【作者】 陈彦佐； 常柏松； 方晓玲； 钟伟童； 杨武利； 沙先谊；

【Author】 Yanzuo Chen 1,Baisong Chang 2,Xiaoling Fang 1,Weitong Zhong 1 Wuli Yang 2,Xianyi Sha 1 (1.School of Pharmacy,Fudan University,Shanghai 201203,China;2.Department of Macromolecular Science,Fudan University,Shanghai 200433,China)

【机构】 复旦大学药学院； 复旦大学高分子科学系；

【摘要】 目的以pH敏感材料甲基丙烯酸(MAA)和异丙基丙烯酰胺(NIPAM)修饰介孔硅(MSN)作为阿霉素(Doxorubicin,DOX)的载体制备了P-MSN-DOX,研究其pH敏感特性与体内药动学,组织分布和药效学。方法用激光动态光散射粒度仪检测P-MSN-DOX的粒度分布,透射电镜和扫描电镜观察粒子形态。进行了体外释放和H-460细胞器共定位研究考察其pH敏感与释药的关系。采用MTT法进行细胞毒性评价,进行了药动学和S-180荷瘤小鼠组织分布考察结合抗肿瘤实验评价抑瘤效果和安全性。结果 P-MSN-DOX的粒径在190nm左右。透射电镜显示粒子呈圆整的球形。P-MSN-DOX的体外释放具有pH和时间依赖性,并可以在溶酶体中快速释放出药物。药动学结果表明,P-MSN-DOX延长了药物在血液循环时间;P-MSN-DOX改变了药物在体内的分布行为,药物在肺部和血浆的蓄积明显增加,约为DOX组的2倍和3倍;在心脏和肾脏的蓄积分别是DOX组的17.5%和24.7%。药效学研究结果表明,P-MSN-DOX的抑瘤率略高于DOX溶液组,分别为64.4%和54.8%,但体重没有明显降低,心脏的H&E染色切片未见异常,所测血液生化指标均在正常的范围。结论 pH敏感介孔硅盐酸阿霉素纳米粒具有控制药物释放的作用,降低了DOX的心脏毒性,增加了药物的治疗指数。P-MSN作为肿瘤化学治疗的药物传递系统具有良好的应用前景。更多还原

【Abstract】 OBJECTIVE To develop DOX-loaded MSN coated with pH-sensitive polymer-N-isopropylacrylamide (NIPAM) and methacrylic acid (MAA).To decrease the toxicity of DOX,and reveal the relationship between pH-sensitive property and in vivo effects.METHODS The particle size and morphology of P-MSN-DOX was analyzed by dynamic light scattering and transmission electron microscopy and scanning electron microscopy.In vitro release of P-MSN-DOX and confocal laser scanning microscopy were used to study drug release in different pH conditions.MTT assay was used to evaluated in vitro cytotoxicity,in vivo pharmacokinetic and tissue distribution studies binding to antitumor activity to study the effect and safty.RESULTS P-MSN-DOX were close to 190nm with core-shell structure of the composite particles.DOX released from P-MSN was both time and pH dependently.In lysosomes P-MSN-DOX can release DOX quickly.The pharmacokinetic results indicated that the P-MSN-DOX had much longer systemic circulation time than DOX.P-MSN-DOX increased accumulation with 2-fold in lung and 3-fold in plasma while in heart and kidney,only 17.5% and 24.7% accumulation compared with DOX.P-MSN-DOX exhibited a higher inhibitory rate of tumor of 64.4% than DOX,which is 54.8%,without body weight lost.Moreover,the results of subacute toxicity test demonstrated the low cardio toxicity of P-MSN-DOX.CONCLUSION Drug released from P-MSN-DOX was controlled by pH.P-MSN-DOX decreased cardio toxicity of DOX and maintains or enhances chemical effects in animal systems.P-MSN seems to be a potential drug delivery system for cancer chemotherapy.更多还原