2. Academic Validation
  3. Enhanced endosomal/lysosomal escape by distearoyl phosphoethanolamine-polycarboxybetaine lipid for systemic delivery of siRNA

Enhanced endosomal/lysosomal escape by distearoyl phosphoethanolamine-polycarboxybetaine lipid for systemic delivery of siRNA

  • J Control Release. 2014 Feb 28:176:104-14. doi: 10.1016/j.jconrel.2013.12.007.
Yan Li 1,  Qiang Cheng 2,  Qian Jiang 2,  Yuanyu Huang 2,  Hongmei Liu 1,  Yuliang Zhao 3,  Weipeng Cao 3,  Guanghui Ma 4,  Fengying Dai 5,  Xingjie Liang 6,  Zicai Liang 7,  Xin Zhang 8
Affiliations

Affiliations

  • 1 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.
  • 2 Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing 100871, PR China.
  • 3 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing 100190, PR China.
  • 4 National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.
  • 5 National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China. Electronic address: fydai@home.ipe.ac.cn.
  • 6 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing 100190, PR China. Electronic address: liangxj@nanoctr.cn.
  • 7 Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing 100871, PR China. Electronic address: liangz@pku.edu.cn.
  • 8 National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China. Electronic address: xzhang@home.ipe.ac.cn.
PMID: 24365128 DOI: 10.1016/j.jconrel.2013.12.007
Abstract

Cationic Liposome based siRNA delivery system has improved the efficiencies of siRNA. However, cationic liposomes are prone to be rapidly cleared by the reticuloendothelial system (RES). Although modification of cationic liposomes with polyethylene glycol (PEG) could prolong circulation lifetime, PEG significantly inhibits siRNA entrapment efficiency, cellular uptake and endosomal/lysosomal escape process, resulting in low gene silencing efficiency of siRNA. In this study, we report the synthesis of zwitterionic polycarboxybetaine (PCB) based distearoyl phosphoethanolamine-polycarboxybetaine (DSPE-PCB) lipid for cationic Liposome modification. The DSPE-PCB20 cationic Liposome/siRNA complexes (lipoplexes) show an excellent stability in serum medium. The siRNA encapsulation efficiency of DSPE-PCB20 lipoplexes could reach 92% at N/P ratio of 20/1, but only 73% for DSPE-PEG lipoplexes. The zeta potential of DSPE-PCB20 lipoplexes is 8.19±0.53mV at pH 7.4, and increases to 24.6±0.87mV when the pH value is decreased to 4.5, which promotes the endosomal/lysosomal escape of siRNA. The DSPE-PCB20 modification could enhance the silencing efficiency of siRNA by approximately 20% over the DSPE-PEG 2000 lipoplexes at the same N/P ratio in vitro. Furthermore, DSPE-PCB20 lipoplexes could efficiently mediate the down-regulation of Apolipoprotein B (apoB) mRNA in the liver and consequently decrease the total Cholesterol in the serum in vivo, suggesting therapeutic potentials for siRNA delivery in hypercholesterolemia-related diseases.

Keywords

Cationic liposomes; Endosomal/lysosomal escape; Polycarboxybetaine; pH-sensitive; siRNA delivery.

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