Cheng Mingrong, Ma Daxi, Zhi Kangkang, Liu Baochi, Zhu Weiping
School of Life Sciences and Technology, Tongji University, Shanghai, China.
Department of General Surgery, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China.
Cell Physiol Biochem. 2018;50(2):569-584. doi: 10.1159/000494169. Epub 2018 Oct 11.
BACKGROUND/AIMS: Our previous study found that a nanoparticle drug delivery system that operates as a drug carrier and controlled release system not only improves the efficacy of the drugs but also reduces their side effects. However, this system could not efficiently target hepatoma cells. The aim of this study was to synthesize biotin-modified galactosylated chitosan nanoparticles (Bio-GC) and evaluate their characteristics in vitro and in vivo.
Bio-GC nanomaterials were synthesized, and confirmed by fourier transform infrared spectroscopy (FT-IR) and hydrogen-1 nuclear magnetic resonance (1H-NMR). The liver position and cancer target property of Bio-GC nanoparticles in vitro and in vivo was tested by confocal laser and small animal imaging system. The characteristics of Bio-GC/5-fluorouracil (5-FU) nanoparticles in vitro and in vivo were explored by cell proliferation, migration and cytotoxicity test, or by animal experiment.
Bio-GC nanoparticles were synthesized with biodegradable chitosan as the nanomaterial skeleton with biotin and galactose grafts. Bio-GC was confirmed by FT-IR and 1H-NMR. Bio-GC/5-FU nanoparticles were synthesized according to the optimal mass ratio for Bio-GC/5-FU (1: 4) and had a mean particle size of 81.1 nm, zeta potential of +39.2 mV, and drug loading capacity of 8.98%. Bio-GC/5-FU nanoparticles had sustained release properties (rapid, steady, and slow release phases). Bio-GC nanoparticles targeted liver and liver cancer cell in vitro and in vivo, and this was confirmed by confocal laser scanning and small animal imaging system. Compared with GC/5-FU nanoparticles, Bio-GC/5-FU nanoparticles showed more specific cytotoxic activity in a dose- and time-dependent manner and a more obvious inhibitory effect on the migration of liver cancer cells. In addition, Bio-GC/5-FU nanoparticles significantly prolonged the survival time of mice in orthotopic liver cancer transplantation model compared with other 5-FU nanoparticles or 5-FU alone. Bio-GC (0.64%) nanomaterial had no obvious cytotoxic effects on cells; thus, the concentration of Bio-GC/5-FU nanoparticles used was only 0.04% and showed no toxic effects on the cells.
Bio-GC is a liver- and cancer-targeting nanomaterial. Bio-GC/5-FU nanoparticles as drug carriers have stronger inhibitory effects on the proliferation and migration of liver cancer cells compared with 5-FU in vitro and in vivo.
背景/目的：我们之前的研究发现，一种作为药物载体和控释系统的纳米颗粒给药系统不仅能提高药物疗效，还能降低其副作用。然而，该系统不能有效地靶向肝癌细胞。本研究的目的是合成生物素修饰的半乳糖化壳聚糖纳米颗粒（Bio-GC），并评估其体外和体内特性。
合成Bio-GC纳米材料，并通过傅里叶变换红外光谱（FT-IR）和氢-1核磁共振（1H-NMR）进行确认。通过共聚焦激光和小动物成像系统测试Bio-GC纳米颗粒在体外和体内的肝脏定位及癌症靶向特性。通过细胞增殖、迁移和细胞毒性试验或动物实验，探索Bio-GC/5-氟尿嘧啶（5-FU）纳米颗粒的体外和体内特性。
以可生物降解的壳聚糖为纳米材料骨架，接枝生物素和半乳糖，合成了Bio-GC纳米颗粒。通过FT-IR和1H-NMR对Bio-GC进行了确认。按照Bio-GC/5-FU的最佳质量比（1:4）合成了Bio-GC/5-FU纳米颗粒，其平均粒径为81.1nm，zeta电位为+39.2mV，载药率为8.98%。Bio-GC/5-FU纳米颗粒具有缓释特性（快速、稳定和缓慢释放阶段）。Bio-GC纳米颗粒在体外和体内均靶向肝脏和肝癌细胞，这通过共聚焦激光扫描和小动物成像系统得到了证实。与GC/5-FU纳米颗粒相比，Bio-GC/5-FU纳米颗粒在剂量和时间依赖性方面表现出更特异的细胞毒性活性，对肝癌细胞迁移的抑制作用更明显。此外，与其他5-FU纳米颗粒或单独使用氟尿嘧啶相比，Bio-GC/5-FU纳米颗粒显著延长了原位肝癌移植模型小鼠的生存时间。Bio-GC（0.64%）纳米材料对细胞无明显细胞毒性作用；因此，所使用的Bio-GC/5-FU纳米颗粒浓度仅为0.04%，对细胞无毒性作用。
Bio-GC是一种肝脏和癌症靶向纳米材料。与5-FU相比，Bio-GC/5-FU纳米颗粒作为药物载体在体外和体内对肝癌细胞的增殖和迁移具有更强的抑制作用。
