Abstract RNA interference (RNAi) is an emerging
therapeutic modality for tumors. However, lack of a safe and efficient
small interfering RNA (siRNA) delivery system limits its clinical
application. Here, we report a bioreducible and less-cationic siRNA
delivery carrier by conjugating Zn(II)−dipicolylamine complexes (Zn−DPA)
onto hyaluronic acid (HA) via a redoxsensitive disulfide (-SS-) linker.
Such polymer conjugates can formulate stable siRNA nanomedicines via
coordination between zinc ions of DPA and the anionic phosphate of
siRNA. After the conjugates are taken up by cells, intracellular
reduction stimulus subsequently triggers the release of siRNAs and
elucidates the desired RNAi effect. Our studies showed the formulated
siRNA nanomedicines can be efficiently delivered into tumor
cells/tissues and mediates less cytotoxicities both in vitro and in
vivo. More importantly, when applied in a xenograft glioblastoma tumor
model, this siRNA nanomedicine demonstrated significantly enhanced
antitumor ability comparing to naked siRNA. This work demonstrates that
such bioreducible Zn−DPA-functionalized HA conjugates without using
cationic material as a siRNA carrier represents a promising direction
for RNAi-based cancer therapy. ACS Appl. Bio Mater. DOI: 10.1021/acsabm.8b00622 acsabm.pdf
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