Investigação do potencial terapêutico do cetoprofeno em nanocápsulas para o tratamento de gliomas.

Abstract

Gliomas are the most common and devastating primary brain tumors characterized by rapid progression and high recurrence rate. Moreover, the blood-brain barrier (BBB) limits the delivery of chemotherapeutic the CNS, restricting the glioma therapy. The use of nanocapsules formulations of ketoprofen become a promising tool for a new therapeutic modality to glioma treatment. Nanocapsules have been shown to cross the BBB and the ketoprofen, a well known COX inhibitor, may be an interesting alternative to glioma treatment, since the inflammatory environment and the COX-2 overexpression are associated to increased tumor malignity. Therefore the aim of this study was to evaluate the effect of ketoprofen in nanocapsules on the in vitro and in vivo glioma proliferation. We first evaluated the antiproliferative effect of ketoprofen innanocapsules in rat (C6) and human (U138MG, U251MG) glioma cell lines. Indeed, ketoprofen in nanocapsules reduced the glioma cell viability and increased the PI incorporation, an indicative of cell death by necrosis. The cell death induced by ketoprofen in nanocapsules was selective for tumor cells as evidenced by the lack of toxicity on primary cultures of rat astrocytes. Next, the antitumor effect of ketoprofen in nanocapsules was evaluated in the in vivo rat glioma model. The histological analysis revealed that ketoprofen in nanocapsules reduced the glioma size as well as the characteristics of tumor malignity. As evaluated by the open field paradigm, the ketoprofen in nanocapsules treatment promoted an improvement of the locomotion activity of animals, which is related to increased survival of patients. In addition, ketoprofen free and in nanocapsules increased the ATPase and ADPase activity in lymphocytes, while the adenosine deaminase activity was decreased. The alterations on extracellular nucleotide metabolism by lymphocytes may be related to an increase of the immunessupressive, which can control the lymphocyte activation reducing the process of cancer-related inflammation.The formulations of ketoprofen in nanocapsules also did not cause systemic damage as verified through analysis of ALT, AST, creatinine and urea, markers of hepatic and nefrotoxicity. Our results suggest that the formulation of ketoprofen in nanocapsules can play an important role in controlling the proliferation tumor, contributing in the adjuvant treatment of gliomas.