Liu Yuanyuan, Chang Ying, Yang Chao, Sang Zitai, Yang Tao, Ang Wei, Ye Weiwei, Wei Yuquan, Gong Changyang, Luo Youfu
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
Nanoscale. 2014 Apr 21;6(8):4325-37. doi: 10.1039/c3nr06599e.
Piperlongumine (PL) shows an inhibitory effect on tumor growth; however, lipophilicity has restricted its further applications. Nanotechnology provides an effective method to overcome the poor water solubility of lipophilic drugs. Polymeric micelles with small particle size can passively target tumors by the enhanced permeability and retention (EPR) effect, thus improving their anti-tumor effects. In this study, to improve the water solubility and anti-tumor activity of PL, PL encapsulated polymeric micelles (PL micelles) were prepared by a solid dispersion method. The prepared PL micelles showed a small particle size and high encapsulation efficiency, which could be lyophilized into powder, and the re-dissolved PL micelles are homogenous and stable in water. In addition, a sustained release behavior of PL micelles was observed in vitro. Encapsulation of PL into polymeric micelles could increase the cytotoxicity, cellular uptake, reactive oxygen species (ROS) and oxidized glutathione (GSSG), and reduce glutathione (GSH) levels in vitro. Encapsulation of PL into polymeric micelles enhanced its inhibitory effect on neovascularization both in vitro and in vivo. Compared with free PL, PL micelles showed a stronger inhibitory effect on the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). Additionally, in a transgenic zebrafish model, embryonic angiogenesis was inhibited by PL micelles. Furthermore, PL micelles were more effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT-26 murine tumor model in vivo. Therefore, our data revealed that the encapsulation of PL into biodegradable polymeric micelles enhanced its anti-angiogenesis and anti-tumor activities both in vitro and in vivo.
胡椒碱（PL）对肿瘤生长具有抑制作用；然而，其亲脂性限制了它的进一步应用。纳米技术提供了一种有效方法来克服亲脂性药物水溶性差的问题。粒径小的聚合物胶束可通过增强的渗透与滞留（EPR）效应被动靶向肿瘤，从而提高其抗肿瘤效果。在本研究中，为提高PL的水溶性和抗肿瘤活性，采用固体分散法制备了PL包封的聚合物胶束（PL胶束）。所制备的PL胶束粒径小且包封率高，可冻干成粉末，重新溶解后的PL胶束在水中均匀且稳定。此外，在体外观察到PL胶束具有缓释行为。将PL包封到聚合物胶束中可增加其体外细胞毒性、细胞摄取、活性氧（ROS）和氧化型谷胱甘肽（GSSG）水平，并降低谷胱甘肽（GSH）水平。将PL包封到聚合物胶束中增强了其在体外和体内对新生血管形成的抑制作用。与游离PL相比，PL胶束对人脐静脉内皮细胞（HUVECs）的增殖、迁移、侵袭和管腔形成具有更强的抑制作用。此外，在转基因斑马鱼模型中，PL胶束可抑制胚胎血管生成。此外，在皮下CT-26小鼠肿瘤模型中，PL胶束在体内抑制肿瘤生长和延长生存期方面更有效。因此，我们的数据表明，将PL包封到可生物降解的聚合物胶束中可增强其在体外和体内的抗血管生成及抗肿瘤活性。
