The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 112

This dual function chimera blocked HIV-1 infectivity and also selectively delivered
siRNAs into HIV-1 infected cells which suppressed HIV-1 replication. Continued
efforts to improve the aptamer delivery resulted in an aptamer-mediated combinato-
rial multi-targeting RNAi therapeutic, in which a single anti-gp120 aptamer was
tightly tethered with three different siRNAs targeting HIV-1 tat/rev transcripts and
HIV-1 host dependency factors (CD4 and TNPO3) through a “sticky” bridge (Zhou
et al. 2009 ). The resulting aptamer-stick-cocktail siRNA conjugates suppressed
viral loads in cell culture and in vivo in a humanized mouse model for HIV-1 infec-
tion (Zhou et al., unpublished).

3.6.3 Anti-PTK7 DNA Aptamer

Protein tyrosine kinase-7 (PTK7) is a member of the receptor tyrosine kinase family,
which is highly expressed during thymocyte development in both mice and humans.
Receptor protein tyrosine kinases transduce extracellular signals across the cell
membrane. Tan and colleagues have isolated a panel of DNA aptamers against
CCRF-CEM cells using a whole cell-SELEX (systematic evolution of ligands by
exponential enrichment) procedure (Shangguan et al. 2006 ). One of the selected
DNA aptamers, sgc8 identified to target PTK7, has been demonstrated to be
specifically taken up into lymphoblastic leukemia T-cells via a receptor-mediated
endocytosis (Shangguan et al. 2007 ). Recent studies have exploited the anti-PTK7
aptamer as a promising targeting ligand for targeted drug delivery. For example, an
anti-PTK7 aptamer with a thiol group was covalently attached to Dox via an acid-
labile linkage (Taghdisi et al. 2009 ). Once the aptamer-Dox conjugates specifically
internalized into target cancer cells, Dox was easily released inside the acidic endo-
somal environment, selectively killing cancer cells. Recently, an anti-PTK7
aptamer-modified liposome was also used to facilitate targeted Dextran delivery
(Kang et al. 2010 ). Additionally, an aptamer-conjugated Au-Ag nanorod (NR) was
designed as a selective photo-thermal agent to efficiently kill tumor cells (Huang
et al. 2008b ).

3.6.4 Anti-NCL DNA Aptamer

Human nucleolin (NCL), a multifunctional protein involved in the synthesis and
maturation of ribosomes, is over-expressed on the plasma membrane of several
cancer cells such as breast, prostate, and lymphocytic leukemia. Moreover, NCL
can transfer molecules between the cell surface and the nucleus. Therefore, it pro-
vides a potential target for the higher NCL-expressing cancer cell specific therapy.
An anti-NCL DNA aptamer AS1411 (also known as AGRO100), a 26-mer guanine-
rich oligonucleotide with high affinity and specificity to NCL, has been found to
internalize into several cancer cell lines, including breast cancer cells (Bates et al.
1999 ; Soundararajan et al. 2008 ). A reversible AS1411 aptamer-liposome biocon-
jugate was developed to effectively deliver cisplatin to cancer cells and to improve
therapeutic efficacy (Cao et al. 2009 ). Importantly, when a complementary antidote