Deep tumor penetration of doxorubicin‐loaded glycol chitosan nanoparticles using high‐intensity focused ultrasound

The dense extracellular matrix (ECM) in heterogeneous tumor tissues can prevent the deep tumor penetration of drug‐loaded nanoparticles, resulting in a limited therapeutic efficacy in cancer treatment. Herein, we suggest that the deep tumor penetration of doxorubicin (DOX)‐loaded glycol chitosan nanoparticles (CNPs) can be improved using high‐intensity focused ultrasound (HIFU) technology. Firstly, we prepared amphiphilic glycol chitosan‐5β‐cholanic acid conjugates that can self‐assemble to form stable nanoparticles with an average of 283.7 ± 5.3 nm. Next, the anticancer drug DOX was simply loaded into the CNPs via a dialysis method. DOX‐loaded CNPs (DOX‐CNPs) had stable nanoparticle structures with an average size of 265.9 ± 35.5 nm in aqueous condition. In cultured cells, HIFU‐treated DOX‐CNPs showed rapid drug release and enhanced cellular uptake in A549 cells, resulting in increased cytotoxicity, compared to untreated DOX‐CNPs. In ECM‐rich A549 tumor‐bearing mice, the tumor‐targeting efficacy of intravenously injected DOX‐ CNPs with HIFU treatment was 1.84 times higher than that of untreated DOX‐CNPs. Furthermore, the deep tumor penetration of HIFU‐treated DOX‐CNPs was clearly observed at targeted tumor tissues, due to the destruction of the ECM structure via HIFU treatment. Finally, HIFU‐treated DOX‐ CNPs greatly increased the therapeutic efficacy at ECM‐rich A549 tumor‐bearing mice, compared to free DOX and untreated DOX‐CNPs. This deep penetration of drug‐loaded nanoparticles via HIFU treatment is a promising strategy to treat heterogeneous tumors with dense ECM structures.