Self-assembled nanoparticles from hyaluronic acid–paclitaxel prodrugs for direct cytosolic delivery and enhanced antitumor activity

A prodrug-based nanosystem obtained by formulating prodrug and nanotechnology into a system is one of the most promising strategies to enhance drug delivery for disease treatment. Herein, we report a new nanosystem based on HA–PTX conjugates (HA–PTX Ns), which penetrated across cell membranes into cytosol, thus enhancing paclitaxel (PTX) delivery. HA–PTX Ns were successfully obtained based on HA–PTX, and their average particle size was approximately 200   nm. Importantly, unlike other prodrug-based nanosystems, HA–PTX Ns obtained cellular entry without entrapment within the lysosomal–endosomal system by using pathways including clathrin-mediated endocytosis, microtubule-associated internalization, macropinocytosis and cholesterol-dependence. Due to significant accumulation in tumors, HA–PTX Ns had more than a 4-fold decrease in tumor volume on day 14 in contrast with PTX alone. In conclusion, HA–PTX Ns could enter cells, bypass the lysosomal–endosomal system and improve PTX delivery.