title: Efficient systemic delivery of siRNA by using high-density lipoprotein-mimicking peptide lipid nanoparticles.
abstract: The main challenge for RNAi therapeutics lies in systemic delivery of siRNA to the correct tissues and transporting them into the cytoplasm of targeted cells, at safe, therapeutic levels. Recently, we developed a high-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) and demonstrated its direct cytosolic delivery of siRNA in vitro, thereby bypassing endosomal trapping.
  
  
  OBJECTIVE
  We investigate the in vivo implementation of HPPS for siRNA delivery.
  
  
  RESULTS
  After systemic administration in KB tumor-bearing mice, HPPS prolonged the blood circulation time of cholesterol-modified siRNA (chol-siRNA) by a factor of four, improved its biodistribution and facilitated its uptake in scavenger receptor class B type I overexpressed tumors. For therapeutic targeting to the bcl-2 gene, the HPPS-chol-si-bcl-2 nanoparticles downregulated Bcl-2 protein, induced enhanced apoptosis (2.5-fold) in tumors when compared with controls (saline, HPPS, HPPS-chol-si-scramble and chol-si-bcl-2) and significantly inhibited tumor growth with no adverse effect.
  
  
  CONCLUSIONS
  HPPS is a safe, efficient nanocarrier for RNAi therapeutics in vivo.
authors: Ontario Cancer Institute & Techna Institute, University Health Network, Toronto, ON, Canada.
authors: Qiaoya
authors: Q
authors: Lin
authors: Juan
authors: J
authors: Chen
authors: Honglin
authors: H
authors: Jin
authors: Kenneth K
authors: KK
authors: Ng
authors: Mi
authors: M
authors: Yang
authors: Weiguo
authors: W
authors: Cao
authors: Lili
authors: L
authors: Ding
authors: Zhihong
authors: Z
authors: Zhang
authors: Gang
authors: G
authors: Zheng
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000009:adverse effects / Q000737:chemistry*; D019254:Genes, bcl-2; D015316:Genetic Therapy; D008075:Lipoproteins, HDL / Q000009:adverse effects / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010455:Peptides / Q000009:adverse effects / Q000737:chemistry*; D010743:Phospholipids / Q000009:adverse effects / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D008075:Lipoproteins, HDL; D010455:Peptides; D010743:Phospholipids; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering