Abstract

The physicochemical properties of nanocarriers are closely related to their performance. Hyaluronic acid (HA) has been widely employed in tumor-targeting nanodrugs owing to its excellent active-targeting capability and enzymatic degradability. However, the impact of its molecular weight (MW) on the efficiency of drug delivery by nanoparticles remains unclear. Herein, HA of various MWs (10, 20, 50, 100, and 200 kDa) is adopted to modify cationic nanomicelles, producing a series of active-targeting and enzyme-responsive nanodrugs (HAPs), i.e. , HAP 10 , HAP 20 , HAP 50 , HAP 100 , and HAP 200 . HAPs binding affinities for CD44 and their sensitivity to hyaluronidase (HAase) are systematically compared. As MW decreases, the affinity for CD44 and sensitivity to HAase gradually increase. In vitro and in vivo efficacy tests confirm that HAP 10 and HAP 20 display the best anti-tumor therapeutic effects. In conclusion, low MW HA (10 or 20 kDa) is relatively favorable for constructing tumor-targeted drug delivery systems. This work provides valuable insight into the rational HA-based nanotherapeutics and highlights how variations in biomaterial specifications may lead to major differences in preparative performance.