Antisense Oligonucleotides and RNA Interference - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 356

7.8.2.3 Lipid-Polymer Hybrid Systems
Lipid-polymer hybrid systems have also been reported to deliver ODNs intracellularly.
These include ODNs precondensed with polycations and then coated with either cationic
or anionic lipids, or amphiphilic polymers with or without helper lipids. Polypeptides,
such as PLL, protamine, histone, and so on, have been used to precondense ODNs to
form polyplexes that are then coated with a lipid layer to form a lipid-polymer hybrid
system [162,173-176] . Such systems are also addressed as LPD (lipid-polycation-DNA)
systems. AS ODNs are better protected in these lipid-coated polyplexes. These systems
appear to be more efficient in transfection than lipoplexes ex vivo and are equally active
in vivo [162,173,174] .
7.8.2.4 Peptide-Based Delivery Systems
One approach to deliver antisense agents intracellularly is to use synthetic or nat-
ural peptides. This system makes use of small proteins such as enzymes, recep-
tors, or antibodies to complex with antisense drugs and may provide site-specific
delivery of these agents [12,157,162,177] . An example of such a peptide is tetra-
amine spermine [178,179] . Schiffelers et al. have reported direct siRNA uptake to
tumor neovasculature by coupling of integrin-binding RGD peptide to PEGylated
PEI [12] . MPG ( N -methylpurine DNA glycosylase), a short amphipathic peptide,
has been utilized to form stable nanoparticles for efficient cellular delivery of
siRNA [157] .
7.8.2.5 Hydrogels
Hydrogels are hydrophilic polymeric networks capable of imbibing large amounts
of water or biological fluids. When placed in aqueous media, hydrogels swell to
form insoluble three-dimensional networks via chemical crosslinks (tie-points, junc-
tions) or physical crosslinks, such as entanglements or crystallites. These networks
are composed of either homopolymers or copolymers and are used to control drug
release in reservoir-based or controlled release systems or as carriers in swelling-
controlled release devices. Hydrogels can be used to modulate antisense drug release
in response to pH, temperature, ionic strength, electric field, or specific analyte con-
centration differences, thus making them enviro-intelligent and stimuli-sensitive
delivery systems [162] . Antisense activity of oligonucleotides immobilized in a cat-
ionic crosslinked poly(ethylene oxide) (PEO) and PEI nanogel has been evaluated
in a cell model [180] . A poly[1-vinyl-2-pyrrolidinone- co -(2-hydroxyethyl methacry-
late)] hydrogel has been reported as a potential carrier for AS ODNs [181] . Also,
cationic agarose-based hydrogel has been developed to deliver AS ODNs targeting
the mRNA of TNF- for the prevention of arthritis in animal models [182] . In hydro-
gels, release can be designed to occur within specific areas of the body (e.g., within
a certain pH of the digestive tract or within cancerous cells) and also to specific
sites (using adhesive or cell-receptor specific gels with modified hydrogel surface).
Hydrogels can be prepared from polymers like polyacrylic acid, pluronic, PEI, PEG,
agarose, etc. [162,168,180-183] .