载三氧化二砷纳米微粒对胰腺癌腹水抑制效应的实验研究

Arsenic trioxide loaded PLGA nanoparticles inhibits formation of malignant ascites of pancreatic carcinoma.

目的探讨用纳米载体包裹的三氧化二砷（As2O3）在荷胰腺癌SCID小鼠体内的分布及对腹水生成和存活时间的影响。方法用超声乳化法制备载As2O3乳酸羟基乙酸共聚物纳米微粒（As2O3-NPs）,用体外释药方法研究其释放特性。于小鼠右前腋下接种SW1990细胞12d后,静脉给As2O3-NPs5.0mg/kg体重,采用高压液相色谱法（HPLC）测定血浆、正常和肿瘤组织中As2O3含量。观察不同浓度As2O3-NPs对腹水生成的抑制作用。观察10.0mg/kg体重As2O3-NPs处理的胰腺癌小鼠的存活期、体重、腹腔渗透性及腹水中凋亡细胞的变化。结果As2O3-NPs直径为（210±23）nm,含药量为29%（重量比）,体外释药速度明显慢于单纯的As2O3。As2O3-NPs在体内呈浓度依赖性抑制腹水形成,减少腹膜的通透性,增加腹水内凋亡细胞量,延长荷瘤小鼠的存活时间。结论As2O3-NPs具有明显的缓释药物功能,能有效积聚在肿瘤组织,并抑制癌性腹水生成,是一种有希望的抗肿瘤药物。

Objective To investigate the biodistribution of arsenic trioxide （As2O3） encapsulated by polylactic coglycolic acid （PLGA） nanoparticles and its therapeutic efficacy on the formation of carcinomatous ascites of pancreatic carcinoma in severe combined immunodeficiency （SCID） mice. Methods As2O3 encapsulated by polylactic coglycolic acid （PLGA） nanoparticles （As2O3 NPs） was prepared with the method of matrix and ultrasound emulsification, the release of the As2O3 from the As2O3 NPs was assessed by a dissolution test in vitro. SCID mice inoculated with carcinoma of pancreas cells at the anterior right subaxilla for twelve days were given intravascular injection with As2O3 NPs at 5.0 mg/kg/body （based on As2O3） at different time points. The levels of As2O3 in the plasma, tumor tissues and normal organs were tested by high pressure liquid chromatography （HPLC）. Various dosages of As2O3 NPs were peritoneally given to tumor baring mice to determine the optimal dose. The tumor baring mice were treated intraperitoneally with 10.0 mg/kg As2O3 NPs once a day for 14 days. The formation of malignant ascites, increase of body weight, improvement of survival and peritoneal capillary permeability were assessed. Apoptotic cells in ascites were detected by flow cytometry. Results As2O3 NPs was a spherical particle with 25% drug content （W/W） and 210 ± 23 nm in diameter, the slower sustained release of As2O3 NPs was attainable compared with the conventional dosage form of As2O3. As2O3 NPs effectively aggregated in tumor tissues and its half-life was 4 h. As2O3 NPs inhibited the formation of malignant ascites of pancreas carcinoma model in a dose-dependent manner. Moreover, it significantly enhanced the apoptosis of cancer cells in ascites, inhibited the increase of body weight, reduced peritoneal capillary permeability and prolonged the survival of tumor bearing mice compared with PBS control. Conclusions The optimal As2O3 NPs feature the sustained release, As2O3 NPs can effectively accumulate in tumor tissues and inhibit the formation of malignant ascites, and thus it might be used as a potential anti-cancer drug which deserves further study.