School of Pharmacy.
Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Int J Nanomedicine. 2018 Mar 29;13:1927-1944. doi: 10.2147/IJN.S153107. eCollection 2018.
Timosaponin AIII (TAIII), as a steroid saponin in , has favorable potential as an antitumor candidate. However, its hydrophobicity and low bioavailability severely limit its in vivo antitumor efficacy.
To overcome this drawback, TAIII-loaded liposomes (LP) were prepared to improve TAIII solubility and extend its circulation time. Furthermore, anti-CD44 antibody-modified LP (CD44-LP) was prepared to enhance the therapeutic index of TAIII. The LP and CD44-LP were also characterized through their biological activity, target selective binding and uptake, and in vivo pharmacokinetics.
Compared with free TAIII, both LP and CD44-LP possessed a desirable sustained-release profile in vitro, with ~14.2- and 10.7-fold longer TAIII half-life, respectively, and 1.7- and 1.9-fold larger area under the curve, respectively. LP and CD44-LP enhanced TAIII antitumor activity against HepG2 cells and in a xenograft mouse model without detectable toxicity. In particular, CD44-LP exhibited notably higher cytotoxicity than did LP, with a lower half-maximal inhibitory concentration (48 h). CD44-LP exhibited stronger tumor inhibition, and the tumor inhibitory effect was 1.3-fold that of LP. Furthermore, confocal laser scanning microscopy and in vivo near-infrared imaging of a xenograft mouse model revealed that compared with LP, CD44-LP could effectively enhance tumor accumulation.
Taken together, the results indicate that both CD44-LP and LP can considerably extend TAIII circulation time, increase tumor-targeted accumulation, and enhance antitumor activity. Thus, the anti-CD44 antibody-modified liposome is a promising candidate for treating CD44-positive cancer with considerable antitumor effects.
作为一种甾体皂苷，知母皂苷 AIII（TAIII）具有作为抗肿瘤候选药物的良好潜力。然而，其疏水性和低生物利用度严重限制了其体内抗肿瘤疗效。
为了克服这一缺点，制备了 TAIII 载脂蛋白（LP）以提高 TAIII 的溶解度并延长其循环时间。此外，还制备了抗 CD44 抗体修饰的 LP（CD44-LP）以提高 TAIII 的治疗指数。通过生物活性、靶向选择性结合和摄取以及体内药代动力学对 LP 和 CD44-LP 进行了表征。
与游离 TAIII 相比，LP 和 CD44-LP 在体外均具有理想的持续释放特性，TAIII 的半衰期分别延长了约 14.2 倍和 10.7 倍，曲线下面积分别增加了 1.7 倍和 1.9 倍。LP 和 CD44-LP 增强了 TAIII 对 HepG2 细胞的抗肿瘤活性，并在无明显毒性的异种移植小鼠模型中发挥作用。特别是，CD44-LP 表现出比 LP 更高的细胞毒性，半抑制浓度（48 h）低 1.7 倍。CD44-LP 表现出更强的肿瘤抑制作用，肿瘤抑制作用是 LP 的 1.3 倍。此外，对异种移植小鼠模型的共聚焦激光扫描显微镜和体内近红外成像显示，与 LP 相比，CD44-LP 可以有效地增强肿瘤积聚。
综上所述，结果表明，CD44-LP 和 LP 都可以显著延长 TAIII 的循环时间，增加肿瘤靶向积累，并增强抗肿瘤活性。因此，抗 CD44 抗体修饰的脂质体是治疗 CD44 阳性癌症的有前途的候选药物，具有相当的抗肿瘤效果。
