Acute myeloid leukemia (AML) mainly affects adult patients, and for older ones unfit for intensive chemotherapy only few therapies are available. Hypomethylating agents, as decitabine, is a labeled option but its plasma half-life is short whereas a long cell exposure time improves response rate. Only intravenous administration is available, whereas an oral route is generally preferred by patients. Consequently, to enhance plasma half-life and to develop an oral decitabine formulation, in this work decitabine was encapsulated in nanoparticles. Two different strategies were tested: decitabine loaded into lipid nanocapsules (DAC-LNC), and a decitabine-prodrug synthesis [3’(OH)-5’(OH)-(lauroyl)2-modified DAC] encapsulated into LNC (DAC-(C12)2-LNC).
DAC-LNC and DAC-(C12)2-LNC particles were obtained with sizes of 26.5 ± 0.5 nm and 27.45 ± 0.05 nm respectively, and drug payloads of 0.47 ± 0.06 mg/mL and 5.8 ± 0.5 mg/mL (corresponding to 2.3 ± 0.2 mg/mL of decitabine). Both formulations were able to increase in vitro human plasma half-life by protecting decitabine from degradations. Compared to free-decitabine solutions, both nanoparticle formulations were able to preserve decitabine cytotoxicity on an AML cell line (HEL). Moreover, permeability studies across an adenocarcinoma cell model (Caco-2 cells) demonstrated that DAC-LNC improve decitabine’s intestinal permeability whereas DAC-(C12)2-LNC decreased it. However, this drawback could be countered by the enhanced decitabine’s stability in gastrointestinal fluids thanks to DAC-(C12)2-LNC, leading to more available drug for absorption.
Globally, both formulation have demonstrated their ability to improve DAC plasma half-life in vitro and their potential for oral administration. In vivo pharmacokinetics evaluations may now confirm interests of such strategies
