Polymeric Micelles for siRNA Delivery - RNA Interference from Biology to Therapeutics - page 159

in the twentieth century. Among other characteristics, the flexibility of synthetic
polymer chemistry allows the synthesis of polymers with different solvent affinities
and tailored molecular weight, as well as the addition of biomimetic features and
bioresponsive elements to a construct [ 1 ] .
Blocks of two or more repeating monomers in the same polymer chain can result
in molecules with regions that have opposite affinities for a solvent. These
amphiphilic block copolymers were found to have the ability to form micelles in
selective solvents by organizing themselves according to the solvent affinity.
Polymeric micelles are spherical supramolecular nanoassemblies with the size range
of several tens of nanometers and are characterized by a core-shell architecture in
which the inner compartment can be used as nanocarriers for versatile compounds
[ 2, 3 ]. The concept of nanoassembly arrangement of amphiphilic block copolymers
through the formation of a hydrophilic corona surrounding a water-incompatible
core can be extended to include macromolecular association through electrostatic
interaction [ 3 ]. Supramolecular assembly is obtained by utilizing the opposite
charges of negative oligonucleotides with positive polycations to form polyion com-
plexes through electrostatic interactions [ 3- 6 ] .
Although viral vectors are natural vehicles for nucleic acids, the inherent immu-
nogenic characteristic and safety concerns have substantially impeded their transla-
tion into approved pharmaceuticals [ 7 ]. As an alternative, nonviral vectors for
nucleic acid encapsulation that mimic viral size and structure can be produced by
the application of nanotechnology. Among the nonviral nanocarrier systems, the
polymeric nanocarriers offer great biological stability and versatility in design due
to copolymerization and inclusion of chemical components such as targeting ligands
during the polymer synthesis to achieve surface functionalization [ 8 ] .
A fundamental pathway in eukaryotic cells by which short sequences of RNA
can promote the cleavage of a complementary endogenous messenger RNA (mRNA)
transcript is called RNA interference (RNAi). Although researchers had been using
exogenous single-stranded antisense oligonucleotides in cell experiments to cleave
specific mRNA and silence genes, Mello and Fire [ 9 ] described the process of dou-
ble-stranded RNA-mediated gene silencing, while Elbashir and colleagues proved
the principle in mammalian cells [ 10 ]. These studies provide the basis for the poten-
tial application of RNAi-based therapeutic intervention to control gene expression
at the posttranscriptional level. Clinical translation of RNAi, however, requires non-
toxic and biocompatible delivery systems. In this sense, the knowledge obtained
from the development of plasmid DNA (pDNA) nanocarriers as gene delivery vehi-
cles can be applied to RNAi-based therapeutics due to similar polyanionic and mac-
romolecular characteristics.
This chapter gives an overview of the rational design of polymeric micelles for
siRNA delivery directed toward therapeutic application. The design of block copo-
lymers for the assembly into multifunctional vehicles takes into account require-
ments needed to overcome extracellular and intracellular delivery barriers. Strategies
for the formation of stable polymeric micelles are discussed, and smart polymers to
overcome barriers are presented.