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selective association with cancer cells for the treatment and to protein targets. [147] Aptamers can be used for therapeutic
diagnosis of brain tumors. [129] purposes in the same way as monoclonal antibodies. [147]
However, unlike traditional methods for producing monoclonal
Yang and David formulated magnetic iron oxide nanoparticles antibodies, no organisms are required for the in vitro selection
(MIONs) coated with a molecule that is noncovalently associated of oligonucleotides. [147] For this reason, aptamers avoid the
with a brain-targeting molecule. The coated MIONs comprise immunogenicity of antibodies while maintaining all their
an anti-tumor agent linked to a cell-penetrating peptide. [130] properties. [147] However, there still remain largely unknown
MIONs are oriented at the site of the brain tumor with an pharmacokinetic properties which make them harder to develop
external magnetic field. [130] In a patent by Dixit et al. [131] gold than any given therapeutic antibody. [147]
nanoparticles conjugated with peptides against both EGFR
and TfR and loaded with the photosensitizer phthalocyanine 4 Aptamers, consisting of a single-stranded nucleic acid having
have been designed and characterized. Laser was then applied 100 nucleotides or less that specifically bind to tumor-initiating
to activate the photosensitizer, causing subsequent cell death. [131] cancer cells, were developed and described by Rich et al. [148] The
aptamer specifically binds to tumor-initiating cells of GBM. [148]
On the other hand, nonthermal techniques to reversibly open Aptamers were the targeting agent of choice for a patent by
BBB have been studied. One of these techniques is using Bloembergen et al. [149] where they used an aptamer-biopolymer-
ultrasound in the presence of microbubbles (MB). [132,133] MB active agent conjugate system for the treatment of cancer.
work by resonating in an ultrasound beam, rapidly contracting
and expanding in response to the pressure changes of the sound CONCLUSIONS AND FUTURE DIRECTIONS
wave. [134] Inertial cavitation and destruction of microbubbles
are capable of producing strong mechanical stress to enhance The development cycle of new therapeutic drug entities for brain
the permeability of the surrounding tissues and further increase and CNS costs from $500 million to $1.5 billion to get to market.
the extravasation of drugs into the cytoplasm or interstitial Such huge expense could be directly attributed to drugs failing
cells. [135] Chen et al. [136] studied MB-carrying TGFβ1 inhibitor late in clinical trials or during the post-market follow-up (Phase
combined with ultrasound sonication to induce BBB/BTB IV). [150] In spite of the advances in drug discovery technologies
disruption and enhance drug delivery. Pulsed-mode ultrasound and high-throughput screening techniques, the development
exposure therapy was recently shown to enhance the antitumor cycle of new therapeutic entities is still costly and lengthy. It is
effect of an EGFR-targeting chemotherapeutic drug facilitating challenging to ensure efficacy and safety throughout the four
antiglioma treatment. [137] phases of clinical trials. [151,152]

NUCLEIC ACID TECHNOLOGIES To overcome these problems and alleviate some of the costs
MicroRNA associated with new drug entity letdown, pharmaceutical
MicroRNAs (miRNAs) are endogenous RNAs composed formulators spend effort modifying and reinventing therapeutic
and diagnostic agents, giving them new characteristics with
of about 22 nucleotides. The miRNAs can play important enhanced safety and efficacy profiles. The use of novel nano-
regulatory roles in animals and plants by targeting mRNAs
for cleavage or translational repression. [138,139] Currently, about sized drug delivery systems (nanoDDS) is a major approach in
2% of known human genes encode microRNAs. [140] A growing such reinvention process. The nanoDDS can provide methods
body of evidence shows that miRNAs are one of the key players for targeting and releasing large quantities of therapeutic agents
in cell differentiation and growth, mobility, and apoptosis. [141-143] in exact, well-defined organs or tissues. Furthermore, they
Most microRNAs in animals are thought to function by can easily be tailored, decorated, and modified via various
inhibition of effective mRNA translation of target genes through agents such as stimuli-sensitive moieties, targeting agents,
imperfect base pairing with the 3-untranslated region of target pharmacokinetics-modifying mediators, diagnostic agents, cell-
mRNAs. [138,140] penetrating peptides, protective PEGylation layer, or antibodies.
Such modifying moieties can provide novel functions and
MiRNAs are appealing therapeutic targets and potential better efficacy or safety profiles to current therapeutic agents.
biomarkers of GBMs. [141-143] Chan et al. [144] were the first to Furthermore, most nanoDDSs provide both hydrophobic and
investigate the functional properties of a single miRNA in GBM hydrophilic environments, facilitating better drug solubility and
cell lines. They discovered that high expression of miR-21 is a enhanced physicochemical characteristics. [153]
common feature of GBM. [144] In GBM, 15 types of miRNAs are
the most studied (miR-7, miR-10b, miR-15b, miR-17, miR-21, Despite their advantages, nanoDDS suffer from many problems
miR-23a, miR-25, miR-124, miR-128a, miR-128b, miR-132, such as stability issues, formulation scale-up difficulties, and
miR-137, miR-195, miR-221 and miR-222). [145] In a patent by short shelf life. Developing novel complexes and sophisticated
Park et al. [146] hypoxia-induced angiogenesis-associated diseases systems that could never reach the market due to high cost,
including cancers was suggested to be treated by miRNA-125. inability of scaling-up the system, or instability of the final
formulation is a major problem. Major process and formulation
Aptamers development concerns exist with respect to the scale-up
Aptamers are nonbiological oligonucleotides that can bind process of complex nanoparticulate carriers. To overcome

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 15, 2016 ¦