Biomedical Engineering Reference
In-Depth Information
The present series harbor disulfide bonds in every important
position of the cationic lipid. Similarly to RPR120535, these cationic
lipids are not formulated with DOPE or other additive for optimal
transfection activity. Exhaustive structure-activity relationships
studies were accomplished. From one side, results indicate that
compound RPR-128522 with a disulfide bridge at the linker position
is completely devoid of transfection activity, probably due to an early
release of the DNA from complexes upon cell penetration. From the
other side, RPR-132688 with a triple lipid chain, but only one of
them cleavable by reductive conditions, is 10 times more active than
RPR120535 (previously described as being 100-1000 times more
efficient than first generation quaternary ammonium salt lipids such
as DOTAP/DOPE depending on the cell line model). Physico-chemical
characterization studies of the complexes [34-36] demonstrate
that DNA release from complexes can be modulated as a function
of the surrounding reducing conditions of the complexes and of the
localization of the disulfide bridge within the lipopolyamine.
Overall we have shown that modulation of gene delivery and
expression can be accomplished by proper introduction of
-
reducible disulfide bridges at key positions in the backbone of the
lipopolyamine. Our results suggest that RSL is a promising new
approach for gene delivery.
in situ
1..  Biodegradable Polyplexes:  
Reduction-Sensitive Dendrimers
Although non-viral DNA delivery agents are devoid of immunogeni-
city, they display high toxicity in many cases. This is especially
significant in the case of polyplexes such as polylysine and cationic
dendrimers, which were extensively used for non-viral gene
delivery, and some of them were abandoned due to high toxicity. The
integration of a biodegradable entity into non-viral gene delivery
systems promises improved gene expression and decreased toxicity
in the attended area as a result of the modulated release of DNA
from complexes induced by the new biodegradable system [34]. We
have designed and synthesized biodegradable polymers derived
from polylysine, polyarginine, and polyhistidine of various lengths
containing disulfide bridges along the backbone. Additionally, a
biodegradable dendrimer was synthesized [37]. These polymers
Search WWH ::




Custom Search