Biomedical Engineering Reference
In-Depth Information
development and delivery of future gene therapies for atrial fibrillation, a common
disorder in which the electrical signaling that triggers the heartbeat goes awry.
A controlled study evaluated whether gene therapy using the gene HERG-G628S
that helps regulate the heartbeat, could effectively alter the heartbeat in pigs with
an irregular heart rhythm. The gene was contained in a plastic, gel-like substance
that was painted onto the surface of the right atrium of the heart. The gel also con-
tained a dye so that its spread could be tracked inside the organ. After 3 weeks, the
heartbeat had returned to normal, and the dye had penetrated only the atria.
Gene Delivery to Vascular Endothelium
In general, viral methods have been shown to be very effective at delivering genes
to cardiovascular endothelium. The immunogenicity and pathogenicity associated
with viral vectors have led increased efforts to seek alternative means of “ferrying”
therapeutic genes to endothelium or to decrease the shortcomings of viral vectors.
Various nonviral methods such as chemical vectors can deliver DNA to cells and
may represent a robust and versatile technology to “ferry” therapeutic genes to
vascular endothelium in order to modify the endothelial dysfunction associated
with many cardiovascular diseases (Theoharis et al.
2007
).
Targeted Plasmid DNA Delivery to the Cardiovascular System
with Nanoparticles
Targeting gene therapy to the cardiovascular system is a challenge. Biodegradable
polymeric superparamagnetic nanoparticle formulations have been formulated
using a modified emulsification-solvent evaporation methodology with both the
incorporation of oleate-coated iron oxide and a polyethylenimine oleate ion-pair
surface modification for DNA binding (Chorny et al.
2007
). The DNA was in the
form of a plasmid, a circular molecule that carried a gene that coded for a growth-
inhibiting protein adiponectin.
Magnetically driven nanoparticle-mediated gene transfer was studied using a
green fluorescent protein reporter plasmid in cultured arterial smooth muscle cells
and endothelial cells. Nanoparticle-DNA internalization and trafficking were exam-
ined by confocal microscopy. Cell growth inhibition after Nanoparticle-mediated
adiponectin plasmid transfection was studied as an example of a therapeutic end
point. Nanoparticle-DNA complexes protected DNA from degradation and effi-
ciently transfected quiescent cells under both low and high serum conditions after
a 15 min exposure to a magnetic field. There was negligible transfection with nano-
particle in the absence of a magnetic field. Larger sized nanoparticles (375 nm
diameter) exhibited higher transfection rates compared with 185 nm- and 240 nm-
sized nanoparticles. Internalized larger sized nanoparticles escaped lysosomal
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