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We found that when inserted intra-vaginally, PLAS offered a six-fold
increase in siRNA delivery compared to cationic lipoplexes. More
importantly, we were able to achieve 85% knockdown of lamin
A/C in vaginal epithelial cells using PLAS [52]. In a cervical cancer
model system (C57BL/6 mice expressing HPV16 E6 and E7 under
the keratin 14 promoter), we showed that delivery of siRNA against
E6/E7 resulted in a significant loss of cells undergoing division, as
measured by BrdU incorporation (Fig. 9.4). While the mechanism
of alginate-only decrease in proliferation is currently unclear, a
significant decrease was observed in siE6/7 group, suggesting
effective siRNA delivery. E6 and E7 have been shown to drive
suprabasal epithelial cells into cycle [63]
These cells are normally
pushed of the basal layer and initiate differentiation. While E6/E7
siRNA does not alter the level of basal cell growth, as expected, the
suprabasal cells in cycle are almost completely absent.
.
Figureā€ƒ9.4
Reduced proliferation in the vaginal tract of K14E7 mice upon
siRNA treatment. PLAS containing 10 ug of siRNA were inserted
into mice pretreated with 5% citric acid for 2 h. Treatment was
repeated at days 2 and 4, and mice were sacrificed at day 5.
Overall, PLAS offers a significant improvement in our ability
to deliver siRNA in the mucosal setting compared to previous
technologies. We envisage PLAS being developed for use in the
human vaginal or anal setting for infections such as HSV2 and HPV.
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