紫杉醇纳米粒腹腔给药对大鼠卵巢癌的抑制作用及淋巴靶向性

The inhibitory effect of paclitaxel nanoparticles on ovarian cancer xenografts and lymphatic targeting

目的：探讨紫杉醇纳米粒（PLA）腹腔给药对大鼠卵巢癌的治疗效果及作用机制，并研究PLA在大鼠体内的分布。方法：用超声乳化法合成PLA。制备大鼠腹腔种植性卵巢癌模型，将40只荷瘤鼠随机分为4组，PLA组及市售紫杉醇（PTX）组各15只，生理盐水及PLA空白支架组各5只。每周腹腔给药5mg／kg，共5次。末次给药后处死大鼠，比较荷瘤量及腹水量，用免疫组化法检测肿瘤组织增殖与凋亡。以高压液相色谱（HPLC）方法检测大鼠血浆及肝、心、肿瘤组织及盆腔淋巴结中的药物浓度。结果：合成的PLA包封率达70％，粒径分布为185—385nm。PLA组大鼠荷瘤量及腹水量分别为（4．55±0．11）g及（3．55±0．50）mL，显著低于PTX组（10．13±0．52）g及（30．45±1．55）mL，P〈0．01。免疫组化检测PLA组TUNEL阳性细胞数为（105±15），PCNA阳性细胞数为（20±5），与PTX组[分别为（55±10）及（85±10）]相比，差异有统计学意义（P〈0．01）。HPLC结果显示，末次给药后48hPLA组肿瘤及盆腔淋巴结紫杉醇的药物含量分别为（1．53±0．35）μg／g及（0．75±0．05）μg／g，明显高于PTX组[（0．0636±0，015）μg／g及（0．188±0．045）μg／g，P〈0．01]。结论：PLA腹腔给药可显著抑制大鼠卵巢癌生长，并具有淋巴靶向性。

Objective： To develop a polymeric drug delivery system for paclitaxel and determine whether paclitaxel can inhibit the growth of ovarian carcinoma xenografts in F344 rats by intraperitoneal administration. Methods： Paclitaxel loading nanoparticles （PLA） were synthesized by ultrasonic emulsification; rat ovarian carcinoma cells were injected into the peritoneal cavity of F344 rats. The antitumor effect of paclitaxel nanoparticles in vivo has been evaluated by measuring tumor weight and ascite volume. At the end of the procedure the rats were killed, tumors were excised and processed for PCNA staining, tissue terminal deoxynucleotide transferase -mediated dUTP nick and labeling （TUNEL） assay. Paclitaxel concentration in plasma, pelvic lymph nodes, liver, heart were determined by high -performance liquid chromatography （ HPLC ）. Results： In the implanted carcinoma cells, paclitaxel nanoparticles significantly reduced tumor weight [ （4.55±0.11 ） g vs （ 10.13 ±0.52） g ] and ascites volume [ （3.55 ± 0.50） mL vs （30.45 ± 1.55） mL], and induced apoptosis of tumor cells[ （ 105 ± 15） vs （55 ± 10） 1. The paclitaxel concentration of pelvic lymph nodes in PLA treated animals was significantly higher than that of free PTX treated animals 48 h after intraperitoneal administration[ （0.75 ±0.05 ）μg/g vs （0. 188 ±0. 045 ）μg/g]. Conclusion： The intraperitoneal administration of paclitaxel nanoparticles can significantly inhibit the progression of ovarian carcinoma in peritoneal cavity of female F344 rats. The paclitaxel nanoparticle is safe and lymphatic targeting.