Combinatorial-designed Hyaluronic Acid Nanoparticles for Tumour Targeted Drug and Small Interfering Ribonucleic Acid Delivery - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 80

genes (survivin, bcl-2) . We then designed target-specific, potent siRNA
sequences, first by computational in silico methods followed by a
rigorous screening in cells in order to down-regulate those resistant
genes that are overexpressed in the resistance cells. Subsequently, we
introduced the standard 2'OMe modifications in the nucleic acids in
order to reduce or minimise the off-target/immune stimulatory effects
coming from an unmodified sequence. Since the delivery to the H69/
H69AR cells/tumours seemed to be difficult with our HA system due
to the lower level CD44 expression, we primarily focused on reversing
the resistance of only A549 DDP cells/ tumours [23].
3.5.2 Combination Small Interfering Ribonucleic Acid and
Chemotherapy Drug Treatment using Hyaluronic Acid
Particles
Initially, combinations of all four siRNA (mdr-1, mrp-1, bcl-2 and
survivin) were extensively tested with cisplatin in A549 DDP cells to
identify the combination that gives a synergistic effect in cell killing.
For this purpose, the siRNA dose that gives >90% gene down-
regulation was used in combination with the IC 50 cisplatin dose at
different time points. Our data suggested that the combination of
survivin and/or bcl-2 with cisplatin demonstrated a combination/
synergistic effect but not the mrp1 and mdr1 siRNA. Down-
regulation of both survivin and bcl-2 together with cisplatin treatment
showed slightly better cell killing effect (approximately 80% versus
approximately 72%) compared to the single agent combinations
(survivin+cisplatin or bcl-2+cisplatin) suggesting a higher level of
reversal of resistance with the down-regulation of both anti-apoptotic
genes [23].
A few other groups have also worked on the combination
strategies using siRNA and chemotherapeutic drugs. Saad and
co-workers managed to co-deliver siRNA and Dox together using
a cationic liposomal system and demonstrated synergistic effect in
resistant cells [34]. Chen and co-workers developed two different,
but novel nanoparticle formulations, i.e., cationic liposome-