Biomedical Engineering Reference
In-Depth Information
loss. In this case, as an unmodified siRNA, bevasiranib was given by
intravitreal injection without a particular formulation that could
enhance its silencing performance. Since negatively charged nucleic
acids do not readily traverse cellular membranes and are vulnerable
to degradation without some protective covering or/and appropriate
chemical modifications, such direct administration ultimately
resulted in poor pharmacokinetics and indirect gene silencing. In
this regard, some optimized strategies should be considered, which
could include appropriate chemical backbone modifications, an
effective delivery vehicle, a new dosing schedule and a combinatorial
formulation with other therapeutic nucleic acids, and so on.
While this frustration tempered the early excitement in RNAi
technology, it triggered extensive efforts to surmount these key
hurdles to the widespread use of RNAi as a therapy. Among these
hurdles, one of the most important is delivery of RNAi agent (such
as siRNAs) to specific cells or tissues at therapeutic doses [19].
With the intent of developing a targeted intracellular delivery
system, numerous strategies have been reported, in which various
internalizing molecules with high specificity and affinity to a
cellular receptor were assembled or complexed with the siRNA.
Based on specific interaction between the targeting ligand and
its cellular receptor, the recognition and internalization of the
therapeutic siRNAs by the target tissue should be capable of
dramatic improvement.
Most recently, another type of therapeutic nucleic acids termed
aptamers show promise as potential candidates for targeted siRNA
delivery. These cell-specific aptamers can actively target a distinct
cell population or tissue in a cell-type-specific manner [20, 21].
By functionalizing the cell-specific aptamers to therapeutic agents
or delivery vehicles, the cellular uptake is enhanced and the local
concentration of the drug in the targeted cells or tissues is increased,
thereby improving the therapeutic efficacy. Currently, a number
of aptamer-functionalized therapeutics has been successfully
developed for targeted delivery [22, 23]. In particular, with the
technological maturation and increasing knowledge of RNAi as
well as aptamers and their mechanism of action, it seems natural to
partner the two therapeutic nucleic acids for expanding the options
for targeted RNAi (Fig. 5.1). In this chapter, we review recent progress
of cell-specific aptamers that mediate targeted therapy of nucleic
acid drugs placing particular attention to development of aptamer-
functionalized siRNAs or nanocarrier for targeted gene silencing.
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