Antisense Oligonucleotides and RNA Interference - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 355

7.8.2.1 Cationic Lipid-Based Vectors
These include lipidic delivery systems to enhance transfection efficiency like liposomes
and lipoplexes with or without any surface modifications. Liposomes are spherical
vesicles composed of a central aqueous compartment enclosed within a phospholipid
bilayer. Cationic lipids in combination with neutral lipids are used to formulate lipo-
somes to deliver AS ODNs and siRNA intracellularly [155] . Neutral lipids are used
to facilitate fusion with cell membranes. The cationic lipids widely used in formulat-
ing cationic liposomes include DOTAP (1,2-dioleoyl-3-trimethylammonium-propane)
and DOTMA (1,2-dioleoyl-3-trimethylammonium-propane) [12,157,159] . However,
lipoplexes, along with cationic lipids, contain anionic amphiphilic molecules, facilitat-
ing the release of negatively charged oligonucleotides from the lipoplex, thus assisting
in nuclear localization of oligonucleotides [12,160-162] . Overall neutral charge of the
formulation reduces the biological toxic effects of cationic lipids Lipofectin RNAifect,
Oligofectamine, Lipofectamine, TransIT TKO, synthetically cationized cholesterol,
and natural analogues of cardiolipin are the most widely explored lipids for improv-
ing the delivery, safety, and efficacy of antisense drugs [12,160] . Thiocholesterol-based
cationic lipids have been used as components in self-assembled cationic micelles and
nanolipoparticles, which can efficiently entrap anionic oligonucleotides and deliver
them intracellularly [12,157,163] . However, because this complex is unstable, it should
be prepared immediately before use.
7.8.2.2 Cationic Polymer-Based Vectors
Complexes of polymers with DNA are called polyplexes. Amphiphilic block copoly-
mers spontaneously self-assemble to form core shell-type micelles in aqueous media
called polymeric micelles. Their solid core shell, small size, and modifiable surface
make them a suitable carrier for AS ODNs [162] . These cationic hydrophilic copoly-
mers efficiently entrap anionic oligonucleotides. Some examples of such copolymers
are PEG-block-polylysine copolymer, PEG-block-polyethylenimine copolymer, and
poly(lactic- co -glycolicacid)/PLGA-block-polyarginine copolymer [162,164-167] .
Polymeric nanoaparticulate systems have also been reported for intracellular deliv-
ery of AS ODNs. These proteinaceous biopolymer-based nanoparticles are biocom-
patible, and their surfaces can be modified for improved transfection efficiencies.
Examples of such biopolymers include atelocollagen, gelatine, sodium alginate,
and hyaluronic acid. Many authors have also reported chitosan-based nanoparticles
for antisense drug delivery [12,157,162,168] . Cyclodextrin-based nanoparticles
have also been developed by Mark Davis for efficient intracellular siRNA delivery
to tumors, and this has recently been approved by the FDA [169] . This is a three-
component system comprising a cyclodextrin-containing polymer (CDP), PEG as
a steric stabilization agent, and human transferrin (Tf) as a targeting ligand. This
system has been reported to improve the diseased state in tumor-bearing mice.
Nanoparticles of inorganic material, like silica and gold with or without surface
modifications, to deliver antisense drugs intracellularly have also been reported by
several authors [162,170-172] .