Síntese de nano-veículos poliméricos para entrega de fármacos com atividade anti-tumoral

• Autor(a) principal: Diogo, Duarte Miguel de Melo
• Data de Publicação: 2014
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/4717
• topic: Cancer treatment; Cell resistance; Micellar carriers; Multidrug therapy; TPGS-PLA; Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas

Lung cancer is presently one of the most incident diseases that affects the worldwide population and is also considered one of the most deadly. In Portugal, lung cancer mortality and incidence has also been growing in the last decade. Despite all the efforts towards the development of efficient treatments no cure is yet available for this type of cancer. Chemotherapy is currently the gold standard therapy for lung cancer treatment, however, this strategy has proven to be rather inefficient mostly due to the intrinsic properties of chemotherapeutic drugs. In fact, these type of drugs are known for their poor solubility, low bioavailability and non-specific accumulation, which leads to systemic toxicity and undesired side effects. Moreover, cancer cells promptly adapt to the presence of these therapeutic agents, becoming resistant to their action and promoting their elimination. Such activity is mediated by drug-resistance mechanisms that take advantage of drug efflux through ABC transmembranar transporters. These transporters play a crucial role in the shuttle of drugs to the extracellular medium, thus promoting cancer resistance. Based on these facts, it is urgent to develop strategies that can overcome these issues, improving chemotherapy efficacy and patient survival rates. In the past two decades, nanotechnology-based solutions have been developed to circumvent these problems. Several specialized vehicles have been developed with the aim to reduce the drawbacks of chemotherapy problems. These drug delivery systems are nanoscale platforms that are capable of encapsulating anti-tumoral drugs and usually accumulate in tumoral tissues due to tumor leaky vasculature. However, strategies that can overcome cancer drug resistance are yet poorly explored since only in the past years this issue has become a major priority. In the present thesis, a nanocarrier capable of self-assembly and of encapsulating a novel triple drug combination was formulated with amphiphilic polymers to be used in cancer therapy. This nanovehicle was formulated with D-α-tocopherol polyethylene glycol 1000 succinate-poly(lactic acid) (TPGS-PLA) diblock copolymers, which can assemble into nanosized and stable micelles, with a core-shell architecture. When dispersed in aqueous environments these micelles were capable of encapsulating with high efficiency, a novel and untested triple drug combination. This combination has the ability to target different altered pathways in cancer cells and, at the same time, has the potential to act on drug efflux pumps that are linked to cancer drug resistance. This combination comprises an FDA approved drug for NSCLC (Crizotinib), a novel and potent cell cycle arrester that is under clinical trials (Palbociclib) and an ABC efflux transporters inhibitor (Sildenafil). Moreover, the micellar system has TPGS in its composition and so it can also benefit from TPGS MDR1 inherent inhibiting activity. The novel triple free drug combination revealed to have a synergistic cytotoxic effect in lung cancer cells. On the other hand, the dual drug combination of Crizotinib and Palbociclib reflected an additive effect. These results validate the triple drug combination encapsulation strategy in TPGS-PLA micelles herein employed for lung cancer therapy. Moreover, the uptake studies revealed that micelles were internalized by cancer cells, a crucial parameter to increase the drugs bioavailability and to reduce systemic toxicity associated with chemotherapy. As expected, the triple drug loaded micellar formulations exhibited the highest cytotoxic effect, reflecting the synergy obtained for its free drug combination. In summary, the novel and versatile drug delivery approach developed herein with two strong chemotherapeutic drugs (Crizotinib and Palbociclib) and two agents with the capacity to target cancer drug resistance mechanisms (Sildenafil and TPGS) demonstrates enormous potential for lung cancer therapy.