Induction of apoptosis in murine neuroblastoma by systemic delivery of transferrin-shielded siRNA polyplexes for downregulation of Ran.
The polymer, OEI-HD, based on beta-propionamide-cross-linked oligoethylenimine and its chemical transferrin conjugate were evaluated for siRNA delivery into murine Neuro2A neuroblastoma cells in vitro and in vivo. An 80% silencing of luciferase expression in neuroblastoma cells, stably transfected with a luciferase gene, was obtained using standard OEI-HD polyplexes or transferrin-conjugated shielded OEI-HD polyplexes. The Ras-related nuclear protein Ran was selected as a therapeutically relevant target protein. Systemic delivery of transferrin-conjugated OEI-HD/RAN siRNA formulations (three intravenous applications at 3 days interval) resulted in >80% reduced Ran protein expression, apoptosis, and a reduced tumor growth in Neuro2A tumors of treated mice. The treatment was not associated with signs of acute toxicity or significant changes in weight, hematology parameters, or liver enzymes (AST, ALT, or AP) of mice. All our results demonstrate that OEI-HD/siRNA formulations can knockdown genes in tumor cells in vitro and in vivo in mice in the absence of unspecific toxicity.
Tietze
Nicole
N
Department of Pharmacy, Pharmaceutical Biotechnology, Center of Drug Research, LMU Munich, Germany.
Pelisek
Jaroslav
J
Philipp
Alexander
A
Roedl
Wolfgang
W
Merdan
Thomas
T
Tarcha
Peter
P
Ogris
Manfred
M
Wagner
Ernst
E
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D051379:Mice; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D011094:Polyethyleneimine / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D014162:Transfection; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000378:metabolism*
D034741:RNA, Small Interfering; C102460:Ran protein, mouse; D014168:Transferrin; D011094:Polyethyleneimine; D020931:ran GTP-Binding Protein