A new platform for oligonucleotide delivery utilizing the PEG prodrug approach.
The oligonucleotide (oligo, ODN), Genasense (GS), an ODN currently waiting for FDA approval, was chosen as a model and modified with a 5' or 3' aminohexyl functionality (1 and 4, respectively) using solid-state synthesis. These amino derivatives were reacted with different releasable PEGs (rPEGs). The in vitro results of the PEG-modified oligos (Table 1) clearly show a substantial increase in rat plasma half-life and enhanced stability against a variety of nucleases, especially the predominant nuclease (PEII) in mammals, which is the main source of oligo degradation in cells. The advantage of using a PEG prodrug approach was further demonstrated by the pharmacokinetic (PK) results, which exhibited much greater C(max), plasma half-life, and area under the curve (AUC) for 3 compared to unmodified GS. A key step in the synthesis of ODN prodrug conjugates with a dye label was also accomplished successfully by employing dihydropyran derivatives of alcohols and acids as orthogonal protecting groups during the synthesis.
Zhao
Hong
H
Enzon Pharmaceuticals Inc., 20 Kingsbridge Road, Piscataway, New Jersey 08854, USA. hong.zhao@enzon.com
Greenwald
Richard B
RB
Reddy
Prasanna
P
Xia
Jing
J
Peng
Ping
P
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D009841:Oligonucleotides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D014966:Xanthenes / Q000737:chemistry
D009841:Oligonucleotides; D011355:Prodrugs; D014966:Xanthenes; D011092:Polyethylene Glycols; C034657:Texas red