He Ruiyu, Du Yawei, Ling Longbing, Ismail Muhammad, Hou Yongpeng, Yao Chen, Li Xinsong
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210018, China.
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210018, China..
Eur J Pharm Sci. 2017 Mar 30;100:197-204. doi: 10.1016/j.ejps.2017.01.012. Epub 2017 Jan 12.
Bexarotene (Bex), a synthetic retinoid X receptor-selective activator, has been proved to be an efficacious chemotherapeutic agent. But, its clinical application is limited due to the poor solubility. In this report, dual bexarotene-tailed phospholipid (DBTP) conjugate based nanovesicles were prepared in order to develop new nanoformulation. DBTP conjugate was first synthesized by conjugating two Bex molecules with glycerophosphorylcholine (GPC) through facial esterification. The amphiphilic DBTP nanovesicles were prepared without any additive by reverse-phase evaporation method. They were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results revealed that the DBTP nanovesicles have a spherical structure with an average diameter approximately 138.7nm and a negatively charged surface (-33.3±2.5mV). The loading efficiency of Bex is 76wt% after a simple calculation. In vitro degradation of DBTP nanovesicles and the release of Bex were further studied in detail. The results demonstrated that DBTP nanovesicles were stable in neutral environment but degraded in a weakly acidic condition and released parent drug Bex effectively. Cellular uptake was investigated by confocal laser scanning microscope (CLSM) and liquid chromatography-mass spectroscopy (LC-MS). The results demonstrated the successful internalization and intracellular release of DBTP nanovesicles. Furthermore, the cytotoxicity analysis and apoptosis of the nanovesicles showed higher antitumor activities compared with free Bex. In a conclusion, DBTP nanovesicles could be an effective nanoformulation of Bex.
贝沙罗汀（Bex）是一种合成的视黄酸X受体选择性激活剂，已被证明是一种有效的化疗药物。但是，由于其溶解度差，其临床应用受到限制。在本报告中，制备了基于双贝沙罗汀尾磷脂（DBTP）共轭物的纳米囊泡，以开发新的纳米制剂。DBTP共轭物首先通过将两个贝沙罗汀分子与甘油磷酰胆碱（GPC）通过表面酯化反应共轭合成。通过反相蒸发法在无任何添加剂的情况下制备了两亲性DBTP纳米囊泡。通过动态光散射（DLS）和透射电子显微镜（TEM）对其进行了表征。结果表明，DBTP纳米囊泡具有球形结构，平均直径约为138.7nm，表面带负电荷（-33.3±2.5mV）。经简单计算，贝沙罗汀的负载效率为76wt%。进一步详细研究了DBTP纳米囊泡的体外降解和贝沙罗汀的释放。结果表明，DBTP纳米囊泡在中性环境中稳定，但在弱酸性条件下会降解并有效释放母体药物贝沙罗汀。通过共聚焦激光扫描显微镜（CLSM）和液相色谱-质谱联用（LC-MS）研究了细胞摄取情况。结果表明DBTP纳米囊泡成功内化并在细胞内释放。此外，纳米囊泡的细胞毒性分析和凋亡显示出比游离贝沙罗汀更高的抗肿瘤活性。总之，DBTP纳米囊泡可能是贝沙罗汀的一种有效纳米制剂。
