Biomedical Engineering Reference
In-Depth Information
HA-based functional macrostructures that can form self-assembled
nanosystems encapsulating a siRNA payload as discussed. Several
HA-based nanosystems were effective in entering tumour cells
overexpressing CD44 receptors but only selected candidate HA
derivatives showed gene silencing activity
in vitro
and
in vivo
.
A linear correlation between CD44 expression levels and activity in
cells was observed; however, it was not exactly translated
in vivo
in solid tumour models in mice. We demonstrated how the factors
other than the receptors, such as vascularity of the tumours, play a
critical role in tumour delivery and penetration. As our ultimate goal
was to reverse the drug resistance in a drug resistant tumour model
to improve the efficacy, we chose the best HA candidates that can
encapsulate siRNA and cisplatin. We also picked a cisplatin resistant
model that expresses higher levels of CD44. Once the overexpressed
resistant genes in tumour cells were identified, we designed potent
sequences to down-regulate those genes. Using the appropriate
delivery system, we effectively delivered the siRNA to down-
regulate those overexpressed genes and thus managed to enhance
the sensitivity to the chemotherapy drug, cisplatin. We demonstrated
that, with the combination treatment, we could reverse the resistance
and significantly improve the efficacy.
In summary, the HA-based self-assembling nanosystems developed
in our laboratory and several others are promising candidates for
effective treatment of sensitive and resistant tumours overexpressing
CD44 receptors at very low doses. They can be used to deliver multiple
siRNA sequences and multiple small molecule drugs including
tumour initiating stem cells and metastatic lesions so warrant further
evaluation. It was also clear from those studies that the combination
of siRNA-mediated gene silencing strategy with chemotherapeutic
agents using these HA-based self-assembling nanosystems constitutes
a valuable and safe approach for the treatment of MDR tumours.
Acknowledgments
Our work on hyaluronic acid-based combinatorial-designed
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