Biomedical Engineering Reference
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regression of PSMA-expressing tumors following systemic aptamer-
siRNA conjugate administration. By using a similar strategy,
Wullner
[72] generated bivalent anti-PSMA aptamer-siRNA
chimeras, further promoting internalization of chimeras and their
therapeutic potential. Most recently, Gliboa and his coworkers [73]
also demonstrated that the NMD (nonsense-mediated messenger
RNA decay) factor targeting siRNAs could be selectively targeted to
tumor cells using anti-PSMA aptamer-siRNA chimeras, resulting in
significant inhibition of tumor growth after systemic administration
in both subcutaneous and metastatic tumor models.
In addition to siRNA or dsiRNA, a short hairpin (sh)RNA specific
to DNAPK (DNA-activated protein kinase) was covalently fused to
the anti-PSMA aptamer (A-10) and selectively reduced DNAPK
expression in PCa (PSMA-positive) cell xenografts and human
prostate tissues [74]. It was shown that radiation therapy for locally
advanced PCa was specifically improved when the aptamer-shRNA
chimeras were combined with ionizing radiation (IR).
et al.
5.3.1.2 HIV gp120 RNA aptamer-functionalized siRNAs
The HIV-1 envelop glycoprotein gp120 is exposed on the surface
of virus particles and the plasma membrane of HIV-1 infected
cells [75]. The interaction of HIV-1 gp120 with the cellular CD4
receptor is crucial step in the entry of HIV into T-cells [76]. HIV-1
gp120 therefore represents a potential therapeutic target to block
HIV-1 infection [77]. Recently, our group successfully used 2
-F-
modified anti-HIV-1 gp120 RNA aptamers for cell type-specific
delivery of anti-HIV-1 dsiRNAs in cultured cells [31, 78] and in
HIV-1 infected humanized Rag-hu mice [79]. In our system, the
anti-gp120 aptamers had dual functions acting as targeted siRNA
delivery agents and as HIV-1 inhibitors. We developed two different
types of aptamer-siRNA conjugates: One is a covalent aptamer-
siRNA chimera; another one is a noncovalent aptamer-stick-siRNA
conjugate in which the aptamer and siRNA portions are joined
′
via
hybridization using
a GC-rich sticky bridge sequence. The aptamer-
siRNA conjugates were selectively internalized into HIV-1 infected
cells, resulting in several logs of inhibition of HIV-1 replication in
the humanized mouse model following systemic administration.
Our results also demonstrated that the aptamer anti-HIV-1
tat
/
rev
dsiRNA was processed by Dicer, resulting in site specific cleavage of
the target mRNA
in vivo
.
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