The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 111

they already have become popular cell-specific internalizing molecules for targeted
drug delivery (Zhou and Rossi 2009 ).
Three independent studies have demonstrated anti-PSMA aptamer-mediated
small interfering RNA (siRNA) delivery to PSMA-positive cells or human cancer
cells-transplanted into nude mice. Through Streptavidin-biotin interactions, Chu
et al. non-covalently assembled two biotinylated anti-PSMA aptamers and two
biotinylated siRNAs into a Streptavidin connector (Chu et al. 2006b ). The multiva-
lent construct was effectively internalized into targeted cells and triggered specific
gene silencing. Using a somewhat different approach, Giangrande and coworkers
have developed a simple covalent aptamer-siRNA chimeric RNA which allowed
effective PSMA mediated cell uptake along with siRNA-mediated gene silencing in
athymic mice following both intra-tumoral delivery and systemic administration
(McNamara et al. 2006 ; Dassie et al. 2009 ).
By taking advantage of the targeting properties of aptamers, a gelonin toxin has
been successfully conjugated to an anti-PSMA aptamer (Chu et al. 2006a ). The
resulting conjugates dramatically increased cellular uptake and therapeutic efficacy
in PSMA-positive cells. Reports from Farokhzad and colleagues also demonstrated
the potential of anti-PSMA aptamers to mediate nanoparticles delivery (Peer et al.
2007 ). For example, they have constructed an anti-PSMA aptamer - poly (lactic
acid)-block-PEG copolymer nanoparticle conjugate encapsulating the chemothera-
peutic drug Docetaxel (Dtxl-NP-aptamer) (Farokhzad et al. 2004 ). Such Dtxl-NP-
aptamer conjugates showed remarkable efficacy and completely suppressed tumor
growth in a xenograft nude mouse model with a single intra-tumoral injection
(Farokhzad et al. 2006 ).
A simple physical conjugation also was employed to assemble an aptamer with
drugs. Anthracycline drugs (e.g. Dox) non-covalently intercalated into double-
strand regions of an anti-PSMA aptamer via the flat aromatic ring, and formed a
stable physical conjugate capable of effectively targeting PSMA-positive cells
(Bagalkot et al. 2006 ). In another example, Bagalkot et al. functionalized a quantum
dot (QD) with anti-PSMA aptamers to achieve a multifunctional QD-aptamer con-
jugate, serving both as a fluorescence imager and a drug delivery carrier (Bagalkot
et al. 2007 ). Dox was loaded into QD-aptamer conjugate via physical intercalation
within the aptamer strand. Once internalized inside cancer cells, the QD-aptamer-
Dox system gradually released Dox (for targeting therapy) and recovered the fluo-
rescence of the QD (for synchronous cancer imaging).

3.6.2 Anti-HIV-1 gp120 RNA Aptamer

As described in sect. 3.1.4, the HIV-1 gp120 envelope protein represents an attrac-
tive molecular target for receptor-mediated drug delivery. Several 2¢-F modified
RNA aptamers have been isolated against HIV-1 gp120, which can specifically bind
and be rapidly internalized into HIV-1 infected cells (Zhou et al. 2008, 2009 ). Using
an afore-mentioned strategy described by Giangrande, a dual-action anti-gp120
aptamer-siRNA chimeric RNA was developed (Zhou et al. 2008 ; Neff et al. 2011 ).