Biomedical Engineering Reference
In-Depth Information
breast cancer cells with siRNAs or antisense oligonucleotides targeting polo-
like kinase 1 (Plk1) improved the sensitivity of cancer cells to paclitaxel.
120,121
Macdiarmid et al. reported that sequential administration of targeted minicells
containing specific siRNA or a cytotoxic drug showed more significant
therapeutic efficiency in the treatment of drug-resistant tumors than single
administration of minicells loaded with siRNA or chemotherapeutics.
122
Nevertheless, to exert their maximal effect in vivo, it is expected the
chemotherapeutic drug and the siRNA should be simultaneously delivered
to the same tumor cell after systemic administration and, ideally, be distributed
in the cells at an optimized ratio for maximal intracellular cooperation.
123
Polymeric micelles are self-assembled nanoparticles composed of amphiphilic
materials with a structure that includes a hydrophobic core and a hydrophilic
corona. The amphiphilic structure of micelles can provide advantages for
multifunctional tasks, such that the hydrophilic shell modified with cationic
charges
d
n
4
y
3
n
g
|
8
can
electrostatically
interact
with
siRNA
or
DNA,
and
the
hydrophobic core can serve as a payload for hydrophobic drugs.
124
Zhu et al. have reported cationic micelles based on well-defined poly(-
dimethylaminoethyl methacrylate)-poly(e-caprolactone)-poly(dimethylami-
noethyl methacrylate) (PDMAEMA-PCL-PDMAEMA) triblock copolymers
for the combinatorial delivery of siRNA and paclitaxel. The molecular weights
of PDMAEMA blocks varied at 2700, 4800, and 9100 (denoted as polymer 1,
2, and 3, respectively). A gel retardation assay showed that micelle 1 could
effectively complex with siRNA at and above N/P ratios of 4:1 and achieved
over 70% GFP gene-silencing efficiency at an N/P ratio of 36:1, more
efficiently than 25 kDa bPEI and the 20 kDa PDMAEMA homopolymer
due to its improved siRNA condensation and endosomal escaping ability.
Paclitaxel-loaded micelle 1 with a drug loading content of 6.8 wt% demon-
strated clearly higher drug efficacy compared to free paclitaxel. The com-
binatorial delivery of VEGF siRNA and paclitaxel using PDMAEMA-
PCL-PDMAEMA micelles resulted in significantly lower VEGF expression
compared to delivery of VEGF siRNA
alone, reaching a high silencing
efficiency of ca. 85%.
125
Polyethylenimine (PEI) can be modified by grafting stearic acid (SA) and
further formulated into polymeric micelles (PEI-SA) with a positive surface
charge. Huang's work showed that PEI-SA micelles provided high siRNA
cellular uptake efficiency and improved post-transcriptional gene-silencing
capacity. The transfection results demonstrated that 65% and 25% reduction of
VEGF expression were observed for siVEGF delivered with 10k PEI-SA and
1.8k PEI-SA, respectively, compared with cells which received no treatment. In
contrast, siVEGF delivered by complexing with 10k and 1.8k PEI only resulted
in 20% and 10% inhibition of VEGF expression, respectively. Loading of
doxorubicin to 10k PEI-SA could achieve a high encapsulation efficiency (EE)
of 91.9% with a drug loading (DL) percentage of 4.3% without a significant
change in particle size and zeta potential. In the animal Huh-7 cancer cell
intratumoral model study, at day 30 after injection the relative tumor volumes
