基于K5多糖的pH响应型药物载体的制备及其抗肿瘤活性

Preparation and Antitumor Activity of p H-Responsive Drug Carriers Based on K5 Polysaccharide

采用组氨酸(His)对K5多糖进行修饰,制得了His取代度分别为20%、28%和39%的两亲性缀合物(KH1、KH2和KH3),再利用其可自组装形成纳米粒的性质包载多柔比星。随着取代度的增大,所得的载药及空白纳米粒的粒径均减小。其中,采用KH3的载药(DKH3)纳米粒在水溶液中分散均匀,水合粒径为207.7 nm,?电位为-22.1 m V,载药量和包封率为(10.25±0.05)%和(51.26±0.27)%。体外释放结果显示,与中性环境中相比,DKH3纳米粒在酸性环境下的释放快速而完全。细胞毒性试验表明,空白的KH3纳米粒对B16细胞和COS7细胞无明显毒性;而DKH3纳米粒对B16细胞和COS7细胞的IC50为1.97和13.3?g/ml,原料药则为0.66和0.86?g/ml。结合细胞摄取试验结果,可见所制备的DKH3纳米粒能有效提高药物对肿瘤细胞的治疗选择性。

In this study, K5 polysaccharide was modified with histidine to obtain a series of amphiphilic conjugates （KH1, KH2, KH3） with degrees of substitution （DS） of 20 %, 28 % and 39%, respectively. These conjugates could self-assemble into nanoparticles in water and encapsulate doxorubicin （DOX）. The particle size of drug-loaded or unloaded nanoparticles decreased with the increasing of DS values. Among them, the drug-loaded KH3 （DKH3） nanoparticles dispersed well in aqueous solution with the average particle size of 207.7 nm, ζ potential of-22.1 mV, drug loading of （10.25±0.05） % and encapsulation efficiency of （51.26%0.27） %. In accordance with the results of in vitro release test, DKH3 nanoparticles exhibited a fast and complete drug release behavior in the acidic milieus compared with that in neutral medium. Cytotoxicity assay indicated that KH3 nanoparticles had no obvious toxicity against B 16 cells and COS7 ceils. The half maximal inhibitory concentration （IC50） of DKH3 nanoparticles against B16 cells and COS7 cells were 1.97 and 13.3 μg/ml, meanwhile, the IC50 values of DOX were 0.66 and 0.86 μg/ml correspondingly. Combining with the results of cellular uptake experiments, DKH3 nanoparticles could significantly improve the selectivity in cancer chemotherapy.