title: Enhanced retention and anti-tumor efficacy of liposomes by changing their cellular uptake and pharmacokinetics behavior.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ruiyuan
authors.initials: R
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: School of Life Sciences, University of Beijing Institute of Technology, Beijing 100081, PR China.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Shi
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China. Electronic address: zhangzz08@126.com.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China. Electronic address: xzhang@ipe.ac.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001622:Betaine / Q000737:chemistry; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000648:ultrastructure; D008297:Male; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D010714:Phosphatidylethanolamines; C038089:1,2-distearoylphosphatidylethanolamine; D001622:Betaine; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Accelerated blood clearance phenomenon; Liposomes; Poly(carboxybetaine); Poly(ethylene glycol); Tumor accumulation