National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China.
Biomaterials. 2015 Feb;41:1-14. doi: 10.1016/j.biomaterials.2014.11.010. Epub 2014 Nov 29.
Although PEGylated liposome-based drug delivery systems hold great promising applications for cancer therapy due to their prolonged blood circulation time, PEGylation significantly reduces their cellular uptake, which markedly impairs the in vivo tumor retention and antitumor efficiency of drug-loaded liposomes. Most importantly, it has been proved that repeated injections of PEGylated liposomes with cell cycle specific drug such as topotecan (TPT) in the same animal at certain time intervals will induce "accelerated blood clearance" (ABC) phenomenon, which decreases the tumor accumulation of drug-loaded liposomes and presents a tremendous challenge to the clinical use of liposome-based drug delivery systems. Herein, we developed a zwitterionic poly(carboxybetaine) (PCB) modified liposome-based drug delivery system. The presence of PCB could avoid protein adsorption and enhance the stability of liposomes as that for PEG. Quite different from the PEGylated liposomes, the pH-sensitive PCBylated liposomes were internalized into cells via endocytosis with excellent cellular uptake and drug release ability. Furthermore, the PCBylated liposomes would avoid ABC phenomenon, which promoted the tumor accumulation of drug-loaded liposomes in vivo. With higher tumor accumulation and cellular uptake, the PCBylated drug-loaded liposomes significantly inhibited tumor growth and provided a promising approach for cancer therapy.
虽然基于 PEG 化脂质体的药物递送系统由于其延长的血液循环时间而在癌症治疗中具有很大的应用前景，但 PEG 化会显著降低其细胞摄取率，从而明显降低载药脂质体在体内的肿瘤保留和抗肿瘤效率。最重要的是，已经证明，在同一动物中，在一定时间间隔内重复注射具有细胞周期特异性药物（如拓扑替康（TPT））的 PEG 化脂质体，将诱导“加速血液清除”（ABC）现象，从而降低载药脂质体在肿瘤中的积累，并对脂质体为基础的药物递送系统的临床应用提出了巨大挑战。在此，我们开发了一种两性离子聚（羧基甜菜碱）（PCB）修饰的脂质体药物递送系统。PCB 的存在可以避免蛋白质吸附并增强脂质体的稳定性，与 PEG 一样。与 PEG 化脂质体非常不同的是，pH 敏感的 PCB 化脂质体通过内吞作用被细胞内化，具有优异的细胞摄取和药物释放能力。此外，PCB 化脂质体将避免 ABC 现象，从而促进载药脂质体在体内的肿瘤积累。由于具有更高的肿瘤积累和细胞摄取率，PCB 化载药脂质体显著抑制了肿瘤生长，为癌症治疗提供了一种有前途的方法。
