1 research outputs found
In Vivo Biodistribution of Prion- and GM1-Targeted Polymersomes following Intravenous Administration in Mice
Due to the aging of the population, the incidence of
neurodegenerative
diseases, such as Parkinsonās and Alzheimerās, is expected
to grow and, hence, the demand for adequate treatment modalities.
However, the delivery of medicines into the brain for the treatment
of brain-related diseases is hampered by the presence of a tight layer
of endothelial cells that forms the bloodābrain barrier (BBB).
Furthermore, most conventional drugs lack stability and/or bioavailability.
These obstacles can be overcome by the application of nanocarriers,
in which the therapeutic entity has been incorporated, provided that
they are effectively targeted to the brain endothelial cell layer.
Drug nanocarriers decorated with targeting ligands that bind BBB receptors
may accumulate efficiently at/in brain microvascular endothelium and
hence represent a promising tool for brain drug delivery. Following
the accumulation of drug nanocarriers at the brain vasculature, the
drug needs to be transported across the brain endothelial cells into
the brain. Transport across brain endothelial cells can occur via
passive diffusion, transport proteins, and the vesicular transport
pathways of receptor-mediated and adsorptive-mediated transcytosis.
When a small lipophilic drug is released from its carrier at the brain
vasculature, it may enter the brain via passive diffusion. On the
other hand, the passage of intact nanocarriers, which is necessary
for the delivery of larger and more hydrophilic drugs into brain,
may occur via active transport by means of transcytosis. In previous
work we identified GM1 ganglioside and prion protein as potential
transcytotic receptors at the BBB. GM1 is a glycosphingolipid that
is ubiquitously present on the endothelial surface and capable of
acting as the transcytotic receptor for cholera toxin B. Likewise,
prion protein has been shown to have transcytotic capacity at brain
endothelial cells. Here we determine the transcytotic potential of
polymersome nanocarriers functionalized with GM1- and prion-targeting
peptides (G23, P50 and P9), that were identified by phage display,
in an in vitro BBB model. In addition, the biodistribution of polymersomes
functionalized with either the prion-targeting peptide P50 or the
GM1-targeting peptide G23 is determined following intravenous injection
in mice. We show that the prion-targeting peptides do not induce efficient
transcytosis of polymersomes across the BBB in vitro nor induce accumulation
of polymersomes in the brain in vivo. In contrast, the G23 peptide
is shown to have transcytotic capacity in brain endothelial cells
in vitro, as well as a brain-targeting potential in vivo, as reflected
by the accumulation of G23-polymersomes in the brain in vivo at a
level comparable to that of RI7217-polymersomes, which are targeted
toward the transferrin receptor. Thus the G23 peptide seems to serve
both of the requirements that are needed for efficient brain drug
delivery of nanocarriers. An unexpected finding was the efficient
accumulation of G23-polymersomes in lung. In conclusion, because of
its combined brain-targeting and transcytotic capacity, the G23 peptide
could be useful in the development of targeted nanocarriers for drug
delivery into the brain, but appears especially attractive for specific
drug delivery to the lung