Decitabine encapsulation in nanovector to improve acute myeloid leukemia treatment

Abstract

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

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