Toxicogenomics of drug delivery systems: Exploiting delivery system-induced changes in target gene expression to enhance siRNA activity

Andrew J. Hollins; Yadollah Omidi; Ibrahim F. Benter; Saghir Akhtar

doi:10.1080/10611860601151860

Toxicogenomics of drug delivery systems: Exploiting delivery system-induced changes in target gene expression to enhance siRNA activity

Andrew J. Hollins
, Yadollah Omidi
, Ibrahim F. Benter
, Saghir Akhtar

Research output: Contribution to journal › Article › peer-review

109 Scopus citations

Abstract

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 ∼ 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.

Original language	English
Pages (from-to)	83-88
Number of pages	6
Journal	Journal of Drug Targeting
Volume	15
Issue number	1
DOIs	https://doi.org/10.1080/10611860601151860
State	Published - Jan 2007
Externally published	Yes

ASJC Scopus Subject Areas

Pharmaceutical Science

Keywords

Dendrimer
Drug delivery systems
Epidermal growth factor receptor
Gene expression
Microarray
SiRNAs
RNA, Small Interfering/administration & dosage
Gene Expression/physiology
Oligonucleotide Array Sequence Analysis
Humans
Polyamines
Reverse Transcriptase Polymerase Chain Reaction
Blotting, Western
Drug Delivery Systems
Dendrimers
Flow Cytometry
Transfection
Toxicogenetics
Cell Line, Tumor
Electrochemistry
Biocompatible Materials
Electrophoresis

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10.1080/10611860601151860

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title = "Toxicogenomics of drug delivery systems: Exploiting delivery system-induced changes in target gene expression to enhance siRNA activity",

abstract = "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 ∼ 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. ",

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author = "Hollins, \{Andrew J.\} and Yadollah Omidi and Benter, \{Ibrahim F.\} and Saghir Akhtar",

year = "2007",

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doi = "10.1080/10611860601151860",

language = "English",

volume = "15",

pages = "83--88",

journal = "Journal of Drug Targeting",

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T2 - Exploiting delivery system-induced changes in target gene expression to enhance siRNA activity

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AU - Omidi, Yadollah

AU - Benter, Ibrahim F.

AU - Akhtar, Saghir

PY - 2007/1

Y1 - 2007/1

N2 - 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 ∼ 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.

AB - 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 ∼ 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.

KW - Dendrimer

KW - Drug delivery systems

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KW - Gene expression

KW - Microarray

KW - SiRNAs

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KW - Gene Expression/physiology

KW - Oligonucleotide Array Sequence Analysis

KW - Humans

KW - Polyamines

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Blotting, Western

KW - Drug Delivery Systems

KW - Dendrimers

KW - Flow Cytometry

KW - Transfection

KW - Toxicogenetics

KW - Cell Line, Tumor

KW - Electrochemistry

KW - Biocompatible Materials

KW - Electrophoresis

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Toxicogenomics of drug delivery systems: Exploiting delivery system-induced changes in target gene expression to enhance siRNA activity

Abstract

ASJC Scopus Subject Areas

Keywords

Access to Document

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