Desenvolvimento de nanossistemas com óleo de pequi (Caryocar brasiliense Cambess) para nanoestruturação do artemeter e avaliação do potencial antitumoral in vitro

Abstract

Central nervous system tumors are among the ten tumors which present the highest risk of new cases in Brazil. Considering these tumors, glioblastoma stands out as it has a high mortality rate, with an estimated survival time between 6 and 15 months. There is increasing evidence that artemisinin derivatives, such as artemether, represent a new class of semi-synthetic sesquiterpene lactones with antitumor activity, possibly through inducing the intracellular formation of reactive oxygen species and apoptosis. However, artemether presents characteristics that limit its pharmacological action, such as low bioavailability, low water solubility, and physicochemical instability. Nanoencapsulation is an alternative to minimize these effects and potentiate the action of the drug, besides promoting the passage through the blood-brain barrier. In this scenario, pequi oil (Caryocar brasiliense Cambess) represents a promising candidate for use as a structural component in nanosystems, as it promotes drug solubilization and is also known for its ability to reduce adverse effects of chemotherapy on normal cells. Considering the high lethality of glioblastomas, the ineffectiveness of current therapies and the prospect of using artemether for this purpose, the objective of this work was to develop polymeric lipid core nanocapsules containing pequi oil (Caryocar brasiliense Cambess) as a structuring agent for artemether nanocarrying and evaluation of its effect on human glioblastoma cells (U-87 MG). Nanocapsule suspensions were developed by interfacial deposition preformed polymer and characterized by determining the mean particle diameter, zeta potential, and pH. Cytotoxicity was assessed by mitochondrial viability (MTT) and cell density and proliferation by sulforhodamine B staining. Total antioxidant capacity and antioxidant enzymes activity were determined to evaluate the effect of free and nanostructured artemether on the redox state of the cells. The nanosystems presented a mean size of 200 nm, low polydispersity index, zeta potential close to -10 mV, and slightly acidic pH. The free artemether reduced cell viability after 24h of treatment and proliferation after 48h of treatment at concentrations equal to or above 40 µg.mL-1 (134 µM). The nanoencapsulated artemether reduced these parameters after 24h of treatment, at the concentration of 1.25 µg.mL-1 . When evaluating the effect of nanostructured artemether (1.25 µg.mL-1 ) on the antioxidant enzymes, there was an increase in the activity of SOD and decrease in GR activity in U-87 MG cells. However, this effect was not observed when the cells were treated with free artemether at the same concentration. These findings are consistent with the proposed mechanism for the action of artemether, which is the induction of oxidative stress, and indicate potentiation of its antitumor action. From the data presented, we conclude that pequi oil (Caryocar brasiliense Cambess) presents appropriate characteristics to be used as a structuring agent in the development of nanocapsules containing artemether, as well as other chemotherapeutic agents, and we open the prospect for further studies on this nanosystem.