Biomedical Engineering Reference
In-Depth Information
and is dissimilar to any human estrous phase [53]. Progesterone use
has additionally been associated with increased susceptibility and
decreased immune responses to vaginal infections [54, 55].
Another strategy of evaluating siRNA silencing in the vaginal
tract has used manual removal of the mucus layer [51]. This study
also provided an alternative to siRNA lipoplexes with the use of
biodegradable polymer-based PLGA nanoparticles. A single dose
of siRNA-loaded nanoparticles resulted in efficient and sustained
gene silencing from the proximal vaginal lumen to the distal uterine
horns.
However, a non-liquid formulation for siRNA vaginal delivery
had not been developed. A solid vaginal siRNA delivery system has
many benefits over liquid formulations, including the ability to be
retained in the vaginal cavity following administration without
prolonged anaesthesia, and the capability to be administered at any
stage during the estrous cycle. Therefore, our group has developed
a more clinically applicable vaginal siRNA delivery platform which
could be retained in the vaginal cavity after administration and
achieve efficient delivery to the cervicovaginal epithelium under
normal physiological conditions.
9.5
Vaginal Delivery of siRNA Using a Novel
PEGylated Lipoplex-Entrapped Alginate
Scaffold System
To overcome the major limitation of vaginal delivery of siRNAs,
we have designed the PEGylated lipoplex-entrapped alginate
scaffold (PLAS) delivery system, which is described in detail in
our recent paper [52]. As outlined above, the major limitations of
past efforts have been poor siRNA or nanoparticle retention time,
resulting in reduced efficacy of gene silencing. The mucosal barrier
represents the most significant barrier to delivery followed by the
hyperkeratotic layer of cells that varies with estrous cycle. The fluid
flow and low pH offer additional challenges. Therefore, we have
taken the approach of developing a sustained release system based
on the entrapment of muco-inert PEG-lipoplexes in a biodegradable
scaffold (Fig. 9.3). Thus, we can provide continuous release of siRNA
in the vaginal cavity over at least 24 h, and the use of PEG enhances
particle stability in the presence of mucin [56]. We chose alginate, a
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