Tumor-targeting and pH-responsive nanoparticles from hyaluronic acid for the enhanced delivery of doxorubicin.

In this study, intracellular pH-responsive nanoparticles (NPs) of hyaluronic acid-hydrazone linkage-doxorubicin (HA-hyd-DOX) were designed and prepared for acid-triggered release of doxorubicin through a hydrazone linkage. A series of amphiphilic polymeric prodrugs were obtained, which can be self-assembled in aqueous media, the formed NPs exhibited a spherical core-shell type and the uniform size was ranging from 167 to 220nm. Moreover, the HA-hyd-DOX NPs exhibited a good stability in vitro and the drug release profiles showed that the DOX release was obviously mediated by pH gradient. Additionally, the cell counting assay kit-8 (CCK-8) demonstrated that the drug delivery system in this study performed a lower cytotoxicity on normal cells (Mouse fibroblast cells, L929) and higher inhibition ratio on tumor cells (Human cervical cancer cells, HeLa) in response to drug release with the intracellular pH environment. Furthermore, confocal laser scanning microscopy (CLSM) images and flow cytometric profiles of HeLa cells showed an efficiently cellular uptake due to the receptor-mediated affinity of CD44 for HA with high specificity. These results suggest that this pH dependent drug delivery system based on HA will provide insights into the design of potential prodrugs for the cancer therapy.