Detalhes do Documento

Development of intelligent vehicles for co-livery of anti-tumoral drugs to breast cancer cells

Autor(es): Marques, João Filipe Gonçalves

Data: 2013

Identificador Persistente:

Origem: uBibliorum

Assunto(s): Cancro da mama - Fármacos anti-tumorais; Cancro da mama - Co-polímeros em bloco


Presently breast cancer arises as one of the most prevalent malignancy in women worldwide, contributing for high rates of mortality and morbidity in several million patients. Currently there is still no available cure for this disease and to further aggravate this scenario the existing treatments such as chemotherapy, are generally ineffective due to poor tumor bioavailability. Moreover, the commonly used anti-tumoral compounds also lead to the development of drug resistant malignant cells after repeated administration, a fact that originates the development of more aggressive cells that possess the capacity to metastasize and spread to healthy organs. These facts evidence the urgent need for the development of novel therapeutic approaches that improve the therapeutic outcome and patient survival. The recent developments in the field of Nanotechnology, particularly regarding the capacity to manipulate matter at the nanoscale, has brought forth the opportunity to devise novel drug delivery systems to tackle some of these issues. From this stand point, the research work presented in this thesis describes the development of a novel drug delivery system based on micellar carriers, with a core-shell structure, that are capable to simultaneously deliver multiple drugs to breast cancer cells. These nanocarriers are comprised by a hydrophilic and a hydrophobic polymer organized in a block-by-block structure that was synthesized through macromolecular chemistry. The manipulation of the various reaction conditions yielded block co-polymers with different hydrophobic chains, which influenced the available space in the nanocarrier core. The nanocarriers were formulated by co-polymer self-assembly into nanosized micelles that demonstrated the capacity to encapsulate with high efficiency, an anti-tumoral drug, Crizotinib and a potent inhibitor of the cell transporters responsible for drug resistance, Sildenafil. The drug release profile of the micellar carriers revealed a spatiotemporally controlled release that was faster for Sildenafil than Crizotinib. Moreover, the drug loaded micelles demonstrated to be highly biocompatible and accomplished uptake into adherent breast adenocarcinoma cells. This relevant finding let to the intracellular localization of both the anti-tumoral drug and the drug resistance inhibitor, and thus, improved the bioavailability of the bioactive therapeutics. Subsequently, the study of the therapeutic performance of the co-delivery systems illustrated that the simultaneous delivery of both drugs improved the anti-tumoral capacity of Crizotinib evidencing the existence of a highly synergistic effect. Strikingly, the micellar systems achieved the same anti-tumoral effect of the free drugs, using 2-fold less drug concentration. Besides indicating that the release profile maintains drug concentrations in the therapeutic window, these crucial results highlight the effect of dual drug conjugation and the use of Crizotinib as an anti-tumoral compound for breast cancer therapy and Sildenafil as a multidrug resistance inhibitor. Overall, the unique approach developed in this thesis possesses tremendous potential for a future clinical application in breast cancer patients that acquired resistance to standard therapies.

Tipo de Documento Dissertação de mestrado
Idioma Inglês
Orientador(es) Correia, Ilídio Joaquim Sobreira; Gaspar, Vítor Manuel Abreu
Contribuidor(es) Marques, João Filipe Gonçalves
facebook logo  linkedin logo  twitter logo 
mendeley logo

Documentos Relacionados