Briot Thomas, Roger Emilie, Lautram Nolwenn, Verger Alexis, Clavreul Anne, Lagarce Frederic
Micro & Nanomédecines Translationelles - MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, MINT IBS-CHU.
Pharmacy Department, University Hospital of Angers.
Int J Nanomedicine. 2017 Nov 23;12:8427-8442. doi: 10.2147/IJN.S147659. eCollection 2017.
Decitabine is a hydrophilic drug that acts by hypomethylating DNA. Decitabine is used in Europe for the treatment of acute myeloid leukemia (AML) in patients aged ≥65 years. However, it can only be administered intravenously due to very low oral bioavailability and a large distribution volume. Oral administration would allow outpatient treatment, improving quality of life and reducing treatment costs. The present study proposes to develop lipid nanocapsules (LNCs), originally designed for lipophilic drugs, to encapsulate decitabine. Two different formulations of LNCs were designed: LNCs based on a high proportion of Transcutol HP (THP-LNCs) and LNCs associated with a mixture of Transcutol HP and Tween 80 (THP-T80-LNCs). The second formulation had a diameter of 26.5±0.5 nm, high encapsulation efficiency (>85%), and a drug payload of 472±64 µg/mL. Decitabine-loaded THP-T80-LNC cytotoxicity was evaluated on two AML cell lines depending on their decitabine resistance: HEL (not resistant) and HL-60 (resistant). The permeability of decitabine-loaded THP-T80-LNCs was also evaluated on Caco-2 cell monolayers. Decitabine cytotoxicity against HEL and HL-60 was higher when decitabine was loaded in THP-T80-LNCs than when free. Apparent permeability on Caco-2 cell monolayers was also increased, suggesting a potentially useful formulation to increase the oral bioavailability of decitabine.
地西他滨是一种亲水性药物，通过使DNA去甲基化发挥作用。在欧洲，地西他滨用于治疗年龄≥65岁的急性髓系白血病（AML）患者。然而，由于其口服生物利用度极低且分布容积大，只能静脉给药。口服给药可实现门诊治疗，提高生活质量并降低治疗成本。本研究建议开发最初用于亲脂性药物的脂质纳米囊（LNC）来包封地西他滨。设计了两种不同的LNC制剂：基于高比例的二乙二醇单乙醚醋酸酯（THP-LNC）的LNC和与二乙二醇单乙醚醋酸酯和吐温80混合物相关的LNC（THP-T80-LNC）。第二种制剂的直径为26.5±0.5纳米，包封效率高（>85%），药物载量为472±64微克/毫升。根据两种AML细胞系对地西他滨的耐药性，评估了载有地西他滨的THP-T80-LNC的细胞毒性：HEL（不耐药）和HL-60（耐药）。还在Caco-2细胞单层上评估了载有地西他滨的THP-T80-LNC的渗透性。当将地西他滨载入THP-T80-LNC时，其对HEL和HL-60的细胞毒性高于游离地西他滨。在Caco-2细胞单层上的表观渗透率也有所增加，表明这是一种可能有助于提高地西他滨口服生物利用度的制剂。
