Biomedical Engineering Reference
In-Depth Information
Both mRNA and protein levels of survivin were down-regulated
30% and 70% in LPD-PEG and LPD-PEG-AA NPs, respectively, while
the scrambled siRNA showed a reduced effect (20% and not
statistically significant). Also, the down-regulation of survivin
induces significant apoptosis and remarkable cellular growth
inhibition effects in a dose dependent manner.
95
In a xenograft mouse model using NCI-H460 human lung
cancer cells, both non-targeted and anisamide-targeted LPD NPs
showed a predominant accumulation in the tumor. However, free
FAM-siRNA exhibited little tissue uptake due to the high susceptibility
of siRNA to degradation, followed by fast elimination from the
systemic circulation. Since there was no difference between non-
targeted and targeted LPD NPs in tumor uptake, a targeting ligand is
likely to have no influence on the biodistribution of the NPs
in vivo
.
95
Thus, in this case, anisamide served as an internalization, but not
targeting, ligand for the NPs.
Based on
study and biodistribution study in the mouse
model, tumor-targeted PEGylated LPD NPs showed a remarkable
gene silencing effect mediated by siRNA with an increased cellular
uptake via specific receptor-mediated endocytosis. The fact that the
targeted LPD formulation was able to deliver siRNA predominantly
to the tumor with a low RES uptake suggests that LPD NPs could be
a plausible delivery system for RNAi-based tumor therapy.
in vitro
3.4.1.3.2
EGFR siRNA
The epidermal growth factor receptor (EGFR) is related to many
of the negative features of tumors, including decreased apoptosis,
increased proliferation, and resistance to chemo as well as radiation
therapy
117-120
and is frequently over-expressed in various type
of tumors. Several studies have demonstrated that anti-EGFR
therapy via tyrosine kinase inhibitors and monoclonal antibodies
has a great therapeutic effect in cancer patients.
117-120
As RNAi
has emerged as a promising therapy for cancer, silencing EGFR via
RNAi has been considered as an alternative approach to anti-EGFR
therapy.
121-126
EGFR siRNA delivered by the targeted LPD showed
excellent silencing activity in NCI-H460 tumor, whereas the same
siRNA delivered by non-targeted NPs exhibited only partial effect.
Both free siRNA and the control siRNA in targeted NPs revealed no
effect. Silencing EGFR in the tumor was associated with tumor cell
apoptosis and tumor growth inhibition. However, maximal anti-
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