Wu Hangyi, Yu Miaorong, Miao Yunqiu, He Shufang, Dai Zhuo, Song Wenyi, Liu Yuan, Song Sha, Ahmad Ejaj, Wang Dongkai, Gan Yong
Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 117004, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharm Sin B. 2019 Jul;9(4):858-870. doi: 10.1016/j.apsb.2019.02.010. Epub 2019 Mar 2.
Recently, liposomes have been widely used in cancer therapeutics, but their anti-tumor effects are suboptimal due to limited tumor penetration. To solve this problem, researchers have made significant efforts to optimize liposomal diameters and potentials, but little attention has been paid to liposomal membrane rigidity. Herein, we sought to demonstrate the effects of cholesterol-tuned liposomal membrane rigidity on tumor penetration and anti-tumor effects. In this study, liposomes composed of hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl--glycero-3-phosphoethanolamine--[methoxy(polyethylene glycol)-2000] (DSPE-PEG) and different concentrations of cholesterol were prepared. It was revealed that liposomal membrane rigidity decreased with the addition of cholesterol. Moderate cholesterol content conferred excellent diffusivity to liposomes in simulated diffusion medium, while excessive cholesterol limited the diffusion process. We concluded that the differences of the diffusion rates likely stemmed from the alterations in liposomal membrane rigidity, with moderate rigidity leading to improved diffusion. Next, the tumor penetration and the anti-tumor effects were analyzed. The results showed that liposomes with moderate rigidity gained excellent tumor penetration and enhanced anti-tumor effects. These findings illustrate a feasible and effective way to improve tumor penetration and therapeutic efficacy of liposomes by changing the cholesterol content, and highlight the importance of liposomal membrane rigidity.
近年来，脂质体已广泛应用于癌症治疗，但由于肿瘤穿透性有限，其抗肿瘤效果并不理想。为了解决这一问题，研究人员在优化脂质体直径和电位方面做出了巨大努力，但对脂质体膜刚性的关注却很少。在此，我们试图证明胆固醇调节的脂质体膜刚性对肿瘤穿透性和抗肿瘤效果的影响。在本研究中，制备了由氢化大豆磷脂（HSPC）、1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-[甲氧基（聚乙二醇）-2000]（DSPE-PEG）和不同浓度胆固醇组成的脂质体。结果表明，随着胆固醇的加入，脂质体膜刚性降低。适度的胆固醇含量赋予脂质体在模拟扩散介质中优异的扩散性，而过量的胆固醇则限制了扩散过程。我们得出结论，扩散速率的差异可能源于脂质体膜刚性的改变，适度的刚性导致扩散改善。接下来，分析了肿瘤穿透性和抗肿瘤效果。结果表明，具有适度刚性的脂质体具有优异的肿瘤穿透性并增强了抗肿瘤效果。这些发现说明了一种通过改变胆固醇含量来提高脂质体肿瘤穿透性和治疗效果的可行且有效的方法，并突出了脂质体膜刚性的重要性。
