Li Su, Wang Anxun, Jiang Wenqi, Guan Zhongzhen
Department of Medicine, Tumor Hospital, Sun Yat-sen University, Guangzhou, China.
BMC Cancer. 2008 Apr 15;8:103. doi: 10.1186/1471-2407-8-103.
It is expected that prolonged circulation of anticancer drugs will increase their anticancer activity while decreasing their toxic side effects. The purpose of this study was to prepare 5-fluorouracil (5-FU) loaded block copolymers, with poly(gamma-benzyl-L-glutamate) (PBLG) as the hydrophobic block and poly(ethylene glycol) (PEG) as the hydrophilic block, and then examine the 5-FU release characteristics, pharmacokinetics, and anticancer effects of this novel compound.
5-FU loaded PEG-PBLG (5-FU/PEG-PBLG) nanoparticles were prepared by dialysis and then scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to observe the shape and size of the nanoparticles, and ultraviolet spectrophotometry was used to evaluate the 5-FU in vitro release characteristics. The pharmacokinetic parameters of 5-FU/PEG-PBLG nanoparticles in rabbit plasma were determined by measuring the 5-FUby high-performance liquid chromatography (HPLC). To study in vivo effects, LoVo cells (human colon cancer cell line) or Tca8113 cells (human oral squamous cell carcinoma cell line) were implanted in BALB/c nude mice that were subsequently treated with 5-FU or 5-FU/PEG-PBLG nanospheres.
5-FU/PEG-PBLG nanoparticles had a core-shell spherical structure with a diameter of 200 nm and a shell thickness of 30 nm. The drug loading capacity was 27.1% and the drug encapsulation was 61.5%. Compared with 5-FU, 5-FU/PEG-PBLG nanoparticles had a longer elimination half-life (t1/2, 33.3 h vs. 5 min), lower peak concentration (C, 4563.5 microg/L vs. 17047.3 microg/L), and greater distribution volume (VD, 0.114 L vs. 0.069 L). Compared with a blank control, LoVo cell xenografts and Tca8113 cell xenografts treated with 5-FU or 5-FU/PEG-PBLG nanoparticles grew slower and had prolonged tumor doubling times. 5-FU/PEG-PBLG nanoparticles showed greater inhibition of tumor growth than 5-FU (p < 0.01). In the PEG-PBLG nanoparticle control group, there was no tumor inhibition (p > 0.05).
In our model system, 5-FU/PEG-PBLG nanoparticles changed the pharmacokinetic behavior of 5-FU, thus increasing its anticancer activity. 5-Fluorouracil loaded nanoparticles have potential as a novel anticancer drug that may have useful clinical applications.
预计抗癌药物的延长循环时间会增强其抗癌活性，同时降低其毒副作用。本研究的目的是制备以聚（γ-苄基-L-谷氨酸）（PBLG）为疏水嵌段、聚乙二醇（PEG）为亲水嵌段的负载5-氟尿嘧啶（5-FU）的嵌段共聚物，然后研究该新型化合物的5-FU释放特性、药代动力学及抗癌效果。
通过透析法制备负载5-FU的PEG-PBLG（5-FU/PEG-PBLG）纳米颗粒，然后用扫描电子显微镜（SEM）和透射电子显微镜（TEM）观察纳米颗粒的形状和大小，并用紫外分光光度法评估5-FU的体外释放特性。通过高效液相色谱（HPLC）测定5-FU来确定5-FU/PEG-PBLG纳米颗粒在兔血浆中的药代动力学参数。为研究体内效果，将LoVo细胞（人结肠癌细胞系）或Tca8113细胞（人口腔鳞状癌细胞系）接种于BALB/c裸鼠，随后用5-FU或5-FU/PEG-PBLG纳米球进行治疗。
5-FU/PEG-PBLG纳米颗粒具有核壳球形结构，直径为200 nm，壳厚度为30 nm。载药量为27.1%，药物包封率为61.5%。与5-FU相比，5-FU/PEG-PBLG纳米颗粒的消除半衰期更长（t1/2，33.3小时对5分钟），峰浓度更低（C，4563.5μg/L对17047.3μg/L），分布容积更大（VD，0.114 L对0.069 L）。与空白对照组相比，用5-FU或5-FU/PEG-PBLG纳米颗粒治疗的LoVo细胞异种移植瘤和Tca8113细胞异种移植瘤生长较慢，肿瘤倍增时间延长。5-FU/PEG-PBLG纳米颗粒对肿瘤生长的抑制作用比
