Nanopartículas de quitosana pH-sensíveis contendo doxorrubicina: desenvolvimento e estudo da atividade antitumoral in vitro

• Autor(a) principal: Scheeren, Laís Engroff
• Data de Publicação: 2015
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Manancial - Repositório Digital da UFSM
• Texto Completo: http://repositorio.ufsm.br/handle/1/17513
• topic: Atividade antitumoral in vitro; Doxorrubicina; Métodos analíticos; Nanopartículas de quitosana pH-sensíveis; Polietilenoglicol; Poloxamer; Tensoativo derivado de lisina; Doxorubicin; Analytical methods; In vitro antitumor activity; Lysine-based surfactant; pH-sensitive chitosan-based nanoparticles; Poloxamer; Polyethylene glycol; CNPQ::CIENCIAS DA SAUDE::FARMACIA

Cancer is a highly complex disease and the most common treatments are limited to chemotherapy, radiation and surgery. However, the occurrence of side effects is frequent, especially due to limited drug capability to act specifically on cancer cells. The anthracycline antibiotic doxorubicin (DOX) is widely used in cancer therapy because it is effective against several tumors, such as breast cancer, sarcomas and lymphomas. Nevertheless, its main side effect is cardiotoxicity. In order to overcome this problem, nanotechnology is an alternative to improve the antitumor treatment and to prevent the toxicity in normal cells. Furthermore, pH-responsive bioactive adjuvants are promising for the technological development of nanostructures, as they can mediate greater drug release to tumor microenvironment (pHe ~ 6.6) and/or intracellular compartments. Previous studies have showed the pH-sensitive membrane-lytic behavior of the surfactant Nα,Nε-dioctanoyl lysine with an inorganic sodium counterion (77KS), as well as low toxicity. Thus, pH-sensitive chitosan-based nanoparticles (CS-NPs) incorporating the surfactant 77KS were developed by ionotropic gelation as DOX delivery system in an attempt to achieve a specific drug release on tumor tissue and intracellular compartments. Furthermore, modifications on NPs were performed, as inclusion of polyethylene glycol (PEG) and poloxamer. The physicochemical characterization of NPs showed mean hydrodynamic size lower than 227 nm, as well as positive zeta potential values and encapsulation efficiency around 65%. The validated analytical methods were suitable for the quantitative analysis of the entrapped drug. In vitro release studies displayed accelerated DOX release under acidic conditions, regardless the modifiers included. The hemolysis assay, with the erythrocyte as a model for the endosomal membrane, proved the pH-dependent membrane-lytic behavior of NPs with 77KS. Moreover, the designed NPs showed higher cytotoxicity in tumor cells than free drug, especially when the in vitro experiments were performed at pH 6.6. On the other hand, low cytotoxic effects were obtained in tests using a control non-tumor cell line. Therefore, it can be considered that the pH-responsive polymeric NPs developed in this work are promising carriers to trigger DOX release in the tumor microenvironment and/or inside the cancer cell.