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

Abstract

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 carbonate-co-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 MDA-MB-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.