Modulation of tumor microenvironment towards cancer therapy
Year: 2022
Type: dissertation
Abstract: Over the recent years, the role of the tumor microenvironment (TME) in tumor formation and progression has become increasingly recognized. Three-dimensional tumor models, such as spheroids, are powerful tools with great potential in preclinical research, as they recapitulate an array of TME features. While conventional therapies are effective in many cases, resistance phenomena and the occurrence of severe side effects are recurrent. Hence, it is of utmost importance the development of therapeutic approaches (e.g., combination therapies) that enable the reduction of the administered drug dosages, improving the therapeutic efficacy and decreasing the occurrence of side effects. In this thesis, colorectal cancer (CRC) 3D models were developed by using cells from CRC- derived cell lines alone or cocultured with fibroblasts, and their characterization was performed. Subsequently, functionalization of gold nanoparticles (AuNPs) with polyethylene glycol (PEG) was conducted, and the nanoconjugates obtained were characterized. Lastly, the dispersion of the nanoconjugates in spheroids was evaluated, as well as the effect that their irradiation caused on doxorubicin (Dox) diffusion. Characterization of monoculture models demonstrated the formation of a necrotic core. In coculture models, it was observed that the use of higher proportions of fibroblasts led to an increase in their dispersion in the 3D structure. Gold nanoparticles functionalization resulted in alterations in their surface chemistry, surface charge, and mean size. AuNPs dispersion in spheroids revealed the internalization of nanoconjugates through the formation of cell vacuoles. Preliminary results demonstrate a synergistic effect of AuNPs on Dox diffusion. Overall, the results obtained in this thesis unveil a potential application of these models in preclinical research, being preponderant in revolutionizing modern medicine. The great advantage of using AuNPs in combination therapies was also demonstrated.
Author: Valente, Ruben Filipe Pacheco
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7058012812