Reduction-responsive core-crosslinked hyaluronic acid-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate) micelles: synthesis and CD44-mediated potent delivery of docetaxel to triple negative breast tumor in vivo

Future cancer therapy relies on the development of simple, selective and bioresponsive nanomedicines. Herein, we report that reduction-responsive core-crosslinked hyaluronic acid-b-poly(trimethylene carbonateco- dithiolane trimethylene carbonate) micelles (HA-CCMs) can be easily synthesized and achieve efficient CD44-mediated delivery and triggered cytoplasmic release of docetaxel (DTX) to MDA-MB-231 human triple negative breast tumor in vivo. DTX-loaded HA-CCMs exhibited a favorable size of 85 nm, low drug leakage and glutathione-responsive DTX release. HA-CCMs were efficiently taken up by CD44-overexpressing MDAMB- 231 cells as indicated by flow cytometry. DTX-loaded HA-CCMs induced selective apoptotic activity toward MDA-MB-231 cells in vitro. Notably, over 7-fold longer blood circulation time and 4-fold stronger tumor accumulation were observed for DTX-loaded HA-CCMs compared to free DTX. Cy5-labeled HA-CCMs revealed deep tumor penetration at 6 h post injection. DTX-loaded HA-CCMs were shown to effectively suppress the progression of MDA-MB-231 tumor and significantly extend mice survival time. These hyaluronic acid-shelled and disulfide-crosslinked micelles with great simplicity and selectivity are highly promising for treating various CD44-overexpressing cancers.