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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 a polymer micelle modified with FQSIYPp IKRRRRRRRHHHHHC (FRH), which is sensitive to the tumor microenvironment, has the ability of targeting tumor cells and penetrates the membrane, and its in vitro properties were preliminarily investigated. Methods HPH polymer micelles (FRH-M) were modified by FRH-modified β-SITO to investigate its physico-chemical properties , Uptake of tumor cells and the effect of inhibiting tumor cell growth. Results Transmission electron microscopy showed that the micelles were uniformly spherical. The particle size of FRH-M micelles was about 55 nm and the doxorubicin drug loading was 8.3%. Under the condition of p H7.4, the micelle has a Zeta potential of -3.01 ± 0.05 mV and a charge of 5.27 ± 0.32 mV under p H6.4. The rate of drug release from FRH-M is accelerated by the decrease of p H in the release medium. The cellular uptake of FRH-M was 1.9-fold higher than that of unmodified micelles and the cellular uptake at p H6.4 was significantly higher than p H7.4 with an IC50 value of 1.40 ± 0.41 μg for FRH-M · M L -1, which was significantly lower than that of the micelles without ligand modification (5.08 ± 0.33 μg · m L -1). Conclusion The polymer micelles modified by FRH peptides have good tumor microenvironment response ability, better cell uptake ability and antitumor activity in vitro, which have great prospects for development.