Desenvolvimento e funcionalização de nanopartículas de ouro com revestimento de sílica para aplicação na terapia do cancro

• Main Author: Rodrigues, Ana Carolina Félix
• Publication Date: 2018
• Format: Master thesis
• Language: eng
• Source: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Download full: http://hdl.handle.net/10400.6/9858
• topic: Cancro; Nanopartículas de Ouro Com Revestimento de Sílica; Pei; Terapia Fototérmica; Tpgs; Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas

Cancer is one of the leading causes of death in the world and its incidence has been increasing over the years. On the other side, the currently available treatments, such as surgery, radiotherapy, and chemotherapy, are characterized by presenting a low efficacy and non-specific toxicity. Particularly, the chemotherapeutic agents are poorly soluble, rapidly degraded or removed from blood circulation and present low selectivity towards the cancer cells. Therefore, there is a huge demand for novel and more effective anti-cancer therapeutics. The recent breakthroughs in nanotechnology paved the way for a new era of anti-cancer medicines. Nanoparticles can be produced with different materials and organizations, among them, the gold-core silica shell (Au-MSS) nanoparticles present advantageous physicochemical and biological properties that make them a promising nanoplatform for cancer therapy. Nevertheless, the successful application of Au-MSS nanoparticles as an effective cancer nanomedicine is hindered by the uncontrolled release of the therapeutic payloads, limited blood circulation time and unfavorable pharmacokinetics. This dissertation work plan aimed at designing and developing a novel Au-MSS surface modification with biofunctional polymers for overcoming the uncontrolled drug release profile, limited nanoparticles’ blood circulation time and ultimately potentiate the therapeutic effect. For that purpose, two different methodologies, electrostatic interaction or chemical linkage, were explored and optimized to functionalize Au-MSS, displaying a rod-like shape, with D-a tocopherol polyethylene glycol 1000 succinate (TPGS) and branched polyethyleneimine (PEI). TPGS was selected based on its amphiphilic nature that can act as solubilizer and consequently increase the particles’ colloidal stability. On the other side, PEI due to its cationic nature will be attracted to the negatively charged mesoporous silica surface blocking the particle’ pores and consequently the drug release. Additionally, the rod-like shape of Au-MSS allows the combination of drug delivery with photothermal therapy. The produced Au-MSS nanorods display a uniform morphology and a well-defined gold nucleus and silica shell. Further, the particles’ surface charge was dependent on the synthesis methodology. The particles modified by electrostatic interactions (Au-MSS/TPGS-PEI) were negative (-16.9 and -5.1 mV) whereas the formulations produced by chemical linkage (Au-MSS/TPGS/PEI) resulted in positively charged nanoparticles (+30.9 and +6.8 mV). The successful incorporation of the polymers was confirmed by Fourier Transformed Infrared spectroscopy and thermogravimetric analysis. Moreover, the Au-MSS functionalization did not affect the particles photothermal capacity. However, the Au-MSS/TPGS/PEI nanorods displayed a decreased drug encapsulation efficiency. In vitro assays demonstrated the biocompatibility of Au-MSS and Au-MSS/TPGS-PEI up to concentrations of 200 µg/mL, however, the positively charged formulations only remained biocompatible until 100 and 125 µg/mL. Overall, the results presented in this thesis confirm the successful modification of Au-MSS nanorods with TPGS and PEI. Additionally, it was also demonstrated the potential of Au-MSS formulations for being applied in cancer therapy, where they can act simultaneously as photothermal, drug delivery and bioimaging agents.