Modification of adenoviral vectors with polyethylene glycol modulates in vivo tissue tropism and gene expression.
Polyethylene glycol (PEG) is a hydrophilic polymer that has been used to coat adenoviral (Ad) vectors to improve their pharmacology. To analyze the effects of PEG on Ad5 tropism, Ad5 was covalently modified with different sizes of PEG and in vitro and in vivo transduction was analyzed. All tested PEGs ablated in vitro transduction. When protein C (PC) and factors VII, IX, and X were added, only factors IX and X increased transduction by the PEGylated vectors with the largest effect by X. Inactivation of these factors with warfarin drastically reduced liver transduction in mice by the PEGylated vectors after intravenous (i.v.) injection. Ad5 conjugated with 5 kd PEG maintained normal liver transduction while conjugation with larger 20 and 35 kd PEGs significantly reduced liver transduction. When intraperitoneal (i.p.) injection was tested, Ad transduced the peritoneum efficiently with only low level liver transduction. When Ad5 was modified with 5 kd PEG, peritoneal transduction was reduced and the virus preferentially transduced the liver. These data demonstrate the effects of different sizes of PEG on in vivo Ad tropism and suggest that this approach may be useful in retargeting and detargeting Ad in vivo.
Hofherr
Sean E
SE
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Shashkova
Elena V
EV
Weaver
Eric A
EA
Khare
Reeti
R
Barry
Michael A
MA
D000256:Adenoviridae; D000818:Animals; D005164:Factor IX / Q000737:chemistry; D005170:Factor X / Q000737:chemistry; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D008099:Liver; D051379:Mice; D008815:Mice, Inbred Strains; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry*; D014161:Transduction, Genetic / Q000379:methods*
D011092:Polyethylene Glycols; D005164:Factor IX; D005170:Factor X