Zhang Jing, Zhang Di, Hu Xu, Liu Ruiling, Li Zhonghao, Luan Yuxia
School of Pharmaceutical Science, Shandong University 44 West Wenhua Road Jinan Shandong Province 250012 China
Key Laboratry of Colloid & Interface Chemistry, Shandong University, Ministry of Education 250100 China.
RSC Adv. 2018 Apr 9;8(24):13103-13111. doi: 10.1039/c8ra01225c.
Because of the drawbacks of cytarabine (Ara-C) such as poor lipid solubility, deamination inactivation and low oral bioavailability limiting its application by oral administration, herein we propose a novel amphiphilic low molecular weight cytarabine prodrug (PA-Ara) by conjugating palmitic acid (PA) to Ara-C, making it possible to avoid the deamination inactivation by protecting the active 4-amino, as well as improving lipid solubility. Thanks to the rational design, the oil/water partition coefficient () of PA-Ara was improved tremendously compared with Ara-C, and the PA-Ara conjugation was stable enough in artificial digestive juice, ensuring that most molecules could be absorbed in the form of the prodrug. Results from an MTT assay conducted to measure the cytotoxicity of Ara-C and PA-Ara to HL60 (acute myeloblastic leukemia cell line) and K562 cells (chronic granulocytic leukemia cell line) showed that PA-Ara had significantly stronger antiproliferation activities than Ara-C. Significantly, we firstly compared the bioavailability of the oral fatty acid chain modified cytarabine prodrug preparation with injection and the relative bioavailability was up to 61.77% for our PA-Ara, which was much superior to that of oral Ara-C solution (3.23%). Overall, these findings make it clear that the PA-Ara suspension has the potential to be a promising new cytarabine oral preparation for leukemia therapy.
由于阿糖胞苷（Ara-C）存在诸如脂溶性差、脱氨基失活以及口服生物利用度低等缺点，限制了其口服给药的应用，在此我们通过将棕榈酸（PA）与阿糖胞苷共轭，提出了一种新型两亲性低分子量阿糖胞苷前药（PA-Ara），这使得通过保护活性4-氨基避免脱氨基失活以及提高脂溶性成为可能。得益于合理设计，与阿糖胞苷相比，PA-Ara的油/水分配系数大幅提高，并且PA-Ara共轭物在人工消化液中足够稳定，确保大多数分子能够以前药形式被吸收。为测量阿糖胞苷和PA-Ara对HL60（急性髓性白血病细胞系）和K562细胞（慢性粒细胞白血病细胞系）的细胞毒性而进行的MTT试验结果表明，PA-Ara具有比阿糖胞苷显著更强的抗增殖活性。值得注意的是，我们首次比较了口服脂肪酸链修饰的阿糖胞苷前药制剂与注射剂的生物利用度，我们的PA-Ara相对生物利用度高达61.77%，远优于口服阿糖胞苷溶液（3.23%）。总体而言，这些发现表明PA-Ara混悬液有潜力成为一种用于白血病治疗的有前景的新型阿糖胞苷口服制剂。
