NGR-单壁碳纳米管-紫杉醇复合物的制备及其靶向性研究

Preparation and Tumor Targeting of NGR-SWCNTs-Paclitaxel

目的探讨NGR-单壁碳纳米管-紫杉醇复合物的最佳制备方法及其靶向性。方法溶液共混法制备单壁碳纳米管-紫杉醇,将其连接NGR构建NGR-单壁碳纳米管-紫杉醇载药系统,并对其进行表征。考察单壁碳纳米管-紫杉醇制备中表面活性剂的种类、探头超声次数、碳纳米管的量等因素对载药量和包封率的影响。以S180荷瘤小鼠为模型,分别静注NGR-单壁碳纳米管-紫杉醇,单壁碳纳米管-紫杉醇和紫杉醇,采用高效液相色谱法测定小鼠脾、心、肝、肺、肾、肿瘤各组织的药物浓度,用靶向效率(TE)评价制剂的靶向性。结果碳纳米管-紫杉醇为1∶2;表面活性剂Poloxamer188和苯丙氨酸以7∶3混合;选择功率600 W,超声15次为探头超声条件制得单壁碳纳米管-紫杉醇,与NGR反应得到NGR-单壁碳纳米管-紫杉醇复合物,其包封率为(83.9±2.7)%,载药量为(69.3±1.5)%,Zeta电位为(-22.6±1.5)mV,平均粒径为(182.1±2.4)nm。在小鼠脾、肝、肺和肿瘤组织中NGR-单壁碳纳米管-紫杉醇和单壁碳纳米管-紫杉醇的AUC显著大于紫杉醇组(P<0.05,P<0.01)。在小鼠脾、肝、肺组织中单壁碳纳米管-紫杉醇和NGR-单壁碳纳米管-紫杉醇的靶向效率无明显差别,在心、肾组织中的靶向效率有所下降(P<0.05),在肿瘤中靶向效率分别为6.78%和21.33%,差异显著(P<0.01)。结论优化条件制备的NGR-单壁碳纳米管-紫杉醇复合物制备工艺和储存稳定性好,载药量和包封率高,且能显著提高紫杉醇的肿瘤靶向性。

OBJECTIVE To investigate the best method for preparing NGR-SWCNTs-paclitaxel and observe its targeting efficen- cy. METHODS SWCNTs-paclitaxel was prepared by solution mixing, and then conjugated with NGR to obtain a novel paclitaxel de- livery system：NGR-SWCNTs-paclitaxel. Taking loading efficiency and encapsulate efficiency as index, studied the influential factors of the preparation of NGR-SWCNTs-paclitaxel by surfactant,times and frequency of probe sonography, quantity of carbon nano tube. The drug concentration in different tissue were detected by high performance liquid chromatography （ HPLC ）. The targeting efficiency were used to evaluate the tissue targeting of NGR-SWCNTs-pacfitaxel, SWCNTs-paclitaxel and paclitaxel. RESULTS SWCNTs-paclit^Lxel was prepared by SWCNTs-paclitaxel was 1： 2; Poloxamer188-phenylalanine was 7：3 ;probe sonography 600 W,15 times. SWCNTs-pa- clitaxel conjugated with NGR fot^aed NGR-SWCNTs-paclitaxel . Its loading efficiency was （ 83.9 -＋ 2. 7 ） % and encapsulate efficiency was （69.3 -＋ 1.5） %. The Zeta potential was（ - 22. 6 _＋ 1.5） mV, partical size was about（ 182. 1 ＋ 2.4） nm. The AUC of NGR-SWC- NTs-paclitaxel and SWCNTs-paclitaxel in mice slpeen ,liver, lung and tumor were increased obviously compared with paclitaxel （P 〈 0. 05,P 〈 0. 01 ）. The targeting efficiency of SWCNTs-paclitaxel and NGR-SWCNTs-paclitaxel in heart and kidney were decreased （P 〈 0. 05 ）, and in tumor the targeting efficiency was 6. 78% and 21.33% separately, the difference was significantly （P 〈 0. 01 ）. CONCLUSION The preparation of NGR-SWCNTs- paclitaxel was practicable by solution mixing. The loading efficiency and encap- sulate efficiency of NGR-SWCNTs-paclitaxel are higher. NGR-SWCNTs-paclitaxel can enhance tumor targeting of paclitaxel obviously.