Biomedical Engineering Reference
In-Depth Information
Chapter 4
Delivery of Single siRNA Molecules
Caroline Palm-Apergi and Steven F. Dowdy *
Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine,
UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0686, USA
* sdowdy@ucsd.edu
The major impediment in development of macromolecular drug
therapeutics, including peptides, proteins, and siRNAs, is delivery of
the drug into the cytoplasm or nucleus of cells where it will exert its
biological effect. Macromolecular siRNAs are too large, too charged,
and too hydrophilic to cross the hydrophobic plasma membrane,
which serves as a protective barrier to protect keep foreign molecules
and pathogens out of the cell. Thus, cellular delivery of siRNAs
remains a significant barrier and rate-limiting step for development
of siRNA therapeutics. Current, siRNA delivery approaches rely
on condensing and packaging siRNAs into ~100 nm liposome
or polymer nanoparticles. However, lipid nanoparticles are 100
megaDaltons in size, roughly 5,000-fold larger than the 14 kDaltons
siRNA being delivered, which severely limits the diffusion coefficient,
pharmacokinetics, and potential of lipid nanoparticle therapeutics.
An alternative siRNA delivery approach is to deliver one siRNA into
a cell at a time using Peptide Transduction Domains (PTDs) delivery
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