pH敏感的肿瘤靶向聚合物胶束的体外性质

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FQSIYPpIKRRRRRRRRHHHHC (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pH7.4条件下,Zeta电位为-3.01±0.05 mV,在pH6.4条件下,电荷翻转为5.27-0.32 mV.FRH-M的药物释放速度随释放介质的pH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pH6.4条件下的细胞摄取明显高于pH7.4的,FRH-M的IC50值为1.40 ±0.41 μg·mL-1,明显低于未经配体修饰的胶束(5.08±0.33 μg· mL-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.

In vitro properties of pH sensitive tumor cell targeting polymer micelles

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 mV at pH 7.4 to 5.27 ± 0.32 mV at pH 6.4.In vitro drug release study showed controlled release of micelles under physiological condition,and faster release was achieved by decreasing pH.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 pH 6.4 was significantly higher than that at pH 7.4.The IC50 value of FRH micelles was 1.40 ± 0.41 μg· mL-1,which was significantly lower than the unmodified micelle (5.08 ±0.33 μg· mL-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.