Development and in vitro evaluations of new decitabine nanocarriers for the treatment of acute myeloid leukemia.
Development and in vitro evaluations of new decitabine nanocarriers for the treatment of acute myeloid leukemia.
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DOI：
10.2147/ijn.s147659
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发表时间：
2017
影响因子：
8
通讯作者：
Lagarce F
中科院分区：
文献类型：
--
作者：
Briot T;Roger E;Lautram N;Verger A;Clavreul A;Lagarce F
地西他滨是一种亲水性药物，通过DNA的低甲基化起作用。地西他滨在欧洲用于治疗年龄≥65岁的急性髓性白血病（AML）患者。然而，由于口服生物利用度极低且分布体积大，只能静脉给药。口腔政府将允许门诊治疗，提高生活质量，降低治疗费用。本研究建议开发脂质纳米胶囊（LNCs），最初是为亲脂性药物设计的，用于封装地西他滨。设计了两种不同的LNCs配方：基于高比例Transcutol®HP的LNCs （THP-LNCs）和与Transcutol®HP和Tween®80混合的LNCs （THP-T80-LNCs）。第二种剂型直径为26.5±0.5 nm，包封率高达85%，有效药量为472±64µg/mL。负载地西他滨的THP-T80-LNC在两种AML细胞系上的细胞毒性评估取决于它们的地西他滨耐药性：HEL（不耐药）和HL-60（耐药）。在Caco-2细胞单层上也评价了负载地西他滨的THP-T80-LNCs的通透性。地西他滨在THP-T80-LNCs中转染时对HEL和HL-60的细胞毒性高于未转染时。Caco-2细胞单层的通透性也增加了，这表明地西他滨可能是一种有用的制剂，可以提高口服生物利用度。
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.