Toxicogenomics of drug delivery systems: Exploiting delivery system-induced changes in target gene expression to enhance siRNA activity.
Synthetic siRNAs are typically formulated with drug delivery systems (DDS) that improve cellular uptake for optimal gene silencing activity. Here, we show that two PAMAM dendrimer DDS, differing only in their structural architecture, elicit many different gene expression changes in human cells including opposing effects on the expression of epidermal growth factor receptor (EGFR), a gene targeted for silencing by siRNA. Despite providing similar improvements in siRNA uptake, these two formulations led to a approximately 10-fold variation in anti-EGFR siRNA activity. These data show that gene expression changes induced by DDS, separate from their ability to enhance cell uptake, determine 'apparent' siRNA potency and thus offer the possibility of tailoring delivery system-siRNA combinations for additive or synergistic effects on gene silencing.
Hollins
Andrew J
AJ
Centre for Genome Based therapeutics, Cardiff University School of Pharmacy, Cardiff, CF10 3XF, UK.
Omidi
Yadollah
Y
Benter
Ibrahim F
IF
Akhtar
Saghir
S
D001672:Biocompatible Materials; D015153:Blotting, Western; D045744:Cell Line, Tumor; D050091:Dendrimers; D016503:Drug Delivery Systems; D004563:Electrochemistry; D004586:Electrophoresis; D005434:Flow Cytometry; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011073:Polyamines; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043922:Toxicogenetics; D014162:Transfection
D001672:Biocompatible Materials; D050091:Dendrimers; C104700:PAMAM Starburst; D011073:Polyamines; D034741:RNA, Small Interfering