Biomedical Engineering Reference
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from melanoma patients obtained after treatment via systemic administration show
the presence of intracellularly localized nanoparticles in amounts that correlate
with dose levels of the nanoparticles administered. Furthermore, a reduction was
found in both the specific mRNA (M2 subunit of ribonucleotide reductase (RRM2))
and the protein (RRM2) levels when compared to pre-dosing tissue. Most impor-
tantly, the presence of an mRNA fragment was detected, which demonstrates that
siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an
RNAi mechanism from a patient who received the highest dose of the nanoparti-
cles. These results evidence that siRNA administered systemically to a human can
produce a specific gene inhibition by an RNAi mechanism of action.
8
Concluding Remarks
Tremendous progress in the design and synthesis of nonviral vectors has been
achieved in the past decade, which significantly richens the carrier library that
can be selected for gene delivery. A large number of studies, however, still
focused on
in vitro
transfections. Even in this case, the nonviral vectors that pos-
sess higher transfection efficiency and minimal cytotoxicity compared with com-
mercially available transfer reagents such as Lipofectamine 2000 and PEI25, are
still limited. Currently, only a small percentage of non-viral vectors have been in
clinical trials, especially the extensively investigated cationic polymers. Based on
the growing understanding of mechanisms underlying the gene delivery of non-
viral systems, delicate design and discovery of transfer vectors that can overcome
each of the extracellular and intracellular barriers is highly necessary for efficient
gene therapy.
For lipoplexes and polyplexes, the establishment of the structure-activity rela-
tionships, based on a better understanding of complex structure and characters,
stability in serum, and cellular uptake, intracellular translocation as well as nuclear
entry, may facilitate the advances towards the rationalized and conceptualized new
vectors. High throughput screening technique combined with combinatorial chem-
istry has already showed their advantages to rapidly identify effective vectors, and
accordingly establish reliable structure-function correlations (Sunshine et al.
2009
;
Love et al.
2010
). Besides chemical tailoring on currently studied compounds,
materials with entirely new structures should be discovered to provide gene vectors
with clinical significance.
Emerging delivery systems based on nanomaterials like nanocrystals and inor-
ganic nanostructures have partly showed their benefits over organic compounds,
such as ease in real-time tracing via electronic or optical imaging techniques,
unique photo-, magnetic-, and thermo-responsiveness for signal-directed smart
delivery, especially the capacity for penetrating some tissue barriers. Honeycomb
mesoporous silica nanoparticles with 3 nm pores have been shown able to transport
the payload DNA molecules into isolated plant cells and intact leaves, and achieve
significant transgene expression in these organisms (Torney et al.
2007
).
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