Biomedical Engineering Reference
In-Depth Information
achieve tissue targeting and enhance the intracellular penetration of drugs. A nor-
mally significant portion of PACA nanoparticles is taken up by the RES system of the
body in the liver, spleen, lungs, and bone marrow. Thus, it can be exploited for target-
ing DNA delivery to these RES organs, thereby reducing the side effects and toxicity
associated with unwanted distribution of the drug or gene [152] . The PACA particles
are taken up by endocytosis and finally reach the lysosomal compartment, where
they are degraded [152] . The degradation in lysosome generates low-molecular-
weight soluble compounds that are eliminated from the body by renal excretion
[153] . The lysosomal degradation limits the delivery of PACA particles comprised of
oligodeoxynucleotide (ODN) to the cytoplasm of the cell. Attempts have been made
to facilitate lysosomal escape by destabilization of the membrane. Several cationic
surfactant or cationic hydrophobic peptides associated with the nanoparticles were
able to destabilize the lysosomal membrane and release its contents to the cell cyto-
plasm [154,155] . A strategy consisting of linkage to PACA nanospheres of polyethyl-
ene glycol derivatives was proposed to avoid mononuclear phagocyte system (MPS)
uptake [156-159] . This strategy has resulted in a lower uptake of nanoparticles by
the MPS and in a longer circulation time [159] . As a result of an increase in residence
time, long-circulating nanoparticles would be able to extravasate in a selective man-
ner across endothelium that becomes permeable due to the presence of solid tumors
[160,161] or inflamed tissues [162] . Also, the specific ligands such as FOL can be
conjugated to the PACA, thereby enabling targeted drug delivery to tumor cells
overexpressing FOL receptors [163] . Although, these strategies are not worked out
for delivery of ODN, usually ODNs were absorbed on the surface of nanoparticles
bearing cationic surfactant or a hydrophobic peptide [164] .
4.2.2.3.1 PACA Nanoparticles of ODN
PACA NPs have been used for the intracellular delivery of various ODN sequences.
The major challenge with ODN delivery using PACA nanoparticles is the hydro-
philic and anionic nature of ODN, which makes it difficult to incorporate in PACA.
Hence, ODNs can be incorporated in PACA NPs using modified techniques, either
by covalently linking ODN to a hydrophobic molecule (cholesterol), which can then
be anchored at the NP surface [165] , or by coating the NPs with cationic surfactants
cetyltrimethylammonium bromide (CTAB) or polymers (diethylaminoethyl-dextran),
which can be used for complexing ODNs via electrostatic interactions [154] . ODN
adsorption onto nanoparticles was arbitrated by the formation of an ion pair between
the negatively charged phosphate groups of the nucleic acid chain in ODN and the
positively charged cationic surfactant preadsorbed onto nanoparticles.
The major parameters affecting the adsorption efficacy of ODN-cation complexes
on PACA nanospheres were ODN chain length, the nature of the cyanoacrylic poly-
mer, the hydrophobicity of the cation used as an ion-pairing agent, and the ionic
strength of the dispersing medium. The use of cholesterol as the hydrophobic moi-
ety was not as effective as CTAB because the complex formed using cholesterol was
negatively charged and was partially repulsed by the negative charges displayed by
the polymer surface, thereby resulting in lower loading efficiency [165,166] .
Search WWH ::




Custom Search