Biology Reference
In-Depth Information
Chapter 7
Lipidoids: A Combinatorial Approach
to siRNA Delivery
Michael Goldberg
Abstract
The safe and effective delivery of siRNA remains the principal challenge
to the realization of its clinical potential. The present collection of delivery materi-
als and their diversity remains limited, in part due to their slow, multistep syntheses.
This chapter will describe a class of lipid-like delivery molecules, termed “lipi-
doids,” as carriers for RNAi therapeutics. Specifically, the chapter will address the
rationale underlying the combinatorial approach; the synthetic chemical methods
employed; the screening assay utilized; the structure-activity relationships deter-
mined; the formulation considerations learned; several applications of the platform;
and the evolution of the strategy to generate next-generation libraries.
7.1
Introduction
RNA interference (RNAi) is a conserved process by which double-stranded RNA
molecules direct the sequence-specific degradation of complementary mRNA targets
[
1
]. The utility of this powerful phenomenon in the dissection of gene function
through genome-wide screening experiments was rapidly realized [
2-
4
] . This appli-
cation allowed for the large-scale investigation of mammalian genetics, enabling
direct analysis of human cells rather than relying on the use of traditional model
organisms such as
Caenorhabditis elegans
,
Saccharomyces cerevisiae
, and
Drosophila
melanogaster
. Though it was immediately apparent that this powerful application of
gene silencing could be complemented by the knockdown of disease-causing genes
in patients [
5
], the delivery of siRNAs into cells in animals was a profound obstacle
to the realization of this potential. The ability to generate systems that could deliver
these molecules in a safe and efficacious manner was highly desirable.
M. Goldberg (
*
)
Department of Cancer Immunology and AIDS , Dana-Farber Cancer Institute,
Harvard Medical School , 450 Brookline Avenue , Boston , MA 02215 , USA
e-mail: michael_goldberg1@dfci.harvard.edu
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