1 research outputs found
Targeted Decationized Polyplexes for siRNA Delivery
The
applicability of small interfering RNA (siRNA) in future therapies
depends on the availability of safe and efficient carrier systems.
Ideally, siRNA delivery requires a system that is stable in the circulation
but upon specific uptake into target cells can rapidly release its
cargo into the cytoplasm. Previously, we evaluated a novel generation
of carrier systems (“decationized” polyplexes) for DNA
delivery, and it was shown that folate targeted decationized polyplexes
had an excellent safety profile and showed intracellular triggered
release upon cell specific uptake. Targeted decationized polyplexes
consist of a core of disulfide cross-linked poly(hydroxypropyl methacrylamide)
(pHPMA) stably entrapping nucleic acids and a shell of poly(ethylene
glycol) (PEG) decorated with folate molecules. In the present study,
the applicability of folate targeted decationized polyplexes for siRNA
delivery was investigated. This required optimization of the carrier
system particularly regarding the cross-linking density of the core
of the polyplexes. Stable and nanosized siRNA decationized polyplexes
were successfully prepared by optimizing the cross-link density of
their core. Upon incubation in human plasma, a significant portion
of siRNA remained entrapped in the decationized polyplexes as determined
by fluorescence correlation spectroscopy (FCS). When tested in a folate
receptor overexpressing cell line stably expressing luciferase, Skov3-luc,
sequence specific gene silencing was observed. As expected, neither
interference on the intrinsic luciferase expression nor on the cell
metabolic activity (determined by XTT) was induced by the free-polymer
or the siRNA polyplexes. In conclusion, targeted decationized polyplexes
are safe and stable carriers that interact with the targeted cells
and rapidly disassemble upon cell entry making them promising siRNA
delivery systems