Institute of Biomedical Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College, The Key Laboratory of Biomedical Material of Tianjin, Tianjin 300192, People's Republic of China.
Nanotechnology. 2010 Jul 2;21(26):265601. doi: 10.1088/0957-4484/21/26/265601. Epub 2010 Jun 4.
The purpose of this study was to develop nanoparticles made of cholesterol-conjugated carboxymethyl curdlan (CCMC) entrapping epirubicin (EPB) and establish their in vitro and in vivo potential. CCMC was synthesized and characterized by Fourier transform infrared spectra (FT-IR) and proton nuclear magnetic resonance spectra ((1)H NMR). The degrees of substitution (DS) of the cholesterol moiety were 2.3, 3.5 and 6.4, respectively. EPB-loaded CCMC-3.5 nanoparticles were prepared by the remote loading method. The physicochemical characteristics, drug loading efficiency and drug release kinetics of EPB-loaded CCMC-3.5 nanoparticles were characterized. The in vitro release profiles revealed that EPB release was sensitive to the pH as well as the drug loading contents. The cellular cytotoxicity and cellular uptake were accessed by using human cervical carcinoma (HeLa) cells. The EPB-loaded CCMC-3.5 nanoparticles were found to be more cytotoxic and have a broader distribution within the cells than the free EPB. The in vivo pharmacokinetics and biodistribution were investigated after intravenous injection in rats. Promisingly, a 4.0-fold increase in the mean residence time (MRT), a 4.31-fold increase in the half-life time and a 6.69-fold increase in the area under the curve (AUC 0-->infinity) of EPB were achieved for the EPB-loaded CCMC-3.5 self-assembled nanoparticles compared with the free EPB. The drug level was significantly increased in liver at 24 and 72 h; however, it decreased in heart at 8 and 24 h compared with the free EPB. The in vivo anti-tumor study indicated that the EPB-loaded CCMC-3.5 self-assembled nanoparticles showed greater anti-tumor efficacy than the free EPB. Taken together, the novel CCMC self-assembled nanoparticles might have potential application as anti-cancer drug carriers in a drug delivery system due to good results in vitro and in vivo.
本研究旨在开发载有表阿霉素（EPB）的胆固醇共轭羧甲基环糊精（CCMC）纳米粒子，并建立其体外和体内潜力。通过傅里叶变换红外光谱（FT-IR）和质子核磁共振谱（1H NMR）对 CCMC 进行了合成和表征。胆固醇部分的取代度（DS）分别为 2.3、3.5 和 6.4。通过远程加载法制备了载有 EPB 的 CCMC-3.5 纳米粒子。对载有 EPB 的 CCMC-3.5 纳米粒子的理化特性、载药效率和药物释放动力学进行了表征。体外释放曲线表明，EPB 的释放对 pH 值以及药物载药量均敏感。采用人宫颈癌（HeLa）细胞评估载有 EPB 的 CCMC-3.5 纳米粒子的细胞毒性和细胞摄取。结果发现，载有 EPB 的 CCMC-3.5 纳米粒子比游离 EPB 更具细胞毒性，并且在细胞内分布更广泛。在大鼠体内进行了药代动力学和生物分布研究。令人鼓舞的是，与游离 EPB 相比，载有 EPB 的 CCMC-3.5 自组装纳米粒子的平均驻留时间（MRT）增加了 4.0 倍，半衰期（t1/2）增加了 4.31 倍，曲线下面积（AUC 0-->无穷大）增加了 6.69 倍。与游离 EPB 相比，24 和 72 h 时肝脏中的药物水平显著升高，但 8 和 24 h 时心脏中的药物水平降低。体内抗肿瘤研究表明，载有 EPB 的 CCMC-3.5 自组装纳米粒子的抗肿瘤效果优于游离 EPB。综上所述，由于在体外和体内均取得了良好的效果，新型 CCMC 自组装纳米粒子可能具有作为药物传递系统中抗癌药物载体的潜力。
