Long-circulating and liver-targeted nanoassemblies of cyclic phosphoryl N-dodecanoyl gemcitabine for the treatment of hepatocellular carcinoma
Long-circulating and liver-targeted nanoassemblies of cyclic phosphoryl N-dodecanoyl gemcitabine for the treatment of hepatocellular carcinoma
复制标题
用于治疗肝细胞癌的长循环和肝脏靶向的环磷酰基N-十二酰基吉西他滨纳米组件
DOI：
10.1016/j.biopha.2016.02.024
复制
发表时间：
2016-04-01
影响因子：
7.5
通讯作者：
Jin, Yiguang
中科院分区：
文献类型：
--
作者：
Du, Lina;Zhang, Baolei;Jin, Yiguang
肝细胞癌（HCC）是世界范围内死亡率高的严重癌症。吉西他滨（GEM）在循环中容易降解，没有肿瘤靶向作用。在我们之前的研究中，基于HepDirect前药和自组装给药系统（SADDS）的技术，制备了一种两亲性的GEM衍生物环磷酰n -十二烷基吉西他滨（CPDG），该系统在水中自组装成稳定的纳米组件。本研究制备了CPDG/CHS-PEG1500长循环纳米组件（9:1,mol/mol）用于HCC治疗。对长循环CPDG纳米组件进行了体外和体内研究。CPDG的降解速率与介质有关。CPDG在酸性环境（pH 2.0）中的降解速度明显快于弱酸性和中性环境（pH 5.0、pH 7.4）。CPDG在小鼠血浆中的降解半衰期（t(1/2)）约为43 h， pH为2.0时比t1/2长。因此，长循环的CPDG纳米组件在体内到达目标之前可以保持稳定。在生物分布研究中，长循环的CPDG纳米组件被静脉注射到肝细胞荷瘤小鼠体内。CPDG在肿瘤中的分布远高于血液中的分布，表明长循环纳米组件具有肿瘤靶向性。在药效学研究中，将长循环CPDG纳米组件以（37.5,75 mu mol/kg）的剂量静脉注射到荷瘤小鼠体内，与GEM （150 mu mol/kg）进行比较。小鼠每3天注射1次，共3次。长循环纳米组件几乎总是表现出比GEM更高的抗癌作用。GEM、长循环CPDG纳米组装体（37.5、75 μ m ol/kg）的抑瘤率分别为49.54%、42.97、65.10%。因此，长循环的CPDG纳米组件具有比GEM更高的抗癌效果。长循环的CPDG纳米组件是治疗HCC的有前途的纳米药物。基于HepDirect前药技术和sadd理论的肿瘤靶向纳米组件组合设计是一种有效的方法来修饰具有药理活性的核苷来治疗一些肝脏疾病。(C) 2016年由Elsevier Masson SAS出版。
Hepatocellular carcinoma (HCC) is a serious cancer with high mortality worldwide. Gemcitabine (GEM) is easily degraded in the circulation and has no tumor-targeted effect. In our previous research, an amphiphilic GEM derivative, cyclic phosphoryl N-dodecanoyl gemcitabine (CPDG) was prepared based on the techniques of HepDirect prodrug and self-assembled drug delivery systems (SADDS), which self-assembled into the stable nanoassemblies in water. In this study, the long-circulating nanoassemblies of CPDG/CHS-PEG1500 (9:1, mol/mol) were prepared for HCC treatment. In vitro and in vivo studies of the long-circulating CPDG nanoassemblies were explored. The degradation rates of CPDG depended on the media. CPDG showed much faster degradation in the acidic environment (pH 2.0) than the weak acidic and neutral media (pH 5.0, pH 7.4). However, the degradation half-life (t(1/2)) of CPDG was about 43 h in the mouse plasma, longer than the t1/2 at pH 2.0. Therefore, the long-circulating CPDG nanoassemblies could keep stable before reaching the targets in vivo. In the biodistribution study, the long-circulating CPDG nanoassemblies were bolus intravenously (i.v.) injected into the hepatocellular tumor-bearing mice. The distribution of CPDG in the tumors was much higher than that in the blood, indicating the tumor targeting of the long-circulating nanoassemblies. In the pharmacodynamic study, the long-circulating CPDG nanoassemblies were i.v. injected into the tumor-bearing mice with doses of (37.5, 75 mu mol/kg) compared with GEM (150 mu mol/kg). The mice were injected once every 3 days for totally 3 times. The long-circulating nanoassemblies nearly always showed the higher anti-cancer effects than GEM. The tumor inhibitory rates of GEM, the long circulating CPDG nanoassemblies (37.5, 75 mu m ol/kg) were 49.54, 42.97, 65.10%, respectively. Therefore, the long-circulating CPDG nanoassemblies had the much higher anti-cancer effect than GEM. The long-circulating CPDG nanoassemblies are promising nanomedicines to treat HCC. The combination design of tumor-targeted nanoassemblies based on HepDirect prodrug technique and SADDS theory is an effective method to modify the pharmacologically active nucleosides to treat some liver diseases. (C) 2016 Published by Elsevier Masson SAS.