pH敏感的肿瘤靶向聚合物胶束的体外性质  

In vitro properties of p H sensitive tumor cell targeting polymer micelles

作　　者：刘妍曦 黄园[1] 周洲 

机构地区：[1]四川大学华西药学院靶向药物及释药系统教育部重点实验室,四川成都610041

出　　处：《华西药学杂志》2017年第5期459-463,共5页West China Journal of Pharmaceutical Sciences

摘　　要：目的制备肿瘤微环境敏感、具有肿瘤细胞靶向能力和穿膜能力的融合肽FQSIYPp IKRRRRRRRRHHHHC(FRH)修饰的聚合物胶束,并对其体外性质进行初步考察。方法采用FRH修饰N-(2-羟丙基)-甲基丙烯酰胺(HPMA)聚合物-β-谷甾醇(β-SITO),形成HPMA聚合物胶束(FRH-M),考察其理化性质、肿瘤细胞的摄取和抑制肿瘤细胞生长的效果。结果透射电镜显示:胶束为均匀的类球形。FRH-M胶束粒径约为55 nm,阿霉素载药量8.3%。该胶束在p H7.4条件下,Zeta电位为-3.01±0.05 m V,在p H6.4条件下,电荷翻转为5.27±0.32 m V。FRH-M的药物释放速度随释放介质的p H降低而加快。FRH-M的细胞摄取较未经修饰胶束的P-M提升了1.9倍;且在p H6.4条件下的细胞摄取明显高于p H7.4的,FRH-M的IC50值为1.40±0.41μg·m L^(-1),明显低于未经配体修饰的胶束(5.08±0.33μg·m L^(-1))。结论经FRH多肽修饰的聚合物胶束具有良好的肿瘤微环境响应能力,且有更好的细胞摄取能力和体外抗肿瘤活性,极具发展前景。OBJECTIVE To prepare tumor microenvironment-sensitive,tumor-cell-targeting and membrane-penetrating peptide modified polymer micelles and to investigate its in vitro characteristics. METHODS Attaching the ligand onto N-（ 2-hydroxypropyl）-methyl acrylamide（ HPMA）-beta sitosterol（ β-SITO） conjugates to form a tumor microenvironment-responsive and active targeting HPMA polymer micelle（ FRH-M） by self-assembly. The characteristics,cellular uptake and tumor cell antiproliferation were evaluated. RESULTS The particle size of FRH micelles was around 55 nm,and the drug loading of Doxorubicin was 8. 3%.Transmission electron microscopy（ TEM） showed FRH micelle was in uniform spherical shape. Zeta potential of FRH-M could reverse from-3. 01 ± 0. 05 m V at p H 7. 4 to 5. 27 ± 0. 32 m V at p H 6. 4. In vitro drug release study showed controlled release of micelles under physiological condition,and faster release was achieved by decreasing p H. Cellular uptake experiments showed that the uptake of FRH-M cells was 1. 9-fold higher than that of unmodified micelle（ P-M）,indicating the good tumor microenvironment responsibility and cellular uptake enhancement of FRH peptide. And the cellular uptake of FRH-M at p H 6. 4 was significantly higher than that at p H 7. 4. The IC50 value of FRH micelles was 1. 40 ± 0. 41 μg·m L^（-1）,which was significantly lower than the unmodified micelle（ 5. 08 ±0. 33 μg·m L^（-1））. CONCLUSION The prepared FRH-M in this study has a good response to the tumor microenvironment and the good antiproliferation effect,which makes it a very promising drug delivery system.

关 键 词：FQS多肽 整合素ΑVΒ3 融合肽 肿瘤微环境 肿瘤细胞靶向 聚合物胶束 HPMA聚合物 阿霉素 

分 类 号：R94[医药卫生—药剂学]