Miltefosine-loaded polymeric micelles of Pluronic® F 127. Development, physicochemical characterization and in vitro evaluation

VALENZUELA-OSES, JOHANNA; GARCÍA, MÓNICA C; GOMES-FILHO, SANDRO; LOURENÇO, FELIPE; BASSÉRES, DANIELA; RANGEL-YAGUI, CARLOTA

Encuentro; Encuentro Científico Internacional (ECI) de verano; 2017

Miltefosine (MT) is an alkylphosphocholine drug with antineoplastic activity but high hemolytic potential1. In this work, we encapsulated MT into polymeric micelles of the copolymer Pluronic F127 (PF127). A central composite design was applied to optimize the formulation parameters and to study the effects of hydration temperature, stirring speed and stirring time on the hydrodynamic diameter (Dh) and polydispersity index (PI) (response variables)2. Second order models were obtained to adequately describe the influence of the independent variables on the selected response. Analysis of variance showed that temperature had significant effect (p<0.05) on the PI. The optimum level of Dh and PI predicted by the model and experimentally confirmed were 29.09 nm and 0.105, respectively, corresponding to hydration temperature of 23 oC, stirring speed of 480 rpm and 20 min of stirring time. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) confirmed that the drug was molecularly dispersed within the micelles. Physical stability of the lyophilized optimal formulation after 3 months storage at 4°C showed high stability with low PI (0.189). In vitro cytotoxicity against HeLa and H358 cells demonstrated that the cytotoxic effect of PF127-MT micelles was similar to free MT. The PF127-MT micelles with 80 µM of MT presented a significant reduction of hemolytic effect (80%, p<0.05) in comparison to the same concentration of free drug. Our results suggest that by lowering hemolytic potential, PF127-MT micelles represent a promising strategy to broader the use of this drug as well as of other alkylphosphocholines, in cancer therapy.Keywords: alkylphosphocholines, miltefosine, polymeric micelles, cancer therapyReferences:[1] Khademvatan, S., Gharavi, M.J., Rahim, F., Saki, J. Miltefosine induced apoptotic cell death on Leishmania major and L.tropical strains. The Korean Journal of Parasitology, 49 (1), p. 17 ? 23, 2011.[2] Kumari, P., Omkara, M., Kumar, S., Myneni, S., Ghsh, B., Biswas, S. Curcumin Delivery by Poly (Lactide)-Based Co-Polymeric Micelles: An In vitro Anticancer Study. Pharm Res, 33, p. 826 ? 841, 2015.