Biomedical Engineering Reference
In-Depth Information
the authors describe the synthesis and target-specific delivery of multifunc-
tional siRNA-QD constructs for selectively inhibiting the expression of
epidermal growth factor receptor variant III (EGFRvIII) in target human
U87 glioblastoma cells, and subsequently monitoring the resulting down-
regulated signaling pathway with high efficiency. This study demonstrates
the multi-functional siRNA-QD strategy focusing on targeted delivery,
high transfection efficiency, and multi-modal imaging/tracking. These novel
methods and applications complement recent advances in nanomaterial-
based siRNA delivery, nanomaterial-based molecular imaging, and siRNA-
based chemotherapeutic strategies reported recently. This strategy could
also provide highly useful information regarding biosurface chemistry of
nanomaterials. In addition, the application of multi-functional siRNAQDs
to modulate the key cancer signaling pathways is important not only for se-
lective chemotherapeutic strategy but also for dissecting signaling cascades
triggered by inhibiting specific proteins [253].
Although immunotherapy is being investigated as an adjunct treatment,
the ability of gliomas to escape immune response will continue to be a sig-
nificant obstacle to this strategy. One approach to overcome the local im-
munosuppressive tumor microenvironment is the activation of the innate
immune system by toll-like receptor (TLR) agonists such as CpG oligonu-
cleotides (CpG). Because the TLR9, CpG receptor, is located intracellularly,
the authors have hypothesized that methods that enhance CpG internaliza-
tion may also potentiate its immunostimulatory response. In this study, it
has been reported that carbon nanotubes enhanced CpG uptake by tumor-
associated phagocytic cells, and resulted in their activation both in vitro and
in vivo. Furthermore, a single injection of low-dose CNTCpG complexes
eradicated intracranial gliomas through activation of NK and CD8 cells.
These findings demonstrate that CNTs are nontoxic vehicles that can im-
prove CpG uptake into tumor-associated inflammatory cells, leading to a
more robust anti-tumor response [254]. Alizadeh et al. [255] evaluated
the mechanism of cyclodextrin-based nanoparticle (CDP-NP) uptake into
a murine glioma model. Using mixed in vitro culture systems, the authors
demonstrated that CDP-NP was preferentially taken up by BV2 and N9
microglia (MG) cells as compared to GL261 glioma cells. Fluorescent mi-
croscopy and flow cytometry analysis of intracranial GL261 gliomas con-
firmed these findings, and demonstrated a predominant CDP-NP uptake by
macrophages (MP) and MG within and around the tumor site. In conclu-
sion, these studies better characterize the cellular distribution of CDP-NP
in brain tumors, and demonstrate that MP and MG could potentially be
used as nanoparticle drug carriers into malignant brain tumors. Schneider
et al. [195] recently examined a “double-punched” approach to overcome the
escape of glioblastoma cells from immune surveillance through an active
specific immunization. The authors, using Newcastle disease virus-infected
tumor cells and an antisense oligonucleotide against the TGF-b loaded in
