Biomedical Engineering Reference
In-Depth Information
The main barrier for efficient vaginal siRNA delivery is the mucosal
layer. It is a protective barrier for underlying tissues and removes
foreign particles efficiently [47], thus complicating sustained release.
An additional factor that may dramatically affect the efficiency of
delivery in the vaginal cavity is the physical environment changes
that occur throughout the estrous cycle [48].
To date, several groups have reported varying success in
delivering siRNA to the vaginal tract. Previous strategies to overcome
vaginal delivery barriers have included the simple application
of lipoplexes into the vaginal cavity with [49, 50] or without [29]
progesterone treatment and mucus removal in the vaginal cavity
prior to siRNA administration [51]. Unsurprisingly, investigations
into naked siRNA uptake into vaginal tissues after intravaginal
administration reported inefficient delivery [29] under normal
physiological conditions. This was likely caused by rapid degradation
and inefficient mucosal uptake of naked siRNAs in the vaginal cavity.
However, the same study showed dramatically improved delivery
with the use of the cationic transfection reagent Lipofectamine
®
. In
contrast to this report, we and others have found that conventional
lipoplexes were not able to reach the cervicovaginal epithelium and
were not retained in the vaginal cavity following administration
under normal physiological conditions [52].
Progesterone has been used prior to treatment in multiple
studies to arrest mice in the diestrus phase of the estrous cycle.
Initial studies that used this method investigated vaginal instillation
of siRNAs targeting herpes simplex virus 2 (HSV-2) in a lipid
formulation. Palliser and colleagues reported that siRNAs mixed
with Oligofectamine
®
lipid transfection reagent resulted in efficient
delivery to the epithelial and lamina propria cells and protected mice
from lethal HSV-2 infection [49]. Further investigations into cationic
lipidic systems for intravaginal delivery raised concerns regarding
their safety
[50]. Wu and colleagues reported that inflammation
occurred in vaginal tissues following administration of the cationic
lipidic transfecting reagent Oligofectamine
in vivo
. Furthermore, they
found that the transfection lipid on its own enhanced transmission of
HSV-2. Prevention and protection from HSV-2 was instead obtained
by a cholesterol-conjugated siRNA that caused virus gene silencing
in the vaginal tract without inflammation or cytokine induction.
However, progesterone pre-treatment is typically associated with
thinned vaginal epithelia that may facilitate epithelial penetration
®
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