Combinatorial-designed Hyaluronic Acid Nanoparticles for Tumour Targeted Drug and Small Interfering Ribonucleic Acid Delivery - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 76

only marginal activity in CD44 overexpressing resistant A549 DDP
tumours (approximately 15%) at the time point tested (24 h after
the third dose of 0.5 mg/kg) [19] . It was surprising at that time, but
we later found that these resistant tumours demonstrated different
kinetics of siRNA accumulation and activity compared to the A549
tumours. We found a very similar level of target knockdown in the
resistant A549 tumours, also at a later time point, which supports
the fact that the particles reached/accumulated in these tumours with
different kinetics compared to the sensitive A549 tumours. However,
there was absolutely no activity seen in the other two subcutaneous
SCLC tumours (H69 and H69AR) at the doses administered to mice,
supporting the fact that these cells as well as the tumours do not
express high levels of CD44 [19] ( Figure 3.6 ).
In addition, it was also realised that there are factors other than
the receptor levels which play a role in the delivery of the drugs
to solid tumours [31]. In order to understand if a factor such as
tumour vascularity also plays a role in tumour delivery apart from
the receptors, we tested these particles in different tumour types
that express CD44 receptors at higher or lower levels and which
had different levels of vascularity [31]. To address this, we picked a
murine melanoma model B16F10, that expresses reasonable levels
of CD44 receptors (approximately 65%) with very high vascularity,
a highly vascularised Hep3B model with very low levels of CD44
(approximately 4%) and another model with saturating levels of
CD44 but with a very low level of vascularity along with the A549
tumour pair that has equal levels of CD44 levels and vascularity
[19] ( Figure 3.7 ). When the Hep3B tumours were treated with the
similar doses of HA-PEI/PEG/siRNA nanosystems, the activity was
very minimal (approximately 15%), but not completely absent.
Reasonable gene knockdown activity of approximately 40% was seen
in the highly vascularised B16F10 tumours that express reasonable
levels of CD44. When we used the hypovascular MDA-MB468
tumour model that expresses very high levels of CD44, the activity
was minimal (approximately 15%).