Combinatorial-designed Hyaluronic Acid Nanoparticles for Tumour Targeted Drug and Small Interfering Ribonucleic Acid Delivery - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 71

capabilities to come out of the endosomes showed target knockdown.
In our library of HA derivatives, although all the fatty amine-modified
HA derivatives demonstrated good cellular uptake, most of them
were unsuccessful in down-regulating PLK1 gene expression in
vitro . Only HA-spermine, HA-PEI and HA-PLL demonstrated target
knockdown at the messenger RNA levels. Also, they demonstrated
activity only at a specific mass ratio of 54:1 (polymer:siRNA) and
failed to demonstrate gene silencing at other ratios of 45:1, 27:1 or
9:1 (polymer:siRNA) or lower, suggesting that a critical balance of
charge is essential in order to design nanosystems that can promote
endosome escape and at the same time remain as a safe carrier for
in vivo delivery ( Figure 3.5 ).
3.4 Targeting CD44-Expressing Tumours In Vivo with
Hyaluronic Acid-based Nanoparticles
3.4.1 Small Interfering Ribonucleic Acid and
Chemotherapeutic Drugs as Therapeutic Agents
As discussed in the previous sections, we and others manipulated
the HA system to get a derivative that can encapsulate siRNA and
mediate efficient gene silencing in cells. Since our ultimate goal was
to do a combination therapy with siRNA and cisplatin to reverse
the resistance and increase the efficacy, we needed to identify a
derivative that could encapsulate and deliver cisplatin efficiently to
resistant tumours. The encapsulation of a small molecule drug such as
cisplatin in hydrophilic HA polymer or PEI-derivatised HA seemed to
be highly challenging due to the hydrophobic nature of the cisplatin
and the difficulty it poses in encapsulation to form water soluble
nanoparticles. Thus, we introduced fatty acid side chains onto the
HA backbone to generate a functionally variant HA derivative of
1,8-diaminooctane (HA-ODA) to facilitate the cisplatin encapsulation
by self-assembly [23]. Additionally, we fabricated NP containing
PEG-modified HA (HA-PEG) to assess if the PEG component could
increase the residence time and achieve better tumour delivery. These