Biomedical Engineering Reference
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exhibit low toxicity with no elevation of alanine transaminase (ALT)
observed, unlike SNALP particles where ALT and aspartate amino
transferase (AST) levels were transiently elevated after a single
administration of 2.5 mg/kg [38].
Each sample contained 40 µg siRNA in 300 µL isotonic sucrose
solution. Lipids used in these formulations include DOTAP,
cholesterol, and PEG 2000-C16 Ceramide with a molar ratio of
45:45:10. N/P ratio of 4:1 was used for all formulations. Three
batches were made for each formulation method (
n
= 3).
9.4
The Challenge of the Vaginal Tract
Delivery of RNAi mediators to the vaginal tract holds great potential
for the treatment of various viral infections responsible for diseases
such as acquired immune deficiency syndrome (AIDS), genital herpes,
and cervical cancer (reviewed in [46]). Topical vaginal delivery is
superior to systemic delivery as it bypasses first pass hepatic and
kidney clearance and enables local delivery to the infected target
tissue.
However, to be effective as a topical application for the treatment
of cancer or viral infections, siRNA molecules must be able to resist
rapid degradation by nucleases, inactivation by the low pH vaginal
environment, or entrapment in the mucosal layer. Additionally, they
must be formulated so that they remain available for cellular uptake
by cells targeted by the virus (Fig. 9.2).
Figure 9.2
Hematoxylin and eosin staining of mouse cervicovaginal section
displaying VIN2. siRNAs must be protected from nucleases and
the vaginal low pH environment and also be able to penetrate
the mucosal layer and outer layer of hyperkeratotic epithelial
cells (arrows) to access the dividing tumour cells below. The
scale bar represents 100 µM.
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