Synthesis and characterization of chemically condensed oligoethylenimine containing beta-aminopropionamide linkages for siRNA delivery.
Polyethylenimines (PEI) are often inefficient in gene knockdown experiments with small interfering RNA (siRNA), presumably due to the strong complexing properties. A more efficient and potentially degradable oligoethylenimine-based carrier was synthesized by the condensation of 800 molecular weight PEI oligomers with hexanedioldiacrylate. Reaction conditions were chosen such that Michael reaction occurs followed by complete N-acylation of all residual ester bonds resulting in beta-aminopropionamide linkage sites and an average molecular weight of 30,000. Based on NMR analysis, these conditions produced 38% tertiary amides and 62% secondary amides, with about 2% residual carboxylate, presumably from hydrolysis. The ionizable equivalent weight of the carrier increased to 51, compared to a value of 43 for standard PEI. Sensible in vitro knockdown of the luciferase gene in stably transfected HUH7 cells, up to 80% in comparison to non-specific siRNA, demonstrated its suitability for siRNA delivery.
Tarcha
Peter J
PJ
Departments of Advanced Drug Delivery, Abbott Laboratories, North Chicago, IL, USA. peter.tarcha@abbott.com <peter.tarcha@abbott.com>
Pelisek
Jaroslav
J
Merdan
Thomas
T
Waters
Jan
J
Cheung
Kent
K
von Gersdorff
Katharina
K
Culmsee
Carsten
C
Wagner
Ernst
E
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D001672:Biocompatible Materials / Q000138:chemical synthesis* / Q000737:chemistry; D045744:Cell Line, Tumor; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010316:Particle Size; D011094:Polyethyleneimine / Q000138:chemical synthesis* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D014162:Transfection / Q000379:methods*
D000577:Amides; D001672:Biocompatible Materials; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D011094:Polyethyleneimine; D008156:Luciferases