Estella-Hermoso de Mendoza A, Castello-Cros R, Imbuluzqueta E, Cirauqui C, Pippa R, Odero M D, Blanco-Prieto M J
J Biomed Nanotechnol. 2015 Apr;11(4):691-701. doi: 10.1166/jbn.2015.1944.
Protein phosphatase 2A (PP2A) is a serin-threonin phosphatase that regulates many proteins critical for malignant cell behavior; therefore, PP2A is considered to be a human tumor suppressor. In this study, we assessed the pharmacokinetic profile and the antileukemic effects of the PP2A activator FTY720, free or encapsulated in lipid nanoparticles, in in vitro and in vivo models of acute myeloid leukemia. FTY720 lipid nanoparticles presented diameters around 210 nm, with an encapsulation efficiency up to 75% and significantly increased FTY720 oral bioavailability. In addition, FTY720 restores PP2A phosphatase activity and decreases phosphorylation of PP2A and its targets Akt, ERK1/2 and STAT5, all implicated in the pathogenesis of acute myeloid leukemia. Moreover, FTY720 exerts an additive anti-leukemic effect in combination with drugs used in standard induction therapy. Importantly, FTY720 lipid nanoparticles were more efficient at inducing cell growth arrest and apoptosis than FTY720 solution. Finally, oral administration of FTY720 lipid nanoparticles to mice every three days was as effective in reducing acute myeloid leukemia xenograft tumor growth as daily oral administration of FTY720. These results provide the first evidence for the potential use of FTY720 lipid nanoparticles as an oral therapeutic agent in acute myeloid leukemia.
蛋白磷酸酶2A（PP2A）是一种丝氨酸 - 苏氨酸磷酸酶，可调节许多对恶性细胞行为至关重要的蛋白质；因此，PP2A被认为是一种人类肿瘤抑制因子。在本研究中，我们评估了游离或包裹在脂质纳米颗粒中的PP2A激活剂FTY720在急性髓性白血病的体外和体内模型中的药代动力学特征和抗白血病作用。FTY720脂质纳米颗粒的直径约为210nm，包封效率高达75%，并显著提高了FTY720的口服生物利用度。此外，FTY720可恢复PP2A磷酸酶活性，并降低PP2A及其靶点Akt、ERK1/2和STAT5的磷酸化，所有这些都与急性髓性白血病的发病机制有关。此外，FTY720与标准诱导治疗中使用的药物联合使用时具有相加的抗白血病作用。重要地，FTY720脂质纳米颗粒在诱导细胞生长停滞和凋亡方面比FTY720溶液更有效。最后，每三天给小鼠口服FTY720脂质纳米颗粒在减少急性髓性白血病异种移植肿瘤生长方面与每天口服FTY720一样有效。这些结果为FTY720脂质纳米颗粒作为急性髓性白血病的口服治疗药物的潜在用途提供了首个证据。
