【摘要】 目的探讨改良羟基喜树碱纳米微球剂型对口腔鳞癌疗效提升的作用。方法制备闭环羟基喜树碱/聚乙二醇-聚谷氨酸苄酯(HCPT/PEG-PBLG)纳米微球,对金黄地鼠颊囊鳞癌动物模型进行干预实验:设生理氯化钠、PEG-PBLG对照组和HCPT、HCPT/PEG-PBLG治疗组,药物腹腔注射(3mg/kg,qd)连续5d。计算肿瘤体积变化、肿瘤倍增时间(DT)和抑瘤率并检测药代动力学各参数。结果成功制备HCPT/PEG-PBLG纳米微球,包封率56.8%;载药率7.5%。金黄地鼠颊囊癌干预实验:HCPT治疗组肿瘤体积于化疗第4天缩小达到最小值后复又开始增大,DT延长,抑瘤率:63.58%;HCPT/PEG-PBLG治疗组肿瘤体积于化疗第4天缩小,第8天达到最小值,DT与HCPT组比较明显延长(P=0.01),抑瘤率(76.50%)提高。HCPT体内代谢呈二室模型;HCPT/PEG-PBLG呈缓释-突释模型,峰值浓度减少,达峰时间、消除半衰期延长;浓度-时间曲线下面积、表观分布容积增加。结论HCPT对金黄地鼠颊囊癌具有较强的抑瘤作用,但开环HCPT羧酸钠盐助溶剂型降低了抑瘤活性,体内代谢快,组织亲和力差,限制其临床应用。HCPT/PEG-PBLG纳米微球剂型可保留抑瘤关键结构内酯环,增加难溶性闭环HCPT水溶性、提高内酯环稳定性,具有药物缓释、延长体内代谢时间、增加组织亲和力等优点,提高了抑癌疗效。更多还原

【Abstract】 Objective To explore the improvement effect of HCPT /PEG-PBLG nanoparticles on the treatment of oral squamous cell carcinoma.Methods PEG-PBLG nanoparticles loaded closed ring form HCPT were synthesized and measured.Intervention was performed in Golden Hamster cheek pouch squamous cell carcinoma model:normal saline,PEG-PBLG were used as blank control and HCPT & HCPT /PEG-PBLG was given through intraperitoneal injection once a day for 5 days at a dosage of 3 mg /kg.The gross volume of the tumor,the tumor’s doubling time(DT),repression rate and pharmacokinetics index were calculated.Results HCPT /PEG-PBLG nanoparticles had been successfully synthesized,with 56.8% in encapsulation efficiency and 7.5% in loading level.Gross volume of tumor treated by HCPT decreased since 4th day reached its minimum,tumor doubling time delayed and the tumor repression rate was 63.58%.In HCPT /PEG-PBLG group,the tumor gross volume decreased on 4th day,reached their minimum on 8th day,tumor doubling time was obviously longer than HCPT group(P =0.01) and tumor repression rate was 76.50%.The pharmacokinetics of HCPT carboxylic sodium salt dosage form showed two-compartment model,that of HCPT /PEG-PBLG showed a burst-and-delayed release model in vivo:Tmax and t1/2β were longer,Cmax lower,AUC and Vd increased than HCPT.Conclusions HCPT fairly restrained tumor growth of OSCC in vivo.But in clinical,HCPT is usually converted to carboxylic sodium salt dosage form with E-lactone ring opened to make the agent solvable,which has weakened its activity of tumor-depressing,and given the agent a fast rate of metabolism as well as lower affinity to tissue in vivo,leading to the limitation of application.HCPT /PEG-PBLG nanoparticles,which has preserved the key structure of tumor-depressing,E-lactone ring,increase the solubility and stabilized the lactone ring,slow down the drug release,prolong the metabolic elimination,scale up the drug affinity to tissue and make tumor-targetting possible.Compared with open ring form HCPT,it showed better therapeutic effects.更多还原