Biology Reference
In-Depth Information
10.3.3
Aptamer-Nanoparticle Conjugates
In the past decade, the advances in nanotechnology have greatly accelerated develop-
ments in the material, life, and medical sciences [ 81, 82 ]. A variety of natural and
synthetic nanocarriers for drug delivery, including liposomes, micelles, synthetic
polymers, carbon nanotubes, and quantum dots, have been developed [ 83 ] . The inte-
gration of cell-specific aptamers with nanocarriers is expected to develop more versa-
tile and multifunctional cell-type-specific delivery systems [ 55 ] . Through engineering
of cell-specific aptamers with a nanoscale delivery vehicle, specific molecular recog-
nition and cellular internalization of the therapeutic agents by the target tissue can be
achieved via aptamer-mediated targeting [ 84 ]. In contrast to the average size of a
single siRNA molecule which is well below 10 nm in diameter, aptamer-functional-
ized nanoparticles have an appropriate nanoscale size in the mid-nanometer range
thereby allowing preferential accumulation in target tissues and organs via a passive
targeting mode (EPR, enhanced permeability and retention effect) [ 85, 86 ] and facili-
tating cellular entry by endocytosis. These nanocarriers can also reduce renal clear-
ance, improve circulation half-life, and biodistribution in vivo .
Self-assembling nanoparticles represent an attractive approach for siRNA target-
ing. The packaging RNA (pRNA) component of the bacteriophage phi29 DNA-
packaging motor has been developed and manipulated to produce chimeric RNAs
that form dimer, trimer, hexamer, and larger arrays ranging in size from nanometers
to micrometers via interlocking right- and left-hand loops [ 87, 88 ] . pRNA mono-
mers can fold into a stable and unique secondary structure that serves as the build-
ing blocks to form nanostructures via bottom-up assembly [ 89 ]. Fusion of the pRNA
with a variety of therapeutic and chemical compounds does not impede the forma-
tion of dimers or interfere with function. By taking advantage of the self-assembling
property of the pRNA, Guo and coworkers fabricated pRNA-based nanoparticles
with a variety of structures and shapes [ 90 ]. For example, a CD4 aptamer and an
siRNA against survivin, GFP, BAD, or lucoferase were, respectively, covalently
fused with pRNAs. Subsequently, the pRNA-aptamer or pRNA-siRNA chimeras
were incubated to form a dimer of 25 nm length as measured by atomic force
microscopy (AFM) [ 91, 92 ]. The resulting nanoscale RNA dimer specifically bound
to and was internalized in CD4-expressing T cells, delivering the siRNA to trigger
specific knockdown of the target transcripts.
By taking advantage of straightforward chemical synthesis and modification,
cell-specific aptamers can be conjugated to functional groups with relative ease,
enabling their conjugation to the nanocarriers. The large surface areas of nanopar-
ticles provide excellent platforms for conjugating multiple aptamers. For example,
a PSMA aptamer was chemically conjugated with a synthetic branched polyethyl-
enimine-grafted-polyethylene glycol (PEI-PEG) polymer [ 93 ] . The resulting PSMA
aptamer-functionalized polymer specifically delivered to prostate cancer cells an
shRNA targeting the anti-apoptotic gene (Bcl-xl).
The interior volumes of nanoparticles have been used to encapsulate large
quantities of various drug molecules. Using a somewhat different strategy, a
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