Copolymer of poly(ethylene glycol) and poly(L-lysine) grafting polyethylenimine through a reducible disulfide linkage for siRNA delivery

Nanoscale. 2014;6(3):1732-40. doi: 10.1039/c3nr05024f.

Abstract

siRNA therapy research has primarily focused on the synthesis and development of effective siRNA delivery vectors with easy biodegradability and low toxicity. In the present study, we synthesized a ternary copolymer mPEG-b-PLL-g-(ss-lPEI), denoted as PLI, by introducing disulfide bond linkages to graft low molecular weight linear polyethylenimine (lPEI) to the block copolymer of poly(L-lysine) (PLL) and poly(ethylene glycol) (PEG) for siRNA delivery. The PLL block and disulfide linkage rendered the carrier biodegradability, while lPEI grafting brought about the proton buffering capacity for lysosomal siRNA release and low cationic toxicity. Conjugation of a single chain monoclonal antibody (Herceptin) to the carrier as a targeting ligand for the Her2/neu receptor significantly increased the transfection activity of the copolymer/siRNA nanocomplex (i.e. the polyplex) in Skov-3, a human ovarian cancer cell line. Determination of gene expression at both the mRNA and protein levels demonstrated that Her2-targeted delivery of siRNA (XIAP siRNA) effectively downregulated the targeted XIAP (X-linked inhibitor of apoptosis protein) gene, resulting in enhanced cancer cell apoptosis and improved therapeutic efficacy in vitro and in vivo. The distinct features of low cytotoxicity, easy degradability, and high siRNA transfection efficiency make the copolymer a promising candidate for siRNA therapy in tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Disulfides
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Silencing
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Ovarian Neoplasms / therapy
  • Polyethylene Glycols / chemistry*
  • Polyethyleneimine / chemistry*
  • Polylysine / chemistry*
  • Protons
  • RNA, Small Interfering / chemistry*
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • Disulfides
  • Protons
  • RNA, Small Interfering
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Polylysine
  • Polyethylene Glycols
  • Polyethyleneimine