fundamental contributions to the imaging contrast agents field or to drug delivery systems development. Several studies have shown that the effect of drugs could be improved when linked to nanoparticles (NPs). A similar approach may be relevant to the treatment of central nervous system (CNS) diseases. In the last decades the knowledge of the brain has increased and the advance in technology has led to several biomedical applications to treat human disorders. However, diseases such as Alzheimer’s, Parkinson or cancer continue to be devastating and poorly treatable. There are several therapeutic molecules likely to treat these disorders, but more than 98% of all small molecules drugs, and ~100% of all large proteins are not able to cross the blood-brain-barrier (BBB) and get to the CNS. The BBB is formed by endothelial cells that are aligned with the capillaries to prevent unwanted substances crossing from blood to nervous tissue. One approach to overtake this difficulty is to find a controlled delivery system able to supply the drug to the affected tissue. However, such systems have the potential to affect the correct BBB behavior. An alternative method is the use of peptides with translocation capacity. These cell penetrating peptides (CPPs) have capacity to translocate various types of cargo molecules to the cells interior, e.g. low molecular weight drugs, liposomes, antibodies and NPs. CPPs are degraded in non-toxic compounds, they have low potential to drug-drug interactions and low probability to cause immunologic reactions when compared with larger proteins. Alzheimer’s disease is characterized by an accumulation of insoluble protein as -amyloid (A), senile plaques (SP) and neurofibrillary tangles (NFT). The accumulation of these aggregates leads to a loss of synapses and neurodegeneration resulting in memory impairment and cognitive decline. In the present work we have used iron oxide nanoparticles a dual functionalization, with a small peptide with translocation capacity and with therapeutic antibody against -amyloid peptides. The system has the ability to function as a theranostic system by taking advantage of the magnetic properties of the nanoparticles. The nanoparticles were characterized by several techniques at different phases of the functionalization process. The iron oxide nanoparticles revealed a simple cubic crystalline structure (by powder x-ray diffraction), a size of 9 nm (by transmission electron microscopy) and a hydrodynamic size of 32.4 ± 2.1 nm for the coated nanoparticles with dimercaptosuccinic acid (DMSA) (by dynamic light scattering). To mimic the BBB, a transwell in vitro system was used to study the translocation of functionalized nanoparticles across this barrier. After 6 h, 23.7 ± 3.7 % of functionalized nanoparticles were able to cross the BBB. In addition, to assess if the developed nanoparticle is able decrease or stop -amyloid aggregation, the SensoLyte Thioflavin-T Beta-Amyloid (1-42) aggregation assay was used. It was found that functionalized iron oxide nanoparticles were able to inhibit -amyloid aggregation when compared to a known inhibitor (morin).