Feng Chan, Li Xiaoyan, Dong Chunyan, Zhang Xuemei, Zhang Xie, Gao Yong
Department of Oncology, Shanghai East Hospital, Tongji University, Shanghai, People's Republic of China.
Shanghai Tenth People's Hospital, Tongji University, Shanghai, People's Republic of China.
Drug Des Devel Ther. 2015 Aug 11;9:4613-20. doi: 10.2147/DDDT.S85993. eCollection 2015.
In this study, long-circulating Arg-Gly-Asp (RGD)-modified aclacinomycin A (ACM) liposomes were prepared by thin film hydration method. Their morphology, particle size, encapsulation efficiency, and in vitro release were investigated. The RGD-ACM liposomes was about 160 nm in size and had the visual appearance of a yellowish suspension. The zeta potential was -22.2 mV and the encapsulation efficiency was more than 93%. The drug-release behavior of the RGD-ACM liposomes showed a biphasic pattern, with an initial burst release and followed by sustained release at a constant rate. After being dissolved in phosphate-buffered saline (pH 7.4) and kept at 4°C for one month, the liposomes did not aggregate and still had the appearance of a milky white colloidal solution. In a pharmacokinetic study, rats treated with RGD-ACM liposomes showed slightly higher plasma concentrations than those treated with ACM liposomes. Maximum plasma concentrations of RGD-ACM liposomes and ACM liposomes were 4,532 and 3,425 ng/mL, respectively. RGD-ACM liposomes had a higher AUC0-∞ (1.54-fold), mean residence time (2.09-fold), and elimination half-life (1.2-fold) when compared with ACM liposomes. In an in vivo study in mice, both types of liposomes inhibited growth of human lung adenocarcinoma (A549) cells and markedly decreased tumor size when compared with the control group. There were no obvious pathological tissue changes in any of the treatment groups. Our results indicate that RGD-modified ACM liposomes have a better antitumor effect in vivo than their unmodified counterparts.
在本研究中，采用薄膜水化法制备了长循环的精氨酸-甘氨酸-天冬氨酸（RGD）修饰的阿克拉霉素A（ACM）脂质体。研究了其形态、粒径、包封率和体外释放情况。RGD-ACM脂质体的粒径约为160 nm，外观为淡黄色悬浮液。ζ电位为-22.2 mV，包封率超过93%。RGD-ACM脂质体的药物释放行为呈双相模式，先是初始的突释，然后是恒速持续释放。将其溶解于磷酸盐缓冲液（pH 7.4）中并在4°C保存1个月后，脂质体未发生聚集，仍呈乳白色胶体溶液外观。在一项药代动力学研究中，用RGD-ACM脂质体处理的大鼠血浆浓度略高于用ACM脂质体处理的大鼠。RGD-ACM脂质体和ACM脂质体的最大血浆浓度分别为4532 ng/mL和3425 ng/mL。与ACM脂质体相比，RGD-ACM脂质体的AUC0-∞更高（1.54倍）、平均驻留时间更长（2.09倍）、消除半衰期更长（1.2倍）。在小鼠体内研究中，与对照组相比，两种脂质体均能抑制人肺腺癌（A549）细胞生长并显著减小肿瘤大小。各治疗组均无明显的病理组织变化。我们的结果表明，RGD修饰的ACM脂质体在体内比未修饰的脂质体具有更好的抗肿瘤效果。
