pH敏感右旋糖酐微凝胶偶联羟基喜树碱的制备与性能  

Preparation of Dextran Nanogel Conjugates of HCPT with Acid-Sensitive Spacer and Its Properties

作　　者：邓胜松[1] 刘璐[1] 姚日生[1,2] 尤启冬[2] 

机构地区：[1]合肥工业大学制药工程系,合肥230009 [2]中国药科大学药学院,南京210009

出　　处：《中国药学杂志》2012年第12期965-970,共6页Chinese Pharmaceutical Journal

摘　　要：目的制备新型右旋糖酐微凝胶偶联羟基喜树碱(HCPT)结合物,研究其体外释放及体内抗肿瘤活性。方法以大分子右旋糖酐为载体,己二酰肼为交联剂,同步接枝mPEG己二酰肼单腙、偶联羟基喜树碱丁二酸单酯,制备出以酰腙结构为连接键的纳米凝胶偶联HCPT。结果载药凝胶形成了内疏水外亲水的胶束结构,粒径约为100 nm,可实现对肿瘤组织的被动靶向;载药量达5.63%,药物释放符合Rc=Atn1/(B+Ctn2)动力学方程,在pH 5.4缓冲溶液中的释放速率比在pH 4.5和pH7.4缓冲液中的快;相同时间内纳米凝胶偶联药物的在小鼠体内的抑瘤率与羟基喜树碱相比优势不明显,但生存率明显提高。结论该纳米凝胶偶联物具有pH敏感性,可实验肿瘤组织的被动靶向释药,在小鼠体内毒性降低,呈现显著缓释特性,可望开发成新型高分子前药。OBJECTIVE To synthesize a new drug delivery system of polyaldehyde Dex coupled with SA-10-HCPT and to study the HCPT release in vitro and the anti-tumor activity in vivo. METHODS The new drug delivery system was prepared by polyaldehyde Dex coupled with SA-HCPT,grafted with mPEG-adipic dihydrazide monohydrazone and cross-linked with adipic dihydrazide. RESULTS The conjugate formed micelle with a diameter of 100 nm in water,which could achieve passive targeting of tumor tissue concentration.The drug loading efficiency achieved 5.63%.The drug release processes accorded with kinetic equation Rc=Atn1/（B＋Ctn2） in the buffer solution.The release rate of HCPT from this conjugate in pH 5.4 buffer was much higher than that in the environment of pH 7.4 and pH 4.5.The tumor inhibition of the conjugate was similar to that of HCPT while the toxicity in vivo was significantly reduced. CONCLUSION The structure of the conjugate is unstable in acidic environment,and the drug is released pH-sensitively.The mice survival rate is significantly improved because of the significant slow-release property.Therefore,the conjugate can be developed as a novel prodrug.

关 键 词：PH敏感 右旋糖酐 羟基喜树碱 单甲氧基聚乙二醇 体外释放 肿瘤靶向性 

分 类 号：R944[医药卫生—药剂学]