Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University, Chengdu, People's Republic of China.
Int J Nanomedicine. 2013;8:1959-73. doi: 10.2147/IJN.S43892. Epub 2013 May 21.
Intravenous injection of lycobetaine was found to show significant cytotoxic activity against (inter alia) Lewis lung carcinoma, but its therapeutic use is largely limited due to an extremely short half-life in blood. This study aimed at developing a novel lipid nanocarrier-based formulation for lycobetaine delivery. The formulation is feasible for scale-up production, exhibiting good parenteral acceptability and improved circulation characteristics.
To enhance its lipophilicity, oleic acid was selected to form ionic complexes with lycobetaine (LBT). The nanoemulsion loaded with LBT-oleic acid complex (LBT-OA-nanoemulsion) and PEGylated LBT-OA-nanoemulsion (NE) (LBT-OA-PEG-NE) were prepared by a simple high-pressure homogenization method.
A high-encapsulation efficiency of around 97.32% ± 2.09% was obtained for LBT-OA-PEG-NE under optimized conditions. Furthermore, the in vivo pharmacokinetics and biodistribution of LBT-OA-NE, LBT-OA-PEG-NE, and free LBT were studied in rats. Free LBT and LBT-OA-PEG-NE displayed AUC0-10h (area under the concentration-time curve from 0 to 10 hours) of 112.99 mg/Lminute and 3452.09 mg/Lminute via intravenous administration (P < 0.005), respectively. Moreover, LBT-OA-PEG-NE showed significantly lower LBT concentration in the heart, liver, and kidney, while achieving higher concentration of LBT in the lung when compared to free LBT at the same time (P < 0.005). The LBT-OA-PEG-NE exhibited higher growth inhibitory effect and longer survival time than free LBT in both heterotopic and lung metastatic tumor models.
These results demonstrated that LBT-OA-PEG-NE is an attractive parenteral formulation for cancer therapy.
已发现甜菜碱经静脉注射对（除其他外）Lewis 肺癌具有显著的细胞毒性作用，但由于其在血液中的半衰期极短，其治疗用途在很大程度上受到限制。本研究旨在开发一种新的基于脂质纳米载体的甜菜碱递药系统。该制剂可进行规模化生产，具有良好的肠外可接受性和改善的循环特性。
为了提高其亲脂性，选择油酸与甜菜碱（LBT）形成离子复合物。通过简单的高压匀相法制备载有 LBT-油酸复合物（LBT-OA-纳米乳）和聚乙二醇化 LBT-OA-纳米乳（NE）（LBT-OA-PEG-NE）的纳米乳。
在优化条件下，LBT-OA-PEG-NE 的包封率高达约 97.32%±2.09%。此外，研究了 LBT-OA-NE、LBT-OA-PEG-NE 和游离 LBT 在大鼠体内的药代动力学和生物分布。静脉注射后，游离 LBT 和 LBT-OA-PEG-NE 的 AUC0-10h（0 至 10 小时的浓度-时间曲线下面积）分别为 112.99 mg/Lmin 和 3452.09 mg/Lmin（P＜0.005）。此外，与游离 LBT 相比，LBT-OA-PEG-NE 在心、肝和肾中的 LBT 浓度明显降低，而在同一时间内肺中的 LBT 浓度更高（P＜0.005）。LBT-OA-PEG-NE 在异位和肺转移瘤模型中均表现出比游离 LBT 更高的生长抑制作用和更长的生存时间。
这些结果表明，LBT-OA-PEG-NE 是一种有吸引力的癌症治疗的肠外制剂。
