CD44-targeted pH-responsive micelles for enhanced cellular internalization and intracellular on-demand release of doxorubicin

Poor cellular uptake and slow intracellular drug release remain the main barriers for the efficient application of micellar delivery system. Taking advantage of the overexpressed CD44 receptor and mild acidic microenvironment of tumour cells, CD44-targeted pH-responsive micelles based on the self-assembly of histidine-hyaluronic acid-dodecylamine (His-HA-DA) were prepared for the delivery of doxorubicin (DOX). These micelles exhibited pH-responsive behaviour with increased particle size, decreased encapsulation efficiency (EE%) of DOX and rapid release of DOX triggered by low pH. Compared with free DOX, DOX/HHD exhibited relatively high cellular uptake mainly via the CD44-mediated endocytosis. The on-demand intracellular release of DOX from DOX/HHD led to improved cytotoxicity. DOX/HHD also showed great penetration efficiency in 3D tumour spheres in vitro. Moreover, these micelles with suitable particle size gained excellent tumour-targeting effects, as well as improved anti-tumour effects and reduced side effects in vivo. In conclusion, these micelles with CD44 targeted and pH-responsive behaviours provide a promising strategy for the efficient delivery of anti-tumour drugs in vivo.

Automated summary

The study prepared CD44-targeted pH-responsive micelles for efficient delivery and release of doxorubicin based on the overexpressed CD44 receptor and mild acidic microenvironment of tumor cells. These micelles exhibited enhanced cellular uptake and cytotoxicity, as well as excellent tumor-targeting effects in vitro and improved anti-tumor effects with reduced side effects in vivo.