Biomedical Engineering Reference
In-Depth Information
Although the combination of chemotherapy and siRNA-based therapy for
cancer treatment has received increasing attention, the ideal delivery system
that can maximize the efficiency of the active agents is a great challenge. It has
been proposed that such delivery vehicles should: (i) be able to encapsulate
different payloads with tunable doses; (ii) endow similar pharmacokinetics of
the payloads and be able to systemically deliver them into the same tumor cells;
(iii) synergistically inhibit tumor growth following systemic injection; and (iv)
be safe for in vivo applications.
123
Sun et al. further used the micellar
nanoparticle of a biodegradable mPEG-b-PCL-b-PPEEA triblock copolymer
to systemically deliver siRNA and a chemotherapeutic drug (Figure 7.11).
Efficient siRNA binding occurred at a molar ratio of nitrogen in the N/P ratio
of 5:1 and paclitaxel could be entrapped in the hydrophobic PCL core with
high encapsulation efficiency (.90%) via a hydrophobic-hydrophobic
interaction. The micelleplex showed compact and spherical morphology with
a mean diameter of 50 nm. The micelleplex was capable of delivering siRNA
and paclitaxel simultaneously to the same tumor cells both in vitro and in vivo.
In the MDA-MB-435s xenograft murine model, simultaneous delivery of the
same doses of paclitaxel and siPlk1 by
paclitaxel
micelleplex
siPlk1
(0.667 mgkg
-1
paclitaxel and 0.223 mg kg
-1
siPlk1 per injection) exhibited particularly
significant inhibition of tumor growth compared with PBS treatment (p ,
0.0001). A synergistic inhibitory effect of the two therapeutic agents on tumor
growth was demonstrated (c.i. , 1), requiring 1000-fold less paclitaxel than
needed for paclitaxel monotherapy delivered by the micelleplex. In contrast,
combinatorial delivery of separate siPlk1 and paclitaxel by micelleplex
siPlk1
and
paclitaxel
micelleplex
siNonsense
only showed moderate inhibition of tumor
growth and no synergistic effect was observed. Delivery of siPlk1 by the
micelleplex did not cause an elevation in human or mouse IFN-a,IFN-b, IFN-
c, tumor necrosis factor (TNF)-a, or interleukin (IL)-6 levels. Additionally,
simultaneous delivery of siPlk1 and paclitaxel with the micelleplex did not
result in any sign of toxicity to the mice, as shown by normal heart, liver, and
kidney functions following treatment. The results demonstrate that systemic
administration of a micelleplex carrying Plk1-specific siRNA and paclitaxel
could induce a synergistic tumor suppression effect without activation of the
innate immune response or generation of carrier-associated toxicity.
123
d
n
4
y
3
n
g
|
8
7.5 Future Perspectives
RNAi is a post-transcriptional gene-silencing mechanism that can be induced
by 21-23 nt siRNA to degrade a target mRNA in a highly sequence-dependent
manner. Since the discovery of RNAi, many oncogenic targets, including
proliferation, anti-apoptosis, angiogenesis, and drug resistance, have been
studied for siRNA-mediated cancer therapy. Compared to traditional chemical
drug discovery, the identification of highly selective and inhibitory sequences
of siRNA is much faster. Meanwhile, it is relatively easy to synthesize and
manufacture siRNA on a large scale.
128
Although a number of reports have
